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World Health Organization Classification of Tumours
International Agency for Research on Cancer (IARC)
Pathology and Genetics of
Skin Tumours
Edited by
Philip E. LeBoit
Günter Burg
David Weedon
Alain Sarasin
IARCPress
Lyon, 2006
WHO OMS
World Health Organization Classification of Tumours
Series Editors Paul Kleihues, M.D.
Leslie H. Sobin, M.D.
Pathology and Genetics of Skin Tumours
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Günter Burg, M.D.
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The WHO Classification of Skin Tumours
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September 22-25, 2003.
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Pathology and genetics of skin tumours/ edited by Philip E. LeBoit… [et. al.].
(World Health Organization classification of tumours ; 10)
1. Skin Neoplasms – genetics
2. Skin Neoplasms – pathology
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Classification of Tumours. Pathology and Genetics of Skin Tumours.  IARC Press:
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1Keratinocytic tumours 9
WHO and TNM classification 10
Introduction 11
Basal cell carcinoma 13
Superficial basal cell carcinoma  15
Nodular basal cell carcinoma 16
Micronodular basal cell carcinoma 16
Infiltrating basal cell carcinoma 17
Fibroepithelial basal cell carcinoma 17
Basal cell carcinoma with adnexal differentiation 18
Basosquamous carcinoma 18
Keratotic basal cell carcinoma 19
Other variants 19
Squamous cell carcinoma 20
Acantholytic squamous cell carcinoma 21
Spindle-cell squamous cell carcinoma 22
Verrucous squamous cell carcinoma 22
Pseudovascular squamous cell carcinoma 23
Adenosquamous carcinoma 24
Bowen disease 26
Bowenoid papulosis 28
Actinic keratosis 30
Arsenical keratosis 32
PUVA keratosis 33
Verrucas 34
Verruca vulgaris 36
Verruca plantaris 37
Verruca plana 38
Acanthomas 39
Epidermolytic acanthoma 39
Warty dyskeratoma 39
Acantholytic acanthoma 40
Lentigo simplex 40
Seborrhoeic keratosis 41
Melanoacanthoma 43
Clear cell acanthoma 43
Large cell acanthoma 44
Keratoacanthoma 44
Lichen planus-like keratosis 47
2 Melanocytic tumours 49
WHO classification 50
TNM classification 51
Malignant melanoma: Introduction 52
Superficial spreading melanoma 66
Nodular melanoma 68
Lentigo maligna 70
Acral-lentiginous melanoma 73
Desmoplastic melanoma and desmoplastic
neurotropic melanoma 76
Melanoma arising from blue naevus 79
Melanoma arising in giant congenital naevi 83
Childhood melanoma  84
Naevoid melanoma 86
Persistent melanoma and local
metastasis of melanoma 90
Congenital melanocytic naevus 93
Superficial type 93
Proliferative nodules in congenital
melanocytic naevi 93
Blue naevi 95
Common blue naevus 95
Mongolian spot 96
Naevus of Ito and naevus of Ota 96
Cellular blue naevus 96
Deep penetrating naevus 98
Combined naevus 100
Melanotic macules 103
Simple lentigo – lentiginous melanocytic naevus 104
Dysplastic naevus 105
Site specific and Meyerson naevi 110
Acral naevus 110
Genital naevus 110
Meyerson naevus 111
Persistent (recurrent) melanocytic naevus 113
Spitz naevus 114
Pigmented spindle cell naevus (Reed) 117
Halo naevus 118
3 Appendageal tumours 121
WHO and TNM classification 122
Introduction 123
Malignant tumours with apocrine and
eccrine differentiaton 125
Tubular carcinoma 125
Microcystic adnexal carcinoma 125
Malignant mixed tumour 127
Porocarcinoma 128
Spiradenocarcinoma 130
Hidradenocarcinoma 131
Mucinous carcinoma 131
Digital papillary carcinoma 133
Adenoid cystic carcinoma 134
Apocrine carcinoma 135
Paget disease and extramammary
Paget disease 136
Benign tumours with apocrine and
eccrine differentiation 139
Hidrocystoma 139
Syringoma 140
Poroma 141
Syringofibroadenoma 142
Hidradenoma 143
Spiradenoma 143
Cylindroma 145
Tubular and tubular papillary adenoma 145
Syringocystadenoma papilliferum 146
Hidradenoma papilliferum 147
Contents
Mixed tumour (chondroid syringoma) 147
Malignant tumours with follicular differentiation 149
Pilomatrical carcinoma 149
Proliferating tricholemmal tumour 150
Benign tumours with follicular differentiation 152
Trichoblastoma 152
Pilomatricoma 153
Tricholemmoma 155
Trichofolliculoma 156
Pilar sheath acanthoma 157
Tumour of the follicular infundibulum 158
Fibrofolliculoma / trichodiscoma 158
Tumours with sebaceous differentiation 160
Sebaceous carcinoma 160
Sebaceous adenoma 161
Sebaceoma 162
Cystic sebaceous tumour 163
4 Haematolymphoid tumours 165
WHO / EORTC classification 166
TNM classification 167
Introduction 168
Mycosis fungoides (MF) 169
Pagetoid reticulosis 173
Syringotropic MF 173
Folliculotropic MF 173
Granulomatous MF 174
Sézary syndrome 175
Granulomatous slack skin 178
CD30+ T-cell lymphoproliferative disorders  179
Lymphomatoid papulosis (LyP) 179
Primary cutaneous anaplastic large-cell
lymphoma 180
Subcutaneous panniculitis-like T-cell lymphoma 182
Primary cutaneous peripheral T-cell lymphoma,
unspecified 184
Cutaneous γδ T-cell lymphoma 184
Primary cutaneous aggressive epidermotropic
CD8+ cytotoxic T-cell lymphoma 185
Primary cutaneous small-medium CD4+ T-cell
lymphoma 186
Primary cutaneous PTL, unspecified 186
Cutaneous adult T-cell leukaemia / lymphoma 189
Extranodal NK/T-cell lymphoma, nasal-type 191
Hydroa vacciniforme-like cutaneous T-cell
lymphoma 192
Cutaneous involvement in primary extracutaneous
T-cell lymphoma 193
Systemic anaplastic large cell lymphoma (ALCL) 193
Angioimmunoblastic T-cell lymphoma (AITL) 193
Cutaneous marginal zone B-cell lymphoma 194
Cutaneous follicle centre lymphoma 196
Cutaneous diffuse large B-cell lymphoma 198
Diffuse large B-cell lymphoma, leg-type 198
Diffuse large B-cell lymphoma, other 198
T-cell / histiocyte-rich large B-cell lymphoma 199
Plasmablastic lymphoma 199
Secondary skin involvement by diffuse large
B-cell lymphoma 199
Intravascular large B-cell lymphoma 200
Lymphomatoid granulomatosis 202
Cutaneous involvement in primary extracutaneous
B-cell lymphoma 204
Mantle cell lymphoma 204
Burkitt lymphoma 205
Chronic lymphocytic leukaemia / small
lymphocytic lymphoma 205
Hodgkin lymphoma 207
Blastic NK-cell lymphoma 208
Precursor T-lymphoblastic leukaemia / lymphoma
and precursor B-lymphoblastic
leukaemia / lymphoma 210
Cutaneous involvement by myeloid leukaemia 211
Lymphoid infiltrates of the skin mimicking
lymphoma 212
Parapsoriasis 215
Small plaque parapsoriasis 215
Parapsoriasis – Large patch type,
with or without poikiloderma 215
Langerhans cell histiocytosis 217
Indeterminate cell histiocytosis 220
Sinus histiocytosis with massive lymphadenopathy
(Rosai-Dorfman) 221
Juvenile xanthogranuloma 222
Reticulohistiocytosis 224
Mastocytosis 226
5 Soft tissue tumours 229
WHO and TNM classification 230
Introduction 231
Vascular tumours 233
Haemangioma of infancy 233
Cherry haemangioma 233
Sinusoidal haemangioma 234
Hobnail haemangioma 234
Glomeruloid haemangioma 235
Microvenular haemangioma 236
Angiolymphoid hyperplasia with eosinophilia 237
Spindle cell haemangioma 239
Tufted angioma 239
Bacillary angiomatosis 240
Reactive angioendotheliomatosis 241
Verrucous haemangioma 242
Pyogenic granuloma 243
Cavernous haemangioma 243
Angiokeratomas 244
Arteriovenous haemangioma 245
Cutaneous angiosarcoma 246
Lymphatic tumours 247
Lymphangioma circumscriptum 247
Progressive lymphangioma 248
Lymphangiomatosis 249
Smooth and skeletal muscle tumours 250
Smooth muscle hamartoma 250
Pilar leiomyoma 251
Cutaneous leiomyosarcoma 251
Rhabdomyomatous mesenchymal hamartoma 252
Fibrous, fibrohistiocytic and histiocytic tumours 254
Keloid scar 254
Hypertrophic scar 254
Dermatomyofibroma 255
Infantile myofibromatosis 256
Sclerotic fibroma 256
Digital mucous cyst 257
Digital fibrokeratoma 257
Pleomorphic fibroma 258
Giant cell fibroblastoma 258
Dermatofibrosarcoma protuberans 259
Dermatofibroma (fibrous histiocytoma) 261
6 Neural tumours 263
WHO and TNM classification 264
Palisaded, encapsulated neuroma and traumatic
neuroma 265
Palisaded encapsulated neuroma 265
Traumatic neuroma 266
Primary malignant peripheral primitive
neuroectodermal tumour (PNET) /
Extraskeletal Ewing sarcoma (ES)  268
Nerve sheath myxoma / neurothekeoma 270
Merkel cell carcinoma 272
Granular cell tumour 274
7 Inherited tumour syndromes 277
Familial cutaneous melanoma 279
Xeroderma pigmentosum 282
Naevoid basal cell carcinoma (Gorlin) syndrome 285
Cowden syndrome 288
Carney complex 291
Contributors 295
Source of charts and photographs 300
References 301
Subject index 341
CHAPTER 1
Keratinocytic Tumours
Keratinocytic tumours are derived from epidermal and adnexal
keratinocytes and comprise a large spectrum of lesions rang-ing from benign proliferations (acanthomas) to malignant squa-mous cell carcinomas which occasionally show aggressive
growth and even metastatic potential. Keratinocytic tumours
are very frequent and, despite their low mortality rate, pose a
significant public health problem, The main etiologic factor is
solar radiation which causes DNA alterations, including pyrim-idine dimers which during DNA replication may lead to CC:TT
mutations in the  TP53 tumour suppressor gene. Other genes
involved in the multistep formation of skin cancer include PTCH
and the RAS oncogene.
Verrucas, epidermal proliferations produced by infection with
human papilloma viruses (HPV), are also included in this sec-tion.
10 Keratinocytic tumours
WHO histological classification of keratinocytic skin tumours
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of  Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, /2 for in situ carcinoma and /1 for borderline or uncertain behaviour.
Keratinocytic tumours
Basal cell carcinoma 8090/3
Superficial basal cell carcinoma 8091/3
Nodular (solid) basal cell carcinoma 8097/3
Micronodular basal cell carcinoma 8090/3
Infiltrating basal cell carcinoma 8092/3
Fibroepithelial basal cell carcinoma 8093/3
Basal cell carcinoma with adnexal differentiation 8098/3
Basosquamous carcinoma 8094/3
Keratotic basal cell carcinoma 8090/3
Squamous cell carcinoma 8070/3
Acantholytic squamous cell carcinoma 8075/3
Spindle-cell squamous cell carcinoma 8074/3
Verrucous squamous cell carcinoma 8051/3
Pseudovascular squamous cell carcinoma 8075/3
Adenosquamous carcinoma 8560/3
Bowen disease 8081/2
Bowenoid papulosis
Actinic keratosis
Arsenical keratosis
PUVA keratosis
Verrucas
Verruca vulgaris
Verruca plantaris
Verruca plana
Acanthomas
Epidermolytic acanthoma
Warty dyskeratoma
Acantholytic acanthoma
Lentigo simplex
Seborrhoeic keratosis
Melanoacanthoma
Clear cell acanthoma
Large cell acanthoma
Keratoacanthoma 8071/1
Lichen planus-like keratosis
__________
1
{894,2219}.
2
A help desk for specific questions about the TNM classification is available at http://www.uicc.org/index.php?id=508 .
TNM classification 1,2
T – Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour 2 cm or less in greatest dimension
T2 Tumour more than 2 cm but no more than 5 cm in greatest
dimension
T3 Tumour more than 5 cm in greatest dimension
T4 Tumour invades deep extradermal structures, i.e., cartilage,
skeletal muscle, or bone
Note: In the case of multiple simultaneous tumours, the tumour with the
highest T category is classified and the number of separate tumours is
indicated in parentheses, e.g., T2(5).
N – Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M – Distant metastasis
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Stage grouping
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2, T3 N0 M0
Stage III T4 N0 M0
Any T N1 M0
Stage IV Any T Any N  M1
TNM classification of skin carcinomas
The keratinocytic tumours are a clinically
and histopathologically diverse group of
lesions derived from the proliferation of
epidermal and adnexal keratinocytes. At
one end of the spectrum the prolifera-tions are benign (acanthomas) and usu-ally of cosmetic importance only, while at
the other there are malignant tumours,
which uncommonly may be aggressive
with metastatic potential, as seen with
some squamous cell carcinomas.
Included in the spectrum are the epider-mal dysplasias (actinic keratosis, arseni-cal keratosis and PUVA keratosis) and
intraepidermal carcinomas (Bowen dis-ease and bowenoid papulosis).
Ackerman and others have proposed
that solar keratoses should be regarded
as squamous cell carcinoma de novo
and not as pre-malignancies or pre-can-cers that evolve into squamous cell car-cinoma {994,1443,1701}.
Epidemiology
Keratinocytic tumours are an important
public health problem, despite their com-paratively low mortality rate {2484}. The
lifetime risk for the development of skin
cancer in the USA is now 1 in 5 {1937}. It
is much higher in subtropical Australia.
There is an increasing incidence of squa-mous cell carcinoma of the skin in some
countries {2462}. Keratinocytic tumours
account for approximately 90% or more
of all skin malignancies, of which approx-imately 70% are basal cell carcinomas.
The latter exceed squamous cell carci-nomas in frequency by a factor of
approximately 5:1 although in lower lati-tudes the incidence of squamous cell
carcinoma increases and this ratio
becomes 3:1. If solar keratoses are
regarded as squamous cell carcinomas
(see above), then squamous cell carci-noma becomes the more common
tumour {300}.
Precursor lesions
There are no known precursor lesions to
basal cell carcinoma. On the other hand,
there are a number of intra-epidermal
proliferative disorders (dysplasias) that
may be precursors of squamous cell car-cinoma. These include actinic keratosis
and Bowen disease (intraepidermal car-cinoma/squamous cell carcinoma in-situ).
Actinic keratoses are erythematous,
scaling lesions occurring on heavily sun-light exposed areas that increase in
prevalence with increasing age in fair
skinned people. Histologically, they
demonstrate confluent keratinocytic
atypia involving predominantly the ker-atinocytes in the basal layer of the epi-dermis {2475}.
It is difficult to determine the incidence of
actinic keratoses as they come and go
over time {788}. Longitudinal studies
suggest that they are likely to be a pre-cursor of squamous cell carcinoma,
although the malignant transformation
rate is small, certainly less than one in a
hundred per year {1517}. Data suggest,
also, that remission of these lesions will
occur if sunlight exposure can be
reduced. Thus the majority of lesions do
not progress to squamous cell carcino-ma {1516,2349}.
Bowen disease demonstrates ker-atinocyte atypia involving the full thick-ness of the epidermis. There is also
involvement of the hair follicle and rarely
the sweat duct. Although Bowen disease
has been classified as a full thickness in-situ squamous cell carcinoma, there are
no longitudinal studies published on the
frequency of malignant transformation.
Even if invasive squamous cell carcino-ma does occur within one of these
lesions, it is believed that the in-situ
phase may be very prolonged, lasting
many years {1203}.
Etiology
Findings regarding the genetic basis of
non-melanoma skin cancer (NMSC) have
confirmed that UV radiation, especially
UVB (290-320 nm in the solar spectrum),
contributes to the formation of squamous
{1336} and basal cell carcinomas {602}.
Squamous cell carcinomas (SCCs) of the
skin develop through a multistep process
that involves activation of proto-onco-genes and/or inactivation of tumour sup-pressor genes in the human skin ker-atinocytes. NMSCs are caused by genet-ic abnormalities, most often induced by
UVB exposure. Actinic keratoses, which
lead to SCCs, have gene mutations in K-ras {2235}. H-rasV12 and cyclin depend-ent kinase 4 (CDK4) produce human epi-dermal neoplasia. Therefore, a combina-tion of these genetic abnormalities might
be crucial to the carcinogenesis at least
in a subset of SCCs {1336}.
High doses of ultraviolet light can also
lead to skin cancers by inducing reactive
oxygen species (ROS) that play an
important role in tissue injury. Increased
production of ROS and/or decreased effi-ciency of antioxidant defence system
contribute to a number of degenerative
processes including cancer {1161}. UV
induces pyrimidine dimers and loss of
heterozygosity (LOH). TP53 and PTCH,
two tumour suppressor genes, have LOH
which lead to basal cell carcinoma
(BCC) {1265}. LOH in TP53 is related to
elevated microsatellite instability at
selected tetranucleotide repeats {587}.
LOH at 9q22 loci in PTCH genes causes
non-melanoma skin cancer tumours
{1265}. The type of mutations for TP53
and PTCH are predominantly UV-signa-ture transitions, C->T and CC->TT at
dipyrimidine sites {1265}. SCCs have
mutations of H-Ras gene and the INK4a
locus whereas BCC has missense muta-tions leading to rasGTPase activating
protein {168}. Further, mutations have
been found in both TP53 tumour sup-pressor gene and ras in patients with
xeroderma pigmentosum (XP), a disease
of DNA repair deficiencies {1717}.
Common exogenous carcinogenic
agents in addition to UV radiation include
1) tobacco use {2457}, 2) human papillo-ma viruses {1703}, 3) arsenic {2184}, 4)
industrial chemicals such as vinyl chlo-ride {1362}, polycyclic aromatic hydro-carbons {1086}, 5) MNNG (N-methyl-N’-nitro-N-nitrosoguanidine), an alkylating
agent {335}, and 6) exposure to gasoline
or gasoline vapours {1567}.
D. Weedon
R. Marks
G. F. Kao
C.A. Harwood
Keratinocytic tumours: Introduction
11Introduction
Clinical features
Keratinocytic tumours vary in their clini-cal appearance depending on the type
of lesion and stage of development.
Histopathology
The histopathologic changes noted in
keratinocytic proliferative lesions involve
disturbance of normal surface matura-tion. The degree and extent of ker-atinocytic atypia vary in these lesions.
The atypical keratinocytes show
enlarged nuclei with hyperchromasia,
dyskeratosis and mitoses in any layer of
the epidermis. In lesions of epidermal
dysplasias (AK, arsenical, and PUVA ker-atoses), surface keratinocytic maturation
is present, i.e. a granular cell layer is usu-ally noted.
In intraepidermal carcinomas (Bowen
disease, bowenoid papulosis), there is
full-thickness involvement of the epider-mis by the atypical keratinocytes.
Molecular markers
A number of potentially useful molecular
markers or tests have been proposed.
These include the demonstration of a dif-ferent pattern of basic fibroblast growth
factor expression in neoplastic ker-atinocytes by in situ hybridization and the
persistence of integrated HPV sequen-ces in the host cell genome of HPV asso-ciated keratinocytic lesions detected by
ligation mediated PCR assay. The lower
level of TIG-3 mRNA expression in SCC
is visualized by immunohistochemistry or
by in situ mRNA hybridization. Upre-gulation of S100 protein subtypes in spe-cific keratinocyte disorders is confirmed
by immunohistochemistry.
Prognosis and predictive factors
Most patients with primary cutaneous
non-melanoma skin cancer (NMSC) have
an excellent prognosis. The overall mor-tality rates are generally low, on average
approximately 0.1% of the incidence
rates, but significantly higher for SCCs
than BCCs {2483}. Invasive SCC has the
potential to recur and metastasize with
an overall 5-year rate of recurrence for
primary tumours of 8%. With the excep-tion of lip tumours, sqamous cell carcino-mas arising in actinic keratoses have a
frequency of metastatic spread of 0.5-3%
{1459,1630}. For those with metastatic
disease the long-term prognosis is poor;
10-year survival rates are <20% for
patients with regional lymph node
involvement and <10% for patients with
distant metastases {50}. More than 70%
of SCC recurrences and metastases
develop within 2 years of treatment of the
primary tumour {635}, and 95% within 5
years {1985}. The 3-year cumulative risk
of non-melanoma skin cancer develop-ing in an individual diagnosed with SCC
is 35-60% and the risk of melanoma is
also increased {1507}. Five-year cure
rates for BCC of up to 99% are obtain-able with surgical techniques {1617,
1984}, and metastasis is extremely rare,
occurring in approximately 0.05% of
cases {1440}. As with SCC, patients with
BCC are at high risk of further primary
BCCs; in patients with one lesion the 5-year risk is 27%, and in those with 10
lesions the risk is 90% {1208}, and the
risk of SCC and malignant melanoma is
also increased {1208,1430}.
12 Keratinocytic tumours
Definition
A group of malignant cutaneous tumours
characterised by the presence of lob-ules, columns, bands or cords of basa-loid cells (“germinative cells”).
ICD-O code 8090/3
Synonyms
Basal cell epithelioma, trichoblastic car-cinoma.
Epidemiology
Basal cell carcinomas (BCC) develop
predominantly in sun-damaged skin in
individuals who are fair skinned and
prone to sunburn {330,888,889}.
Migration of such individuals particularly
as children, to countries with high UV
radiance is associated with increased
rates of skin cancer. Although basal cell
carcinomas typically occur in adults, the
tumours also develop in children {1873}.
Arsenic exposure {924} and ionizing
radiation may also induce basal cell car-cinomas.
Nodular basal cell carcinomas occur at a
later age than superficial basal cell car-cinomas and are more frequently on the
head whereas the trunk is the most fre-quent site for superficial tumours {1550,
2121}.
Basal cell carcinomas are very frequent
tumours particularly in light-skinned indi-viduals living in countries at low latitudes.
Incidences of 2000 per 100,000 popula-tion have been recorded in Queensland,
Australia. The rate of basal cell carcino-mas has increased in the older age
groups. Older men have a higher inci-dence of basal cell carcinoma than
women, but women have been found to
outnumber men in younger age groups.
The latter may be due to increased sun
exposure in younger women in associa-tion with tanning bed use as well as
smoking {293}.
Clinical features
Basal cell carcinomas typically have a
pearly appearance with telangiectasia
that may appear as a papule or nodule
that can be eroded or ulcerated. These
features may be more subtle in the
superficial forms that appear as erythe-matous patches resembling an area of
dermatitis. Pale scar-like lesions may
also be a presentation of basal cell car-cinoma and these slowly grow over
years. Pigmented basal cell carcinomas
may masquerade as melanomas but
usually can be distinguished by the pres-ence of a pearly component. Derma-toscopy is also helpful in analysing pig-mented basal cell carcinoma and distin-guishing these from melanocytic tumours
{1587}. Erosive lesions on the lower limbs
may be mistaken for slowly healing trau-matic wounds. Delays in clinical diagno-sis may occur for basal cell carcinomas
that are localized within non-sun
exposed sites {225} such as the perianal
area {1312} or between the toes, young
age of onset, tumours with very slow
growth, or superficial erythematous
patches that appear as a dermatitis or
tumours complicating vaccination scars,
rhinophyma or a venous ulcer. The clini-cal capacity to differentiate some basal
cell carcinomas from squamous cell car-cinoma or even melanoma may be
impossible without skin biopsy. In coun-tries with a high incidence of basal cell
carcinomas it is not unusual to have indi-viduals with multiple basal cell carcino-mas, and regular review is required to
deal with new skin tumours. Incomplete
removal of basal cell carcinoma may
result in delayed recurrences that may
not be recognized for years, particularly
if the tumour recurrence is deep or
masked by skin grafts.
Genetics
Genetic analysis of sporadic basal cell
carcinoma {2024} has been propelled by
the identification of mutations in PTCH1
(chromosome 9q22.3) as the cause of
the basal cell nevus syndrome (BCNS), a
rare autosomal dominant disorder {110,
1146,2395}. These patients develop mul-tiple basal cell carcinomas which may
appear in childhood (see Chapter 2).
PTCH1 encodes a protein that functions
as an inhibitor of the hedgehog signaling
pathway, and BCCs, whether sporadic or
occurring in BCNS patients, all have
abnormalities of this signaling pathway
{110,1146,2272,2395}. In most sporadic
BCCs this is due to somatically-acquired
mutations in PTCH1 {802}, and in many
13Basal cell carcinoma
S. Kossard
E.H. Epstein, Jr.
R. Cerio
L.L. Yu
D. Weedon
Basal cell carcinoma
B CA
Fig. 1.1  Basal cell carcinoma, nodular type. A and B The epidermis is raised with flattening of the rete ridges overlying solid and cystic groups of atypical basaloid
cells with peripheral palisading showing invasion of the deep dermis in a nodular pattern.  C High power view of nodular basal cell carcinoma showing focal cys-tic change, peripheral palisading and cleft between tumour nests and stroma.
tumours the type of PTCH1 mutations are
those expected from UV-mutagenesis
{108,1265}. Approximately 10% of spo-radic BCCs have mutations in
SMOOTHENED which encodes the pro-tein whose function is inhibited by the
PATCHED1 protein {2553}. Thus it
appears that the relevant dysfunction
driving BCCs is abnormal hedgehog sig-naling, irrespective of which gene con-trolling that signaling is mutated. The
identification of hedgehog signaling
abnormalities as crucial to BCC forma-tion has stimulated the development of
genetically-engineered mice with hedge-hog signaling abnormalities {109,708,
1716,2163}. Unlike previously studied
mouse carcinogenesis models, which
uniformly produce tumours of the squa-mous cell lineage, these mice develop
BCCs and either spontaneously or in
response to environmental mutagens
(i.e. UV or ionizing radiation) develop
BCCs and adnexal basaloid tumours.
Histopathology
The multiple variants of basal cell carci-noma are connected by the common his-tological feature of lobules, columns,
bands and cords of basaloid cells (“ger-minative cells”) associated with scant
cytoplasm and a characteristic outer pal-isade of cells associated with a sur-rounding loose fibromucinous stroma
{2147,2282}. Artefactual retraction
spaces between the tumour and stroma
are often present. The tumour-stromal
interaction is weakened by the charac-teristic lack of the hemidesmosomes that
anchor the normal epidermis to the der-mis {475}. Apoptosis is usually apparent.
The release of keratin into the stroma as
a result of apoptosis may lead to the for-mation of amyloid deposits {2067}.
Mucinous cystic degeneration, focal vac-uolation with lipid or ductular differentia-tion, and in rare cases, sebocytes or fol-licular differentiation with squamous
eddies, trichohyaline granules and blue-grey corneocytes may be seen.
Melanocytes may proliferate within some
tumours and produce pigmentation by
melanin production that can be stored in
tumour cells or in surrounding
melanophages {1365}.
Problematic lesions include tumours that
merge with squamous cell carcinoma
(basaloid squamous cell carcinoma) or
those that share adnexal differentiation
demonstrating trichilemmal or seba-14 Keratinocytic tumours
DC
BA
Fig. 1.2 A Basal cell carcinoma, superficial type. A solid group of atypical basaloid cells is present at the dermo-epidermal junction showing peripheral palisading
and cleft formation between tumour nest and dermis. The dermis shows fibrosis and a patchy lymphocytic infiltrate which frequently accompany basal cell carci-noma of the superficial type.  B Basal cell carcinoma, nodular type, pigmented. The appearances are those of typical nodular basal cell carcinoma with the addi-tional feature of melanin pigmentation of the tumour nests.  C Basal cell carcinoma, cystic type.  There is extensive cystic change in an otherwise nodular basal
cell carcinoma. The cystic space contains connective tissue type mucin. In the purely cystic variant, tumour cells may be compressed to only 1 to 2 cell layers thick.
D Basal cell carcinoma, micronodular type. The tumour cell nests are tightly packed, with a diameter of 3 to 10 cells across with deep dermal invasion.  In this exam-ple, there is also tumour-associated amyloid in the stroma.
15Basal cell carcinoma
ceous areas. Some examples of mor-phoeic or sclerotic basal cell carcinoma
may resemble desmoplastic trichoep-ithelioma or microcystic adnexal carcino-ma particularly when a small sample is
obtained for analysis. The growth pattern
of the basal cell carcinoma should be
included in the pathology report as well
as the presence of perineural involve-ment and excision margins particularly if
less than 1 mm. Although the majority of
basal cell carcinomas can be classified
into the nodular, micronodular, superfi-cial, sclerosing/morpheic or infiltrative
subtypes, it is not unusual to have a
mixed pattern.
Immunoprofile
Occasionally in curette specimens, dif-ferentiation from small cell melanoma
may require the use of a combination of
light-weight keratin markers and S100
acidic protein to differentiate the
tumours. BerEP4, a keratin marker, has
been used to differentiate basal cell car-cinoma from squamous cell carcinomas
{2334}. CK20, a marker for Merkel cells,
has been used to differentiate some
forms of trichoblastoma, trichoepithe-lioma or fibroepitheliomas as these have
scattered CK20 positive Merkel cells
compared to basal cell carcinoma where
they are rare or absent {13,2104}.
Prognosis and predictive factors
Basal cell carcinomas are locally inva-sive tumours and metastases occur in
less than 1 in 10,000 tumours {1440,
1950,2443}. Morbidity is increased with
deeply invasive tumours which may
extend into the deep tissue to bone and
follow fusion planes particularly on the
face where they follow nerves through
bony channels. Morbidity also increases
with neglected tumours that may meas-ure more than 10 cm in diameter and
have been described as giant basal cell
carcinomas {1502,2009}. Multiple recur-rences with deep residual tumour on the
head may be associated with particular
morbidity as basal cell carcinomas can
ultimately penetrate the cranium.
Increased recurrences are associated
with infiltrative, morphoeic and micron-odular basal cell carcinomas as surgical
margins may be underestimated {639,
1940}. The possibility of the BCNS
should be considered in children who
develop BCCs. Families can be
screened for mutations of the PTCH1
gene. Low bcl-2 protein expression has
been found to correlate with clinically
aggressive basal cell carcinomas with
infiltrative, sclerosing/morphoeic pat-terns as compared to superficial and
nodular tumours {296,1883}.
BCC recurrences are more common in
lesions on the nose and nasolabial fold,
but this may be in part due to the difficul-ty in achieving adequate margins in
these sites {638,651}. Tumours recurring
after radiotherapy are usually aggressive
and infiltrative {2209}. Lesions which
metastasize are usually large, ulcerated,
deeply infiltrating and recurrent {70}. The
risk of further primary BCCs is increased
by male gender, age over 60 years and
truncal site {1208,1378}.
Rarely, extensive perineural invasion is
seen in infiltrative primary BCCs of the
face, presenting life-threatening compli-cations of CNS extension {317,946}.
Distance to the closest resection margin
is an important predictor of BCC recur-rence {639}.
Superficial basal cell
carcinoma
ICD-O code 8091/3
Clinical features
This variant appears as erythematous
patches that are often multiple and may
vary from a few millimetres to over 10 cm
in diameter. A fine pearly border or cen-tral superficial erosions with a history of
contact bleeding may be present. Areas
of regression may appear as pale patch-es or fibrosis. This variant makes up 10-30% of basal cell carcinomas and occurs
most frequently on the trunk.
Histopathology
The histopathology consists of superfi-cial lobules of basaloid cells which proj-ect from the epidermis or from the sides
of follicles or eccrine ducts into the der-mis and are surrounded by loose myxoid
stroma. The lobules are usually confined
Fig. 1.3 Nodular BCC. Cribriform nodular basal cell carcinoma. Fig. 1.4 Nodular BCC with monster giant cells.
16 Keratinocytic tumours
to the papillary dermis. Some examples
of superficial basal cell carcinoma
appear multifocal on vertical sections but
may be connected by a stroma when
reconstructed by three-dimensional
techniques using digital image analysis.
There are, however, examples of multi-focal superficial basal cell carcinoma
where the lobules are separated by large
distances and represent discrete
tumours that are truly multifocal and may
measure only a few millimetres in diame-ter. Mixed patterns with a nodular,
micronodular or infiltrative component
may be seen in some tumours.
Nodular basal cell carcinoma
ICD-O code 8097/3
Clinical features
Nodular (solid) basal cell carcinomas
often appear as elevated pearly nodules
associated with telangiectasia but may
become ulcerated or cystic. Endophytic
nodules may present as flat indurated
lesions. Haemorrhagic lesions may
resemble haemangiomas or melanoma
when pigmented. Nodular basal cell car-cinomas make up 60-80% of tumours
and occur most frequently on the head.
Histopathology
Histopathology shows large lobules of
basaloid cells (“germinative cells”) with
peripheral palisading nuclei that project
into the reticular dermis or deeper. The
lobules may have associated mucinous
degeneration with cysts or have an ade-noid (cribriform) pattern. Some nodules
may have an organoid appearance with
smaller basaloid lobules that are con-nected by loose fibromucinous stroma.
The periphery of such nodules should be
scanned to ensure that an outlying
micronodular pattern has not developed.
Micronodular basal cell
carcinoma
ICD-O code 8090/3
Clinical features
Micronodular basal cell carcinoma pres-ents as elevated or flat infiltrative
tumours. The most common site is the
back.
Histopathology
This variant has small nodules that per-meate the dermis {1010}. Individual nod-ules may appear to be separated by nor-mal collagen. The tumour nodules may
approximate the size of follicular bulbs
and form subtle extensions into deep tis-sue. In contrast to nodular basal cell car-cinoma the surgical margins of micron-odular basal cell carcinoma may be
underestimated. Perineural extension
may be seen.
Fig. 1.5 A Infiltrative basal cell carcinoma.  B 0172.Mixed nodular and infiltrative basal cell carcinoma.
BA
Fig. 1.6 Nodular cystic BCC  A There are well circumscribed cystic nodules of atypical basaloid cells pushing into the deep dermis in a nodular pattern.  B High
power view of nodulocystic basal cell carcinoma showing cribriform cystic spaces filled with stromal mucin.
BA
17Basal cell carcinoma
Infiltrating basal cell
carcinoma
Definition
This variant of BCC is composed of thin
strands, cords and columns of basaloid
cells that infiltrate between the collagen
bundles of the dermis and may extend
into deeper tissues.
ICD-O code 8092/3
Clinical features
The infiltrative basal cell carcinoma pres-ents as a pale, indurated poorly-defined
plaque. These tumours are usually found
on the upper trunk or face. Paraesthesia
or loss of sensation may develop rarely
as a manifestation of perineural exten-sion, particularly in lesions on the face.
This variant is important in that the mar-gins at the time of surgery may be fre-quently underestimated.
Histopathology
Infiltrative patterns of basal cell carcino-ma appear as strands, cords and
columns of basaloid cells with scant
cytoplasm. Peripheral palisading and
retraction spaces are usually not seen.
There is no fibrosis/sclerosis as seen in
the sclerosing/morphoeic variant. The
infiltrative pattern is particularly associat-ed with perineural invasion. Low molecu-lar-weight keratin markers are useful in
highlighting subtle groups of tumour
cells (that may consist of 1-2 ker-atinocytes on cross section), in assess-ing clearance of the tumour and in con-firming perineural involvement.
Differential diagnosis
Due to the cord-like arrangement of this
variant there is a morphological overlap
with the tumour pattern seen in micro-cystic adnexal carcinoma (sclerosing
sweat duct carcinoma), desmoplastic
squamous cell carcinoma and desmo-plastic trichoepithelioma.
Fibroepithelial basal cell
carcinoma
Definition
This variant of BCC is characterised by a
unique clinicopathological presentation
and an indolent behaviour.
ICD-O code 8093/3
Synonyms
Fibroepithelioma of Pinkus, Pinkus
tumour
Clinical features
These tumours usually appear as an ele-vated flesh coloured or erythematous
nodule that may resemble a seborrhoeic
keratosis or acrochordon. The lesions are
most often found on the back and are
rarely multiple {1834}. Prior radiotherapy
may predispose to these tumours.
Histopathology
The histopathology is characterised by
an arborising network of cords of basa-loid cells that extend downwards from
the epidermis and create a fenestrating
pattern. There are strands of basaloid
cells that surround fibrovascular stroma.
Ductules may be present in some of the
cords which may represent extension of
the tumour down pre-existing eccrine
ducts {2263}. The cords also are associ-ated with small follicle-like bulbs which
project into the surrounding connective
tissue.
Histogenesis
Fibroepitheliomas, like BCCs, may be
best classified as a form of appendageal
tumour. These tumours have mutations of
the PTCH1 gene. In some fibroepithe-liomas transition to classical basal cell
carcinomas may be seen, and this con-version may reflect a further mutation. A
variant of fibroepithelioma with extra-mammary Paget’s cells has been
described in the perianal area {2461}.
Fig. 1.7 Fibroepithelial basal cell carcinoma (fibroepithelioma of Pinkus). Fig. 1.8 BCC with adnexal differentiation; basaloid
follicular hamartoma.
18 Keratinocytic tumours
Basal cell carcinoma with
adnexal differentiation
Definition
This variant is characterized histological-ly by adnexal differentiation in a BCC.
ICD-O code 8098/3
Clinical features
This variant has no distinguishing clinical
features.
Histopathology
This variant is characterized by the pres-ence of adnexal differentiation including
basaloid buds, ductal, sebaceous and
trichilemmal elements. Follicular differen-tiation may be prominent in more superfi-cial BCCs. Eccrine or apocrine differenti-ation has also been observed in some
basal cell carcinomas {997,2022}. It is
important to distinguish such tumours
from sweat gland carcinomas which
have an increased risk for metastases.
Some forms of adnexal basal cell carci-nomas show overlap and may be better
classified as benign adnexal tumour
such as a basaloid follicular hamartoma,
trichoepithelioma, trichoblastoma or
trichilemmoma.
Histogenesis
The cytokeratin profile of basal cell carci-noma is essentially identical to that of tri-choblastomas (immature trichoepithe-lioma) and developing fetal hair follicles
linking all basal cell carcinomas to the
pilosebaceous pathway of differentiation
{2086}. It has been proposed that basal
cell carcinoma be renamed trichoblastic
carcinoma {1623}.
Prognosis and predictive factors
These patterns of adnexal differentiation
do not appear to have any prognostic
implications.
Basosquamous carcinoma
Definition
Basosquamous carcinoma is a term
used to describe basal cell carcinomas
that are associated with squamous differ-entiation {285,2102}.
ICD-O code 8094/3
Synonyms
Metatypical carcinoma, basosquamous
cell carcinoma
Clinical features
This variant has no distinguishing clinical
features.
Histopathology
The tumour cells have more abundant
cytoplasm with more marked keratiniza-tion than typical basal cell carcinomas.
The nuclei have vesicular chromatin with
pleomorphism and palisading may be
focally lost. Some examples of this vari-ant may merge with sebaceous carcino-ma as lipid vacuoles or ducts may be
focally apparent. This tumour may also
have central fibrosis and a radiating
peripheral rim of infiltrative cells extend-ing into the deep dermis or subcutis.
Prognosis and predictive factors
This variant has a more aggressive
behaviour and has been associated with
regional or widespread metastases
{1525}.
CB
A
Fig. 1.9 Basal cell carcinoma, nodular type, with follicular differentiation.   A The overall view shows a
resemblance to typical nodular basal cell carcinoma, with the addition of a cellular fibrous stroma.  B There
is follicular bulbar differentiation in parts of the tumour, with formation of hair bulb accompanied by mes-enchymal bodies. Focal dystrophic calcification.  C 1603 High power view showing groups of atypical basa-loid cells with peripheral palisading with trichohyaline granules and abrupt trichilemmal keratinization.
BA
Fig. 1.10 Basal cell carcinoma, keratotic type.  A Prominent keratin horn cysts in the center of the tumour
nests.  B Detail of trichilemmal keratinization.
19Basal cell carcinoma
Keratotic basal cell carcinoma
Definition
This variant is characterized by the pres-ence of prominent keratin formation (horn
cysts) in the centre of tumour islands.
ICD-O code 8090/3
Clinical features
This variant characteristically appears
pearly and may be studded with small
keratin cysts (milia).
Histopathology
These tumours share the overall archi-tectural features of a nodular BCC.
Keratinization may be laminated and
infundibular in type or hyaline and
trichilemmal in type or consist of kera-tinised shadow cells representing pilo-matricomal differentiation {66}. Dys-trophic calcification is frequently present.
Trichilemmal keratin may be associated
with accentuated apoptosis in surround-ing tumour cells and the presence of
pale keratinocytes.
Differential diagnosis
This variant is distinguished from
basosquamous carcinoma by the pres-ence of numerous, superficial small ker-atin cysts. Basosquamous carcinoma is
usually larger and less well circum-scribed.
Other variants
Other variants account for less than 10%
of all basal cell carcinomas. Many of
them do not have distinctive clinical fea-tures.
Cystic
One or more cystic spaces, of variable
size, are present near the centre of the
tumour nests. There is sometimes in-creased mucin between the cells border-ing the central space {2112}.
Adenoid
There are thin strands of basaloid cells in
a reticulate pattern. Stromal mucin is
often present. The adenoid type may
occur in association with the nodular
(solid) type.
Sclerosing / morpheiform
Strands and nests of tumour cells are
embedded in a dense fibrous stroma
{1932}. Some authors use the term mor-phoeic for any BCC with a fibrous stro-ma, while others restrict it to those BCC’s
with keloidal collagen bundles in the stro-ma {1923}. Enhanced procollagen gene
expression has been found in this variant
{1657}. Furthermore, smooth muscle  α-actin is often present in the stroma. This
variant usually presents as an indurated,
pale plaque with a slightly shiny surface
and indistinct margins.
Infundibulocystic
Often confused with the keratotic type,
this variant is composed of small
infundibular-like structures with a central
keratinous plug and a peripheral compo-nent of basaloid cells {1218}. The nests
are arranged in an anastomosing pat-tern. Multiple lesions are sometimes
present {1178}.
Pigmented
Pigmentation may occur in several of the
variants including the nodular, micron-odular, multifocal superficial and keratot-ic types. Melanocytes are scattered
through the tumour nests, while
melanophages are present in the stroma
{1495}. This variant can be misdiag-nosed clinically as malignant melanoma.
Miscellaneous
Other rare variants, subject to isolated
case reports, include the clear-cell {165},
“signet-ring”-cell {1269,2503}, granular-cell {1659} and giant (“monster”)-cell
{680} types. Adamantanoid {1403}, neu-roendocrine {817} and schwannoid
{2032} variants have also been
described.
DC
Fig. 1.11 Basal cell carcinoma (BCC).  A Adenoid BCC.  B Morpheiform BCC.  C BCC with rosettes.  D BCC
with sebaceous differentiation.
BA
20 Keratinocytic tumours
Definition
Squamous cell carcinoma is a malignant
neoplasm of epidermal (and mucous
membrane) keratinocytes in which the
component cells show variable squa-mous differentation.
ICD-O code 8070/3
Epidemiology
Most cases arise on the sun-exposed
skin of elderly people. They can occur on
all cutaneous surfaces and mucous
membranes, and in younger patients,
especially those with a fair complexion
who tan poorly. Its incidence in an
Australian study was 166 cases per
100,000 of the population, the highest in
the world {828}. It is relatively uncommon
in Black people.
Etiology
Ultraviolet-B radiation is the most impor-tant etiological factor. Less important fac-tors include radiation therapy, previous
burns, arsenic, coal tar {1759}; industrial
carcinogens, immunosuppresion, HPV
infection, and inflammatory lesions and
ulcers of long standing (see Intro-duction). Organ transplant recipients are
particularly prone to develop these
tumours. Most of the fatal cases have
been reported from Australia, suggesting
that sunlight, which also has a profound
effect on the cutaneous immune system
plays a role in the formation of these
aggressive tumours {1974}. HPV infec-tion is commonly found in these immuno-supressed patients {264}.
Localization
Most SCCs arise in areas of direct expo-sure to the sun, such as the forehead,
face, ears, scalp, neck and dorsum of
the hands. The vermilion part of the lower
lip is another common site.
Clinical features
Squamous cell carcinomas present as
shallow ulcers, often with a keratinous
crust and elevated, indurated surrounds,
or as plaques or nodules. The surround-ing skin usually shows changes of actinic
damage.
Histopathology
Squamous cell carcinoma consists of
nests, sheets and strands of squamous
epithelial cells which arise from the epi-dermis and extend into the dermis for a
variable distance. The cells have abun-dant eosinophilic cytoplasm and a large,
often vesicular, nucleus. There are promi-nent intercellular bridges. There is vari-able central keratinization and horn pearl
formation, depending on the differentia-tion of the tumour.
The degree of anaplasia in the tumour
nests is used to grade the tumours. A
rather subjective assessment is usually
made using the categories of ‘well,’
‘moderately’ and ‘poorly’ differentiated.
Most squamous cell carcinomas arise in
solar keratoses and evidence of this
lesion is usually present at the periphery
of the invasive tumour.
Squamous cell carcinomas occasionally
infiltrate along nerve sheaths, the adven-titia of blood vessels, lymphatics, fascial
planes and embryological fusion plates
{218}. The presence of perineural lym-phocytes is a clue to the likely presence
of perineural invasion in deeper sections
{2289}.
There may be a mild to moderate chronic
inflammatory cell infiltrate at the periph-ery of the tumours. This infiltrate some-times includes eosinophils {1455}.
Rare histological variants of SCC include
clear-cell {1344}, signet-ring {1557}, pig-mented {451}, basaloid {573}, inflamma-tory, infiltrative {1395}, desmoplastic
{1546} and rhabdoid {1534} types.
The cells in SCC are positive for epithe-lial membrane antigen and cytokeratin.
The keratins are of higher molecular
weight than those found in basal cell car-cinoma {1672}.
Prognosis and predictive factors
The majority of squamous cell carcino-mas are only locally aggressive and are
cured by several different modalites
{1656}. SCC developing in patients who
are immunocompromised (including
those infected with the human immunod-eficiency virus {1704}, are usually more
aggressive. Tumours with deep invasion,
poor differentiation, perineural invasion
and acantholytic features are more likely
to recur or metastasize. Narrow surgical
margins are another risk factor for recur-rence {2389}.
The clinical setting in which the SCC aris-es also influences the risk of metastasis.
Tumours arising in sun-damaged skin
have the lowest risk, in the order of 0.5%
or less, while for those arising in skin not
exposed to the sun, the risk is 2-3%. The
risk is further increased for tumours aris-ing in Bowen disease {1203}, on the lip,
vulvar, perineal and penile skin and in a
Marjolin ulcer, radiation scar or thermal
burn. Tumour thickness is a prognostic
variable, just as it is for melanoma. SCCs
less than 2 mm in thickness rarely metas-tasize, while those between 2 and 5 mm
thick are of intermediate risk (about 5%).
Tumours greater than 5 mm in thickness
have a risk of metastasis of about 20%
{1254}. Tumours greater than 2 cm in
diameter are more likely to recur and
metastasize than smaller lesions {1985}.
D. Weedon
M.B. Morgan
C. Gross
E. Nagore
L.L. Yu
Squamous cell carcinoma
Fig. 1.12 Squamous cell carcinoma in an elderly
male with delayed medical treatment. This is an
unusually large neoplasm which spread to the
regional lymph nodes.
21Squamous cell carcinoma
Acantholytic squamous cell
carcinoma
Definition
Acantholytic squamous cell carcinoma
(ASCC) is a histologic variant of cuta-neous squamous cell carcinoma (SCC)
that is histologically defined by loosening
of the intercellular bridges resulting in
acantholysis. These tumours may pres-ent as intraepidermal (in-situ) or invasive
SCC.
ICD-O code 8075/3
Synonyms
Adenoid squamous cell carcinoma,
pseudoglandular squamous cell carcino-ma
Epidemiology
The acantholytic variant accounts for 2-4% of all cutaneous SCC {1149,1687,
1819,2549}. The age range is wide but it
usually affects aged individuals with a
male predominance.
Etiology
As in conventional SCC, ultraviolet light
constitutes the most important etiologic
risk factor.
Localization
The tumour involves predominantly the
skin of the head and neck region, partic-ularly on and around the ears {1149,
1687,1819,2549}.
Clinical features
ASCC presents similarly to conventional
SCC, as a slowly growing scaly and
occasionally ulcerated papule/plaque on
the sun-exposed skin.
Histopathology
Invasive lesions typically show a thick-ened, and/or ulcerated epithelium.
Scanning magnification reveals a flat-tened thinned, normal or hyperplastic
epidermis with or without asymmetric
and infiltrating dermal tumour islands. At
intermediate power, prominent
suprabasilar or intratumoural acantholy-sis is seen. Zones of acantholysis are
capable of producing large intra-epider-mal cavities. Acantholytic areas may
extend down adjacent follicular struc-tures involving the follicular epithelium
and rarely, circumscribe the follicle simu-lating a glandular arrangement.
Acantholytic foci may also produce a
pseudovascular pattern mimicking
angiosarcoma (pseudovascular SCC)
{139,1675,1688}. At high power typical
features of squamous malignancy are
identified including dyskeratosis, ker-atinocytic atypia, consisting of an
increased nuclear-to-cytoplasmic ratio
and nuclear hyperchromasia, altered
maturation within the epithelium, and
increased typical and atypical mitotic fig-ures.
Immunoprofile
The lesional cells in ASCC stain for cuta-neous epithelial markers that include
high molecular weight keratins such as
AE-2/3. Involucrin, vimentin and EMA
immunostains may also be positive
{1808,2011}. Low-molecular weight ker-atins such as AE-1, CAM 5.2 are typical-ly negative. Various intercellular peptides
have been invoked in the pathogenesis
of acantholysis including the intercellular
adhesion molecule syndecan, E-cad-herin and the anhidrotic ectodermal dys-plasia gene product {183,1635}. It has
also been recently shown that decreased
TP53 and PCNA expression correlated
with a decrement in desmosomes seen
ultrastructurally {1889}.
Differential diagnosis
The changes described above constitute
an important histologic means of sepa-rating this entity from acantholytic disor-ders. The differential also includes true
adenosquamous cell carcinoma of the
skin that exhibits squamous and glandu-lar differentiation on ultrastructural exam-ination and histochemical staining {2482}.
Prognosis and predictive factors
The behaviour of ASCC like other SCCs
is depth-dependent and may be more
aggressive than conventional SCC {461,
1097,1149,1687,1819,1985}. In-situ le-sions are capable of recurrence and in
up to 10% of cases, may show micro-invasion. The overall rate of metastases
with lesions greater than 2.0 cm of inva-sion ranges from 5-19%.
Fig. 1.13 A Acantholytic SCC, Intermediate-power photomicrograph depicting acantholysis extending down adjacent follicle epithelium.  B Squamous cell carcino-ma (acantholytic)
BA
22
Spindle-cell squamous cell
carcinoma
Definition
This is an uncommon variant of squa-mous cell carcinoma that exhibits a
prominent spindle cell morphology.
ICD-O code 8074/3
Etiology
Lesions usually arise in sun-damaged or
irradiated skin. A case has been report-ed in association with lichen sclerosus of
the vulva {2057}. The incidence of this
variant may be higher in immuosup-pressed patients.
Clinical features
Spindle-cell squamous cell carcinoma
presents as a plaque or nodule on the
skin. It may be clinically indistinguishable
from the more usual type of squamous
cell carcinoma. Sometimes there is a his-tory of rapid growth.
Histopathology
It may be composed entirely of spindle
cells, or have a variable component of
more conventional squamous cell carci-noma. The spindle cells have a large
vesicular nucleus and scanty
eosinophilic cytoplasm, often with indis-tinct cell borders. There is variable pleo-morphism, usually with many mitoses.
Differential diagnosis
It may be difficult to separate from other
cutaneous spindle cell neoplasms
including spindle cell melanoma, atypi-cal fibroxanthoma and, less often,
leiomyosarcoma. Some cases can only
be confirmed ultrastructurally, as all ker-atin markers are negative {2180}. CK5/6
is positive in two-thirds of all cases, a
higher figure than obtained with AE1/3,
CAM5.2 or MNF116. Some tumours may
coexpress cytokeratin and vimentin, sug-gesting metaplastic change to a neo-plasm with mesenchymal characteristics
{1116}.
Prognosis and predictive factors
Spindle-cell squamous cell carcinoma is
a poorly differentiated variant of squa-mous cell carcinoma that may be associ-ated with an aggressive clinical course
{2180}. These tumours account for slight-ly over one-third of cutaneous squamous
cell carcinomas which metastasize
{1985}. Metastases usually occur to the
regional lymph nodes in the first
instance.
Verrucous squamous cell
carcinoma
Definition
Verrucous squamous cell carcinoma is a
rare variant of well-differentiated squa-mous cell carcinoma with low malignant
potential.
ICD-O code  8051/3
Synonyms
Oral florid papillomatosis, Ackerman’s
tumour {32,348}, epithelioma cunicula-tum {41,2096,2108}, giant condyloma
acuminatum, Buschke-Löwenstein tu-mour {359,1347,1947,2124,2570}, papil-lomatosis cutis carcinoides {218,870,
2108}.
Epidemiology
Verrucous carcinoma comprises 2-12%
Keratinocytic tumours
Fig. 1.14 Squamous cell carcinoma (acantholytic) A, B Note the pseudoglandular pattern and the loss of cohesion between tumour cells.
BA
Fig. 1.15 Verrucous squamous cell carcinoma Fig. 1.16 Verrucous squamous cell carcinoma
23Squamous cell carcinoma
of all oral carcinomas, and is found pre-dominantly in men (age peak in 5th
decade, range 34-85) {348}. Verrucous
carcinoma of the extremities (epithelioma
cuniculatum) most often affects men in
the 6th decade {2108}. The incidence of
the genital type (Buschke-Löwenstein
tumour) varies between 5- and 24% of all
penile cancers; the tumour tends to
occur in men younger than 50 years
(range 18-86) {218}.
Etiology
Leading theories of the pathogenesis
include chronic irritation, inflammation
and impaired immune response {2096,
2108}. Important factors for the develop-ment of oral verrucous carcinomas are
poor oral hygiene with ill-fitting dentures
or decaying teeth, chewing of tobacco or
betel nuts, and use of snuff. In genital
lesions poor hygiene and phimosis play
a major role. Other theories include HPV
infection (mostly HPV 6, 11) {898} and
chemical carcinogens {2096,2108}.
Localization
Common sites include buccal and retro-molar mucosa, gingiva, floor of mouth,
tongue and hard palate. They also arise
on the soles, rarely the palms and distal
fingers, and on amputation stumps.
Genital lesions occur primarily on the
glans and prepuce of the penis {778,
2108,2570}. It is uncommon in the vagina
and the perianal region {1347,1947,
2124}. Rare cases have been described
on the scalp, face, back and extremities,
sometimes associated with long-stand-ing ulcerations or scars, especially in the
pretibial area (papillomatosis cutis carci-noides) {218,870,2096,2108}.
Clinical features
These lesions show cauliflower-like
appearance with exophytic and endo-phytic growth, and a papillomatous sur-face. They are pale in colour and some-times have draining sinuses. Some are
tender and painful, particularly on the
sole of the foot. There is slow but relent-less growth over the course of a long
time {2570}.
Histopathology
In all cases a well-differentiated prolifera-tive epithelial process is visible, the
malignant nature of which may easily be
overlooked, particularly if the biopsy is
small and superficial. The squamous
epithelium shows an asymmetric exo-and endophytic growth pattern with
pushing rather than destructive or infiltra-tive margins. Usually, there is deep pen-etration below the level of the surround-ing epidermis / mucosa. Tumour cells
exhibit only minimal atypia and very low
mitotic activity. The presence of neu-trophils is an important diagnostic clue;
they may form small intraepidermal
abscesses. Draining sinuses containing
inflammatory cells and keratin debris
may also be present. No foci of the usual
squamous cell carcinoma should be
found {1833}.
Differential diagnosis
The separation from benign reactive
processes and SCC of the more usual
type can be difficult. The presence of
blunted projections of squamous epithe-lium in the mid and/or deep dermis is
suspicious for verrucous carcinoma. The
squamous downgrowths are bulbous.
Small collections of neutrophils may
extend into the tips. Clinicopathological
correlation and adequate sampling are
often helpful.
Precursor lesions
Oral lesions may develop in areas of pre-vious leukoplakia, lichen planus, lupus
erythematosus or candidiasis {218}.
Prognosis and predictive factors
If the tumour is completely excised,
prognosis is excellent; after inadequate
excision, the recurrence rate is high and
the survival decreases. In long-standing
cases or after irradiation and / or
chemotherapy the biologic character of
the disease may change into a metasta-sizing squamous cell carcinoma {1216}.
Pseudovascular squamous
cell carcinoma
Definition
Pseudovascular SCC is an aggressive
variant of SCC with marked acantholysis
resulting in angiosarcoma-like areas
{139,1688}.
ICD-O code  8075/3
Synonyms
Pseudoangiosarcomatous SCC,
pseudoangiomatous SCC
Epidemiology
The tumour is exceedingly rare.
Clinical features
It usually presents as a circumscribed
white-grey ulcer or a nodular tan-red/pink
tumour, most often located on sun-Fig. 1.17 Verrucous squamous cell carcinoma  A, B Note the well-differentiated proliferative process and
the bulbous nature of the squamous downgrowths.
BA
24 Keratinocytic tumours
exposed areas of middle-aged or elderly
patients.
Histopathology
It is characterized by areas of anasto-mosing cord-like arrays of polygonal or
flattened tumour cells, with internal
pseudolumina that contain detached
tumour cells and amorphous basophilic
material {550,1675,2558}. Erythrocytes
may also be seen in pseudovascular
spaces. Immunohistochemical examina-tion is essential to differentiate it from
angiosarcoma. Pseudovascular SCC is
positive for one or more monoclonal anti-bodies to cytokeratin and consistently
negative for CD31 and factor VIII-related
antigen.
Differential diagnosis
In classical angiosarcoma vascular
markers are positive, keratin staining is
negative; in epithelioid angiosarcoma in
addition to vascular markers epithelial
markers are frequently expressed.
Prognosis and predictive factors
The prognosis is worse than it is for other
variants of SCC, with a mortality up to
50%. Large size may confer a worse
prognosis {1675}.
Adenosquamous carcinoma
Definition
Adenosquamous carcinoma is a rare
variant of squamous cell carcinoma aris-ing from pluripotential cells related to
acrosyringia, characterized by the for-mation of mucin secreting glands.
ICD-code 8560/3
Epidemiology
Most reported cases occurred on the
head and neck of elderly patients, with
male predominance {120,140,572,
1933,2482}. The penis can also be
involved {120}.
Clinical features
It can present as an asymptomatic
smooth surfaced dermal nodule or a
large ulcerated deeply invasive tumour
indistinguishable from squamous cell
carcinoma or basal cell carcinoma.
Histopathology
The tumour consists of invasive tongues,
sheets, columns and strands of atypical
dyskeratotic squamous cells, merging
with glandular structures with epithelial
mucin secretion, which can be demon-strated by a PAS, mucicarmine or alcian
blue stain at pH 2.5. The mucin is
hyaluronidase resistant and sialidase
sensitive.  Intracytoplasmic neolumina
containing targetoid mucin secretions
can also be seen. The tumour cells are
positive for cytokeratin and epithelial
membrane antigen, whereas those cells
forming glands stain with carcinoembry-onic antigen. There may be connection
between tumour cells and acrosyringia,
as well as perineural invasion.
Differential diagnosis
Adenosquamous carcinoma should be
distinguished from mucoepidermoid car-cinoma, which had been reported as
adenosquamous carcinoma in early
reports.  Adenosquamous carcinoma
has well formed glands with mucin
secretion and no goblet cells.  Muco-epidermoid carcinoma consists of polyg-onal squamous cells and goblet cells
without glands. Signet ring squamous
Fig. 1.18  Adenosquamous carcinoma of the ear.
There are deeply invasive tongues, columns and
strands of atypical dyskeratotic squamous cells
abutting the cartilage.
Fig. 1.19 Adenosquamous carcinoma.  A Overt squamous differentiation in parts of the tumour.  B Sheets of atypical dyskeratotic squamous cells from the squa-mous area of the tumour.
BA
25Squamous cell carcinoma
cell carcinoma has foamy cytoplasmic
mucin globules with displacement of the
cell nucleus but no glands.  Microcystic
adnexal carcinoma (syringomatous car-cinoma, sclerosing sweat duct carcino-ma) shows a more ductal appearance
with prominent tubular structures but no
mucin secretion.  Metastatic adenosqua-mous carcinoma from other primary sites
such as the lung, salivary gland, female
genital tract should also be excluded.
Prognosis and predictive factors
The tumours usually follow an aggressive
course with the capacity for metastasis
and local recurrence.   Early superficially
located tumours tend to have a better
prognosis.
B CA
Fig. 1.20  Adenosquamous carcinoma.   A Well formed glandular structures containing mucinous secretion in the glandular area of the tumour.   B PAS stain.
Intracytoplasmic targetoid PAS positive and diastase sensitive globules in the glandular areas of the tumour.  C CEA immunohistochemical stain. Positive luminal
staining in glandular structures.
26 Keratinocytic tumours
Definition
Bowen disease (BD) is a form of squa-mous cell carcinoma in situ. It is a distinct
clinicopathologic entity of the skin and
mucocutaneous junction.
ICD-O code 8081/2
Synonyms
Squamous cell carcinoma in situ
(SCCIS), intraepidermal carcinoma,
bowenoid dysplasia, bowenoid squa-mous carcinoma in situ (BSCIS), vulvar
intraepithelial neoplasia (VIN III).
The terms bowenoid dysplasia and
BSCIS are customarily applied to cuta-neous and mucocutaneous lesions of the
male and female external genitalia. BD is
no longer used in gynaecological pathol-ogy. It has been replaced by the concept
of vulvar intraepithelial neoplasia (VIN).
The degree of epithelial atypia seen in
BD corresponds to VIN, grade III (VIN III)
{362,1580}.
Epidemiology
Bowen disease occurs predominantly in
fair-complexioned Caucasian men, but
both sexes are affected. One in five
patients (20%) is a woman. The disease
commonly affects patients in the 6-8th
decades of life. However, the average
age at onset of the disease is 48 years,
and the average age at first biopsy is 55
years. Both exposed and non-exposed
skin sites are equally affected. The dis-ease uncommonly affects black skin, in
which it is found more commonly on non-sun-exposed areas.
Etiology
The exact underlying cause of BD
remains unclear, although multiple fac-tors are likely to be responsible for it.
Many lesions arise without an apparent
cause. However, it is known that chronic
sun damage disrupts normal keratinocyt-ic maturation, causes mutation of the
tumour suppressor gene protein (TP53)
{375,1075}, and results in the develop-ment of keratinocytic atypia as seen in
lesions of BD. The predilection for
anatomic sites affected by BD on sun-exposed glabrous skin and lesions being
reported more commonly in patients with
a history of PUVA or UVB therapy {1410},
attest to the critical role of causal rela-tionship between UV damage and BD.
Ingestion of inorganic arsenic may play a
role, as lesions of arsenical keratosis (As-K) may display identical histopathologic
features to BD. A large number of cases
of As-K with associated invasive carcino-ma have been reported in a rural popula-tion using well water containing a high
concentration of inorganic arsenic
{2567,2572}. Human papillomavirus
(HPV) genomes have been demonstrat-ed by in situ hybridization in the nuclei of
keratinocytes in the stratum malpighii
and stratum corneum of the BD lesions.
HPV types 16 and 18 have been linked to
lesions of genital BD and non-condylo-matous genital warts, i.e., bowenoid
papulosis {1098}. HPV is less commonly
associated with nongenital BD. HPV
types 15 and 16 have been identified in
some cases of BD of the distal extremi-ties. Evidence of other papillomavirus
types, including HPV31, 54, 58, 61, 62
and 73, have also been identified in
some cases of BD. Aberrations in local
and systemic immunity, trauma, chronic
irritation, mutagenic factors, and tobacco
exposure are other possible etiologies of
BD.
Localization
Based upon a large series  of 1001 biop-sy-proven BD in Australia, most lesions
occurred on a sun-exposed glabrous
area {1315}. About one-third (33%) of the
lesions occured in the head and neck
areas, especially the face. Men had pre-dominance of lesions on the scalp and
ears, whereas women had a predomi-nant involvement of the legs and cheeks.
BD rarely affects the nail bed and peri-ungual area {2070}.
Clinical features
The classic appearance of cutaneous
BD is a single or multiple erythematous,
rounded to irregular, lenticular, scaly, ker-atotic, fissured, crusty, nodular, eroded,
pigmented patches or plaques. The
plaques are devoid of hair, and usually
appear sharply demarcated from the sur-rounding unaffected skin. Areas of nor-mal-appearing skin may occur within the
boundaries of larger lesions of BD. The
plaques vary from 1-5 cm in overall
dimensions. In intertriginous areas, BD
may appear as moist patches without
scale. In anogenital locations, the lesions
appear polypoid or verrucoid, frequently
pigmented. Erythroplasia of Queyrat
(EPQ) presents as an asymptomatic,
G.F. Kao
R. Cerio
R. Salom
S. Pala
Bowen disease
Fig. 1.21 A Bowen disease. Sharply circumscribed, bright red plaque of erythroplasia of Queyrat (EPQ).
B Bowen disease. Erythematous, scaly, fissuring plaques of BD on lower leg of a middle-aged woman.
BA
27Bowen disease
bright red, velvety to shiny, sharply cir-cumscribed plaque. The mucocuta-neous junction of the glans penis, coro-nal sulcus, or undersurface of the fore-skin is involved, and lesions are usually
found in older, uncircumcised men.
There are two clinical variants of BD:
those involving glabrous skin, and those
of the anogenital area. On the glabrous
skin, BD manifests as asymptomatic,
slowly enlarging, scaly patches or
plaques. The average duration of the
lesion is 6.4 years. Plaques of BD
enlarge slowly, and expand centrifugally,
sometimes for decades. Anogenital BD
involves the mucocutaneous junction
and adjacent mucosa. If untreated, 5-8%
of patients may develop invasive carci-noma. The invasive carcinomas are larg-er (up to 15 cm), rapidly growing tumours
that occur in pre-existing scaly plaques
{1203}.
The clinical entity of erythroplasia of
Queyrat (EPQ) is regarded as BD of the
glans penis. Such lesions have a greater
potential for developing into invasive car-cinoma than does BD involving glabrous
skin {875}. Although evidence for the
association of BD and internal malignan-cies is reported in earlier studies, more
recent population-based cohort studies
do not confirm the link {484}.
Histopathology
The typical low-power microscopic fea-tures of BD are hyperkeratosis, paraker-atosis, hypo- or hypergranulosis, plaque-like acanthosis with increased cellularity,
and a chronic inflammatory infiltrate in
the upper corium. The epidermis exhibits
loss of normal polarity and progression of
normal surface keratinocytic maturation.
A “windblown” appearance of crowding
of atypical keratinocytes, with hyperchro-matism, pale-staining to vacuolated
cells, occasional multinucleated cells,
individual cell keratinization (dyskerato-sis), and abnormal mitoses are noted.
These changes are confined by an intact
dermoepidermal basement membrane.
Lesions of BD from hair-bearing areas
invariably demonstrate involvement of
the pilar acrotrichium, infundibulum, and
sebaceous gland. In some lesions,
prominent vacuolated atypical cells
focally mimic koilocytotic viral cytopathic
change and exhibit a pagetoid appear-ance. The acrosyringium is occasionally
involved. An inflammatory infiltrate of
lymphocytes, macrophages, and plasma
cells is seen in the upper dermis.
Capillary ectasia is commonly noted.
Prominent solar elastosis is also present
in lesions on sun-exposed skin. An inva-sive carcinoma arising in BD shows vari-able histologic differentiation, with squa-mous, basosquamous, pilar, sebaceous
{1120}, pilosebaceous, poorly-differenti-ated, and occasionally ductal features
{1203,2016}. The atypical vacuolated
keratinocytes are negative for cytoplas-mic mucin; some, however, contain
DC
BA
Fig. 1.22 Bowen disease (BD).  A Low-power photomicrograph of BD. Note hyperkeratosis, full-thickness of epidermal atypia, extensive pilar epithelial involvement,
and a lichenoid upper dermal mixed chronic inflammatory infiltrate.  B Atypical keratinocytes encircle an acrosyringium.  C Atypical squamous cells extend along
acrosyringia.  D Prominent vacuolated atypical cells, focally mimicking koilocytotic change and pagetoid appearance seen in BD.
28 Keratinocytic tumours
glycogen. Melanin pigment may be pres-ent in the atypical cells, and in the pig-mented genital lesions, melanophages
are numerous. The abnormal keratinizing
cells are intensely reactive with glucose-6-phosphate dehydrogenase. Ultrastruc-tural changes of BD include decrease in
tonofilament-desmosomal attachments,
aggregated tonofilaments and nuclear
substance, and absence of keratohya-line granules {1204}.
Differential diagnosis
Bowenoid solar keratosis differs from BD
by its clinically smaller size, exclusive
location on sun-exposed skin, and pres-ence of superficial keratinocytic matura-tion. Bowenoid papulosis is distin-guished from BD by its clinical appear-ance of multiple papular to coalescing
lesions on the anogenital areas, and the
typical microscopic salt and pepper dis-tribution of atypical keratinocytes and
mitoses in the affected cutaneous and
mucocutaneous lesions, as well as fre-quent HPV positive koilocytotic cells
{1790}. The pagetoid variant of BD is
sometimes difficult to distinguish from
extramammary Paget disease. In the lat-ter, mucicarmine, Cam 5.2 and CEA pos-itive tumour cells are present in the epi-dermis, individually or in small nests,
forming glandular structures at the der-moepidermal junction. These features
are absent in BD. The vacuolated cells in
BD contain glycogen and not mucin. In
malignant melanoma in situ, the basilar
keratinocytes are replaced by neoplastic
melanocytes. The presence of intercellu-lar bridges and prominent dyskeratotic
keratinocytes are features favouring the
diagnosis of BD. Melanoma cells do not
contain cytokeratins of 54 and 66 kilodal-tons (kd); the reverse applies with the
cells in BD.
Histogenesis
It has been suggested that BD most like-ly originates from germinal cells of the
pilar outer root sheath and the pluripo-tential epidermal cells of the acrotrichi-um. This concept is substantiated by the
findings of various types of histologic dif-ferentiation in carcinoma arising in BD
{1120,1203,2016}. Using immunohisto-chemical localization of keratins and
involucrin, the atypical cells of BD exhib-it a diversity of differentiation {1093}.
Genetics
The atypical keratinocytes of BD contain
large numbers of aneuploid cells {241}.
Increased expression and mutation of
TP53 observed in lesions of BD suggest
that loss of normal TP53 tumour suppres-sor activity may be an important mecha-nism of oncogenesis in BD {375,1075,
1946}. Allelic deletion of one or more 9q
chromosome markers has been detected
in occasional lesions of BD. However, no
deletion of 9p markers was seen {1866}.
There have been no clonal chromosomal
abnormalities by cytogenetic analysis of
cell cultures from BD {1003}.
Prognosis and predictive factors
Surgical excision with complete removal
may cure BD. The origin of BD from pilar
outer root sheath cells at the sebaceous
gland level explains in part the high
recurrence rate, following treatment with
superficial curettage and desiccation,
topical fluorouracil, and X-ray. Invasive
adnexal carcinoma may develop in
untreated plaques of BD of prolonged
duration following expansile growth. The
metastatic rate in these uncommon
tumours was 18% and fatality was
observed in 10% of cases in a large case
series {1203}.
Bowenoid papulosis
Definition
Bowenoid papulosis is a clinicopatholog-ical entity characterised by the presence
on the genitalia of solitary or multiple ver-ruca-like papules or plaques with histol-ogy resembling full thickness epidermal
dysplasia as seen in Bowen disease.
Synonyms
Multicentric pigmented Bowen disease,
multifocal indolent pigmented penile
papules
Epidemiology
Bowenoid papulosis occurs mainly in
young individuals and although uncom-mon the incidence is increasing. There is
a male predominance.
Etiology
The etiopathogenesis of this condition
almost certainly favours linkage to
human papillomavirus infection particu-larly oncogenic types 16, 18, 33,35 and
39. DNA sequences have been identified
by various workers {908,1737,2113}.
Consequently in females there is a high-er incidence of abnormal cervical/vagi-nal smears both in affected patients and
in partners of men with penile lesions.
Whilst controversies regarding the bio-DC
Fig. 1.23 Bowen disease.  A Full thickness squamous cell atypia.  B There is full thickness squamous cell
atypia with apparent sparing of the basal keratinocytes and hyperpigmentation of the basal keratinocytes.
C Full thickness squamous cell atypia with scattered bizzare keratinocytes.  D Full thickness squamous cell
atypia with marked nuclear pleomorphism.
BA
29Bowen disease
logical potential of bowenoid papulosis
exist, with the possibility of invasive
malignancy, in most cases the clinical
course is benign and some lesions
regress.
Localization
Bowenoid papulosis was first described
as a condition affecting the groin {1438}.
It was later defined {1305,2447} as an
entity involving the genitalia or perigeni-tal areas. Isolated cases of extragenital
bowenoid papulosis have been
described {902,1147}.
Clinical features
The lesions are usually asymptomatic
with variable clinical presentation: multi-ple generally small, round fleshy
papules, isolated or confluent (2.0-20
mm), with a smooth papillomatous sur-face, sometimes with desquamation
resembling lichenoid or psoriasiform der-matoses. The colour of lesions can vary
from pink to reddish-purple to brown /
black.
Histopathology
The histological features demonstrate
epidermal atypia ranging from partial to
full thickness atypia similar to in situ
squamous cell carcinoma i.e. Bowen dis-ease. On the genitalia changes may be
termed vulvar intraepithelial neoplasia
(VIN) III or penile intraepithelial neoplasia
(PIN) III by some pathologists {570}.
There is loss of architecture. The base-ment membrane is intact. Mitoses are
frequent, sometimes with abnormal
forms often in metaphase. Dyskeratotic
cells are also seen. Typical koilocytes are
uncommon {908}. The stratum corneum
and granular cell layer often contain
small inclusion – like bodies which are
deeply basophilic, rounded and sur-rounded by a halo.
Differential diagnosis
The basophilic bodies, together with the
numerous metaphase mitoses, are the
features which suggest a diagnosis of
bowenoid papulosis rather than Bowen
disease itself.
Histogenesis
A study based on histomorphology and
DNA ploidy analysis has suggested that
bowenoid papulosis is a form of low-grade squamous cell carcinoma in situ
{269}. Electron microscopy has shown
structures resembling viral particles
{1274,1790} within the granular layer.
Somatic genetics
Many of the atypical keratinocytes of
bowenoid papulosis not unlike Bowen
disease, contain large numbers of aneu-ploid cells. Increased expression and
mutation of TP53 observed in lesions
suggest that loss of normal TP53 tumour
suppressor activity is likely to be an
important mechanism of oncogenesis in
bowenoid papulosis. To date, there have
been no clonal chromosomal abnormali-ties by cytogenetic analysis of cell cul-tures from bowenoid papulosis.
Prognosis and predictive factors
Bowenoid papulosis appears in many
cases to remain benign {1790} and spon-taneous regression has occasionally
occurred; however, close follow up is
essential.
30 Keratinocytic tumours
Definition
A common intraepidermal neoplasm of
sun-damaged skin characterized by vari-able atypia of keratinocytes.
Synonyms
Solar keratosis
Epidemiology
Actinic keratoses (AK’s) usually present
in older individuals. The fair-skinned, the
freckled and those who do not tan easily
are at increased risk. Lesions have
developed in areas of vitiligo {2023,
2564}. The rate is higher in men because
of greater sun exposure {1049}. In the
Australian Caucasian population, AK’s
are discovered in 40-60% of individuals
over 40 {789,1515}, rising to 80% in the
seventh decade {1049}. Patients with
Rothmund-Thompson, Cockayne and
Bloom syndromes and xeroderma pig-mentosum are at increased risk {791}.
Etiology
Both cumulative and intermittent sunlight
exposure is implicated {790}. Ultraviolet
B (UVB) is the most harmful, but a sup-plemental effect of ultraviolet A (UVA) is
demonstrated {694}. AK’s are increased
after PUVA therapy {11}. UVB induces
DNA thymidine dimer formation, which
can target TP53, with impaired apoptosis
of damaged keratinocytes in cells with
two TP53 mutations {1150,1396,1696,
2602}. Clonal proliferations of these cells
form actinic keratoses and after further
genetic damage, invasive SCC may
develop. Ultraviolet light can act as an
initiator and promoter of carcinogenesis
{2602}. Epidermodysplasia verruci-formis–associated HPV types have been
discovered in AK’s after renal transplan-tation {2354}.
Localization
Sun-exposed areas are involved: face,
ears, balding scalp, dorsal hands, fore-arms and lateral neck {2218}.
Clinical features
Patients commonly present with multiple
persistent, asymptomatic erythematous
lesions. Most measure less than 1 cm
and are hyperkeratotic. Atrophic lesions
predominate on the face. Thickening and
tenderness may indicate the develop-ment of invasive carcinoma.
Macroscopy
Most lesions are circumscribed <1cm
scaly macules or slightly elevated
papules or plaques, ranging from erythe-matous to grey-brown with adherent yel-low-brown scale. Some are larger, more
irregularly shaped and pigmented
{1128}, whilst others, particularly on the
dorsal hands and forearms, are hyperk-eratotic or verrucous {244}. A keratin
horn may be produced.
Histopathology
Six types of AK are described: hyper-trophic, atrophic, bowenoid, acantholyt-ic, pigmented and lichenoid {233,1446}.
Most lesions reveal parakeratosis and
hypogranulosis. Disordered keratinocyte
maturation with cytologic atypia is pres-ent, including nuclear enlargement,
hyperchromasia, pleomorphism, nucleo-lar prominence, mitotic activity, dysker-atosis and cytoplasmic pallor. Grading
as Keratinocyte Intraepidermal Neopla-sia (KIN I, II and III) in a manner similar to
that used for the uterine cervix {506} has
Fig. 1.24  Actinic keratosis on the face, presenting
as a group of irregularly shaped small papules.
Fig. 1.25 Actinic keratosis.  A There is focal parakeratosis, acanthosis and basal squamous atypia overlying a dense lichenoid inflammatory infiltrate.  B Actinic ker-atosis. There are elongated rete ridges with squamous cell atypia and focal acantholysis.
BA
Actinic keratosis C. James
R.I. Crawford
M. Martinka
R. Marks
31Actinic keratosis
been proposed, however, invasive SCC
commonly arises from KIN I or II.
Lesions in which impaired maturation
and atypia appear to involve the full epi-dermal thickness have been labelled
“bowenoid actinic keratoses” (BAK)
{1128}. Multinucleate keratinocytes and
a verrucous architecture, can be seen in
AKs in the setting of immunosuppression
{294,1856}.
The abnormal keratinization often
involves the epidermis between spared
acrotrichia and acrosyringia, which in
contrast retain columns of normal kera-tinization. Some lesions show spread into
the infundibular and isthmic segments of
follicles or less commonly along eccrine
ducts {1835}. Dermal changes include
solar elastosis, an infiltrate of lympho-cytes and plasma cells and increased
vascularity. Inflammation is most frequent
in lesions of the head and neck, particu-larly the lips.
The hypertrophic variant shows acantho-sis, papillomatosis and conspicuous
hyperkeratosis with alternating paraker-atosis {244}. Elongation of rete ridges,
dilated vessels and vertically oriented
collagen bundles in the papillary dermis
suggest superimposed lichenification.
The  atrophic AK variant is easily misdi-agnosed if the basal keratinocytic atypia
in a parakeratotic epidermis devoid of
rete ridges is missed. Budding of the
basal epidermis and extension of atypia
into adnexae are common.
The bowenoid variant is difficult to differ-entiate from Bowen disease. Whilst some
claim they are identical, others empha-size the lack of full thickness atypia, less
defined edge, follicular sparing and
acrosyringeal involvement in BAK
{1128,2476}.
The acantholytic variant reveals clefting,
usually suprabasal, with varying acan-tholysis and dyskeratosis {1409}.
Keratinocyte atypia aids distinction from
acantholytic dermatoses. Downward
extensions of the basal epidermis can
induce pseudoducts, and acantholysis
may spread along appendages.
The  pigmented variant shows increased
melanization of atypical keratinocytes
and dermal macrophages {1128}.
The  lichenoid variant has keratinocyte
apoptosis and vacuolation, exocytotic
lymphocytes and a band-like superficial
dermal lymphocytic infiltrate including
colloid bodies {2318}. The epidermis in
early lesions is acanthotic, but more
advanced regressing lesions are atroph-ic with pigment incontinence.
Keratinocyte atypia exceeding that
expected in a reactive process differenti-ates this lesion from benign lichenoid
keratosis.
The confident identification of early SCC
in an AK can be difficult {1158}.
Detachment of individual irregular aggre-DC
BA
Fig.1.26  Actinic keratosis.  A Atrophic variant with atypical basal keratinocytes and focal parakeratosis.  B Medium power magnification shows keratinocyte atyp-ia in the stratum malpighii with a loss of polarity, nuclear enlargement, hyperchromasia, dyskeratosis, increased mitotic activity and parakeratosis.  C Downward
prolongations and buds of atypical squamous cells does not indicate true stromal invasion. Note severe dermal solar elastosis and telangiectasia.  D Acantholytic
variant with suprabasal acantholysis, squamous atypia, dyskeratosis and superficial follicular involvement.
32 Keratinocytic tumours
gates of keratinocytes from the epider-mis, keratin pearl formation and exten-sion of atypical squamous cells into the
reticular dermis are helpful {1158,2476}
Immunoprofile
Keratin and involucrin distribution is sim-ilar to normal epidermis {1093} whilst
CD95 (Fas) is lost in two thirds of AK
{741} and retinoid receptors are reduced
{2554}. Expression of E-cadherin/catenin
and TP53 increases in the progression to
invasive SCC {1770,2170}.
Genetics
There is a 2-fold risk of AK in an
Australian Caucasian population carry-ing the glutathione-S-transferase null
genotype {386}, further increased by fair
skin and an inability to tan.
Around 50% of AK’s show TP53 muta-tions {1696,2602} and over-expression of
cyclin D1 {2235} whilst independent acti-vation of HRAS is identified in 16%
{2235,2307}.
The majority of TP53 mutations involve
single cytosine to thymine substitution
{1396,1696,2307}. Progression of AK into
invasive SCC may involve deletion of the
9p21 region of the p16 (CDKN2A)
tumour suppressor gene {1653}.
Loss of heterozygosity (LOH) at four or
more loci has been demonstrated in
>50% of AK’s in a UK Caucasian popula-tion {1913} and in just under 20% of
lesions in a Japanese group {1350}. PCR
microsatellite analysis has exposed loss
on 17p(64%), 13q(52%), 17q(46%),
9p(39%), 3p(31%) and 9q(22%) {1914}.
The higher rate of LOH in AK than inva-sive SCC could reflect the low progres-sion rate of the former {1350}.
69% of AK were aneuploid in one image
analysis DNA-cytometry study {241}.
Recurrent chromosomal changes are
numerical (+7,+20) and structural,
involving the distal long arm of chromo-some 4,1p31,3p13 and the centromeric
region of chromosome 3 {1143}.
Prognosis and predictive factors
Untreated AK have been reported to
develop into invasive SCC in 8-20% of
patients {838}. AK’s are also risk markers
for basal cell carcinoma and melanoma
{2023}. Individual AK’s can however be
stable for many years, and may regress
after sun protection. One estimate has
suggested a rate of malignant transfor-mation less than 0.1% yearly {1516,
1517}. Older patients with multiple
lesions followed over 10 years demon-strate a lifetime risk of progression
between 6-10% {641} whilst 14% of
patients with >10 AK’s develop invasive
SCC within 5 years {1639}. Sixty percent
of invasive SCC’s have been proposed to
develop from AK’s and, more recently,
contiguous AK has been identified in
82.4-97% of SCC {1085,1517,1627}.
Clinically hypertrophic lesions reveal
invasive SCC in 36% {2290}.
Some classify AK as a type of SCC
{791,994,1442} rather than a precursor. It
cannot however be proven that AK
inescapably progresses to invasive SCC.
The hypothesis that AK requires further
genetic aberrations before the expres-sion of clinical malignancy, is plausible
{1810}.
Immune responses and adjacent normal
keratinocytes modulate the behaviour of
AK {791}. Metastases from invasive car-cinomas arising in AK are infrequent if
the lip is excluded, occurring in 0.5-3%
of such carcinomas {1459,1630}.
Arsenical keratosis
Definition
Arsenical keratosis is a precancerous
lesion occurring in patients exposed
(therapeutic, environmental or occupa-tional) to arsenic {2109}. This is a clinico-pathological diagnosis. Arsenic is con-centrated in a variety of tissues, includ-ing skin, hair, and nails {49,421,2007,
2109}.
Epidemiology
Lesions may occur after a latent period of
2 years, but usually take 20-30 years to
manifest {2568}. A study of 262 exposed
individuals revealed characteristic ker-atoses of the palms and soles in over
40% {49}. Other skin lesions include
melanosis, Bowen disease, squamous
cell and basal cell carcinoma {421,2007,
2109}. Visceral cancers, particularly
involving the lung, and genitourinary
tract can also occur {49,421,2007,2109}.
There is a high arsenic content in some
drinking waters and naturopathic medi-cines {1823,2007,2109}.
Clinical features
Arsenical keratoses begin as yellowish
verrucous papules, 4-10 mm in diameter.
These typically occur on thenar emi-nences, lateral borders of palms, base or
lateral surfaces of fingers, soles, heels
and toes {49}. A combination of mela-Fig. 1.27 Arsenical keratosis.  A Arsenical keratosis with vacuolation of the keratinocytes.  B Arsenical keratosis showing acanthotic epidermis, some vacuolation
of the keratinocytes and dysplasia.
BA
33Actinic keratosis
nosis and multiple keratoses in non-sun-exposed areas in adults is highly sug-gestive of chronic arsenic exposure
{2007}.
Histopathology
A spectrum of histological appearances
exists {49,421,2007,2109}. Lesions may
show compact hyperkeratosis, acantho-sis, papillomatosis, hypertrophic actinic
keratosis-like lesions and a pattern
resembling seborrhoeic keratosis {2007,
2109,2568}. Vacuolated cells in the
Malpighian layer suggest arsenical ker-atosis, but this is not a reliable criterion.
Arsenical keratoses may spare adnexae,
similar to solar-related keratoses {2109}.
Bowenoid arsenical keratoses may dis-play vacuolated, dyskeratotic cells with
abnormal mitoses and multinucleated
giant cells {1823}. Arsenical-induced
pigmentation comprises melanosis and
dermal arsenic deposition {49}.
Histogenesis
The exact nature of arsenical carcino-genesis is unclear.
Arsenic and its metabolites are shown to
cause chromosomal abnormalities and
gene amplification {421,1823,2109}.
Human papillomavirus may be a co-fac-tor in the pathogenesis {820}.
PUVA keratosis
Definition
PUVA keratosis is a form of keratosis that
arises in response to PUVA therapy.
Epidemiology
There are no detailed studies on the true
frequency of actinic keratoses attributa-ble solely to PUVA, but estimates have
varied from 2-5% {11,1057}. There are
long term epidemiological data indicat-ing increased risk of squamous cell car-cinoma in patients on high dose PUVA,
recorded as 300 treatments or more
{2265}. More recently, phototherapy
using a narrow band of ultra-violet radia-tion in the UVB range has been used with
increasing frequency, substituting for
PUVA therapy in a substantial proportion
of patients {2264}. There are no long-term data published as yet on the risk of
actinic keratoses and squamous cell car-cinoma in patients receiving narrow band
UVB phototherapy.
Etiology
PUVA is a photochemotherapy using
either an oral or topical psoralen product
in association with long-wave ultraviolet
radiation (UVA) {374}. This treatment is
locally immunosuppressive, and delivers
high doses of UVA to epidermal ker-atinocytes. PUVA is used in the treatment
of patients with psoriasis and other disor-ders.
Patients treated with long-term PUVA
therapy are at increased risk for develop-ment of actinic keratoses and squamous
cell carcinoma.
Clinical features
PUVA keratoses resemble actinic ker-atoses. They occur on PUVA-treated
skin.
Histopathology
PUVA keratoses are said to have less
keratinocytic atypia than sunlight-induced actinic keratoses {2417}.
Fig. 1.28 Arsenical keratosis.  A .Arsenical keratosis with full thickness dysplasia, resembling Bowen disease.  B Hyperkeratotic type.
BA
34 Keratinocytic tumours
Definition
Verrucas or condyloma are common,
contagious, epithelial tumours caused by
human papillomaviruses (HPV).
Synonyms
Verrucae vulgares (common warts); ver-rucae palmares (deep palmar or hand
warts); verrucae plantares (deep foot
warts, myrmecia); superficial plantar
warts (mosaic warts); verrucae planae
(plane warts, flat warts); condylomata
acuminata (genital warts); condylomata
plana (flat cervical condylomas, plane
condylomas).
Epidemiology
HPVs are widespread in nature and the
prevalence of cutaneous warts is up to
10% in children 2-12 years old, occurring
with equal frequency in both sexes and
regressing spontaneously in 1-2 years
{1282}. HPV infection of the lower genital
tract is one of the most common sexually
transmitted diseases among adolescents
and adults. Most benign genital warts
resolve spontaneously and are usually
caused by HPV types 6 and 11, which
are considered low-risk types as they are
rarely found in high-grade genital dys-plasias and almost never in invasive can-cer. However, persistent infection with
high-risk types, predominantly HPV-16
and 18, represents the most important
risk factor for development of anogenital
malignancies and their precursors, squa-mous intraepithelial lesions {288}. HPV
infection occurs by direct contact with
individuals who harbour clinical or sub-clinical HPV-associated lesions, or indi-rectly via contaminated surfaces and
objects. Autoinnoculation from the lesion
to surrounding skin is frequently
observed {1282,1641}. Impaired cell-mediated immunity is associated with
markedly increased incidence of viral
warts, for example after organ transplan-tation, HIV infection, chronic lymphocytic
leukaemia and lymphoma {1641}.
Etiology
Verrucas are caused human papillo-maviruses (HPV), a large family of DNA
viruses which are epitheliotropic and
induce benign and malignant epithelial
tumours in skin and mucosa. The defini-tion of an HPV type is based upon
nucleotide sequence homology; more
than 95 HPV types have been fully char-acterized to date, and additional partial
DNA sequences have been obtained
indicating the existence of at least 130
HPV genotypes {188,605,1738}.
HPV structure and lifecycle  {2283,
2608,2609}: HPVs are 55 nm diameter,
non-enveloped, double-stranded DNA
viruses. The icosohedral capsid sur-rounds the viral genome which is approx-imately 8kb in length and is composed of
the upstream regulatory region contain-ing the origin of replication and control
elements for transcription and replica-tion, the early region containing the open
reading frames for viral genes that are
principally expressed early in the papillo-mavirus lifecycle (E1, E2, E4, E5, E6, E7),
and the late region encoding the viral
capsid proteins (L1, L2). Productive
infection and induction of hyperprolifera-tion are initiated when the virus enters
proliferating basal epithelial cells, and
this requires abrasion or other minor trau-ma to the epithelium. The HPV lifecycle is
only completed in fully differentiated
squamous epithelia since the pro-gramme of viral gene expression is inti-mately linked to the differentiation state
of keratinocytes. HPV does not encode
Table 1.01
Clinical manifestations and associated HPV types
Frequently   Less frequently
Skin lesions     detected HPV detected
Common, palmar, plantar, mosaic 1,2,4  26,27,29,41,57,60,63,65
Flat warts 3,10  28,29
Butcher’s warts  2,7  1,3,4,10,28
Epidermodysplasia verruciformis 3,5,8,10  9,12,14,15,17,19-25,36-38,
46,47,49,50
EV-squamous cell carcinoma  5,8  14,17,20,47
Periungual SCC  16  34,35
Other SCCs  EV HPV types  Other cutaneous types
Mucosal lesions
Condyloma acuminata 6,11  42-44,54,55,70, 2,27,57
High grade intraepithelial neoplasia
(including cervical tumours, bowenoid papulosis) 16,18 31,33-35,39,40,51-59,61,62
Buschke-Lowenstein tumours 6,11
Recurrent respiratory papillomatosis,
conjunctival papillomas 6,11
Focal epithelial hyperplasia (Heck’s disease)  13,32
Verrucas J.N. Breuer-McHam
M. Tommasino
C.A. Harwood
D. Weedon
M. Martinka
C. Gross
35Verrucas
the enzymes required for transcription or
replication of viral DNA and therefore is
entirely dependent on subverting cellular
proteins for these functions. In particular,
in HPV types 16 and 18, proteins E6 and
E7 promote continued cell cycling of
suprabasal epidermal cells by abroga-tion of the functions of TP53 and pRb
respectively. HPV genomes are thereby
amplified to high levels during vegetative
viral replication for assembly into infec-tious virions after encapsulation by L1
and L2 proteins in the granular layer and
above. Virus assembly does not lyse ker-atinocytes, but rather the infectious virus
is shed with desquamating cornified
cells, and viral release is facilitated by
disruption of the keratinocyte intracellular
filamentous network by viral E4 proteins.
Host immune response {2246,2608}:
Persistent papillomavirus infections are
common, indicating that HPVs have
evolved mechanisms to evade immune
surveillance. There is no viraemic phase,
low levels of viral proteins are expressed
in the basal cell layer, and extensive viri-on production only occurs in the more
immunologically privileged terminally dif-ferentiated layers. However, a successful
immune response is eventually generat-ed in most cases, since two thirds of
cutaneous warts regress spontaneously
within 2 years and multifocal lesions
often regress concomitantly. Cell mediat-ed immune responses appear to be pri-marily responsible.
Localization
Warts can occur on any skin or mucosal
surface. Certain HPV subtypes cause
specific kinds of warts and show special
affinity for particular body locations.
Subtypes causing common warts are
found on the hands, fingers, and palms.
Periungual subtypes are often seen in
nail biters. Verruca plantaris is seen on
the sole of the feet. Condylomata acumi-nata lesions (genital HPV infection)
appear on the vulva, cervix, perineum,
anus, or penis. Scrotal condylomata are
very rare and only seen in 1% of HIV pos-itive males.
Table 1.02
Correlation between cytopathological changes of verrucas and causal HPV types
Clinical manifestation  HPV typesa Epidermal changesb Cytopathic effect (location)
Verruca vulgaris
2  Prominent   Eccentric nucleus; condensed heterogeneous
keratohyaline granules (granular)
4  Prominent; endophytic  Large, vacuolated keratinocytes with no keratohyaline
granules and small, peripherally located, ‘signet ring’
nuclei (granular)
7 (Butcher’s wart)  Prominent   Central, small, shrunken nuclei within proliferating
rete ridges (granular)
Palmo-plantar
1 (Myrmecia)  Prominent, endophytic  Vacuolated cells with large, eosinophilic keratohyaline
granules forming ring-like and sickle-like figures. Basophilic
nuclear inclusions (spinous, granular)
60 (Ridged wart)  Acanthosis and mild  Eosinophilic, homogeneous and solitary inclusions
papillomatosis; endophytic
65 (Pigmented plantar wart)  Prominent; endophytic  Eosinophilic, homogeneous and solitary inclusions
63  Prominent; endophytic  Intracytoplasmic, heavily stained keratohyaline material with
filamentous inclusions that encase the vacuolated nucleus
Verruca Plana  3  Subtle; no parakeratosis   Central, pyknotic, strongly basophilic ‘bird’s eyes’ nuclei
and basket-weave like  (upper spinous and granular)
appearance of stratum corneum
Epidermodysplasia   5  Nests of large, clear cells;  Basophilic cytoplasm containing keratohyaline granules of
verruciformis stratum corneum loose with various shapes and sizes; clear nucleoplasm (upper
basket-weave like appearance spinous and granular)
Condyloma acuminata  6,11  Marked acanthosis, some  Less prominent vacuolisation of granular cells
papillomatosis and hyperkeratosis
a Most common associated HPV genotype
b Epidermal changes comprise papillomatosis, compact hyperkeratosis, focal parakeratosis, hypergranulosis, acanthosis.
36 Keratinocytic tumours
Clinical features and correlation with
viral genotyping
Cutaneous and mucosal HPV types form
two distinct groups that infect skin or
mucosa, although viral tropism is not
absolute {605}. Clinical manifestations
depend on the HPV type involved, the
anatomical location and the immune sta-tus of the host {1282}.
Cutaneous infections: In general, classifi-cation of warts is based on morphology
and anatomic localization and cutaneous
warts have traditionally been classified
as verruca vulgaris or common warts,
palmoplantar warts, including superficial
and deep types, verruca plana or plane
warts and epidermodysplasia verruci-formis (EV). Recent studies suggest that
histological and clinical characteristics of
warts are mainly determined by viral
genotype, indicating that HPV typing
may allow a more accurate classification.
However, the use of highly sensitive PCR
techniques for HPV detection and geno-typing has highlighted the presence of a
greater diversity of HPV types than was
previously appreciated {975}. These indi-viduals often harbour multiple HPV types,
particularly epidermodysplasia-verruci-formis (EV)-HPV types. These HPVs were
previously thought to occur only in the
context of the rare genodermatosis EV,
characterised by infection with unusual,
widespread, cutaneous warts and asso-ciated with increased risk of non-melanoma skin cancers harbouring EV-HPV types on ultraviolet radiation
exposed sites {1492}. There is also
mounting evidence that EV-HPV types
play a cofactor role with UVR in NMSCs
arising in immunosuppressed individuals
{974}.
Mucosal infections: Over 25 HPV types
are recognized to infect anogenital and
aerodigestive mucosa {605}, and sub-clinical infections are more common than
visible warts {1282}. Genital warts are
generally caused by low-risk mucosal
HPV types rather than the high-risk types
associated with anogenital neoplasia
{605}. Bowenoid papulosis (section
1.5.01) may clinically resemble genital
warts, but histologically resembles squa-mous cell carcinoma in situ and contains
high-risk HPV types. Giant condyloma
acuminata (Buschke-Lowenstein tumour)
may also resemble genital warts but is an
anogenital verrucous carcinoma har-bouring low -risk HPV types {2476}. Oral
warts are also associated with HPV types
6 and 11 and focal epithelial hyperplasia
(Heck’s disease) resembling gingival,
buccal and labial flat warts or condylo-mata usually harbours HPV 13 or 32
{2476}.
Verruca vulgaris
Definition
Verruca vulgaris is a benign, squamous
papillomatous lesion caused by infection
with the human papilloma virus (HPV).
Synonym
Common wart.
Epidemiology
Verruca vulgaris occurs predominantly in
children and adolescents, although
adults are also frequently infected. They
have been found in up to 20% of school
students {1262}. Clinically detectable
verrucae develop from a few weeks to 18
months after inoculation {1691}.
Etiology
Common warts are preferentially associ-ated with HPV-2, but they may also be
caused by other types such as HPV-1,
HPV-4 and HPV-7. In children, HPV-6
and/or HPV-11 are rarely found. Other
HPV types have rarely been implicated,
usually in immunosuppressed individuals
{106}.
Localization
Common warts may be solitary or multi-ple, and they are usually found on
exposed parts, particularly the fingers
and on the dorsum of the hands.
Clinical features
They are hard, rough-surfaced papules
that range in diameter from about
0.2:1.5-2.0 cm. New warts may some-times form at sites of trauma (Koebner
phenomenon).
Histopathology
Common warts show marked hyperker-atosis and acanthosis. There are out-growths of epidermis presenting as slen-der spires in filiform warts or blunter dig-itate processes in other variants.
Columns of parakeratosis overlie the
papillomatous projections. There may be
haemorrhage into these columns.
Hypergranulosis is present where the
cells contain coarse clumps of kerato-hyaline granules. Koilocytes (large vac-uolated cells with small pyknotic nuclei)
are present in the upper malpighian layer
and the granular layer. Small amounts of
keratohyalin may be present in the cyto-plasm of these cells. There is often some
inward turning of the elongated rete
ridges at the edges of the lesion.
Tricholemmal differentiation and squa-mous eddies may be seen in old warts.
Dilated vessels are often found in the
core of the papillomatous projections. A
variable lymphocytic infiltrate is some-times seen, and this may be lichenoid in
presumptive regressing lesions.
Prognosis and predictive factors
Most warts are only a cosmetic problem.
Rarely, Bowen disease or squamous cell
carcinoma may develop in a common
wart, usually in immunocompromised
patients {1611}. Thrombosis of superfi-cial vessels, haemorrhage and necrosis
of the epidermis are rarely seen in
regressing common warts.
Fig. 1.29 Verruca vulgaris showing the Koebner
phenomenon. Note the linear arrangement of the
lesions as a consequence of scratching.
Fig. 1.30 Verruca vulgaris. There is hyperkeratosis,
papillomatosis and interning of the elongated rete
ridges.
37Verrucas
Verruca plantaris
Definition
Verruca plantaris is a benign, human
papillomavirus (HPV)-induced epithelial
proliferation occurring on the sole of the
foot. It is characterized by the formation
of thick, hyperkeratotic lesions {505,648,
1214}.
Synonyms
Plantar wart, deep foot warts, myrmecia
Epidemiology
Plantar warts are most common in chil-dren and young adults; possibly
because of immaturity of the immune
system or sport-related repetitive micro-trauma. They are most frequent over
pressure points {505,648}. Particularly in
children they may spontaneously regress
within a few months, but in adults and
immunocompromised patients they can
persist for years. Rarely chronic lesions
are associated with the development of
verrucous carcinoma {594}.
Clinical features
Plantar warts are sharply defined, round-ed lesions, with a rough keratotic sur-face, surrounded by a thickened horn.
They tend to grow into the foot and are
covered by black dots representing
thrombosed capillaries {505,648,1214}.
They do not retain the normal fingerprint
lines of the feet, as calluses (corns) do.
They often occur in multiples, and can be
painful {1055,2390}. They are traditional-ly divided into the superficial warts
(mosaic), which are ordinary verrucae,
and deep warts (myrmecia). Several
other variants have been recently
described {1055,1214,1556}.
Histopathology
The mosaic–type shows acanthosis,
papillomatosis, hyperkeratosis, vacuolat-ed cells (koilocytes) in the upper
Malpighian layer, vertical tiers of paraker-atotic cells and clumped keratohyaline
granules. Myrmecia are characterized by
an endophytic proliferation of rete ridges
covered by thickened keratin and promi-nent eosinophilic intracytoplasmic inclu-sions. The nuclei are retained in the stra-tum corneum and appear as basophilic
round bodies surrounded by a clear halo
{505,1055,1214}.
Regression of palmo-plantar warts is
often associated with thrombosis of
superficial vessels, haemorrhage and
necrosis of the epidermis and a mixed
inflammatory cell infiltrate.
Pathogenesis
HPV is the established cause.
Correlations between the variety of wart
and the HPV type are as follows:
Fig. 1.31 Verruca plantaris.  A, B Plantar wart. Note papillomatosis, acanthosis, hyperkeratosis, viral cytopathic changes.
BA
Fig. 1.35 Multiple flat warts on the chin of a young
female.
Fig. 1.34 Flat wart.
Fig. 1.33 Plantar wart (myrmecia type). Nuclei are
retained in the stratum corneum as basophillic
round bodies surrounded by a clear halo.
Fig. 1.32 Verruca plantaris on the volar surface of
the toe. Clinically, the lesion was painful.
38 Keratinocytic tumours
Deep plantar wart (myrmecia) – HPV1,
HPV63 {505,2390}.
Common and mosaic wart – HPV2, HPV4
{1055}
Endophytic common wart – HPV4 {1055}
Ridged and flat warts (associated with or
without cyst, respectively) – HPV60 {505,
1055,1214,2390}
Large plantar wart – HPV66 {1556}
Verruca plana
Definition
Verruca plana are benign, HPV-induced,
slightly elevated, flat-topped, smooth
papules.
Synonyms
Flat wart, verruca plana juvenilis.
Epidemiology
Verruca plana are relatively common.
Children, adolescents and young adults
are most frequently affected.
Etiology
HPV types 3 and 10 are most commonly
associated with verruca plana. Minor
trauma, atopic dermatitis and immuno-suppression are possible predisposing
factors {778,909,2262}.
Localization
Most lesions are located on the back of
the hands and fingers, distal forearm,
lower leg and face.
Clinical features
Flat warts generally are smaller than
common warts and typically develop as
small round to oval epidermal papules
measuring 1-4 mm in diameter. Lesions
are mostly skin-coloured with a smooth
and flat surface, but may be hyperpig-mented. The number ranges from one to
several hundred and the distribution is
asymmetric, sometimes linear (Koebner
phenomenon).
Histopathology
Histology reveals a loose hyperkeratosis
with basket-weave-pattern but little or no
papillomatosis as in verruca vulgaris.
There is plate-like epidermal hyperplasia
of about twice the thickness of the sur-rounding normal epidermis with com-pressed papillae but dilatation and tortu-osity of capillaries in the papillary dermis.
Superficial epidermal layers show koilo-cytosis, vacuolated keratinocytes with
perinuclear clearing around centrally
located nuclei (so-called “birds-eye
cells”) and hypergranulosis.
Flat wart-like lesions can be encountered
in patients with epidermodysplasia verru-ciformis. These lesions may show typical
blue-grey cytoplasm {907,909,1491}.
Regression of plane warts is accompa-nied by superficial lymphocytic infiltrate
in the dermis with exocytosis and single
epidermal cell apoptosis {2476}.
Prognosis and predictive factors
Flat warts commonly persist for several
years. Due to immunologic rejection in
some long-standing cases, lesions have
disappeared almost from one day to the
next showing some local inflammation
without leaving a scar. There are no
reports regarding recurrences in such
cases. In other cases warts lose evi-dence of viral cytopathic change and
persist as localized verrucous epidermal
hyperplasia {909}.
Fig. 1.36 Flat wart in a patient with epidermodys-plasia.
Fig. 1.37 Flat wart. There are superficial vacuolated keratinocytes with perinuclear clearing.
39
Definition
Acanthomas are benign tumours of epi-dermal keratinocytes. The proliferating
keratinocytes may show normal epider-moid keratinization or a wide range of
aberrant keratinization, which includes
epidermolytic hyperkeratosis (epider-molytic acanthoma), dyskeratosis with
acantholysis (warty dyskeratoma) or
acantholysis alone (acantholytic acan-thoma). Seborrhoeic keratosis, melano-acanthoma, clear cell acanthoma, large
cell acanthoma and keratoacanthoma all
fulfil the criteria for an acanthoma.
Epidermolytic acanthoma
Definition
A benign tumour presenting as solitary or
multiple discrete lesions and demonstrat-ing the characteristic histologic features
of epidermolytic hyperkeratosis {1628,
2151}.
Epidemiology
The reported age range is 3-72 years
with a slight male predominance and var-ious racial groups affected {515}.
Etiology
The etiology remains unknown but trau-ma {2033}, sun exposure {2298} and
PUVA {1677} have been proposed as
causes of disseminated epidermolytic
acanthoma.
Localiz.ation
They can occur at any skin site and may
involve oral or vaginal mucosa {515,
601,1869,2151}.
Clinical and macroscopic features
Epidermolytic acanthomas are generally
asymptomatic, flat or elevated keratotic
papules 2-12 mm in diameter {515,601,
1291,1628,1677,1712,1869,2033,2151,
2298}. Lesions may be solitary, multiple
(localized to a region), or disseminated
{515}.
Histopathology
Epidermolytic acanthoma is charac-terised by compact hyperkeratosis, per-inuclear vacuolisation of the cells of the
stratum Malpighii sparing only the basal
layer, indistinct reticulate cell boundaries
and hypergranulosis with larger
basophilic keratohyaline granules than
normal and intracytoplasmic amorphous
eosinophilic bodies i.e. epidermolytic
hyperkeratosis {14}.
Genetics
Based on patterns of keratin expression
determined by immunohistochemical
techniques, a somatic mutation involving
K1 and K10 genes has been postulated
{515}.
Patients with disseminated disease may
also have germline mutations, with off-spring at risk for congenital ichthyosiform
erythroderma/generalized epidermolytic
hyperkeratosis.
Warty dyskeratoma
Definition
Warty dyskeratoma is a benign papulo-nodular lesion characterized by an endo-phytic proliferation of squamous epitheli-um typically occurring in relation to a fol-liculosebaceous unit and showing promi-nent acantholytic dyskeratosis.
Synonyms
Isolated dyskeratosis follicularis
Follicular dyskeratoma
Epidemiology
Warty dyskeratoma occurs mostly in mid-dle aged to elderly adults {1166}.
Etiology
There are no known etiological factors. A
recent study showed no evidence of HPV
in 13 cases using PCR {1166}.
Localization
The head and neck region is most com-monly involved {873,1166,2306,2321}.
Cases arising in oral {869} and laryngeal
{1185} mucosa and in a subungual {147}
location have been reported. It has been
suggested that lesions arising in sites
devoid of hair follicles maybe a separate
entity {1166}.
Clinical features
Most lesions are solitary flesh coloured to
Acanthomas
Acanthomas D. Weedon
E. Haneke
M. Martinka
G.W. Elgart
R.J. Mortimore
C. Gross
R.M. Williamson
G.F. Kao
R.E. Wilentz
M. Morgan
S. Chimenti
L.L. Yu
Fig. 1.38 Epidermolytic acanthoma. This lesion shows hypergranulosis and marked cytoplasmic vacuoliza-tion with clumps of eosinophilic material, sparing the basal layer.
40 Keratinocytic tumours
brown papules, nodules or cysts with an
umbilicated or pore-like centre or central
keratin plug {873,1166}. Most are 1-10mm in size {873}. Occasionally the
lesions are multiple {121,2306}.
Histopathology
Warty dyskeratoma is a well-demarcated
endophytic lesion characterized by
prominent acantholytic dyskeratosis.
This results in suprabasal clefting with
formation of villi which protrude into a
lacuna. There is typically abundant ker-atin present within the centre of the pro-liferation forming a plug {829,873,1166,
2306}. Keratin pearls are commonly seen
as are small cysts lined by infundibular
type epithelium {1166}. Mitotic figures
are commonly identified and may
exceed 5 per HPF {1166}.
Three architectural variants have been
described namely cup-shaped, cystic
and nodular and combinations of these
may occur {1166}. There may be an epi-dermal collarette present and the sur-rounding epidermis may show papillo-matosis, hypergranulosis and hyperpla-sia {1166}. A connection to folliculoseba-ceous structures is commonly demon-strable {873,1166}.
The stroma often shows a characteristic
appearance with dense collagen or
fibroblasts and focal intrastromal clefts.
There may be an associated mixed
inflammatory cell infiltrate {873,1166,
2321}.
Differential diagnosis
Comedonal Darier disease shows identi-cal histological features and is differenti-ated on clinical grounds {623}.
Familial dyskeratotic comedones is a
rare condition which tends to spare the
scalp and face and shows less marked
acantholysis and dyskeratosis than warty
dyskeratoma {941}.
Histogenesis
It has been recently suggested that this
lesion is a follicular adnexal neoplasm
{1166}.
Acantholytic acanthoma
Definition
Acantholytic acanthoma is a rare benign
epidermal tumour. The lesion displays a
striking characteristic microscopic fea-ture of acantholysis that bears resem-blance to that seen in several vesiculob-ullous disorders {320,1566,1885,2476}.
Epidemiology
In the 31 cases reported by Brownstein
{320}, the patients ranged in age from
32-87 years. The median age was 60
years; the male to female ratio was 2:1.
Etiology
Although it is known that immunosup-pression increases the incidence of cuta-neous neoplasms, the role of impaired
immune surveillance resulting in acan-tholytic acanthoma is speculative {1885}.
Localization
Truncal skin, i.e., back, chest, or flank, is
most commonly involved, followed by
extremities, neck, groin, axilla, ear, scro-tum and shoulder.
Clinical features
Acantholytic acanthoma is a solitary, ker-atotic, asymptomatic to occasionally pru-ritic papule or nodule. Multiple lesions
have been recorded in a renal transplant
patient {1885}.
Macroscopy
The scaly, flesh-coloured, hyperkeratotic
growths range in size from 0.5-1.2 cm.
Histopathology
The tumour shows a well-defined area of
papillomatous epidermal hyperplasia.
There is hyperkeratosis with prominent
acantholysis involving multiple levels of
the epidermis. Suprabasal or subcorneal
clefts with some dyskeratotic cells (corps
ronds and grains) and occasional villi are
noted. The upper dermis contains a vari-able perivascular lymphohistiocytic and
occasional eosinophilic infiltrate.
Differential diagnosis
Acantholytic acanthoma must be distin-guished from other acantholytic disor-ders and from various acanthomas.
Pemphigus, Grover disease, and Hailey-Hailey disease are disorders with more
extensive clinical papulovesicular erup-tions.
Epidermolytic acanthoma shows epider-molytic hyperkeratosis, and no acanthol-ysis is present. Clear cell acanthoma
contains numerous pale cells, with abun-dant intracytoplasmic glycogen, which is
absent in acantholytic acanthoma.
Lentigo simplex
Definition
Lentigo simplex is characterized by a
clinically flat epidermis with microscopic
acanthosis and highly localized well-cir-cumscribed pigment on sun exposed
skin.
Synonyms
Solar lentigo, actinic lentigo, “ink spot”
lentigo and lichen planus like keratosis.
Epidemiology
Lentigines are common pigmented
lesions most frequently seen on the sun-exposed skin of light skinned individuals.
Localization
These lesions occur essentially only on
skin or mucosa and spare the palms and
soles. There is relative sparing of sun-protected areas, but some lesions may
occur in these sites.
Clinical features
Lentigines are well-circumscribed mainly
flat (macular) localized collections of pig-ment. The lesions are common and are
ubiquitous in light skinned individuals.
Most are somewhat randomly distributed
on sun-exposed skin. The presence of
many lesions may raise the consideration
of a syndrome, particularly when there is
extensive involvement of the lips. Peutz-Jeghers syndrome is the presence of
numerous lentigines associated with mul-tiple hamartomatous gastrointestinal
polyps {893}.
Macroscopy
Individual lesions may be smooth-edged, but many have an irregular out-line. Most appear entirely uniform in
colour and range from light tan to brown
to black. While lesions may approach 1
cm in greatest dimension, nearly all clini-cal lesions are 1-5 mm.
In the large cell acanthoma variant, the
tumours are macroscopically very deeply
pigmented and may simulate malignant
melanoma in situ.
Lichen planus like keratoses have a high-ly variable appearance and may show
pink, orange, or rust coloured hues. Most
are minimally raised from the skin sur-face and have a paving stone outline that
is frequently polygonal rather than round-ed {677}.
41Acanthomas
Histopathology
All lentigines demonstrate a sharply cir-cumscribed focus of epidermal hyper-plasia. The tumours are strikingly
melanized, and many retain residual
melanin in the overlying stratum
corneum. This pigment occasionally sim-ulates parakeratotic nuclei seen in der-matitis, a feature referred to as “pigment-ed parakeratosis”.
While clinically macular, the typical lesion
of lentigo simplex demonstrates a specif-ic form of epidermal hyperplasia charac-terized by elongate rete ridges with
somewhat club shaped or bulbous ends.
This appearance is characteristic of
other settings of epidermal hyperme-lanization, such as in melanocytic nevi.
However, it is so typical of lentigines that
in every circumstance where found, this
form of epidermal hyperplasia is referred
to as lentiginous epidermal hyperplasia.
In most circumstances where it is seen,
the underlying papillary dermis demon-strates a variable amount of eosinophilic
collagen deposition (or fibrosis). This
may imply that the epidermal prolifera-tion requires a scar like response in the
underlying dermis. However, inflamma-tion is an inconstant feature in these
lesions {277,1634}.
Because of the histologic similarity to the
epidermis of melanocytic nevi, lentigines
are defined partially by what is absent in
the tumours: namely nevomelanocytic
nests. The presence of even rare nests is
sufficient to separate the diagnosis as
lentiginous junctional nevus (or “jenti-go”).
Thus, to make a diagnosis of lentigo the
requisite features are: localized lentigi-nous epidermal hyperplasia, marked epi-dermal hypermelanosis, and the lack of
nevomelanocytic nests. In fact, despite
the remarkable melanization of the
tumour, increased numbers of melano-cytes are not found in lentigines.
Two clinical variants are known: large cell
acanthoma and lichen planus like kerato-sis. In large cell acanthoma, the pres-ence of a localized proliferation of larger-than-normal keratinocytes with marked
melanization is seen. These lesions are
strikingly dark and are often clinically
highly suspicious for malignant mela-noma.
The other characteristic histologic fea-ture of this variant is the larger than nor-mal appearance of the keratinocytes.
The reason for this feature is unknown,
but may relate to the marked accumula-tion of melanin pigment {277,1033,1959}.
A final variant is the lichen planus like
keratosis. While some authors maintain
that a variety of lesions may develop into
these lichenoid proliferations, most con-cur that a large proportion begin as
lentigines. Several lines of evidence
point to this origin and have been
reviewed. Histologically, these lesions
often suggest a solitary lesion of lichen
planus as they were initially described.
Most demonstrate hypergranulosis and a
band like superficial infiltrate but unlike
routine lichen planus they may show
overlying parakeratosis or an inflamma-tory infiltrate which contains a mixture of
inflammatory cell types with some neu-trophils or eosinophils. Careful evaluation
of most lesions demonstrates some
residual lentigo simplex and pigment
within dermal melanophages {1373}.
Differential diagnosis
The separation between seborrhoeic ker-atosis and lentigo is somewhat arbitrary,
but most authors describe the epidermis
as flat in lentigo simplex while the skin
surface is clearly raised in seborrhoeic
keratosis.
Seborrhoeic keratosis
Definition
Seborrhoeic keratoses are benign hyper-plastic tumours of epidermis which are
more common in older individuals.
Synonyms
Seborrhoeic wart, senile wart, stucco
keratosis, melanoacanthoma.
Epidemiology
Seborrhoeic keratoses are the most com-mon of the cutaneous neoplasms and
occur in the majority of elderly Caucasian
patients. These lesions are by no means
limited to Caucasians, but are present in
numerous older individuals of any race.
The lesions are unusual in children and
even young adults are rarely affected.
Identical histological features are seen in
certain epidermal naevi.
There is no appreciable sex predilection.
In part due to the very widespread inci-dence of the lesion, most cases are spo-radic although several syndromes are
associated with seborrhoeic keratosis.
Recent studies support the long held
belief that seborrhoeic keratosis is a
clonal process in the skin {1679}.
Fig. 1.40 Pigmented reticulated seborrhoeic keratosis. There are slender elongated interlocking rete ridges
with hyperpigmentation and no squamous cell atypia, accompanied by focal pseudo horn cyst.
Fig. 1.39 Pigmetned seborrhoeic keratosis. There are elongated interlocking retes consisting of a prolifera-tion of bland and pigmented basaloid and squamous cells with formation of pseudo horn cysts
42 Keratinocytic tumours
Clinical features
Seborrhoeic keratoses are slightly
raised, tan to brown or black papules.
Sun exposed skin is especially affected,
but lesions may be present on any site of
the skin except for palms or soles. They
often have a “stuck on” appearance and
may be easily removed. Irritated lesions
often demonstrate a crust and prominent
hyperkeratosis which diminishes the visi-bility of the epidermal pigment. Thus,
many of these irritated seborrhoeic ker-atoses are pink to red and quite scaly.
Many of these lesions appear more
smooth-surfaced and are mistaken for
basal cell carcinoma clinically.
While most seborrhoeic keratoses are
uniform in colour, speckled examples are
common. Pigmented seborrhoeic ker-atoses may be mistaken clinically for
malignant melanoma. There is some cor-relation between the many described
histological variants of seborrhoeic ker-atosis and the clinical appearance of the
tumour.
Keratoses are generally very well circum-scribed clinically. Usual lesions are oval
in configuration, but linear or unusually
shaped lesions are common.
Dermatosis papulosa nigra appears to
be a form of multiple seborrhoeic ker-atoses of the face seen primarily in
patients of African descent. This condi-tion is not known to be associated with
any type of internal malady {658}.
Leser-Trélat syndrome
This syndrome is the rapid onset of mul-tiple pruritic seborrhoeic keratoses asso-ciated with malignancy. The tumours
associated have primarily been of gas-trointestinal origin, but lymphomas and
leukaemias have also been reported. It
should be emphasized that some
authors dispute the syndrome entirely
and favour a coincidental association
due to the high frequency of seborrhoeic
keratoses in the elderly patients {955,
2110}.
Histopathology
Seborrhoeic keratoses are well-defined
proliferations of epidermal keratinocytes
which may be endophytic, exophytic or
flat. There are seven major types of seb-orrhoeic keratosis:
Acanthotic (common) seborrhoeic
keratosis
The acanthotic type is composed of
broad columns or sheets of basaloid or
squamoid cells with intervening horn
cysts. There may be varying degrees of
hyperkeratosis, papillomatosis and acan-thosis.
Reticulated seborrhoeic keratosis
This common variant is often sampled
histologically because clinical examples
are frequently deeply pigmented. They
form a net like or retiform pattern of acan-thosis.
Pigmented seborrhoeic keratosis
Pimented seborrhoeic keratoses are in
every way similar to usual seborrhoeic
keratoses, but in addition demonstrate
pronounced epidermal melanin pigment.
Clonal seborrhoeic keratosis
Clonal seborrhoeic keratosis is an unusu-al variant, which demonstrates whorled
collections or nests of keratinocytes with-in the thickened epidermis. These foci of
enlarged keratinocytes arranged in cir-cular collections are suggestive of the
epidermal collections seen in some
cases of in situ squamous carcinoma,
but lack the cytological atypia inherent in
malignant neoplasms.
Irritated seborrhoeic keratosis
There is a heavy lichenoid inflammatory
cell infiltrate in the upper dermis.
Apoptotic keratinocytes are usually quite
numerous. Features of the hyperkeratotic
type (see below) may also be present.
Sometimes there is a heavy inflammatory
cell infiltrate, including neutrophils, which
may not have lichenoid features.
Squamous eddies are often present in
the epidermis.
Hyperkeratotic seborrhoeic keratosis
This variant shows varying degrees of
hyperkeratosis, papillomatosis and acan-thosis. Some cases show inflammatory
features similar to the irritated variant.
Flat seborrhoeic keratosis
There is mild hyperkeratosis, often mild
basal pigmentation (‘dirty feet’) and only
minimal acanthosis. There are no horn
cysts. The cells contrast with those of the
adjacent normal epidermis by being
more compact.
Immunoprofile
All studies confirm the presence of ker-atins throughout the tumour. Some stud-ies have also demonstrated the pres-ence of carcinoembryonic antigen (CEA)
{314,319,665}.
Fig. 1.41 Pigmented seborrhoeic keratosis.  A and  B There are elongated interlocking retes consisting of a proliferation of bland and pigmented basaloid and squa-mous cells with formation of pseudo horn cysts
BA
43Acanthomas
Differential diagnosis
Dowling Degos disease has lesions
indistinguishable from seborrhoeic ker-atosis except for their small size and the
presence of a reticulated network of
adjacent lesions.
The hyperkeratotic form may resemble a
verruca vulgaris. Seborrhoeic keratoses
lack parakeratotic columns overlying the
digitate hyperkeratosis and there is no
haemorrhage, dialated capillaries, koilo-cytosis or inward turning of the acanthot-ic downgrowths.
Precursor lesions
Some believe that the solar lentigo (lenti-go senilis) is a precursor lesion of reticu-lated seborrhoeic keratosis. Others
regard it as an early form of this lesion.
Prognosis and predictive factors
In a small number of cases Bowen dis-ease coexists with seborrhoeic keratosis.
Melanoacanthoma
Definition
Melanoacanthoma of the skin is a benign
mixed proliferation of keratinocytes and
melanocytes. It is considered to be a
variant of seborrhoeic keratosis.
Melanoacanthoma of the oral mucosa is
an unrelated disorder.
Synonyms
Melanoacanthosis, deeply pigmented
seborrhoeic keratosis.
Epidemiology
Most patients are adults beyond 40 years
of age. Sex predominance is not known.
There are no reliable frequency data.
Localization
Most melanoacanthomas are located on
the trunk.
Clinical features
Clinically, the lesion resembles a darkly
pigmented seborrhoeic keratosis. There
are no characteristic symptoms. It may
resemble a melanoma with der-matoscopy.
Histopathology
Melanoacanthoma has the same archi-tecture as common seborrhoeic ker-atoses. However, they stand out by their
abundant dendritic melanocytes in virtu-ally all layers of the lesion. The ker-atinocytes are rich in melanin granules.
Clear cell acanthoma
Definition
Clear cell acanthoma (CCA), is a benign
epidermal neoplasm characterized by
the presence of glycogen-rich clear/pale
cells.
Synonyms
Degos acanthoma, pale cell acanthoma.
Localization
It is usually located on the lower extremi-ties of middle-aged or elderly individuals.
Other sites are the upper extremities,
head and neck, trunk, buttocks and gen-ital area.
Clinical features
It usually occurs as a solitary, slowly
growing, dome-shaped papule, nodule
or plaque. The lesion has sharp margins,
sometimes with a keratotic scale, and a
red or pink colour, giving the tumour a
vascular appearance. Clinical variants
include multiple, pigmented, giant, atyp-ical, cystic and polypoid CCA {345}.
The clinical differential diagnosis may
include pyogenic granuloma, irritated
seborrhoeic keratosis, squamous and
basal cell carcinoma, melanocytic nae-vus and nodular amelanotic melanoma.
Histopathology
There is a circumscribed, sharply demar-cated epidermal proliferation with psori-asiform elongation of plump and inter-connected rete ridges. The keratinocytes
differ from those of the adjacent normal
epidermis by their pale/clear cytoplasm
containing a large amount of glycogen,
best demonstrated with a periodic acid-Schiff reaction. The keratinocytes of the
basal layer and the intraepidermal por-tion of the adnexae are not involved.
Parakeratosis, infiltration of neutrophils,
which may form microabscess in the
stratum corneum, and the absence of the
granular layer are additional characteris-tic findings. Dilated capillaries and a
scattered inflammatory infiltrate can be
observed in the papillary dermis. The
presence of melanophages in the papil-lary dermis and an increased number of
melanocytes provide clues to the diag-nosis of a pigmented CCA.
Fig. 1.42 Melanoacanthoma.  There are elongated interlocking rete ridges consisting of a proliferation of
bland basaloid and squamous cells with formation of pseudo horn cysts, intimately mixed with numerous
melanocytes throughout the lesion.
44 Keratinocytic tumours
Histogenesis
The histogenesis of CCA is not yet com-pletely clear. Initially considered a
tumour of sweat gland or hair follicle ori-gin, these sites were later excluded
because of the different cytokeratin
expression compared to CCA {1743}.
Some investigators hypothesized that
CCA is a benign epidermal tumour of
unknown etiology, probably caused by a
specific disturbance of keratinocyte dif-ferentiation. The expression of involucrin
and epithelial membrane antigen further
suggest that CCA is derived from surface
epithelium. However, since CCA shows
histopathologic findings and cytokeratin
expression similar to those observed in
psoriasis, others believe that it might rep-resent an inflammatory disease rather
than a neoplastic process {742}.
Large cell acanthoma
Definition
Large cell acanthoma, a benign lesion, is
now considered to be a stage in the evo-lution of a solar lentigo to a reticulated
seborrhoeic keratosis {1576,1959}. It
was thought to represent a particular
type of actinic keratosis {1875,2095},
Bowen disease {2038}, or a distinct enti-ty {69,1871,2039}.
Epidemiology
Most patients are middle-aged to elderly
persons. Sanchez Yus et al (1988) esti-mated that approximately 1-2.5 LCAs are
diagnosed per 1000 skin biopsies
whereas Scholl (1982) saw only 4 cases
among > 1000 actinic keratoses and >
3200 seborrhoeic keratoses.
Etiology
Chronic sun exposure is the probable
cause of LCA.
Localization
Most lesions tend to occur on the trunk
and extremities.
Clinical features
The lesion resembles a solar lentigo, flat
seborrhoeic keratosis or stucco kerato-sis. Most cases are lightly pigmented flat
plaques or patches, usually less than 10
mm in diameter. Hyperkeratosis or even
verrucous appearance has been
described. In Black patients, LCA may
present as darkly pigmented lesions
{2165}. Hypopigmentation is also seen
{69}. Dermatoscopy may rule out
melanoma.
Histopathology
Large cell acanthoma is a sharply delim-ited lesion standing out by its unique
large keratinocytes that have about dou-ble the size both of their cytoplasm and
nuclei compared to normal ker-atinocytes. Often, considerable numbers
of melanocytes are present. Three vari-ants have been described: a basic pat-tern with mild to moderate acanthosis, a
verrucous pattern with papillomatosis
and hyperkeratosis, and a flat-hyperker-atotic pattern {2039}. The granular layer
is thick, there is usually orthohyperker-atosis and the rete ridges may be slight-ly bulbous.
The growth fraction is low {86,1576}
although there is a considerable propor-tion of both aneuploid and hyperdiploid
cells {86}.
Differential diagnosis
Flat seborrhoeic keratoses differ by the
smaller size of the constituent cells. Solar
keratoses show parakeratosis and
greater nuclear pleomorphism.
Keratoacanthoma
Definition
Keratoacanthoma is a squamoprolifera-tive tumour, mainly of hair-bearing skin.
Although it has distinctive clinical and
histological features, some regard it as a
variant of squamous cell carcinoma
{190,1701}.
ICD-O code 8071/1
Synonym
Well-differentiated squamous cell carci-noma (keratoacanthoma type).
Epidemiology
Most cases develop in older persons,
particularly in the sixth and seventh
decades. There is a male preponder-ance. Keratoacanthomas are more fre-quent in subtropical areas.
CB
Fig. 1.43 Clear cell acanthoma.  A There are well circumscribed interlocking columns of pale to clear ker-atinocytes with absent granular layer and no squamous cell atypia.   B Note sharp demarcation between
normal epidermis (right) and tumour (left).  C High power view of tumour cells showing pale cytoplasm due
to glycogen accumulation.
A
45Acanthomas
Etiology
Exposure to excessive sunlight is the
most frequently incriminated factor in
their etiology. Viruses have also been
implicated, particularly in immunosup-pressed patients in whom DNA
sequences of HPV have been detected
in 20% of cases {2270}. Chemical car-cinogens produce similar tumours in
some animals, but their role in humans is
speculative.
Localization
In temperate climates, up to 70% of
lesions develop on the face. In subtropi-cal areas, there is a much greater ten-dency for lesions to arise on the arms,
dorsum of the hands and the lower
extremities.
Clinical features
Keratoacanthomas are usually solitary,
pink or flesh-coloured, dome-shaped
nodules with a central keratin plug. They
measure 1-2 cm in diameter. They tend to
grow rapidly over 1-2 months with spon-taneous involution after 3-6 months.
Uncommonly, lesions persist for more
than 12 months. Because local tissue
destruction can occur during growth and
involution, active treatment is usually
advocated.
Several clinical variants occur:
Giant keratoacanthoma, a lesion greater
than 2-3 cm in diameter
Keratoacanthoma centrifugum margina-tum, which undergoes progressive
peripheral growth with coincident central
healing {1740}
Subungual keratoacanthoma, a destruc-tive form that may produce pressure ero-sion of the distal phalanx. They usually
fail to regress spontaneously {146}
Multiple keratoacanthomas, which may
be eruptive (Grzybowski type), self-heal-ing (the Ferguson Smith type, which is
autosomal dominant in inheritance and
caused by an abnormality on chromo-some 9q22-q31), and a mixed eruptive
and self-healing type (Witten and Zak
type).
Multiple lesions can also occur in
immunosuppressed patients {625}, in the
Muir-Torre syndrome (see below) and at
sites of trauma {1789}.
Macroscopy
They are usually pale nodules with a cen-tral keratin plug.
Histopathology
Keratoacanthomas are exoendophytic,
squamoproliferative nodules with a cen-tral, keratin plug. Fully developed lesions
show lipping (buttressing) of the edges
of the lesion which overlap the central
keratin-filled crater, giving it a symmetri-cal appearance. Blunt downgrowths of
squamous epithelium extend into the
dermis with an irregular lower border to
the tumour. The cells at the periphery of
the squamous islands are basaloid in
type. As they mature, they become large
squamous cells with a distinctive pale
eosinophilic cytoplasm. Mitoses may be
seen, but atypical mitoses and stromal
infiltration suggest a squamous cell car-cinoma. SCCs are acknowledged to
occur in less than 1% of keratoacan-thomas found in subtropical regions. In
one series, the reported incidence of a
supervening squamous cell carcinoma
was approximately one-quarter of all ker-atoacanthomas {2040}.
A mixed inflammatory cell infiltrate, often
including eosinophils and neutrophils
may be present in the stroma.
Neutrophils may extend into the epithelial
nests, producing small microabscesses.
Hyperplasia of sweat duct epithelium
may be present in some cases.
Perineural invasion is an incidental and
infrequent finding, often in facial lesions.
It does not usually affect the prognosis or
behaviour of the lesions, although local
recurrence has been reported in such
cases. Several cases with intravenous
Fig. 1.44 Large cell acanthoma.  A There is abrupt transition between normal epidermis (left) and large cell acanthoma (right). There is hyperkeratosis, hypergran-ulosis and markedly enlarged keratinocytes.  B The tumour cells have enlarged nuclei without hyperchromasia and a low nuclear to cytoplasmic ratio.
BA
Fig. 1.45 Keratoacanthoma. Typical clinical appear-ance of exophytic tumour with central crateriform
ulceration filled with keratin plug.
46 Keratinocytic tumours
growth and a favourable outcome have
been recorded {842}.
Regressing keratoacanthomas are shal-lower lesions with a large keratin plug
and buttressing at the margins. There is
progressive dermal fibrosis and disap-pearance of tumour nests in the dermis.
Foreign body giant cells may be present
around residual keratin fragments.
(PCNA / MIB-1 labelled proliferating cells
are found in the periphery of the squa-mous nests in keratoacanthoma, in con-trast to a more diffuse pattern in squa-mous cell carcinoma. Expression of TP53
is found in both tumours. Subungual ker-atoacanthomas have characteristic
dyskeratotic cells, some showing dys-trophic calcification, towards the centre
of the tumour nests. This variant has
fewer neutrophils and eosinophils.
The differential diagnosis from squamous
cell carcinoma may be difficult or impos-sible in superficial shave and punch
biopsies. Features favouring keratoacan-thoma include the flask-like configuration
with a central keratin plug, the pattern of
keratinization, the large central squa-mous cells, the lack of anaplasia and a
sharp outline between tumour nests and
the stroma {555,2477}.
Histogenesis
The great majority of keratoacanthomas
develop on hair-bearing skin {474} and
are presumed to be derived from follicu-lar keratinocytes, perhaps with a pro-grammed life span. Those rare tumours
that arise on glabrous skin and mucous
membranes presumably derive from
epithelial keratinocytes.
Genetics
A genetic defect has been reported in
patients with the Ferguson Smith type of
“multiple self-healing epitheliomas” (ker-atoacanthomas). The Muir Torre syn-drome, in which sebaceous tumours
develop in association with visceral
tumours, usually gastrointestinal can-cers, and often with keratoacanthomas,
epidermal cysts and colonic polyps, is
inherited as an autosomal dominant trait.
Mutations have been found in some
cases in one of the DNA mismatch repair
genes MLH1 and MSH2.
Prognosis and predictive factors
Most lesions regress spontaneously over
several months {260}. This regression
may, in part, be immunologically mediat-ed {1782}. Even lesions with perineural
and intravenous invasion have a
Fig. 1.47 Keratoacanthoma.  A The tumour cells have abundant pale eosinophilic cytoplasm and pleomorphic nuclei, accompanied by a dermal lymphocytic and
eosinophilic infiltrate.  B Focal neutrophilic aggregates in tumour nests are characteristic of keratoacanthoma.
BA
Fig. 1.46 A A low power view of keratoacanthoma demonstrating a central crateriform lesion filled with a keratotic plug and flanked by epidermal buttresses and
consisting of tongues and lobules of squamous cells pushing into the deep dermis.  B Regressed keratoacanthoma. The crateriform architecture remains but the
tumour cells are replaced by flattened epidermal keratinocytes, accompanied by dermal fibrous scarring, a lichenoid inflammatory infiltrate and focal foreign body
giant cell reaction to keratin in the dermis.
BA
47Acanthomas
favourable outcome. Keratoacanthomas
can recur in up to 8% of cases. This is
more likely with lesions on the fingers,
hands, lips and ears. Trauma may be
responsible for recurrent lesions in some
cases. Rare cases that have developed
metastasis have been reported {1038}.
Possible explanations include misdiag-nosis of the original lesion, the develop-ment of a supervening squamous cell
carcinoma not recognized in the original
material, genuine ‘rogue’ variants or
transformation of the initial lesion into a
squamous cell carcinoma in immunosup-pressed patients {2476}.
Lichen planus-like keratosis
Definition
Lichen planus-like keratosis (LPLK) is a
benign lesion of the skin that represents
the attempted immunologic regression of
a solar lentigo, seborrhoeic keratosis,
large cell acanthoma or other epidermal
proliferative lesion {1569,2150}.
Synonyms
Benign lichenoid keratosis.
Epidemiology
LPLK is a relatively common lesion. Most
patients are middle-aged to elderly.
There is a female predominance.
Etiology
The cause of the lesion is not exactly
known. However, chronic sunlight expo-sure appears to be an important factor.
Localization
Most LPLKs are located on the upper
trunk and upper extremities.
Clinical features
Clinically, LPLK presents as a flat, irregu-larly hyperkeratotic plaque with often
irregular borders. It may be irregularly
pigmented or pale in colour. The lesion
resembles a basal cell carcinoma,
Bowen disease, actinic keratosis or flat
seborrhoeic keratosis. Itching and some
pain may occur {1373}. Dermatoscopy
can rule out melanocytic lesions.
Histopathology
LPLK is characterized by a lichenoid
lymphocytic infiltrate leading to basal
vacuolar change and numerous apoptot-ic cells. There is hypergranulosis and
hyperkeratosis, frequently with parakera-totic foci. Actinic elastosis is often pres-ent {785}. Features of solar lentigo, large
cell acanthoma or early seborrhoeic ker-atosis may be present at the margins.
The inflammatory infiltrate often extends
around the superficial vascular plexus.
Differential diagnosis
Lichenoid solar keratosis shows atypia of
epidermal keratinocytes. In lichen
planus, the inflammatory cells do not
usually extend around the superficial
vascular plexus. Furthermore paraker-atosis, plasma cells and/or eosinophils
may be present in LPLK. Similar changes
may be seen in lichenoid drug eruptions.
Clinical information may be required to
separate these entities.
CHAPTER 2
Melanocytic Tumours
Melanocytic skin tumours include a large variety of benign and
malignant neoplasms with distinct clinical, morphological and
genetic profiles. From a clinical and public health point of view,
the malignant melanomas are the most important group of skin
cancers. Although less common than the familiar basal and
squamous cell tumours of the skin, they are much more fre-quently fatal, due to their intrinsic tendency to lymphatic and
haematogenic metastasis.
Intermittent high-dose UV radiation is the major environmental
risk factor, often in combination with endogenous factors,
including genetic susceptibility. Malignant melanoma affects
predominantly fair-skinned caucasians, although they also
occur in ethnic groups characterized by a more pigmented
skin. The sharp increase in incidence rates largely reflects
lifestyle attitudes towards vacational sun exposure, but recent
data indicate that this trend is now levelling off. Primary pre-vention and screening for early lesions are considered the most
promising approach to a reduction of melanoma mortality.
50 Melanocytic tumours
WHO histological classification of melanocytic tumours
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, /2 for non-invasive tumours, and /1 for borderline or uncertain behaviour.
Malignant melanoma 8720/3
Superficial spreading melanoma 8743/3
Nodular melanoma 8721/3
Lentigo maligna 8742/2
Acral-lentiginous melanoma 8744/3
Desmoplastic melanoma 8745/3
Melanoma arising from blue naevus 8780/3
Melanoma arising in a giant congenital naevus 8761/3
Melanoma of childhood
Naevoid melanoma 8720/3
Persistent melanoma 8720/3
Benign melanocytic tumours
Congenital melanocytic naevi
Superficial type 8761/0
Proliferative nodules in congenital melanocytic naevi 8762/1
Dermal melanocytic lesions
Mongolian spot
Naevus of Ito and Ota
Blue naevus 8780/0
Cellular blue naevus 8790/0
Combined naevus
Melanotic macules, simple lentigo and lentiginous naevus
Dysplastic naevus  8727/0
Site-specific naevi
Acral
Genital
Meyerson naevus
Persistent (recurrent) melanocytic naevus
Spitz naevus 8770/0
Pigmented spindle cell naevus (Reed) 8770/0
Halo naevus 8723/0
51TNM classification of malignant melanoma
TNM classification of malignant melanoma
__________
1
UICC (2002). TNM classification of malignant tumours. Sixth edition. Wiley, New York
2
AJCC (2002). Cancer staging manual. Sixth edition. Springer, New York
A help desk for specific questions about the TNM classification is available at http://www.uicc.org (activities, TNM)
3
Clinical staging includes complete excision of the primary melanoma [pT] with clinical/radiological assessment for regional and distant metastases.
Pathologic staging includes complete excision of the primary melanoma [pT] and pathologic assessment of the regional lymph nodes [pN] after partial or
complete lymphadenectomy. Stage 0 or stage IA patients do not require pathological evaluation of their lymph nodes.
TNM classification 1,2
T – Primary tumour
The extent of the tumour is classified after excision, see pT.
N – Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1: Metastasis in one regional lymph node
N1a: only microscopic metastasis (clinically occult)
N1b:  macroscopic metastasis (clinically apparent)
N2: Metastasis in two or three regional lymph nodes or intralymphatic
regional metastasis
N2a:  only microscopic nodal metastasis
N2b:  macroscopic nodal metastasis
N2c:  satellite or in-transit metastasis without regional nodal
metastasis
N3: Metastasis in four or more regional lymph nodes, or matted
metastatic regional lymph nodes, or satellite or in-transit metasta
sis with metastasis in regional lymph node(s)
Note: Satellites are tumour nests or nodules (macro- or microscopic) within 2cm of
the primary tumour. In-transit metastasis involves skin or subcutaneous tissue more
than 2 cm from the primary tumour but not beyond the regional lymph nodes.
M – Distant metastasis
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
M1a: Skin, subcutaneous tissue or lymph node(s) beyond the
regional lymph nodes
M1b: Lung
M1c: Other sites, or any site with elevated serum lactic dehydro
genase (LDH)
pT – Primary tumour (pathological classification)
pTX Primary tumour cannot be assessed*
pT0 No evidence of primary tumour
pTis Melanoma in situ (Clark level I) (atypical melanocytic hyperplasia,
severe melanocytic dysplacia, not an invasive malignant lesion)
pT1: Tumour 1mm or less in thickness
pT1a: Clark level II or III, without ulceration
pT1b: Clark level IV or V, or with ulceration
pT2: Tumour more than 1mm but not more than 2mm in thickness
pT2a: without ulceration
pT2b: with ulceration
pT3: Tumour more than 2mm but not more than 4mm in thickness
pT3a: without ulceration
pT3b: with ulceration
pT4: Tumour more than 4mm in thickness
pT4a: without ulceration
pT4b: with ulceration
Note: *pTX includes shave biopsies and regressed melanomas.
Stage grouping3
Stage 0 pTis N0 M0
Stage I pT1 N0 M0
Stage IA pT1a N0 M0
Stage IB pT1b N0 M0
pT2a N0 M0
Stage IIA pT2b N0 M0
pT3a N0 M0
Stage IIB pT3b N0 M0
pT4a N0 M0
Stage IIC pT4b N0 M0
Stage III Any pT N1, N2, N3 M0
Stage IIIA pT1a-4a N1a, 2a M0
Stage IIIB  pT1a-4a N1b, 2b, 2c M0
pT1b-4b N1a, 2a, 2c M0
Stage IIIC  pT1b-4b N1b, 2b M0
Any pT N3 M0
Stage IV Any T Any N  M1
52 Melanocytic tumours
Incidence and mortality
Approximately 79,000 males and 81,000
females were diagnosed with melanoma
world-wide in 2002, of which about 80%
occurred in the predominantly white pop-ulations of Northern America, Australia,
New Zealand and Europe. On a global
scale, malignant melanoma was the 16th
and 15th most commonly diagnosed
cancer in males and females respective-ly and occurred most frequently in
Australia and New Zealand (4th most
common males, 3rd in females), North-America (6th in males, 5th in
females),and Europe (16th in males, 8th
in females) {724}.
In 2002, around 22,000 males and
19,000 females died of the disease
worldwide {724}. Melanoma is one of the
most important cancers when consid-ered as a cause of loss of life as it is com-monly diagnosed in relatively young peo-ple {54,310,350,1761}, and can be fatal if
untreated. It has been calculated that, in
the United States, a person dying of
melanoma would die, on average, some
17 years before the age of 65, whereas in
Denmark, the mean figure is put at 14-15
years, and in Belgium 6-8 years {54,
310,1761}.
Melanoma had a poor prognosis in the
1950’s and 1960’s, but from the mid
1970s, mortality rates have been stabilis-ing in many high-risk populations,
although incidence rates are still increas-ing. Survival has improved substantially,
mainly in countries with high incidence
rates. This is mainly due to early detec-tion of melanomas as a result of an
increasing awareness of the disease,
probably partly owing to the success of
primary and secondary prevention cam-paigns.
Geographical differences
The levels of both melanoma incidence
and mortality vary considerably world-wide. Rates are high in populations
where Caucasians predominate, and
correspondingly low in countries where
inhabitants are of mainly Asian or African
origin.
Melanoma in Caucasians
As the most important environmental risk
factor in Caucasians is exposure to ultra-violet radiation, incidence within white
populations generally increases with
increasing proximity to the equator. The
highest rates are observed in Australia,
where many inhabitants are of Northern
European descent and live in a climate
with substantially more sunshine than the
norm in Northern Europe.
In Western Europe, a diverging pattern is
observed: incidence rates are higher in
Northern Europe (more distant from the
equator) than in the South, reflecting a
combination of lighter skin type and high-er wealth in the North of Europe. In
wealthy populations, a high incidence of
melanoma is observed with relatively low
mortality rates, due to the fact that
melanomas are diagnosed in early
stages {609}.
Migrant studies
Groups of migrants from regions of low
melanoma incidence to high incidence
regions acquire higher rates of
melanoma than in their home country, but
lower than those in the host country, in
both sexes {96,689}. Incidence and mor-tality rates of native Australians and New
Zealanders, who are largely of British ori-gin, are estimated to be roughly twice
those of recent British immigrants to
these countries {96,1255}. Likewise,
native Israelis experience a twofold
increased risk of incidence compared to
immigrants to Israel from Europe, a risk
that remains at least three decades fol-lowing immigration {2260}. The risk of
immigrants has been shown to approach
that of the native populations in both
Australia and Israel with increasing dura-tion of residence in the host country {96,
533,689,1255,2260}.
Amongst Northern European migrants to
Australia, the incidence rates of
melanoma have been observed to
increase with duration of residence, but
decrease with later age of arrival, sug-gesting that exposure at young ages is
important in determining risk {1255}. The
lowest risk in immigrants to Australia has
been found to be for Southern European
and Eastern Asian migrants, reflecting
the protective effect of a higher degree of
skin pigmentation {1255}. Differences in
skin colour are also assumed to be the
reason underlying the higher incidence
of melanoma in white immigrants to
Hawaii from the United States mainland
{1031}.
Melanoma in non-Caucasians
U.S. Whites have rates 15 times higher
than U.S. Blacks, and a similar contrast
in risk is observed in the White and Black
populations of South Africa and
Zimbabwe {1780}. Melanoma is also rel-atively uncommon among Asians {1295,
E. de Vries
F. Bray
J.W. Coebergh
L. Cerroni
D.J. Ruiter
Malignant melanoma: Introduction D.E. Elder
J.F. Thompson
R.L. Barnhill
G.N.P. van Muijen
R.A. Scolyer
P.E. LeBoit
Fig. 2.1 Age-specific incidence of cancer. All data are based on data from Europe 1990-1997.
Source: European Network of Cancer Registries. EUROCIM 4.0, Lyon 2001.
53Malignant melanoma: Introduction
1746} and Middle- and South-American
populations {891}, probably due to a bet-ter protection afforded by a larger
amount of pigment in the skin and possi-bly different (‘wiser’) sun-exposure pat-terns. Melanomas appear more often on
the non-pigmented areas of the skin in
non-Caucasians {940}, are often of the
acral lentiginous melanoma type and
appear on the palms of hands, soles of
the feet and under the nails {200,554}. A
common problem in these populations is
that pigmented lesions in the skin are
often more difficult to notice, and are
therefore often detected at relatively late
stages, which, at least in part, explain the
high case-fatality rates {200,554}. In
many African and Asian societies it is
considered beautiful to have a light skin.
The avoidance of sun-exposure and
even more extreme measures, such as
bleaching of the skin, have been report-ed {952,2081}.
Time trends
Since the 1970’s there have been reports
of alarming increases in melanoma, ini-tially in terms of mortality {1393} and then
in incidence {1481}. These reports
observed a doubling in rates every one
or two decades (mean annual incre-ments of between 3% and 7%) per
annum in populations of European origin
for both genders {1761}. The incidence
rates increased markedly for intermittent-ly exposed body sites (trunk, legs, etc.)
whereas increases in the face and neck
were moderate. In males, the largest
increases were found on the trunk, and in
females on the legs and arms {332,459,
1007,1472,1482,1699,2120,2245,2350}.
In an analysis of the SEER data, it was
found that melanomas of all stages
increased from 1988-1997, but that local-ized and in situ lesions increased the
most {1137}.
In the United States, Australia and
Northern Europe, where incidence rates
were very high during the 1980s, the
rates have been rising less sharply or
levelling off since the mid-1990’s, espe-cially in younger age groups {516,609,
1137,1353,1472,2144,2244,2245}. In
contrast, in Southern and Eastern Europe
and in Latin America, rates are increas-ing {7,609,1353,1579,2144}. Incidence
rates in Asia have been rather stable
{1142,1295}. There is insufficient data at
present to report on time trends in
melanoma incidence among African
populations. Over the last decades,
increases in incidence have mainly been
observed for thin melanomas, whereas
the rate of thick melanomas seems to be
relatively stable {618,1433}. This
increase in the number of thin mela-nomas is mainly observed in countries
with high incidence rates, where increas-es in rates are mainly seen in the super-ficial spreading melanomas {414,
560,1052,1137,1472,1501}. In countries
with lower incidence rates, increases are
generally more evenly spread across
thickness categories.
Although trends in incidence rates of
melanoma vary greatly, mortality rates
show less variation. Mortality rates have
been levelling off in many populations
with high melanoma incidence rates,
such as Australia, the United States, and
North-western Europe {516,609,827,
1353,1411,1412}. In some countries, a
levelling off of incidence rates is now also
observed, starting in younger age
groups {609}.
Stabilisation of melanoma incidence
rates
Age-period-cohort analyses indicate that
in Western populations (USA, Australia,
New Zealand, Sweden, the Netherlands,
Germany) the increasing mortality rates
have started to level off, starting in
cohorts born in the 1930s and 1940s
{534,827,1050,1136,1692,1983,2244,
2352}. In Southern Europe, generally
those with lower incidence rates (e.g.
Italy and Spain) there has been no sign,
as yet, of a downwards trend {1480,
1849,2144}.
A recent plateau in melanoma mortality
rates (in some cases followed by inci-dence rates) is reported in high-inci-dence countries, such as Australia, USA,
Sweden, Norway and Germany {609,
1353,1761,2120,2245}. Only the mortali-Table 2.01
Age-standardized incidence rates per 100 000 per-son / year in the SEER registry (USA) {1781A}.
Population Males Females
Blacks 1.00 0.5
Whites 15.4 11.6
Fig. 2.2  Age-standardized incidence rates for malignant melanoma of skin, per 100 000 population and year,
adjusted to the world standard population. From D.M. Parkin et al. {1779}.
54 Melanocytic tumours
ty rates levelled off initially, starting in the
late 1970s, with increasing incidence
rates. This was most likely because of
improving survival {1472, 2245,2351}
due to earlier detection, as there were no
major advances in systemic treatment.
Melanoma incidence rates have been
reported to be levelling off, or even
decreasing in younger age groups, start-ing in the 1980s {609}. Furthermore, the
mean and median stage or thickness at
diagnosis is decreasing {560,618,1433,
1472,2351}, with an increasing registra-tion of thin, superficial spreading mela-nomas.
Changes in the biology of melanoma,
characterized by a tendency towards
less aggressive lesions being observed
{353} could also be consistent with a
continuing rise in melanoma incidence,
and a corresponding moderation or sta-bilisation in the mortality rates.
Etiology
There has been much discussion and
debate as to the reasons underlying the
dramatic increases in melanoma inci-dence and mortality, and in particular,
whether they are real or due to artefacts,
via, for example, increased efforts at
screening and diagnosing the disease,
changes in diagnostic criteria, or the
existence of a non-metastasizing biolog-ically benign form of melanoma.
Although some artefacts may have con-tributed to the increases, a substantial
part of the increases is assumed to be
genuine {610}.
Both familial and environmental factors
play a role in the etiology of melanoma.
The familial/genetic components include
skin type, number of naevi, having clini-cal atypical naevi, and having a family
history of skin cancer. They are the most
important predictors of melanoma risk.
As it is not likely that there has been a
substantial change over time in famil-ial/genetic risk factors in most popula-tions, these cannot have contributed
substantially to the observed increases
in melanoma incidence over the past 50
years.
Exposure to UV radiation
Intermittent exposure to UVR is the major
environmental risk factor for melanoma,
especially in combination with endoge-nous factors (skin types I and II, immune
deficient status, genetic predisposition)
{95}. The association between UVR and
melanoma is ambiguous, with differ-ences in risks associated with the dose,
the way it is delivered (intermittent vs.
chronic exposures) and critical time peri-ods (childhood vs. cumulative exposure
during life). Intermittent exposure to UVR
in white people, especially during child-hood, has been postulated to be the
main risk factor for the development of
melanoma, although exposure in adult-hood also plays a part. The relative risk
of UV exposure for the development of
melanoma is around 2, but when skin
characteristics are taken into account,
the relative risks increase markedly for
those with a sun-sensitive skin. As
sunbeds also emit UV-radiation, they
most likely also confer a risk for the
development of melanoma, as was
recently confirmed in a large prospective
study {2426}.
Although high sun exposure in childhood
is a major determinant {2509}, multiple
sunburns {683} and high exposure
throughout life {117} raise risk of disease
significantly. Cutaneous melanomas
appear to arise by different pathways.
Those on the head and neck relate main-ly to chronic sun exposure while those on
the trunk occur in people with many
melanocytic naevi {2508}. High numbers
of naevi reflect an innate propensity to
melanocytic proliferation {2196,2197}
and stimulation by sun exposure {591}.
The risk of acral melanoma is also
increased by exposure to high cumula-tive UVR and to agricultural chemicals
{890}. Occupational sun exposure, espe-cially farming, is associated with risk of
ocular melanoma {2401}. Inherited muta-tions of tumour-suppressor genes (eg
CDKN2A) are strongly associated with
familial melanoma but probably underlie
less than 1% of all cutaneous melanoma
{42}.
Occupational vs. recreational exposure
Before the Industrial Revolution, many
wealthy people had a pale skin: they
worked or stayed indoors, whereas the
lower classes tended to work mainly out-doors. During the industrialisation of
society (1750-1800), working class peo-ple started working indoors and only the
rich had the time and money to afford
recreational outdoor life. By the early
1920s, daily exposure to sunlight was
also advised as a cure for many diseases
(acne, rickets, tuberculosis), especially
for children. By the 1930s a suntan had
become a symbol for wealth and health
and since the 1950s, holidays to sunny
destinations became popular and affor-dable to many.
The rising melanoma incidence is most
commonly attributed to changes in
lifestyle with increasing intermittent expo-sure to ultraviolet radiation (UVR), due to
Fig. 2.3 Melanoma of the skin in Whites. SEER Incidence, delay adjusted incidence and US death rates.
Despite rising incidence rates, mortality is now stable in men and shows a recent decrease in women. From:
L.A.G. Ries et al. {1936}.  http://seer.cancer.gov/csr/1975_2001/
55Malignant melanoma: Introduction
the popularity of sunbathing and tanning.
Given an induction time of some 20-40
years between exposure and melanoma
occurrence, these factors are in accor-dance with the continuing increases -mainly on the trunk in men and on the
legs in women {331,332,619,620,682,
772,2409}.
Ozone layer
Another explanation for the increases is
the depletion of the ozone layer, which
protects the earth’s surface against UVR
by filtering out a large part of the UVR
from the sunlight before it reaches the
earth’s surface. Chemical substances
released in the earth’s atmosphere are
slowly breaking down the ozone layer
{2199}, increasing the amount of UVR
that reaches the earth’s surface and like-ly increasing the risk of skin cancer.
Estimates indicate that skin cancer inci-dence rates could increase dramatically
by the end of this century compared to
the situation around 2000 {1240}.
Socio-economic status
Melanoma is more common among peo-ple with a higher socio-economic status,
probably due to a higher excessive inter-mittent exposure to UVR (outdoor sports,
winter sports, sunbathing, getting a tan)
in this group. Increasing wealth over the
past 6 decades in large parts of the
Western (i.e. predominantly Caucasian)
populations may indirectly have contribu-ted to the increases in incidence rates of
melanoma and other skin cancers.
Melanoma prevention
Sunscreens
An international group of experts con-vening at the International Agency for
Research on Cancer investigated the
preventive effects of sunscreen use on
the development of skin cancer: They
concluded that the use of protective
cream could indeed prevent erythema
and squamous cell carcinoma after non-intentional sun-exposure (i.e., exposure
to the sun without the objective of getting
exposed, for example, work-related
exposure). Its protective effect for basal
cell carcinoma and melanoma, however,
is not yet determined, as it is difficult to
study due to a long latency period.
Paradoxically, there is inconsistent evi-dence that the use of sunscreens may
increase the risk of melanoma develop-ment by increasing sunbathing-time. Of
fifteen case-control studies examined by
an expert panel, only 3 showed a signifi-cantly reduced risk of melanoma, with
relative risks between 0.2 and 0.6, the
others observing no significant effect (4
studies) or an increased risk (8 studies,
RR between 1.7 and 3.5) {2400A}. The
increasing use of sunscreens may there-fore have contributed to the increases in
melanoma incidence.
Vaccination
Vaccination during childhood against
tuberculosis with the Bacille Calmette-Guérin (BCG) vaccine or against small-pox with the vaccinia vaccine, or having
experienced one or more infectious dis-eases may decrease the risk of develop-ing melanomas (odds ratios between
0.29 and 0.44) {1303,1330,1331,1821,
1822}. Part of the increases in melanoma
incidence could be due to the abolish-ment of this type of vaccination in
Europe.
Clinical features
Sites of involvement
Most commonly affected site per unit sur-face area of skin in both sexes is the face
and male ear head and neck {772,890},
with back and shoulders in men and the
lower limbs in females also having high
rates per unit area.
Major subtypes
Most classification schemes of mela-noma categorize them clinically into four
major types, but such classification has
little prognostic value and diagnostic rel-evance, thus being of very limited useful-ness in clinical practice.
Lentigo maligna melanoma.
This type of melanoma develops when
an invasive tumour arises in a lentigo
maligna. It is most common in the head
and neck region and in elderly people,
and has a relatively favourable progno-sis.
Superficial spreading melanoma.
This type of melanoma grows laterally
before vertical invasion develops.
Increasingly, this is the most common
type of melanoma in Caucasians, and
has a relatively favourable prognosis
being frequently observed in young
patients, and on body sites that are inter-mittently exposed to sunlight.
Nodular melanoma
It usually presents as a rapidly growing
pigmented nodule (amelanotic nodular
melanomas are rarely observed), which
bleeds or ulcerates. This is the most
aggressive type of melanoma. It often
presents on body sites that are intermit-tently exposed to sunlight.
Acral lentiginous melanoma
These lesions are pigmented, arising on
the palm of the hand, sole of the foot or
under the nails. They often present late
and represent the most common type of
melanoma in heavily pigmented people.
Age distribution
Malignant melanoma (hence referred to
as melanoma) is a tumour affecting pre-dominantly adults and elderly patients,
with a peak of incidence around the sixth
decade of life. In recent years, however,
it has been increasingly recognized in
middle-aged and young adults, and can
be observed in children and adolescents
as well. Thus, no age group is spared,
and a high level of suspicion should be
exerted in examination of any dubious
pigmented lesion regardless of the age
of the patient.
Origin
The clinical features of melanoma are
variable and depend on type and stage
of evolution of the tumour, and on loca-tion of it. Melanoma may occur de novo,
that is, without a precursor lesion, or may
develop within a pre-existing benign
melanocytic naevus {1168,1750}. It has
been estimated that 20-30% of
melanomas arise within a pre-existing
melanocytic naevus, but this figure in
truth may be higher, as in many
instances it is very difficult to distinguish
histopathologically residual complexes
of a benign naevus from those of the
melanoma. All types of melanocytic
naevi can give rise to a melanoma, but
some are more frequently involved, such
as congenital melanocytic naevi.
Melanoma has only rarely been
observed in association with Spitz naevi
{1380}, but this may be due also to the
difficulty in discerning histopathological-ly melanocytes of a melanoma from the
atypical melanocytes frequently found in
56 Melanocytic tumours
Spitz naevi. Melanoma arising within a
pre-existing blue naevus is commonly
referred to as malignant blue naevus, an
imprecise term that should be avoided.
Melanoma may arise at the site of pre-existing scars (e.g., burn scar) {1758}.
Recurrence at the site of a scar from pre-vious biopsy or narrow excision is a sign
of incomplete excision of the primary
tumour. Recurrence at the site of a com-plete excision (with negative margins
verified histologically) represents locally
metastatic disease rather than persist-ence {1000}.
ABCD rule
The most useful criteria for clinical diag-nosis of melanoma are asymmetry and
uneven pigmentation of the lesion, and
have been integrated in the acronym
“ABCD” (Asymmetry, irregular Border,
uneven Colour, Diameter > 6 mm) {1552}.
Although the “ABCD” mnemonic is con-sidered the standard approach for the
clinical diagnosis of melanoma, it has
severe limitations when applied to early
lesions of it, that may have a relatively
homogenous pigmentation, sharp mar-gins, and small diameter. Melanomas
less than 5 mm in diameter have been
referred to as “small melanomas” in the
literature, and may be the source of diag-nostic pitfalls both clinically and histo-pathologically {282}. In addition, when
assessed with the ABCD rule many
benign melanocytic naevi have atypical
features, thus decreasing specificity of
this diagnostic criteria, too.
Pigmentation and growth
Most (practically all) de novo melanomas
are pigmented lesions that begin as a flat
macule, representing the neoplastic
growth of malignant melanocytes con-fined to the epidermis (melanoma in situ)
. Lesions in this stage are characterized
by a relatively homogenous brown pig-mentation with slightly irregular borders.
Over time (in most instances probably
several years) lesions spread horizontal-ly showing more irregular contours and
variegations of the pigmentation, and
revealing histopathologically involvement
of the superficial (papillary) dermis.
When the papillary dermis is filled by
neoplastic melanocytes the lesions
appear as irregular, unevenly pigmented
plaques. In later stages the neoplasms
exhibit vertical growth resulting in the for-mation of papules or nodules, usually
confined to one area of the lesion. The
papules and nodules represent areas
where the tumour grows vertically
through the dermis, eventually involving
the subcutaneous tissues. In a minority of
cases, melanoma exhibits a rapid nodu-lar growth from the outset without hori-zontal spread, usually within a few
months (so-called nodular melanoma).
Finally, exceptional cases of dermal
melanomas without any intraepidermal
component have been recorded {2305}.
Regression
Partial regression of part of the lesion
takes place commonly during the entire
process of growth of melanoma, resulting
in the presence of whitish-grey areas that
accentuate the asymmetry and uneven
pigmentation of the lesion. In rare cases,
complete regression can be observed,
leading to the disappearance of all neo-plastic melanocytes. Usually, these
lesions show uneven pigmentation with
whitish, grey and black areas correspon-ding to the presence of variable fibrosis
and infiltrates of melanophages in the
dermis. With time, the pigmentation may
disappear almost completely. Although
regression is an immune-mediated phe-nomenon corresponding to the elimina-tion of malignant melanocytes by cyto-toxic lymphocytes, complete regression
of a melanoma can be associated with
metastatic spread, thus being a bad
rather than a good prognostic sign. The
prognostic role (if any) of partial or focal
regression has not yet been elucidated,
but it seems negligible {764}.
Fig. 2.4 Clinical presentation of melanomas.  A Malignant melanoma arising in a congenital naevus.  B Stereotypical cutaneous melanoma characterized by asym-metry, uneven pigmentation, and irregular margins.  C “Small” melanoma (< 3 mm) characterized by a relatively symmetrical, evenly pigmented small papule.
D Melanoma in situ. Note flat pigmented lesion with different hues of brown and slightly irregular margins.  E Early “invasive” melanoma characterized by marked
asymmetry and variegations in colour.  F A nodule of melanoma arising within an in situ component. Note the irregular pigmentation and asymmetry of the flat part
of the lesion.
FED
CBA
57Malignant melanoma: Introduction
Melanoma is more frequent in particular
settings (so-called “markers”) including
a familial history of melanoma, a previous
melanoma in the same patient, presence
of many melanocytic naevi, presence of
giant congenital naevi, skin type 1 or 2,
as well as in rare conditions such as
xeroderma pigmentosum among others
{53,901,1196,1202,2231,2481}. Patients
presenting with one or more of these fea-tures should be monitored closely, and
suspicious lesions should be biopsied. It
is important to remember that multiple
primary melanomas may be observed
rarely in some patients {1196}.
Clinical variants
Amelanotic melanoma
Although melanoma is a tumour charac-terized by variable degrees of pigmenta-tion, in rare instances the pigment may
be missing altogether (so-called amelan-otic melanoma). Amelanotic melanomas
are more frequent on the face, where
they often display the histopathologic
features of desmoplasia (desmoplastic
melanoma), but can be observed also on
other parts of the body {77,2285}.
Mucosal melanoma
Melanomas arising within a mucosa (oral
mucosa, genital mucosa) are often multi-focal, and are characterized by dark,
uneven pigmentation {670,1963}.
Differentiation of early lesions of mucosal
melanoma from so-called melanosis (a
benign condition characterized by
prominent hyperpigmentation of the
mucosa without or with only slight
increase of melanocytes at the dermo-epidermal junction) may be very difficult
or even impossible clinically as well as
histopathologically.
Subungual melanomas
In early stages these are sometimes
characterized by the presence of a well
demarcated, pigmented longitudinal
streak (longitudinal melanonychia) {263}.
The so-called Hutchinson sign (periun-gual spread of the pigmentation on the
proximal or lateral nail fold) may be
absent in early lesions, thus representing
a pitfall in the clinical diagnosis.
Ulceration
Rapidly growing, ulcerated melanomas
may be misdiagnosed clinically as gran-uloma pyogenicum. Pigmentation in
these cases may be scant and confined
only to small areas of the tumour.
Verrucous phenotype
In rare cases, melanoma may present
with a verrucous surface similar to what
can be observed in seborrhoeic ker-atoses or common warts (verrucous
melanoma) {101}. These cases may be
misinterpreted clinically as pigmented
seborrhoeic keratoses or other verrucous
tumours.
Dermatoscopy
Besides clinical examination, der-matoscopy (dermoscopy, skin surface
microscopy, epiluminescence micros-copy) has been increasingly regarded as
a valuable aid in diagnosis of early
melanoma clinically. Dermatoscopic
instruments enlarge the lesion 6-100-fold, thus allowing detection of structures
and signs not visible to the naked eye. In
addition, connection of the dermato-scopic devices to a computer allows one
to take standardized digital pictures that
can be compared over time, thus being
much more sensitive for detection of min-imal structural changes of the examined
lesion {719}. Finally, computer-assisted
diagnostic systems based on dermato-scopic images are available as aids for
the evaluation of suspicious pigmented
lesions {91}.
Several dermatoscopic diagnostic
approaches have been proposed, all of
them relying on the examination of dis-tinct patterns and structures. Of particu-lar value in the diagnosis of melanoma
are the presence of an irregular pigment
Fig. 2.5 Clinical presentation of melanomas.  A Nodular melanoma. Large, darkly pigmented tumour practically devoid of a flat component.  B Melanoma with promi-nent regression resulting in almost complete disappearance of large part of the lesion.  C Complete regression of melanoma. The grey pigmentation is due to the
presence of heavy infiltrates of melanophages within a fibrotic papillary dermis. The patient had regional lymph node metastases at presentation.  D Ulcerated nodu-lar melanoma resembling a granuloma pyogenicum. Note focally small areas of slight pigmentation at the margins.  E So-called “lentigo maligna” (melanoma in situ
on sun-damaged skin) arising on the nose.  F Acral melanoma. Note the marked irregularity of the margins, confering a “multifocal” appearance to the lesion.
FED
CBA
58 Melanocytic tumours
network (uneven thickness of the lines,
presence of broad lines at the periphery
of the lesion), of black or brown dots
irregularly distributed within the lesion, of
irregular lines at the periphery of the
lesion that are not clearly combined with
the pigment network (streaks), of a blue-whitish veil corresponding to infiltrates of
melanophages below a thick epidermis
with hypergranulosis, of an atypical vas-cular pattern, and of regression struc-tures. A 7-point checklist for dermato-scopic scoring of atypical melanocytic
lesions using the aforementioned criteria
has been proposed, and it has been sug-gested that this approach allows diagno-sis of melanoma with a sensitivity of 95%
and a specificity of 75% {91,1671}. Other
proposed approaches include the
Menzies method and the ABCD rule {91}.
Besides dermatoscopy, the use of sever-al other devices has been proposed for
the early in vivo diagnosis of melanoma,
including confocal laser microscopy
{1509}.
Staging
Staging investigations depend on stage
and extent of the disease and should
always include a complete clinical exam-ination {2218A}. Sonography of the
superficial lymph nodes and of the
abdomen, radiography of the thorax and
evaluation of serum markers such as lac-tate dehydrogenase (LDH), S-100-beta
or melanoma-inhibiting activity (MIA)
seem to be of little value in asymptomatic
patients. Computer tomography (CT)
scan, magnetic resonance imaging
(MRI), bone scintigraphy and positron
emission tomography (PET) are useful
methods for evaluation of patients with
metastatic disease.
Histopathology
Architectural criteria in the epidermis
Lesional breadth
A proliferation of melanocytes wholly
within the epidermis can range in size
from >1 mm to a patch many cm in width.
Both melanocytic naevi (conventional
and Spitz) and melanoma begin as pro-liferations in which single melanocytes
predominate.
By the time most melanomas can be rec-ognized as such clinically they are over 4
mm in diameter, and often far broader
{730}. While a large lesional diameter is a
finding favouring melanoma, there are
many exceptions.
Symmetry of changes in the epidermis
The most important attribute of symmetry
is in reference to that of melanocytes
themselves. The symmetry or lack there-of in terms of the distribution of
melanocytes in the epidermis is more dif-ficult to judge than is the overall silhou-ette of the lesion. It is evaluated by com-paring the density of melanocytes on one
side of the lesion with the other; pattern
of distribution of melanocytes (are they at
the junction or above it) on one side of
the lesion with the other; disposal as
nests or as single cells on one side of the
lesion with the other; cytological findings
(are melanocytes on one side of the
lesion different cytologically with those
on the other side). Asymmetry in any of
these attributes favours melanoma.
Secondary forms of asymmetry, less
important that that of the distribution of
melanocytes include asymmetry in pig-mentation, epidermal thickness and
inflammatory infiltrates. Most of these
attributes are not decisive {2506}.
Pigmentation in the epidermis in
melanocytic neoplasms is usually in the
basal layer (exceptions are particularly
dark lesions, such as so-called hyperme-lanotic naevi) {513}. In such naevi, and in
very dark foci of some melanomas, there
may be copious melanin in keratinocytes
not only in the basal layer but also in the
spinous and cornified layers. Either an
asymmetrical distribution of melanoma in
the basal layer of the epidermis, or
melanin above the basal layer on one
side of the lesion but not on the other
raises the possibility of melanoma. An
irregular distribution of epidermal pig-ment is the cause of one of the “ABCD”
rules (variegated colour) of clinical diag-nosis of melanoma {8}. The distribution of
melanophages also affects pigmenta-tion.
Circumscription
Most melanocytic naevi have sharp bor-ders, and melanomas indistinct ones. A
melanocytic neoplasm is easiest to judge
as well circumscribed if the edge of the
lesion is defined by a nest, rather than by
single melanocytes. In such cases, care
must be taken that the distances
between nests do not exceed or even
approximate those between the most
peripheral nest and the edge of the sec-tion (in other words, one must be sure
that the “last” nest is truly the last one).
One should also assess whether the
nests at the periphery of the lesion are at
irregular intervals. A lesion can have an
entirely nested junctional component,
with small nests at increasingly long
intervals at its edges. This is often the
cause of a “fuzzy” border in a dysplastic
(Clark) naevus.
Predominance of single cells vs. nests
At an early stage in the intraepidermal
development of a melanocytic prolifera-tion, benign or malignant, single
melanocytes in increased number will be
present. Therefore, a 1 or 2 mm lesion, as
noted above in which single melanocytes
predominate is not necessarily aberrant.
In the evolution of most acquired
melanocytic naevi, the single melano-cytes aggregate into nests by the time
the lesion is 2 or 3 mm. in diameter.
The distribution of single melanocytes is
also noteworthy. One can imagine a dot-ted line connecting the tops of dermal
papillae with one another. Very few
melanocytes should reside in the epider-mis above that line.
Confluence of melanocytes is another
BA
Fig. 2.6 Clinical presentation.   A and dermatoscopic picture   B of an early melanoma developing within a
“dysplastic” naevus. Note the marked asymmetry of the lesion and the presence of an area with irregular
pigment network and broad lines at the periphery, representing melanoma in situ.
59Malignant melanoma: Introduction
clue to the diagnosis of melanoma.
Confluent single melanocytes replace
the basal layer in a manner such that, at
least focally, keratinocytes do not seem
to intervene between them. Confluence
of nests of melanocytes is a more sub-jective determination.
Scatter of melanocytes above the
junction
If any criterion expounded herein
emblemizes intraepidermal melanoma in
the minds of pathologists, it is supra-basal scatter of melanocytes. Pagetoid,
buckshot and birdshot scatter also
describe this distribution of neoplastic
cells. It can be difficult to tell if “slight”
suprabasal scatter of melanocytes is
present.
Physical trauma, such as excoriation or
abrasion or by ultraviolet light exposure
provokes scatter of melanocytes above
the epidermis {2374}. Signs of physical
trauma include erosion, necrosis of
superficial keratinocytes, parakeratosis,
subepidermal fibrin deposits and
extravasation of erythrocytes in the pap-illary dermis. Suprabasal scatter of
melanocytes is typical of naevi on acral
skin {292}.
Configuration of the epidermis
An uneven epidermal contour is more apt
to be present in melanoma than in a nae-vus. The most typical diagnostic alter-ation is a thinned epidermis in the area of
the melanoma (or melanoma in situ) and
elongated rete ridges in an area in which
a pre-existent naevus is present. In the
case of melanomas in which a large
mass of neoplastic cells is present in the
dermis, a finding known as “consumption
of the epidermis” can occur. The epider-mis is thinned, and instead of small
cuboidal keratinocytes in the basal layer,
one sees large, flat squamous ones,
often with vacuolar change. This finding
is much more common in melanoma than
in naevi {947}.
Kamino bodies
The finding of many large, well formed
Kamino bodies favours a Spitz naevus
over melanoma. There are few convinc-ing reports of melanomas with Kamino
bodies, and these describe few, and
smaller bodies. In some such reports, the
bodies are not PAS-D positive, suggest-ing that dyskeratotic cells were mistaken
for them. In addition to Spitz naevi, small
Kamino bodies occur in some dysplastic
(Clark) naevi, and in some halo naevi
Cytological features of melanoma in
the epidermis
Cytologic findings are less of a link to the
correct diagnosis in the realm of
melanocytic neoplasia than in other
tumours. Melanocytes can be large or
small, deeply pigmented or amelanotic,
and vary from appearing to be round to
oval to spindled to thin and dendritic.
Most acquired naevi feature small round,
oval or small spindled melanocytes with-in junctional nests. There may be no visi-ble pigment, or some may be intracyto-plasmic. In general, the amount of cyto-plasm is scant in most “common” and
even in most dysplastic naevi. The nuclei
of such cells are usually monomorphous,
allowing for different shapes due to vari-ous planes of sectioning if the cells are
elongated. Melanomas with similar cyto-logically bland cells do occur, and the
diagnosis in such cases must be made
via the architectural features of the
lesion.
Small melanocytes with scant cytoplasm
and angulated, darkly stained nuclei are
particularly apt to be found in melano-mas in severely sun-damaged skin (lenti-go maligna and lentigo maligna
melanoma). A similar appearance can
be induced by processing artefact, and
by the use of some alcohol-based fixa-tives instead of formalin.
Large round or oval, or epithelioid
melanocytes occur in both benign prolif-erations and in melanoma. Such cells
often have abundant pale cytoplasm,
with “dusty” (fine and evenly dispersed)
melanin. These cells are typically seen in
the intraepidermal components of
melanomas of all types. Large, pale
melanocytes are also present in naevi of
the scalp (especially in children and
teens), breast and genitalia, and in some
dysplastic naevi {1532}.
Spindled melanocytes occur within the
epidermis in the junctional nests of dys-plastic naevi and in Spitz naevi, as well
as in melanoma, where their orientation is
haphazard (some nests may be vertical
and some horizontal). The nuclei of spin-dled melanoma cells are more often
pleomorphic, and there is heterochroma-sia, i.e. some may be vesicular and some
stain darkly.
Dendritic melanocytes are present in
melanomas in dark skin patients in
diverse settings, and light skinned ones
in so-called lentigo maligna and the lenti-go maligna pattern of melanoma, and in
melanomas of acral-volar skin, the nail
bed and of mucous membranes. The
nuclei of dendritic melanocytes may be
inconspicuous. The findings of dendrites
that ascent to the mid-spinous zone, and
CB
A
Fig. 2.7 A Melanoma with asymmetry. Asymmetry in the distribution of nests and of pigment- which can be
within keratinocytes, melanocytes or melanophages is typical of intraepidermal melanoma.   B Pagetoid
scatter of melanocytes is practically emblematic of intraepidermal melanoma.  C Consumption of the epi-dermis in melanoma. The epidermis is thinned, with squamous rather than cuboidal cells in the basal layer.
60 Melanocytic tumours
especially variability in the widths of den-drites at the same level of the epidermis
(anisodendrocytosis) are useful clues to
melanoma in these settings.
The extreme cytologic atypia typically
seen in thick melanomas in the dermis
and in metastases of melanoma, with
very large, irregularly shaped and bright-ly eosinophilic nucleoli is not usually to
be found in the intraepidermal compo-nent of a melanoma.
Architectural criteria in the dermis
The presence of the intraepidermal
changes of melanoma is of course a clue
that the dermal component of a
melanocytic neoplasm might represent
melanoma as well. Again, architectural
criteria are more important than cytolog-ic ones, although the balance is more
even than in assessing the intraepider-mal portion of a melanoma.
Symmetry
The most important aspect of symmetry
of the dermal component of a melanocyt-ic neoplasm pertains to its outline, or sil-houette.
Other forms of symmetry pertain to what
lies within the silhouette- the composition
of the neoplasm. The sizes and shapes
of nests, the pigmentation and cytologic
features of the melanocytes and infil-trates of lymphocytes and melano-phages ideally are the same on both
sides of the lesion, at the same level of
the dermis. A disproportionately large
nest of cells with cytologic features that
contrast with those on the other side of
the lesion may be a clue to melanoma.
Contour
Dysplastic naevi have a flat base at the
interface between the papillary and retic-ular dermis, Spitz naevi have flat or
wedge shaped bases, superficial blue
naevi are wedge shaped, congenital and
congenital-like naevi have an uneven
base, with melanocytes clustered around
adnexa and sometimes around vessels,
and deep (often cellular) blue naevi have
a lobulated base, with blunt masses of
cells that protrude into the subcutis .
Melanomas that involve the dermis typi-cally have uneven, sometimes jagged
bases.
Maturation
Maturation of melanocytes is in some
ways a misnomer- a mature melanocyte
is dendritic, and synthesizes pigment
within an epithelium. The process com-monly referred to as maturation is really
senescence; it reflects a loss of metabol-ic activity, reproductive capacity and in
some cases a tendency to become fat-just as mammalian senescence does.
Maturation of melanocytes occurs in
most naevi, with the exception of blue
naevi (including deep penetrating naevi).
The best-known form of maturation is the
progressive diminution in the size of the
nuclei of melanocytes at increasing
depth within a lesion. Nucleoli also dimin-ish in size, and if they are eosinophilic in
the upper part of a lesion they tend to
become basophilic at its base. Nuclear
maturation in melanocytic lesions can be
quantified by morphometric studies
{211,1398}.
In addition to nuclear maturation, the
amount of cytoplasm is less at the base
of a benign melanocytic neoplasm than
in its upper nests. If the cytoplasm of the
upper cells of a naevus is pigmented, its
lower cells tend to be less pigmented or
achromic. The sizes of aggregations of
melanocytes also should be smaller
toward the bottom of a benign neoplasm
of melanocytes.
The scientific basis of maturation rests on
changes in metabolism (less tyrosinase
activity and more acetylcholinesterase
activity) and telomeric exhaustion
{865,1620}.
Maturation occurs to a limited extent in
some melanomas, but in most there are
cells at the base of the lesion nearly as
large as those at the top, and dispersion
from large nests to small ones and single
cells is often absent {1989}. Pigmentation
near the base of a melanocytic neoplasm
can also be a clue to melanoma, but it
commonly occurs in blue naevus.
Mitotic activity
Mitoses in the dermal portion of a lesion
do not mandate a diagnosis of
melanoma. As a rule, the mitotic figures
in benign naevi are found in melanocytes
within the papillary or superficial reticular
dermis. If the lesion in question only
extends to this depth, the number of
mitoses becomes important, as does the
question of whether the mitoses are in
clusters (reflecting “hot spots”) or are
atypical. Atypical (asymmetric, tripolar or
ring) mitotic figures can occur in Spitz
naevi, but are rare in other forms of nae-vus. Ki67 / MIB-1 marks cells that are
actively cycling, and the number of such
Fig. 2.8 A Melanoma, invasive radial growth phase (invasive but non-tumorigenic melanoma). Clusters of cells are present in the dermis (see bottom left) that are
not larger than the largest intraepidermal clusters.  B A thin invasive and tumorigenic melanoma. The cluster of cells in the dermis is slightly larger than the largest
cluster in the epidermis, constituting a pattern consistent with a very early tumorigenic melanoma.
BA
61Malignant melanoma: Introduction
cells should diminish toward the bottom
of a benign melanocytic neoplasm. The
finding of a low proliferation rate is no
guarantee of benignancy. A high rate in a
lesion thought to be benign should trig-ger reassessment.
Cytologic features of melanoma in the
dermis
The cells of a melanoma may be large or
small melanocytes, round or spindled,
amelanotic or deeply pigmented.
Large spindled melanocytes comprise
the dermal component in some
melanomas. They often are not reliably
demarcated from each other by clefts, as
is the case in Spitz naevi. They can form
elongated, sometimes sinuous fascicles,
especially in melanomas with neuroid dif-ferentiation and in desmoplastic melano-mas. The spindled melanocytes of
desmoplastic melanoma can also be
found singly between thickened collagen
bundles. They tend to be hyperchromat-ic, and have irregular nuclear mem-branes and small nucleoli.
Melanocytes with abundant pale cyto-plasm and dusty melanin (large, pale
melanocytes) are typically present in the
dermis in some dysplastic naevi, naevi at
special sites (scalp, breast and genitalia)
and in deep penetrating naevi. They are
a common cytologic type in melanoma,
especially in the superficial spreading
and nodular patterns.
Small round melanocytes with scant
cytoplasm, resembling those of the
mature portion of a naevus can predomi-nate in naevoid melanomas
Radial and vertical growth
Radial growth phase
Most melanomas evolve through an initial
stage of tumor progression, as a flat or
plaque – like lesion which expands along
the radii of an imperfect circle. Because
of this clinical analogy, this phase has
been termed the “radial growth phase”
{494}.
The radial growth phase may be in situ
(confined to the epidermis), or in situ and
invasive, but in the latter case the cells
do not have capacity for proliferation in
the dermis {674,832}. Proliferation in the
epidermis may give rise to a pattern of
single cells, or of clusters or nests of
atypical neoplastic melanocytes. Like the
cells of junctional nevi, which may
migrate into the dermis to form com-pound nevi, the cells of in situ
melanomas may migrate into the papil-lary dermis. In the dermis, these cells
may either undergo apoptosis and dis-appear {1070}, or may survive without
proliferating. In the latter case, the lesion-al cells may persist in the dermis, but
they do not expand to form a tumorigenic
nodule.
Vertical growth phase (tumorigenic)
In the next phase of progression, a tumor
nodule appears either within the confines
of a pre-existing plaque, or, sometimes,
de novo in a lesion which is then termed
“nodular melanoma” {675} cells.
The key biological feature of vertical
growth phase is the ability of the lesional
cells to survive and proliferate in the der-mis. This ability may be manifested by
growth to form a true “tumour” or
swelling, or by the presence of mitotic
activity. Tumorigenic vertical growth is
easily recognized when there is a bulky
nodule present. In thin lesions, such as
AJCC stage I melanomas, either of two
criteria suffices for the diagnosis of verti-cal growth phase, namely the presence
of either “tumorigenicity” or “mitogenici-ty”. The term “mitogenic” refers to the
presence of any mitotic figures in lesion-al cells in the dermis. The term “tumori-genic” is here defined as the presence of
a cluster of cells in the dermis larger than
the largest intraepidermal cluster.
Metastatic spread
Most distant metastases from melanoma
become evident clinically or are detect-ed during follow-up visits within a few
years from excision of the primary
tumour. However, it is important to
remember that late metastases (> 10
years, sometimes even over 25 years
after excision of the primary tumour) are
not uncommon in this neoplasm {566,
2088}. The reason why “dormant” metas-tases begin to grow after such a long
time is yet unknown.
In most patients with metastatic disease,
the regional lymph nodes are affected
first, but distant metastases may be
observed in patients who do not have
obvious lymph node involvement.
Besides lymph nodes, the most common
site of metastatic spread is the skin.
Visceral metastases are more frequently
located in the lungs, liver, central nerv-ous system, and bones, but any organ
may be affected.
In 1992, sentinel node (SN) biopsy was
proposed as a minimally invasive proce-dure that provided accurate assessment
of regional node status in melanoma
patients {1655}, allowing full regional
node dissection to be avoided in the
80% of patients who had negative SNs.
The SN concept is simple: lymph drain-ing from a tumour site passes first to a
so-called sentinel node before onward
Fig. 2.9 Lymphoscintigraphy in a patient with a
melanoma on the central upper back.
Top: summed 10-min dynamic images in posterior
and anterior projections after injection of tech-netium-99m antimony sulphide colloid intradermal-ly at melanoma site. Dominant lymphatic channels
pass laterally to both axillae and upwards to inter-val nodes on back. Delayed scans 2 h later show a
single sentinel node in each axilla and three inter-val nodes (also sentinel nodes in this patient) on
upper back.  From J.F. Thompson et al. {2348A},
with kind permission of The Lancet.
Table 2.02
Melanoma antigens
Type of antigen Antigen
Differentiation antigens Tyrosinase, gp100, Melan-A/MART-1, TRP-1,
TRP-2, MC1R, AIM-1
Gangliosides GM3, GD3, GD2, GM2, 0-acteyl GD3
Mutated proteins CDK4, ß-catenin, CDC27, MUM-2,
triosephosphate isomerase
Products of unusual DNA transcrips TRP-2, N-acteylglucosaminyl transferase
Cancer / testis antigens (CTAs) MAGE, BAGE, GAGE, RAGE, NY-ESO-1
62 Melanocytic tumours
passage to other nodes in the regional
node field. Thus the SN is most likely to
contain tumour cells, and if none are
present in this node, tumour cells are
unlikely to be present in other nodes in
the node field. Within 3 years of the land-mark publication by Morton et al {1915},
confirmation of the accuracy of such
assessment was provided by studies in
the USA {1915} and Australia {2347}.
It soon became clear that identification of
this node was most accurate if three
methods were used: a preoperative lym-phoscintigram, injection of blue dye
around the primary melanoma site imme-diately preoperatively, and the use of a
hand-held gamma probe intraoperative-ly. Preoperative lymphoscintigraphy for
many melanoma patients before SN
biopsy provided important new insights
into cutaneous lymphatic drainage path-ways {2348,2396} and this new informa-tion highlighted the importance of preop-erative lymphoscintigraphy before
undertaking a SN biopsy procedure.
The prognostic value of determining SN
status has now been shown in several
large studies. All show a large difference
in probability of 5-year survival between
patients who are SN positive and those
who are SN negative, independently of
other prognostic variables. Results from
the Sydney Melanoma Unit {2565} are
typical, with a 5-year survival rate of 56%
for SN positive patients (n=145) and 90%
for SN negative patients (n=846).
Prognostic information from SN biopsies
may be further refined by PCR to detect
melanoma-specific mRNA in lymph
nodes that are negative by standard
histopathological techniques {1916}.
SN assessment not only provides impor-tant prognostic information; resent clini-cla trials suggest that as an removal, with
complet regional node field dissecion if
micrometastatic melanoma is found,
improves the survival of patients
{1655A}.
Stage distribution
Survival from melanoma is related to
stage at diagnosis. The stage distribution
is generally more favourable in high-resource settings, and thus countries
with high incidence rates tend to also
have better survival than lower incidence
(and lower resource) countries {608,
1472,2245,2351}.
Most melanomas are localized in high
incidence countries and the proportion
that are localized continues to increase
with time. Of the cases reported in the
U.S. SEER program 1992-1998, 82% had
localized disease, 9% regional disease,
4% distant metastases, and 6% were
unstaged {186}.
Young patients and women are often
diagnosed with melanomas that have a
thinner Breslow thickness than older
patients and men. Because of the shift in
the stage distribution of melanomas
towards thinner lesions, together with a
disproportionate increase in incidence
relative to mortality, some have ques-tioned whether some of these thin lesions
that were removed would have ever pro-gressed to metastatic disease {353}.
Table 2.03
Melanoma markers
Type of marker Marker1
Differentiation Tyrosinase, TRP-1, AIM-1 Mitf,
gp100, TRP-2, S-100 HMW-MAA
Melan-A/MART-1 MC1R
Progression
Proliferation Cyclin A ↑ Cdk2 ↑ p21 ↑ PCNA ↑
Cyclin B1 ↑ p15 ↓ p27 ↓ mdm-2 ↑
Cyclin D1/D3 ↑ p16 ↓ Ki67 ↑ telomerase ↑
Cyclin E ↑
Signaling c-Kit ↓ N-ras ↑ EGFR ↑ PTEN ↓
c-Myc ↑α-catenin ↓ Transferrin
receptor ↑
Transcription ATF-1 ↑ AP-2 ↓
Adhesion E-Cadherin ↓ ICAM-1 ↑ ALCAM ↑α4ß1 ↑
N-Cadherin ↑ MCAM ↑αvß3 ↑ CD44 v6 ↑
VCAM-1 ↓
Proteases MMP-1 ↑ MMP-13 ↑ TIMP-3 ↑ PA-system ↑
MMP-2 ↑ MT1-MMP ↑ EMMPRIN ↑ Cathepsin B,
MMP-9 ↑ TIMP-1 ↑ D, H, L ↑
Other ME491/CD63 ↓ HLA class I ↓ Osteonectin ↑ Fas/Fas ligand
HLA Class II ↑ CTAs ↑↑
1
↑ Upregulation with tumour progression; ↓ downregulation with tumour progression
Fig. 2.10  Immunoreactivity of melanoma.   A Immunohistochemical staining for S-100 of dendritic cells in
reactive lymphadenopathy and  B Melanoma micrometastasis in a sentinel lymph node.
BA
Immunoprofile
Melanoma antigens
The term “melanoma antigen” is used
two-fold. Firstly, it refers to a large variety
of molecules recognized by (monoclon-al) antibodies, that were generated to
explore their potential as biological
and/or clinical markers. Secondly,
melanoma antigen in a strict sense
implies a tumour molecule that evokes an
immune response in the autologous host
{1944}. Some overlap exists between
genuine melanoma antigens and
melanoma markers. Melanoma antigens
currently are used in vaccination trials.
Melanoma markers
Three groups of markers can be distin-guished:
Differentiation markers
These markers indicate melanocytic dif-ferentiation which is manifested by signs
of melanin synthesis. Hereby cells of the
melanocytic lineage are identified, but
also ectopic melanin synthesis in cells of
other lineages. Differentiation markers
show a broad expression in many benign
melanocytic lesions and (most) primary
melanomas. However, in melanoma
metastases expression decreases which
is accompanied by heterogeneity.
Progression markers
These markers are preferentially
expressed in one or few stages in
melanocytic tumour progression. Based
on their tissue distribution, early, interme-diate and late progression markers are
discerned. Progression markers include
molecules that are involved in key
processes in the pathogenesis of metas-tasis, i.e. proliferation, migration and
matrix degradation. They may be derived
from the neoplastic cells and/or the stro-mal cells, and serve as targets for vari-ous clinical interventions.
Other markers
These represent molecules that cannot
be incorporated into either of the above
groups.
Clinical applications
The markers mentioned can be used for
several clinical applications {392}. For
this purpose currently immunohisto-chemistry on paraplast embedded tissue
sections is applied, preferentially
employing a red chromagen in order to
contrast with the brown colour of
melanin. For some applications RT-PCR
is used.
Differential diagnosis of poorly
differentiated malignant tumours
In case of a differential diagnosis
between poorly differentiated carcinoma,
sarcoma, lymphoma and melanoma a
panel of various differentiation markers is
applied. Melanoma is likely if the tumour
is diffusely staining for S-100 and the
markers for the other diagnostic options
are negative. Given the low specificity of
S-100 for melanocytic differentiation the
diagnosis has to be substantiated. For
this purpose MART-1 (syn. Melan-A) is a
powerful marker both having a high sen-sitivity and specificity. Its sensitivity is
higher than gp100 (recognized by
HMB45) in cutaneous melanoma and
metastasis, although in non-cutaneous
melanoma it may be the reverse.
Immunotherapy
Vaccination trials have been started
using gp100 and tyrosinase presented
by dendritic cells, and MAGE3. Patients
are selected on the basis of an appropri-ate HLA haplotype and extent of antigen
expressed {611}. Expression of gp100
and tyrosinase is estimated on immuno-histochemically stained melanoma
slides; for MAGE3 RT-PCR is used.
Genetic susceptibility
If melanoma runs in the family (i.e. if a
parent or sibling was diagnosed with a
malignant cutaneous melanoma), the rel-ative risk of developing a melanoma
compared to persons without a family
history of melanoma is 2-3 {1006} and
some melanoma pedigrees have been
discovered. Clustering of melanoma in
families is however not frequent and the
genes implicated in large melanoma
families probably only play a small role in
population-based melanomas. Two
genes have been discovered in
melanoma families: CDKN2A (p16) on
chromosome 9p21, and CDK4 on chro-mosome 12. Mutations in the CDKN2A
gene have been found in up to 25% of
melanoma families worldwide, whereas
CDK4 has only been observed in a few
rare families. The CDKN2A/p16 gene
acts as a tumour suppressor gene and
plays a crucial role in cell cycle regula-tion and senescence. The p16 protein is
a cyclin-dependent kinase inhibitor
which works by binding to CDK4.The
p16 gene tends to be transmitted in an
autosomal dominant fashion. Its pene-trance varies with population incidence
rates, indicating that the same factors
that affect population incidence of
melanoma may also mediate CDKN2A
penetrance. The frequency of mutated
p16 in the general population is estimat-ed to be 0.01% {176}.
63Malignant melanoma: Introduction
Fig. 2.11  Immunoreactivity for   A gp100 and   B
MART-1 of metastatic melanoma cells. Note the
extranodal tumour embolus in A (arrow).
A B
Table 2.04
Prognostic indicators for melanoma.
Prognostic factor Most favourable when:
Breslow thickness Thin (<1.51 mm)
Histology Superficial spreading melanoma
Age Young
Sex Female
Body site Not on the trunk, hands, feet
Ulceration Absent
Mitotic index Low
Other genes, such as  MC1R (Melano-cortin 1 Receptor) and DNA repair
genes, are likely to be more important in
determining susceptibility for melanoma
in the general population. The  MC1R
gene is involved in skin and hair pigmen-tation and in senescence and immunity
{176,251,2385}. Patients with inherited
abnormalities in the DNA repair system,
like xeroderma pigmentosum patients,
are at a 1000-fold increased risk {891}.
Prognosis and predictive
factors
Melanoma thickness, body site, histolog-ical type of the melanoma, gender of the
patient and ulceration are important indi-cators of patient prognosis {130}.
Generally, older patients do less well
than younger patients for the same
tumour thickness, while females do bet-ter than males. Superficial spreading
melanomas generally have a better prog-nosis compared with other histological
subtypes, because they usually have a
thin Breslow thickness {1471}. One
report suggests that sun exposure is
associated with increased survival from
melanoma {224}.
Reports on prognosis from specialized
centres {130}, may contain survival rates
lower than reported by population based
cancer registries {2051}, possibly
because patients with less favourable
prognosis are being referred to special-ized centres.
Morphological prognostic factors
Several clinical and histologic attributes
are useful in predicting the probability of
survival for patients with melanoma, and,
as targeted therapies begin to be devel-oped, no doubt these or similar attributes
may be useful in predicting therapeutic
responsiveness. Staging of melanoma
has been discussed above, and in the
2002 AJCC classification, this staging
includes clinical as well as histologic
attributes {130}. The basic purpose of
staging is to describe the clinical extent
of disease. This may be done by physical
exam, by clinical investigations, and by
gross and microscopic pathologic exam-ination. The process of predicting prog-nosis using pathological attributes may
be referred to as “microstaging”. Some of
these attributes useful in prognostication
are discussed below.
Clark’s levels of invasion
First described in 1967, these attributes
along with Breslow’s thickness measure-ments are the best known prognostic
attributes for melanoma {492}. In Clark’s
level I, the melanoma is confined to the
epidermis (melanoma in situ). In level II,
melanoma cells are present in the papil-lary dermis, which may be expanded but
has not filled by tumour. Most level II
melanomas are non-tumourigenic, but a
few meet criteria for tumourigenicity dis-cussed above. In level III, there is a
tumour that fills and expands the papil-lary dermis. In level IV, tumour cells infil-trate to the collagen fibres of the reticular
dermis which unlike the papillary dermis
are not specialized maintain epithelium.
In level V, the subcutaneous tissue is infil-trated.
Breslow’s thickness
According to Breslow’s definition, pub-lished in 1969, thickness is measured
from the top of the granular layer to the
deepest invasive tumour cell. This can
occasionally be misleading, for example
when there is marked epithelial hyperpla-sia but only a few tumour cells are pres-ent in the dermis. In the 2002 AJCC stag-ing system, thickness is grouped in 1 mm
intervals {130}. If only one attribute is
known, thickness is the single strongest
prognostic attribute for melanoma.
Ulceration
Ulceration is a significant stage modify-ing factor in the 2002 AJCC classifica-tion. For any given thickness level, the
prognosis is significantly worse when
ulceration is present. In “thin”
melanomas (Breslow thickness less than
1 mm) this remains true however only a
few melanomas are ulcerated. Ulceration
loses its significance when mitotic rate is
included in a population based multivari-able prognostic model {160}.
Mitotic rate
Mitotic rate was the single strongest
attribute in the 1989 Clark prognostic
model, which was developed in a cohort
of patients all of whom had vertical
growth phase. Patients with a mitotic rate
of six or greater were at approximate
twelve-fold greater risk of metastasis
than patients whose tumours had no
mitoses {491}. In addition, the presence
of any mitoses at all in the dermis (“mito-genicity”) is predictive not only of survival
{831} but also of sentinel lymph node
positivity {1251}.
Tumour infiltrating lymphocytes
First demonstrated in the 1989 Clark
model {491} and later confirmed by oth-ers {502,1609}, the presence of “brisk”
tumour infiltrating lymphocytes (lympho-cytes present among and in contiguity
with tumour cells) is almost as powerful
an attribute as mitotic rate.
Lymphovascular invasion
Although not commonly observed, and
therefore not found to be an independent
factor in most prognostic models, vascu-64 Melanocytic tumours
Fig. 2.12  Thickness and prognosis. Kaplan-Meier ten year survival curves by thickness, SEER cohort.
Thickness groups presented in various colours are from top to bottom <1.00mm, 1.01-2mm, 2.01-3.0 mm, 3.0-5.0 and >5mm, respectively. Adapted from Gimotty et al, 2005 {830}.
lar invasion when present appears to be
associated with a worse prognosis
{1213}.
Radial growth phase regression
Several studies have demonstrated
worse prognosis when radial growth
phase regression is present {491}.
Possibly in these cases, a small area of
tumourigenic vertical growth phase was
present before the regression obliterated
it.
Microscopic satellites
Like clinical satellites, microscopic satel-lites are indicative of a lesion with com-petence for metastasis and are associat-ed with a worse prognosis {962}.
Patient gender and lesional cell location
In most series, even when other prog-nostic factors are controlled, female
patients have better survivals, and the
survival is better for patients whose
lesions are on the limbs compared to the
trunk or extremities {491}.
Immunoprofiling for the assessment
of prognosis
Two strategies are followed:
1. Identification of markers suggestive of
aggressive subpopulations in primary
melanoma {1990}. For this purpose late
progression markers are used. Only a
limited number of progression markers
have prognostic implication independent
of the conventional dominant factors, i.e.
tumour thickness and ulceration. A list of
prognostic markers is presented in Table
2.5. It should be noted here that the clin-ical relevance of these markers is
increasing as the primary melanomas
currently diagnosed are relatively thin
(1.0-1.5 mm) and rarely show ulceration.
It is expected that a set of prognostic
markers may help to select melanoma
patients for adjuvant therapy. Such a set
may be designed on the basis of the out-come of ongoing expression array stud-ies.
2. Microstaging. The presence of
melanoma deposits in various stages of
the disease is assessed by the demon-stration of differentiation markers.
However, they may decrease during
tumour progression and do not reveal the
aggressiveness of the tumour cells.
Nevertheless, the extension of the pri-mary tumour that includes thickness
measurement and identification of
microsallelites, can be facilitated by S-100 or MART-1 immunohistochemistry.
This also is applicable for the detection
of melanoma cells in sentinel nodes.
Immunohistochemistry on serial sections
is preferred to molecular staging of sen-tinel nodes as it has a similar sensitivity,
a higher specificity and it preserves mor-phology.
65Malignant melanoma: Introduction
Table 2.05
Prognostic markers in malignant melanoma
Marker Expression Prognosis1
Ki67 ↑ _
PCNA ↑ _
Cyclin A ↑ _
p16 ↓ _
αvβ3 ↑ _
ICAM-1 ↑ _
CD44 ↑ +
MMP-2 ↑ _
t-PA ↑ +
gp100 ↓ _
Mitf ↑ +
c-kit ↓ _
c-myc ↑ _
p53 ↑ +
Osteonectin ↑ _
1
-: Unfavourable: +: favourable
66 Melanocytic tumours
Definition
Superficial spreading melanoma (SSM)
is a subtype of melanoma which tends to
occur on usually covered skin and is
characterized by a radial growth phase
comprised of large neoplastic
melanocytes that extend among ker-atinocytes in a “buckshot” or pagetoid
pattern {493,494}. It is controversial
whether SSM is truly different from other
melanoma forms of the skin or whether
the differences are only due to differ-ences in the skin architecture {22}.
ICD-O 8743/3
Synonym
Pagetoid melanoma.
Epidemiology
SSM makes up almost two thirds of all
melanomas in light-skinned people
(Fitzpatrick skin types 1–3) and is thus
the most frequent subtype of all
melanomas. The sex incidence is identi-cal in most areas.
Etiology
Its etiology is not exactly clarified, how-ever, repeated severe sunburns in child-hood appear to play an important role.
Intermittent sun exposure in adult life is
also important.
Localization
SSM may appear on almost the entire
body, particularly on sites with acute-intermittent sun exposure. SSM in women
is most frequently observed on the legs,
in men more commonly on the trunk.
Clinical features
Signs and symptoms
SSM in situ begins as an irregularly pig-mented and outlined macule. With the
onset of invasion, it develops into a
slightly raised plaque. Its borders are
usually sharply delimited, often irregular
indicating progressive peripheral exten-sion, but they may also be ill-defined.
The pigmentation within an individual
lesion varies from light to dark brown to
even jet-black. Grey or white areas indi-cate regression. White vitiliginous areas,
sometimes even poliosis (white hair) may
be observed. Red areas are due to
inflammation or increased vascularity.
Some SSMs are amelanotic, resembling
Bowen or Paget disease. The tumour
may reach a considerable diameter until
it develops a papule representing the
transition from the radial growth to verti-cal growth phase of SSM. These papules
tend to become erosive, ulcerated and
crusted with a tendency to easy bleed-ing. In rare instances satellite nodules
are present. Most lesions are asympto-matic, but can present with bleeding
once the lesion ulcerates.
Histopathology
SSM in situ or the intraepidermal part of
an invasive lesion stands out by pagetoid
spread throughout the epidermis of atyp-ical melanocytes that often have large
nuclei and nucleoli and abundant pale
cytoplasm. Mitoses are frequently
absent. The melanocytes may be distrib-uted singly or in nests. The distribution is
often irregular and the nests may have
irregular shapes or show confluence.
Poor lateral circumscription is often pres-ent, with single enlarged melanocytes
found lateral to the last nest. Hair follicles
and eccrine duct epithelium can be
involved in a similar pattern. To one side
or in the subjacent dermis there may be
a residuum of a naevus. In MIS the stro-mal and inflammatory reaction tends to
be inconspicuous and can be absent. An
irregular distribution of lymphocytes
and/or melanophages may be a diag-nostic clue that the lesion is a melanoma.
Actinic elastosis may or may not be
present.
With development of invasive melanoma,
an asymmetric outline becomes a major
characteristic. Extensive and highly
irregular junctional tumour nests are
found at a variable distance to each
Fig. 2.13  Superficial spreading melanoma.  A Low power magnification of the papular component.  B Pagetoid spread of single melanocytes as is typically found in
many examples.
BA
E. Haneke
B.C. BastianSuperficial spreading melanoma
67
other and may merge. There is often a
lack of maturation, manifested by a fail-ure of nests, cells, nuclei or nucleoli to
become smaller towards the base of the
lesion. Pigment is often irregularly distrib-uted. Mitoses, sometimes atypical, are
often seen whereas necrotic melano-cytes are rarely identified. A lymphocytic
infiltrate may be present at the base of
the neoplasm or may infiltrate among its
cells (so called tumour infiltrating lym-phocytes or TILS). Melanoma may
undergo regression, which clinically and
grossly most often involves a portion of
the lesion, or occasionally its entirety.
Histologically this regression may be
complete or partial within a given area.
Complete regression of a portion of a
melanoma (“segmental regression”) is
manifested by absence of melanocytes
in the affected area. In partial regression,
there is a strikingly diminished number of
melanocytes compared to the remainder
of the lesion. In both forms there is fibro-sis of the papillary dermis, vascular pro-liferation and ectasia, and variably dense
infiltrates of lymphocytes and melano-phages. The epidermis may show loss of
rete ridges. The type of regression
described above affects the radial
growth phase. Occasionally, a vertical
growth phase may undergo regression,
and sometimes the regressed portion
may be replaced by a large mass of
melanophages, representing a phenom-enon called “tumoural melanosis”.
Immunoprofile
There are no specific differences in the
immunophenotype of SSM and other
forms of melanoma.
Somatic genetics
SSM has a high incidence of mutations in
the BRAF oncogene on chromosome
7q34 {1493}. The most common chromo-somal aberrations in SSM are losses of
chromosomes 9, 10, 6q, 8p and gains of
chromosomes 1q, 6p, 7, 8q and 20 {173}
Melanomas with increased copies of
chromosome 7 that show mutations of B-raf selectively increase the copy number
of the mutated allele suggesting that the
mutation precedes the chromosomal
aberration {1493} The minimal deleted
region on chromosome 9 includes the
CDKN2A locus on 9p21 as can be seen
by high-resolution comparative genomic
hybridization (CGH) {876}
Prognosis and predictive factors
The prognosis of SSM does not differ sig-nificantly from other forms of melanoma
(see Introduction).
Superficial spreading melanoma
Fig. 2.14  Superficial spreading melanoma.  A Single cells and small nests are irregualrly arranged along the junction. Toward the centre a large melanocyte is pres-ent in mid-spinous layer. A Langerhans cell is in nearly the same position toward the edge but is much smaller.  B The invasive portion of the melanoma, showing
nuclear pleomorphism. At the base there is a lymphocytic infiltrate.
BA
68 Melanocytic tumours
Definition
Nodular melanoma (NM) is a subtype of
malignant melanoma (MM) exclusively in
vertical growth phase.
ICD-O code 8721/3
Epidemiology
In most parts of the world, NM is the sec-ond most common subtype of MM, and
accounts for 10 to 15% of all melanomas
in Caucasian people {163,436}. NM
appears on the average, in older individ-uals than the common superficial
spreading MM (SSM) {436,493}.
Etiology
Most of the skin characteristics and risk
factors associated with the development
of NM are similar to those of SSM {1364},
including fair or red hair, blue eyes, fair
skin, tendency to develop freckles and
sunburns, excessive exposure to ultravi-olet radiation, numerous common naevi,
giant congenital naevi, atypical (dysplas-tic) naevi, melanoma in a first degree rel-ative, familial atypical mole-melanoma
syndrome, immunosuppression, xeroder-ma pigmentosum and prior melanoma
{624,2304}.
Localization
NM may occur in any location, but as for
SSM, it is more common on the trunk,
head and neck, and lower legs {163}.
Clinical features
NMs typically present as a rapidly
expanding papule, nodule or plaque.
They are occasionally polypoidal and
even pedunculated. They are usually
well circumscribed and symmetric and
frequently reach a size of approximately
1 cm before diagnosis. The skin mark-ings are often obliterated with frequent
ulceration and crust. The colour is often
black or blue, although a subset of NM is
amelanotic. The amelanotic variety fre-quently has a subtle blush or peripheral
rim of pigment {163,436}.
Macroscopy
As in the clinical features
Tumour spread and staging
The tumour spreads first to the local
lymph nodes and then to internal organs.
The staging system devised by the
American Joint Committee on Cancer
includes aspects of the primary tumour,
the status of lymph nodes, and the pres-ence and location of any metastases
(TNM staging) {130}.
Histopathology
Scanning magnification discloses a
raised, dome-shaped, or polypoid
tumour, often, but not always, exhibiting
some asymmetry. The overlying epider-mis may be thin, effaced or ulcerated.
Melanoma cells may be present in the
overlying epidermis but not beyond the
margins of the dermal component (some
allow an extension up to 3 adjacent epi-dermal rete ridges beyond the dermal
component). The dermal component is
typified by a cohesive nodule or small
nests of tumour cells that have a “push-ing” or “expansile” pattern of growth. The
tumour cells most frequently are epithe-lioid, but other cell types, including spin-dle cells, small epithelioid cells resem-bling naevus cells, and giant mononu-clear or multinucleate forms, may pre-dominate or be admixed with other cell
types. The cell population usually
appears monomorphous but closer
examination reveals frequent cellular
enlargement, nuclear enlargement, vari-ation in nuclear size and shape, hyper-chromatism, and prominent nucleoli.
Fig. 2.15  Nodular melanoma.  A On scanning magnification the tumour has a polypoid configuration with slight asymmetry. Cohesive nodules of tumour cells fill the
dermis.  B Superficial portion of the tumour. Epithelioid melanoma cells are present as single units and in nests that vary in size and shape along the dermoepider-mal junction and above it. Similar nests are present in the upper dermis along with numerous melanophages and lymphocytic infiltrates. Some of the epithelioid
melanoma cells contain fine melanin granules.
BA
R. Bergman
S. Brückner-Tuderman
J. Hercogova
B.C. Bastian
Nodular melanoma
69Nodular melanoma
High nuclear-to-cytoplasmic ratios are
often noted. The tumour cells fail to
“mature” with progressive descent into
the dermis. The cytoplasm of the epithe-lioid cells often has eosinophilic granular
qualities. It may contain melanin gran-ules that vary in size, or appear fine and
“dusty”. There is absence of melanin in
the amelanotic tumours. The surrounding
stroma may demonstrate variable
mononuclear cell infiltrates, fibroplasia,
telangiectasia, and melanophages
{154,163}.
Immunoprofile
S-100 protein, HMB-45, Melan A (MART-1), MAGE-1, NKI/C-3, tyrosinase,
melanoma cell adhesion molecule (Mel-CAM) MUC18 and microphthalmia tran-scription factor (MITF), are expressed by
most melanomas {732,1500,1855}.
Melanoma cells also express bcl-2 pro-tein, neuron specific enolase and
vimentin {626,1861,2131}. Antigens
which may demonstrate higher rates of
expression in melanoma cells than in
naevus cells include Ki-67 (MIB-1), prolif-erating nuclear antigen (PCNA), p53,
cyclin D1, and p21 WAF1(9). The loss of
expression of CDKN2A (cyclin depen-dant kinase inhibitor), and the increased
expression of ß3 integrin, have been
associated with vertical growth phase
and more invasive forms of melanomas
{1029,1500,1904,2277,2278,2406}.
Electron microscopy
The demonstration of stage II
melanosomes is the hallmark of
melanoma diagnosis. They are rarely
found in other tumours. Other frequent
findings are nuclear pseudoinclusions,
prominent nucleoli and cytoplasmic inter-mediate filaments corresponding mor-phologically to vimentin filaments. In a
minority of melanomas poorly developed
intercellular junctions may be present
{1016}.
Precursor lesions and histogenesis
It is more common for NM to begin de
novo than to arise in a pre-existing nae-vus {163}. One hypothesis holds that NM
represents a final common pathway of
very rapid tumour progression from a
brief intraepidermal proliferative phase of
SSM, lentigo maligna, or acral lentigi-nous MM {154,163}.
Somatic genetics
Comparative genomic hybridization and
mutation analyses have revealed marked
differences between melanomas
depending on the anatomic site and sun-exposure patterns {173,1493}. These
studies did not find unique genetic fea-tures in nodular melanomas that justify
regarding them as a unique type, sup-porting the ‘common pathway hypothesis
{154,163}.
Genetic susceptibility
The proportion of melanomas that have a
familial basis ranges from 6% to 14%.
Approximately 20% of all individuals with
a family history of melanoma have muta-tions in CDKN2A which maps to chromo-some 9p21. In a very few families CDK4
mapping to chromosome 12q14 has
been found to be mutated {1851}.
Prognosis and predictive factors
In the T (tumour) category, tumour thick-ness increased mitotic rate and ulcera-tion are the most powerful predictors of
survival, and the level of invasion has a
significant impact only within the sub-group of thin (≤1 mm) melanomas {131}.
Other adverse prognostic factors include
increased tumour vascularity, vascular
invasion, microscopic satellites, male
gender, increased age, and anatomic
location on the head, neck and trunk
{122,1528,2597}. In the N (nodes) cate-gory the following three independent fac-tors have been identified: the number of
metastatic nodes, whether nodal metas-tases were clinically occult or clinically
apparent, and the presence or absence
of primary tumour ulceration. In the M
(metastases) category, nonvisceral
metastases are associated with a better
survival compared with visceral metas-tases {131}.
Fig. 2.16 A Nodular melanoma with asymmetrical distribution of lesional cells, lymphoctic infiltrates and melanophages.  B The tumour is composed of melanocytes
with large, pleomorphic, vesicular nuclei, some in mitosis.
BA
70 Melanocytic tumours
Definition
Lentigo maligna (LM) is a form of
melanoma in situ that occurs on the sun
exposed skin of elderly people, mainly
on the face but also, less often, at
extrafacial sites including the neck,
upper back and forearm. It is character-ized histologically by linear and nested
proliferation of atypical melanocytes
along the dermo-epidermal junction and
down the walls of hair follicles and sweat
ducts. The melanocytic lesion is associ-ated with severe actinic damage, mani-fested by epidermal atrophy and solar
elastosis. When dermal invasion by atyp-ical melanocytes occurs in association
with (LM), the term lentigo maligna
melanoma (LMM) is used.
ICD-O code 8742/2
Synonyms and historical annotation
LM has also been known as Hutchinson
melanotic freckle, after Hutchinson first
described it as “senile freckle” in 1892
{1090} and subsequently as “lentigo-melanosis” {1089}. Dubreuilh {652}
described these lesions as “mélanose
circonscrite précancereuse” which sub-sequently came into common use as
melanosis circumscripta precancerosa
until the classification of Clark {492} in
1967 introduced the category of
melanoma commencing in lentigo
maligna (Hutchinson’s melanotic freckle).
That classification was widely but not uni-versally accepted; the World Health
Organisation (WHO) classification of
1974 classified superficial spreading
melanoma and melanoma arising in
Hutchinson melanotic freckle (lentigo
maligna melanoma) in one category
{2337}. The World Health Organization
(WHO) classification of 1996 separated
melanoma in-situ into superficial spread-ing or pagetoid type and lentigo maligna
melanoma, whilst acknowledging that
there may be no essential biological dif-ference between some or perhaps all
categories of melanoma {999}.
Etiology
The strong association between LM and
its occurrence in the severely sun dam-aged skin of elderly people has been
widely accepted as evidence that LM
and LMM represent a distinctive form of
melanoma, resembling etiologically the
non-melanocytic skin cancers, and sug-gesting that LM arises in response to
accumulated sun exposure, in contrast
with the more common forms of
melanoma that appear to be related to
intermittent sun exposure {1048}. It has
also been suggested, however, that dif-ferences in body site distribution
between the commonly accepted differ-ent types of melanoma, through their
interaction with amount and pattern of
sun exposure, can explain virtually all the
observed pathological and epidemiolog-ical differences between LM and the
more common types of melanoma that
occur in widespread anatomical distribu-tion {16,996}. Recent studies have found
that LM remains the main histologic type
of melanoma in situ on the head and
neck and that patients with LM are less
likely than patients with melanomas of
the trunk to have more than 60 naevi
whereas they had a stronger association
with the number of solar keratoses
{2508}.
Pathogenesis
According to some authorities, the term
LM encompasses a phase regarded as a
melanoma precursor in which there is
proliferation of melanocytes in severely
sun damaged skin in intermittent pattern
without the confluent growth, pagetoid
spread and nesting of atypical melano-cytes that, according to this concept,
represent malignant melanoma in-situ of
LM type, whereas the lesions with less
severe, intermittent junctional prolifera-tion are termed atypical melanocytic
hyperplasia {759} or, preferably, atypical
lentiginous melanocytic proliferation.
Localization
Head and neck are by far the most com-mon sites in both sexes. Extrafacial LMM
differs in its site distribution between
women and men {549}. A study in
Scotland showed that extrafacial LMM in
men occurred mainly on the trunk where-as in women 80% occurred on the limbs,
mainly the lower leg. The mean age of
patients with extrafacial LMM was signif-icantly lower than that of patients with
head and neck LM, suggesting that the
association between LMM and sunlight
may not be related only to the cumulative
effects of solar exposure.
Clinical features
LM may be recognized as a small lesion,
usually as a mottled light brown macule
with irregular margins on the face of a fair
skinned elderly patient with evidence of
severe solar skin damage, only a few mil-limetres in diameter, but usually greater
than 10 mm. The classical lesions are
broad, flat zones of varied pigmentation
with an irregular border. With increasing
size of the lesion, variation in pigment
and irregularity of the border also
P. Heenan
A. Spatz
R. Cerio
B.C. Bastian
Lentigo maligna
Fig. 2.17 Lentigo maligna. Broad, flat, variably pig-mented lesion with a very irregular, ill-defined bor-der on the cheek of a 78-year-old patient.
71Lentigo maligna
become more pronounced, nodules may
develop within the lesion and the borders
may become difficult or impossible to
define where zones of pallor or mottled
pigmentation merge imperceptibly with
the surrounding skin.
Histopathology
LM is characterized by a predominantly
junctional proliferation of atypical
melanocytes, frequently extending down
the walls of hair follicles and sweat ducts,
in association with epidermal atrophy
and severe solar elastosis. Although the
junctional proliferation may form conflu-ent linear pattern in some areas, else-where the atypical melanocytes may be
distributed as single units separated by
basal cells. Irregular junctional nests of
atypical melanocytes are frequently
present, as are multinucleate giant cells
including those of starburst type {512}.
Marked pleomorphism is a feature of the
atypical melanocytes which show cyto-plasmic retraction artefact and nuclei of
stellate, ovoid and crescentic forms,
some of them pressed against the cell
wall, with a variable chromatin pattern
and clear or variably pigmented cyto-plasm. Pagetoid foci of atypical epithe-lioid melanocytes present an appear-ance indistinguishable from melanoma in
situ of so-called superficial spreading
type.
A lymphocytic infiltrate and focal fibro-plasia are frequently present in the papil-lary dermis underlying LM, with severe
solar elastosis and telangiectasia.
Regression, shown by fibrosis, hypervas-cularity, melanophages and a patchy
lymphocytic infiltrate, is a common fea-ture and should prompt a careful search
for invasion by atypical melanocytes. The
presence of regression at a lateral mar-gin of excision should be emphasized in
the report as an indication for re-exci-sion, even when the margins appear
clear of atypical melanocytes.
In LMM, dermal invasion occurs in asso-ciation with LM. The invasive component
may consist of atypical melanocytic spin-dle cells more frequently than is seen in
the other common forms of cutaneous
melanoma, but epithelioid, small naevoid
and tumour giant cells may also be pres-ent in varied proportions. The cells of
these various types may occur in cohe-sive groups, strands or as single cells in
a diffuse pattern, often associated with
lymphocytes and melanophages. The
degree of pigmentation varies, including
cells with abundant clear cytoplasm
adjacent to cells in which the morpholog-ic detail may be obscured by coarse
melanin granules.
The invasive component in LMM may be
desmoplastic and/or neurotropic with
very subtle, diffuse invasion that predis-poses to incomplete excision and true
local recurrence. Dermal invasion may
also originate from atypical melanocytes
in the walls of hair follicles and sweat
ducts, thus creating a problem in meas-urement of tumour thickness because it
is inappropriate to measure tumour thick-ness from the granular layer of the epi-dermis in this instance.
The degree of pigmentation in LM may
vary markedly between different exam-ples of the tumour and within one tumour.
Zones of amelanosis at the periphery of
the lesion may lead to failure by the
pathologist to detect atypical cells at the
margin of excision, thus leading to per-sistent growth and “local recurrence” of
the tumour.
Differential diagnosis
In cases of extensive amelanosis (ame-lanotic LM) {60}, the distinction between
in-situ squamous cell carcinoma or extra-mammary Paget disease may be difficult
in routine sections, necessitating the use
of special stains to demonstrate epithe-Fig. 2.18 Lentigo maligna.   A Atypical melanocytes, mainly epithelioid cells with clear cytoplasm, are
arranged in confluent pattern along the dermo-epidermal junction and extending down the wall of a central
hair follicle.  A few single atypical melanocytes are also present above the basal layer. The epidermis is
atrophic overlying severe elastosis.   B Severe nuclear pleomorphism and scattered multinucleate giant
cells are present in the junctional proliferation and down the walls of adnexal structures including a sweat
duct.
B
A
72
lial mucin in extra-mammary Paget dis-ease, and immunostaining, including the
use of antibodies to cytokeratins, melan-A and S-100 protein and, as further aids
to the diagnosis of Paget disease, carci-noembryonic antigen, and BerEP4.
The distinction between LM and benign
forms of junctional melanocytic prolifera-tion is made on the basis of the charac-teristic cytologic atypia, confluent growth
of atypical cells along the junction with
frequent extension down the walls of
adnexal structures and, commonly,
extension of growth above the basal
layer in pagetoid pattern.
Histogenesis
LM develops from epidermal
melanocytes, most likely due to the
cumulative DNA damage resulting from
long-term sun exposure {1048}. A recent
study of the differential expression of pro-liferation- and apoptosis-related markers
in lentigo maligna and the keratinocytes
in solar keratosis has found that the epi-dermis in LM shows overall low prolifera-tion and a low apoptotic tendency, per-haps aiding aberrant melanocyte prolif-eration in the early stages of melanoma
development {718}.
Somatic genetics
A recent study has shown an association
between DNA repair-deficiency and a
high level of  TP53  mutations in
melanomas of xeroderma pigmentosum
patients {2231}. The LMM found in xero-derma pigmentosum patients of the XP
complementation group, group XP-C,
were associated with an accumulation of
unrepaired DNA lesions. Lentigo maligna
melanomas have been found to rarely
show mutations in BRAF {1493}.
Comparative genomic hybridization
shows more common losses involving
chromosome 13 and less common loss-es of chromosome 10, when compared
to other melanoma types {173}.
Prognosis and predictive factors
Complete excision of lentigo maligna, as
a form of melanoma in situ and, there-fore, incapable of metastasis, is curative.
Prognosis for LMM has been a con-tentious issue. For many years, it was
commonly believed that the prognosis
for melanomas of LMM type is better than
for other types of melanoma. Most evi-dence, however, suggests that for
melanomas classified as different types
according to their histological features,
their differences in survival correspond to
differences in tumour thickness rather
than to their differences in histologic type
{20,1296}.
Melanocytic tumours
Fig. 2.19 Lentigo maligna. Focal pagetoid growth is present in addition to junctional proliferation including
small nests of atypical melanocytes.
73Acral-lentiginous melanoma
Definition
Acral lentiginous melanoma (ALM) is a
distinct variant of cutaneous melanoma,
which occurs on the palms, soles, and
subungual sites, and has a characteristic
histologic picture. Following the three
other major clinicopathological subtypes
of melanoma, i.e. superficial spreading
melanoma, lentigo maligna melanoma,
and nodular melanoma, ALM was pro-posed as the fourth subtype by Reed in
1976 {1905}. In this article, we also use
the term acral melanoma and define it as
a melanoma located on the non-hair
bearing skin of the palms and soles or
under the nails. The reason for this usage
is described below.
ICD-O code 8744/3
Synonyms
Historically, this type of melanoma has
been designated as ALM {1905}, acral
melanoma {494}, palmar-plantar-subun-gal-mucosal melanoma (P-S-M mela-noma) {2129}, or unclassified plantar
melanoma {100}. Although often consid-ered to be interchangeable, ALM and
acral melanoma embody distinct con-cepts that must be distinguished from
each other. ALM is a histologic designa-tion that shows similarities to lentigo
maligna melanoma, while acral
melanoma is an anatomic designation
that refers to melanoma located on the
acral sites. Acral melanoma, thus,
encompasses both ALM and such sub-types as superficial spreading
melanoma and nodular melanoma that
may develop in acral locations.
Occasionally, the terms acral melanoma
and acral lentiginous melanoma are
used interchangeably, since the majority
of cases of acral melanoma are ALM
{1071,1592,1905} and the histological
distinction between ALM and superficial
spreading melanoma is not always pos-sible {2220}. Even if acral melanoma is
an anatomic nomenclature, its use is dif-ferent among articles. We define it as a
melanoma located on the non-hair bear-ing skin of the palms and soles or under
the nails because of presentation of the
genetic data. Although P-S-M melanoma
was described on the basis of clinical
and histologic similarities between the
tumours on these sites, the acral
melanomas and mucosal ones are rec-ommended to be treated separately,
because of their different clinical behav-iours {494}.
Epidemiology
Racial differences are quite pronounced
in the incidence and predilection sites of
melanomas. This is particularly true for
acral melanoma wherein acral melanoma
comprises 2% and 80% of cutaneous
melanomas in Caucasian and dark-skinned patients respectively. In a
German study approximately 7% of
patients with cutaneous melanoma had
Fig. 2.20  Acral-lentiginous melanoma (ALM).  A ALM on the heel, showing varying shades of tan to brown pigmentation.  B ALM on the lateral aspect of the foot,
showing irregularly bordered pigmentation with a slightly ulcerated lesion.  C ALM on the sole, showing an irregularly pigmented macule with notched borders.
D ALM on the second toe, showing subungual pigmented lesion extending to adjacent skin.
BA D
C
Y. Tokura
B.C. Bastian
L. Duncan
Acral-lentiginous melanoma
74
tumours located on acral sites {1337}.
Whereas 77% of cutaneous melanoma in
Japanese patients occurs on acral sites
{2130}. In African and African-Americans, the highest incidence of
cutaneous melanoma has been reported
on relatively non-pigmented areas, such
as the soles, nail plates, and mucous
membranes {1417}. Thus, ALM is the
most common type of melanoma in dark-skinned peoples and Asians {1268,
2129}. Nevertheless the absolute inci-dence of acral melanoma in dark-skinned African and light-skinned
Caucasian populations in North America
is similar, suggesting that the observed
racial difference may relate to a
decreased incidence of non-acral
melanoma in African American popula-tions {2268}. Compared with the escalat-ing incidence that typifies other
melanoma subtypes, the incidence of
ALM has remained static {661}.
Overall, ALM occurs in an older patient
population than does superficial spread-ing or nodular melanoma, and, in popu-lations where ALM is common, this
tumour more often afflicts men than
women. Overall, the age distribution of
ALM is similar to that of lentigo maligna
melanoma, peaking in the seventh
decade of life, whereas superficial
spreading melanoma and nodular
melanoma peak in the sixth decade
{1337}. The mean age of ALM ranges
from 55 to 68 years in European coun-tries {767,1337,2123}. In Japanese
patients, there is a peak in the sixth
decade in both males and females. In
Japan, Korea, and Taiwan, men are
effected twice as often as women {1220,
1268,1428,2130}. On the other hand in
western countries, there is less of a male
predominance in patients with ALM
{1337,2220}.
Localization
The term acral has been used differently
throughout the literature. Most publica-tions use acral for the non-hair bearing,
i.e. glabrous skin of the palms and soles,
and the nail bed, whereas others also
include the dorsal aspect of the hands
and feet under this term. In a German
study, using the latter definition, acral
melanoma occurred on the feet in 87%
cases (plantar sites, 57%; subungual,
5%; and dorsum, 9%) and on the hands
in 23% (palm, 1%; subungal, 14%; and
dorsum, 9%) {1337}. Thus, the plantar
sites were greatly more often affected
than the palmar sites {1337,2130,2201,
2220,2296}. In contrast to ALM, superfi-cial spreading melanoma occurs more
commonly on the sun-exposed dorsal
aspects of the hands and feet, whereas
nodular melanoma occurs on all acral
sites with relatively equal frequency
{1337}. In addition to the sole, nail plate
is an especially frequent site with a fre-quency of 16-19% in ALM {1337,2130}.
In contrast to the palmar/plantar
melanomas, subungual melanomas
occur more often on the hands than on
the feet {745,1221,2130,2315}. In the
Japanese series, the number of subun-gual melanomas on the fingers is 62-72%
and on the toes 28-38%, with an 82%
incidence on the thumbs and great toes
{1221,2130}. The high percentage of
occurrence on the thumbs and great
toes may suggest a role for trauma in the
etiology of subungual melanoma {2130}.
Since sun exposure obviously plays little
role in palmoplantar sites, the causative
role of ultraviolet light is presumed to be
negligible in ALM.
Clinical features
Acral melanomas in the early stages
appear as a pigmented macule similar to
lentigo maligna. Acral melanomas com-monly exhibit clinical evidence of a
biphasic growth pattern, with a more
rapid evolution from an entirely flat clini-cal lesion to a lesion containing an ele-vated focus than is observed in the other
types of melanoma. The radial growth
phase of ALM is characterized by a mac-ular pigmented lesion with highly irregu-lar, notched borders and varying shades
of pigmentation. Within a background
pigmented macule, acral melanomas
often develop a clinically apparent verti-cal growth phase. This is manifest as an
elevated papule or nodule, sometimes
with a verrucous surface, and corre-sponds to the histological vertical growth
phase of malignant melanocytes.
Ulceration is more often seen in ALM
than in other types of melanoma.
Subungual melanomas often begin as
brown to black discolouration of the nail
that frequently become bands or streaks
of pigmentation. Thickening, splitting, or
destruction of the nail plate may occur.
The irregular macular hyperpigmenta-tion, coloured tan to dark brown, is also
recognized around the nail plate {2130}.
In one study, 17% of the patients noticed
Melanocytic tumours
Fig. 2.21 Acral-lentiginous melanoma.  A ALM, showing marked acanthosis, elongation of the rete ridges, broadened horny layer, and large, atypical melanocytes
with large, often bizarre nuclei and nucleoli, and cytoplasm filled with melanin granules.  B ALM, showing lentiginous proliferation of atypical melanocytes at the
border of the tumour.
BA
75Acral-lentiginous melanoma
the pre-existence of some pigmented
skin lesions, and 21% related a history of
trauma {2130}. Pigmented streaks are
not uncommon in patients with deeply
pigmented skin, nevertheless, a history
of a new or recently changing pigmented
lesion should prompt the consideration
of a biopsy for histological evaluation of
the lesion. In this case, reflection of the
proximal nail fold to enable biopsy of the
nail bed may be necessary for definitive
diagnosis.
Unfortunately, clinical misdiagnosis is not
uncommon in patients with ALM {409,
767,1327,1592,2222}. Therefore, aware-ness of atypical presentations of ALM
that may contribute to misdiagnosis or
diagnostic delay assumes particular
importance. ALM lesions are frequently
treated or followed for considerable time
under the clinical diagnosis of wart, cal-lus, fungal disorder, subungual
haematoma, keratoacanthoma, nonheal-ing ulcer, foreign body, naevus, ingrown
toenail, etc {2222}.
Histopathology
The histology of ALM is characteristic but
not distinct. In the radial growth phase,
the lesions are characterized by marked
acanthosis, expanded cornified layer,
elongation of the rete ridges, and lentigi-nous proliferation of atypical melano-cytes along the basal epidermis at the
border of the tumour {1337,1767}. The
intraepidermal component of acral
melanoma includes large, atypical
melanocytes with large, often bizarre
nuclei and nucleoli, and cytoplasm filled
with melanin granules {2130}. These
melanocytes in the basal layer often
exhibit long, elaborate dendritic process-es {2130}.
Atypical melanocytes can extend along
the sweat ducts into the deep dermis.
In the vertical growth phase, tumour nod-ules often contain predominantly spindle-shaped cells and are associated with a
desmoplastic reaction {2130}. The junc-tional component of thicker tumours
often shows nesting of tumour cells and
upward migration to the cornified layer
{1337}.
Immunoprofile
As in the other types of melanomas,
immunohistochemical stainings for S-100
protein, HMB-45, and MART-1 (also
known as Melan-A) are of great diagnos-tic value in ALM. S-100 protein (positive
cases, 95%) is a more sensitive marker
than either HMB-45 (80%) or MART-1
(70%) {1268}. However, S-100 protein-negative ALM has been reported {83}.
The intesitity of HMB-45 but not of S-100
protein is correlated well with the melanin
content. HMB-45-negative cases are all
amelanotic, but amelanotic cases are not
all negative for HMB-45 {1268}. The
melanoma cells also express vimentin
{1268}. Focal staining for CAM5.2 or
epithelial membrane protein may occa-sionally be found {1268}.
Somatic genetics
Comparative genomic hybridization
(CGH) of melanomas on acral non-hair
bearing skin showed distinct differences
to melanomas on non-acral skin {171}. A
study of 15 acral melanomas and 15
superficial spreading melanomas from
non-acral sites showed that all (100%)
acral cases had gene amplifications,
whereas amplifications were found in two
of the superficial spreading melanomas
(13%). The most common amplified
region is chromosome 11q13 which
occurred in 50% of these types of
melanoma. A recent study has shown
that cyclin D1 is one of several candidate
genes in this region. This conclusion was
based on the observation that amplifica-tion of the cyclin D1 gene was always
accompanied with overexpression of the
cyclin D1 protein, and that inhibition of
cyclin D1 expression in vitro and in
xenograft models led to apoptosis or
tumour shrinkage {2072}.
FISH studies on primary lesions of acral
melanoma showed that the amplifica-tions arise early in acral melanoma and
can already be detected at the in situ
stage {171}. The  in situ portion of acral
melanoma may extend beyond what is
recognizable histopathologically. FISH
detected gene amplifications were iden-tified in single basal melanocytes imme-diately adjacent to the in situ component
of acral melanoma; they were equidis-tantly spaced and looked histopathologi-cally inconspicuous {171}. Based on the
observation that these “field cells” were
found at the histopathologically unin-volved excision margins of an acral
melanoma that recurred multiple times
the authors propose that field cells may
be a form of minimal residual melanoma
that leads to persistence if not removed.
More recent studies using array CGH
have confirmed the frequent gene ampli-fications in acral melanoma preferentially
involving chromosome 11q13. In addi-tion, the studies revealed that all
melanomas showed these features, inde-pendent of their histological growth pat-tern, as long as they were located on
glabrous, i.e. non-hair bearing skin of the
palms and soles or subungual sites
(Bastian et al, to be published). In addi-tion, melanomas involving these anatom-ic sites also had a significantly lower
mutation rate of the BRAF oncogene
(6/39, 15%) than melanomas on the trunk
(23/43, 53%) {1493}. The molecular
genetic analyses therefore suggest
melanomas of the palms of soles and
subungual sites represent a genetically
distinct form of melanoma, independent
of their histological growth pattern.
Prognosis and predictive factors
In general, the prognosis of invasive
acral melanoma is poor. This can party
be explained by the above described
diagnostic delay and increased tumour
thickness at the time of diagnosis.
However, there are some studies sug-gesting that acral melanomas may
undergo a more aggressive course inde-pendent of tumours thickness {151,308,
661,1337}. In a study from Germany, 63
out of 64 patients (98.5%) with melanoma
of the sole subsequently developed
metastases {775}; a corresponding fig-ure from Japan in 1983 was 35% {2130}.
The same hospital recorded that the 5-year survival rate of subungal melanoma
increased from 53% in 1969-82 to 83% in
1983-93 {1221}, presumably because of
early awareness of lesions and develop-ment of treatment {2012}. However, oth-ers have reported that ALM is not a sig-nificant prognostic indicator {661,2201},
and adjustment for histologic and clinical
stage renders the prognostic importance
of anatomic location insignificant {151,
308}. These conflicting results can in part
be explained by the different definitions
used for acral melanomas in the studies.
Future studies using refined criteria
including genetic information are neces-sary to assess the prognosis of this
melanoma type.
76 Melanocytic tumours
Definition
Desmoplastic melanoma (DM) is a spin-dle cell melanoma in which the malignant
cells are separated by collagen fibres or
fibrous stroma. It displays variable cyto-logical atypia, cellularity and stromal
fibrosis and more often than not has an
accompanying junctional component.
Neurotropism is a common associated
feature (in at least 30% of cases) and
when it occurs such tumours are termed
desmoplastic neurotropic melanomas
(DNM). The neurotropism may be pe-rineural or intraneural and often extends
beyond the desmoplastic component.
DM may also present as a recurrence or
occasionally as a metastasis from other
types of melanoma.
ICD-O code 8745/3
Historical annotations
DM was first described by Conley et al.
in 1971 {526} as a clinically inconspicu-ous superficial melanocytic lesion, main-ly on the head and neck, with an atypical
junctional component, preceding the
development of a bulky dermal and sub-cutaneous tumour. The latter was com-posed of atypical melanocytes and spin-dle cells often with elongated nuclei and
a dense collagenous ground substance.
Many others subsequently highlighted
the frequent neurotropism of DMs.
Epidemiology
Desmoplastic melanomas represent
between 1-4% of melanomas. In a large
series from the Sydney Melanoma Unit
DC
BA
Fig. 2.22 Desmoplastic neurotropic melanoma.  A Male, 73 yrs, cheek. A few atypical enlarged melanocytes are present in the junctional zone. The fibrohistiocytic
pattern is accompanied by scattered lymphocytes, some in clusters. Mitoses are hard to find. B Female, 24 yrs, lip. There are “neural transforming” areas with thick
neuroid bundles in the upper dermis. Note occasional atypical junctional melanocytes, a few subepidermal spindle cells and scattered lymphocytes. C Male, 73 yrs,
cheek. Malignant spindle cells with elongated nuclei appear to be within and between collagen bundles.  D Female, 24 yrs, lip. “Neural transforming” areas with
neuroid bundle (top of picture) containing atypical elongated spindle nuclei. Intraneural and perineural involvement of a small  nerve is also present. There is a
prominent infiltrate of lymphocytes.
S.W. McCarthy
K.A. Crotty
R.A. Scolyer
Desmoplastic melanoma and
desmoplastic neurotropic melanoma
77Desmoplastic melanoma and desmoplastic neurotropic melanoma
(SMU) the median age at diagnosis was
61.5 years (range 24-91) {1867,1868}.
As in other histogenetic types of
melanoma, males are more often affect-ed (M:F = 1.75:1) {358A,1867,1868}.
Etiology
The etiology is unknown, but the majority
occurs in sun-exposed skin. Some have
occurred in irradiated areas {1125}.
Localization
DM may be found in many sites but most
commonly involves the head and neck
region (37%), including ear, nose and lip
{1077}. Males predominate except on the
lower limbs. The vulva is a rare site for
DM {1664}.
Clinical features
Most present as a painless indurated
plaque but some begin as a small papule
or nodule {2501}. Almost half lack pig-mentation {1867}. Pale lesions are often
mistaken for basal cell carcinoma, der-matofibroma or a scar. Pigment is usual-ly due to an associated lentigo maligna
(LM)/Hutchinson melanotic freckle (HMF)
or superficial spreading melanoma.
Unusual presentations include a young
age {439,1077}, an erythematous nodule
{1326} and alopecia {563}.
Macroscopy
Ulceration is uncommon although it was
found in 17% of the SMU cases {1868}.
Tumour spread and staging
The tumours usually infiltrate deeply into
the reticular dermis but local spread may
involve subcutaneous tissue, deep fas-cia including periosteum and pericrani-um, bone and salivary gland. Neuro-tropic foci may be found well beyond the
main tumour. In the SMU series, neu-rotropism was found only in tumours
exceeding 1.5 mm in thickness and Clark
level 4 or 5 {1867,1868}. Initial metas-tases from DM may involve regional
lymph nodes or distant sites.
Histopathology
In DM the spindle-shaped melanocytes,
which often resemble fibroblasts and are
usually non-pigmented, are found in and
between mature collagen bundles. The
latter may be thickened and/or associat-ed with a mild to marked stromal fibrosis.
The distribution of spindle cells is usually
haphazard but occasionally they form
parallel bundles or storiform areas. The
spindle cells often extend into the sub-cutis diffusely or in fibrous bands and
may involve deep fascia, especially peri-cranium. The overlying epidermis may
be thinned or thickened. Charac-teristically there are accompanying small
islands of lymphocytes and plasma cells
within and/or at the edge of the tumour.
The cytological atypia of the spindle cells
usually varies from mild to moderate.
However, even in cases with mild atypia,
there are usually a few larger or more
elongated hyperchromatic nuclei. The
cytoplasm of the spindle cells is often
poorly defined. In examples where the
spindle cells are small, well scattered
and associated with solar elastosis, the
lymphoid islands may be the main clue to
the diagnosis. Paucicellular variants are
easily missed on punch and shave biop-Fig. 2.23 Desmoplastic melanoma.  A Male, 57 yrs, upper lip. Abnormal junctional melanocytes, spindling dermal melanocytes and a patchy lymphocytic infiltrate.
B Female, 76 yrs, forearm. Abnormal junctional melanocytes and dermal spindle cells with patchy lymphocytes.
BA
B CA
Fig. 2.24 Desmoplastic melanoma.  A The spindle cells stain poorly with S100 unlike the Langerhans cells and interdigitating cells.  B Variable S-100 positive nuclear
and cytoplasmic staining.  C Crowded abnormal spindle cells and atypical mitoses.
78 Melanocytic tumours
sies. Junctional change is sometimes
minimal or absent {1125}. Occasionally
there is an associated banal naevus.
Vascular invasion is rare. Even rarer
cases show heterotopic bone and carti-lage {1644}.
The median Breslow thickness in the
SMU series was 2.5 mm (0.2-18 mm)
{1867,1868}. The thickness and extent of
invasion is usually best determined in S-100 stains. The mitotic rate is variable but
is often low. Abnormal mitoses are com-mon in the more cellular tumours.
The neurotropism is characterized by the
presence of one or more foci in which the
spindle cells extend in a circumferential
fashion around nerves in the dermis or
deeper and/or thickened nerves contain-ing abnormal cells within their nerve
sheath. Spindle cells may also form
structures resembling nerves (“neural
transforming”). Neurotropism may be
present in melanomas without desmopla-sia.
Melanomas of any histogenetic type may
have desmoplastic areas. The proportion
of desmoplasia in a melanoma neces-sary for the diagnosis of DM has been ill
defined in several studies, but proposals
for diagnostic criteria have been made
{358A,985A,1546A}.
Metastases in lymph nodes may be
epithelioid cells, or spindle cells with or
without desmoplasia.
Immunoprofile
The spindle cells are positive with S-100
although only a few nuclei are positive in
some otherwise typical cases. HMB45 is
usually negative except for any foci of
epithelioid cells {2476}. NSE, NKI/C-3
and smooth muscle actin {1929} may be
positive. Melan A (MART-1) is usually
negative. Microphthalmia transcription
factor (MTF) is not a sensitive or specific
marker {356,885,1294}. Type IV collagen
and laminin are frequently expressed in
DM {1857}. Vimentin is usually positive
although positive staining does not usu-ally assist in diagnosis.
Differential diagnosis
The differential diagnosis includes
desmoplastic naevus {958}, which like
DM may have perineural extension but
lacks asymmetry, mitotic activity, marked
nuclear atypia and lymphoid infiltrates.
Well established desmoplastic Spitz
naevi may have many HMB45 negative
spindle cells but these naevi are usually
symmetrical with epidermal thickening,
include at least a few plump cells and
have rare or absent mitoses. Sclerosing
cellular blue naevi, which are most fre-quent on the scalp, also lack mitoses
and are more or less diffusely HMB45
positive. Immature scars, especially in
re-excision specimens, may focally
resemble DM as they may have some S-100 positive spindle cells {476,1951},
foci of lymphocytes and mitoses.
Other differential diagnoses include der-matofibroma/fibrous histiocytoma, fibro-sarcoma, “malignant fibrous histiocy-toma”, malignant peripheral nerve
sheath tumour and leiomyosarcoma.
These tumours can usually be separated
by morphology and appropriate immuno-histochemistry.
Histogenesis
It is most likely that the desmoplastic
cells are derived from melanocytes that
have undergone adaptive fibroplasia.
Some authors have suggested that the
desmoplasia occurs because of a fibrob-lastic stromal response and neurofi-brosarcomatous differentiation of the
tumour cells {2476}. Ultrastructurally,
premelanosomes and melanosomes are
rare and the spindle cells have the fea-tures of fibroblasts. There is abundant
rough endoplasmic reticulum and some-times intracytoplasmic collagen and
macular desmosomes {2476}.
Somatic genetics
Chromosomal aberrations and gene
mutations have been found in sporadic
and familial melanoma {799}. Allelic loss
at the neurofibromatosis type 1 (NF1)
gene locus is frequent in DM {931}. Basic
fibroblast growth factor (bFGF) and other
fibrocytokines are often present in the
nuclei of DMs {1335}. Loss of heterozy-gosity of matrix interacting protein 1
(MXI1) is frequent {1893}. No BRAF
mutations were found in 12 desmoplastic
melanomas {596}, consistent with the
finding that melanomas on chronically
sun-exposed skin only rarely have BRAF
mutations {358B,596,1493}.
Prognosis and predictive factors
Recurrences are common especially
after incomplete excision {526}, marginal
excision <10 mm or if neurotropism is
present {1867,1868}. The conflicting
results regarding the risk of regional
node field metastases and prognosis of
DM patients may be due to a hetero-geneity of tumours classified as DM and
failure to account for tumour thickness
{2115A}. Regional nodal metastases
appear to very uncommon in paucicellu-lar DMs with prominent fibrosis and are
associated with longer survival {358A,
932A, 985A}. Otherwise, disease free
survival rates are similar to other
melanomas of comparable thickness
{126}. Neurotropism, HMB45 positivity,
high mitotic rate, male gender, thickness,
ulceration and site all appear to affect
survival which overall is 79% at 5 years
{1868}. Of patients with a recurrence,
78.2% experienced it within 2 years.
Wide local excision is the treatment of
choice {99A}. Radiation therapy has
been effective in some cases {71,1125}.
BA
Fig. 2.25  Desmoplastic melanoma.  A Firm, skin-coloured plaque.  B Male, 68 yrs, scalp. This punch biopsy
was initially diagnosed as a scar. Only an occasional spindle cell was S-100 positive and no abnormal junc-tional melanocytes were found. A larger desmoplastic melanoma was removed from the same site 6 months
later. Clues to the diagnosis are the small foci of lymphocytes and permeation of the band of dermal elas-tosis by spindle cells.
79Melanoma arising from blue naevus
Definition
A melanoma that arises in association
with dermal melanocytosis, most fre-quently cellular blue naevus.
Synonyms
“Malignant blue naevus” or “blue nae-vus-like melanoma” are terms used to
describe melanomas arising in associa-tion with a cellular blue naevus or those
primary melanomas that resemble blue
naevi and lack an in situ component.
ICD-O 8780/3
Epidemiology
Melanoma associated with blue naevus
is an exceedingly rare tumour with over
165 reported cases. It affects predomi-nately Caucasians and all age groups
with the majority of cases occurring
between 20 and 60 years, with a mean
age at diagnosis of 44 years {2066,
2332}. Slightly more females than males
have been reported (82 females; 76
males). Occasionally, dark-skinned
patients develop melanoma in associa-tion with a blue naevus {548,1352,1629}.
Localization
In decreasing order, the sites most fre-quently affected are the scalp (33%),
orbit and face (32%), trunk- mostly back
and buttocks (19%), extremities (7%)
and hands or feet (7%). Involvement of
the vulva and vagina have also been
reported {422,2233}.
Clinical features
Most melanomas associated with blue
naevus (93%) develop in a pre-existing
dermal melanocytosis that was congeni-tal (35%), acquired during infancy or
childhood (15%) or identified during their
adult years (43%). These associated
lesions were cellular blue naevi (52%),
common blue naevus (16%), naevus of
Ota (14%), naevus of Ito (1%) {2066,
2414}, or ocular melanocytosis {542,
1127,2332,2431}. On average, these
melanocytoses were present for 24 years
before melanoma developed, with a
range of 3 months (infant with congenital
facial blue naevus {2066}) to 78 years
(naevus of Ito {2414}). For congenital and
childhood onset melanocytoses, melano-ma developed after a mean duration of
34 years (range 3 months to 78 years)
whereas for adult onset common or cel-lular blue naevi, melanoma developed on
average after 14 years (range 1 – 56
years). The majority (83%) of affected
patients described recent, often rapid,
growth or presented with proptosis in the
case of orbital melanomas within a year
of diagnosis. Other symptoms include
colour change or ulceration, and in the
case of orbital melanomas, diplopia and
blurred vision. The melanoma is typically
a large black nodule with mean diameter
of 2.1 cm (range 0.5–8.0 cm). In some
cases, satellitosis due to cutaneous
metastatic deposits appear around the
primary nodule {64,276,364,856,1018,
1588,1981,2066}. However, this feature
can also represent the well-known phe-nomenon of satellitosis associated with
the common and cellular blue naevus
(agminated blue naevus) {616,1059,
1195,2008}. Similarly, cellular blue nae-vus can also present with regional lymph
node deposits {143,1357,2261}. In the
former cases, histopathologic examina-tion of the satellite lesions reveals fea-tures of benign blue naevus and the
lesions present benign biological behav-iour with no development of distant
lesions.
Etiology
The etiology of melanoma associated
with blue naevus is unknown, but the
presence of longstanding dermal
melanocytosis is likely a risk factor.
Ocular and oculodermal melanocytosis
(naevus of Ota) is strongly associated
with uveal melanoma {2192,2193} and
has been reported with meningeal
melanocytoma (blue naevus) of the brain
{1877} and primary melanomas of the
central nervous system {253,569,1104,
1713,1930,2046}. Based on this associa-tion and numerous reports of melanoma
of the face, orbit or brain associated with
oculodermal melanocytosis patients pre-senting with naevus of Ota should be
considered at lifetime risk for melanoma
of the skin, orbit or central nervous sys-tem, a risk that maybe similar in nature to
that identified for large congenital
melanocytic naevi with melanoma and
neurocutaneous melanocytosis {254}.
Fig. 2.26  Melanoma arising from blue naevus.
Note the presence of satellitosis (Courtesy of Dr. H.
Kerl).
BA
Fig. 2.27  Melanoma arising from blue naevus.  A Scanning magnification showing a blue naevus with a nod-ule of malignant melanoma in deeper areas.   B  In deeper areas the nodule of malignant melanoma was
composed of sheets of cells destroying pre-existing structures of the dermis.
L. Requena
J. A. CarlsonMelanoma arising from blue naevus
80 Melanocytic tumours
Additional associations of unknown influ-ence include subacute cutaneous lupus
erythematosus, leukoderma, Becker’s
naevus and prostate adenocarcinoma in
one patient {1629}, papillary thyroid car-cinoma {94}, acute lymphocytic
leukaemia {2119}, psoriasis {238}, and
oral contraceptives {1404}. Phototherapy
has been associated with cellular blue
naevus development {810}.
Histopathology
By definition, a melanoma that develops
in a pre-existing blue naevus is a dermal
melanoma without the features of
melanoma in situ involving the dermo-epidermal junction or adnexal epitheli-um. In fact, 82% of all reported cases
described an adjacent common and/or
cellular blue naevus. The absence of an
identifiable benign naevus component in
some reports may be the result of
replacement of it by the melanoma or
incomplete sampling of the benign ele-ment. Although these cases could repre-sent de novo melanomas, a subtle,
hypocellular dermal melanocytosis as
seen in naevi of Ota and Ito, and
Mongolian spots may not have been
observed. Reports of orbital, facial and
shoulder melanomas associated with
naevi of Ota and Ito, and ocular
melanocytoses attest to this latter possi-bility of under-reporting {542,660,1783,
2332,2414}.
At scanning magnification, two
histopathologic patterns are evident.
One is represented by the benign com-ponent of the blue naevus, which may
range from very focal to comprising the
main bulk of the neoplasm. Often this
benign component is represented by a
cellular blue naevus and less frequently
the lesion contains a common blue nae-vus. Most cases, however, show a com-bination of the so-called cellular and
common blue naevi, making this distinc-tion useless. The areas of cellular blue
naevus consist of solid aggregations of
closely arranged monomorphous ovoid
cells with abundant pale cytoplasm con-taining little or no melanin and round
vesicular nuclei with inconspicuous
nucleoli. In contrast, the areas of com-mon blue naevus are made up of elon-gated spindled bipolar melanocytes,
with long branching dendritic processes
most of them filled with abundant gran-ules of melanin. Melanophages and scle-rotic bundles of collagen are also fre-quently observed between the fascicles
of dendritic melanocytes.
Although the malignant component may
involve the superficial dermis and ulcer-ate the epidermis, more often it appears
as a deep-seated expansile asymmetric
nodule involving the reticular dermis and
subcutaneous fat. Usually, there is an
abrupt transition from the benign blue
naevus component to the nodule of
melanoma. The nodule or nodules of
melanoma show both architectural and
cytological features of malignancy. The
melanomatous component consists of
sheets of cells that involve diffusely the
deep dermis destroying the pre-existing
structures with pushing margins and
sharp demarcation between the neo-plasm and adjacent dermis or subcuta-neous tissue. Neoplastic melanocytes
appear as large spindled to epithelioid
cells with abundant cytoplasm and pleo-morphic and hyperchromatic nuclei, with
prominent nucleoli and frequent mitotic
figures. Usually they contain little or no
melanin. Without the associated benign
component, these dermal nodules would
be histopathologically indistinguishable
from typical nodular or metastatic
melanoma. Necrosis of individual cells
as well as necrosis en masse may be
also seen in the melanoma component,
although this finding seems to be less
Fig. 2.28 A Superficial areas showing stereotypical histopathologic features of a common blue naevus.   B Higher magnification demonstrated that neoplastic
melanocytes of the melanoma showed epithelioid appearance and marked atypia, with large eosinophilic cytoplasm, pleomorphic nuclei and prominent nucleoli.  C
Neoplastic melanocytes of the blue naevus showed small monomorphous nuclei. Note the striking collagenization of the dermis and  the abundant number of
melanophages.
BA C
81Melanoma arising from blue naevus
frequent than in melanomas arising de
novo (“malignant blue naevus”) {973}. A
perivascular inflammatory infiltrate, most-ly composed of lymphocytes, which is
usually lacking in blue naevus, is often
seen around the melanoma arising in
blue naevus.
Melanoma arising in the setting of blue
naevus should be differentiated from the
so-called atypical cellular blue naevus
{118,2371}. These lesions show clinico-pathologic features intermediate
between typical cellular blue naevus and
malignant melanoma associated with
blue naevus. The lesions show architec-tural atypia, characterized by asymmetry
and infiltrative margins, as well as cyto-logic atypia, which consist of hypercellu-larity, nuclear pleomorphism, hyperchro-masia, mitotic figures and necrosis.
However, follow-up data of patients with
atypical cellular blue naevus demonstrat-ed that no patient experienced either a
local recurrence or lymph node or viscer-al metastasis.
Melanoma associated with blue naevus
should be also distinguished from large
plaque-type or giant cellular blue naevus
with subcutaneous cellular nodules {358,
1059}. Large pigmented plaques of
childhood onset that show slow enlarge-ment during adolescence and subse-quent nodule formation clinically charac-terize this rare plaque variant of cellular
blue naevus. Histopathologically, they
exhibit multifocal dermal and subcuta-neous proliferations of fusiform and den-dritic pigmented melanocytes, with high-ly cellular nodules located in deeper
areas of the plaque. The follow-up of
patients with large plaque-type blue nae-vus with subcutaneous cellular nodules
indicates that these lesions behave in a
benign fashion.
Metastatic melanoma mimicking blue
naevus  can also be confused with
melanoma associated with a blue naevus
{354,2517}. These blue-naevus like
metastases occurred in the same
anatomic region as the primary tumour or
near the skin scar of a dissected lymph
node metastasis and were histopatholog-ically characterized by atypical epithe-lioid melanocytes, mitotic figures, and an
associated inflammatory cell infiltrate at
the periphery of the lesions. In contrast
with melanoma arising in a pre-existing
blue naevus, metastatic melanoma to the
skin simulating blue naevus lacks the
benign blue naevus component.
Animal type melanoma (epithelioid
melanocytoma)  is a rare variant of pri-mary cutaneous melanoma that may also
mimic melanoma associated with blue
naevus {567,1917}. Sheets and nodules
of heavily pigmented epithelioid melano-cytes that tend to aggregate along hair
follicles and involve the entire thickness
of the dermis with extension into the sub-cutaneous tissue histopathologically
characterize animal-type melanoma.
Epithelioid melanocytes in deeper areas
show abundant, heavily pigmented cyto-plasm and pleomorphic nuclei with
prominent eosinophilic nucleoli and
mitotic figures. Histopathologic features
of melanoma in situ at the dermo-epider-mal junction are few or absent, and neo-plastic cells do not show evidence of
maturation from superficial to deeper
dermal areas. The overall architectural
and cytologic features of animal-type
melanoma closely resemble those of
melanoma associated with blue naevus,
but animal-type melanoma lacks the
benign component of blue naevus or his-tory of a pre-existing melanocytosis.
Metastatic spread
Melanoma associated with blue naevus
is an aggressive tumour with frequent
metastatic disease to regional lymph
nodes (31% of reported cases) and dis-tant sites (42%). Sites of metastasis, in
decreasing order of frequency, include
liver (36%), lung (22%), brain (16%), skin
(13%), bone (9%), and in less than 6% of
reported cases, spleen, heart, kidney,
pancreas, adrenal, thyroid and parotid
glands, ovary, and gastrointestinal tract.
Melanuria and generalized melanosis
have also been described in its terminal
stage {2185}. Metastases can appear as
late as 20 years after diagnosis {813}, but
the median and mean time of discovery
is 1.75 and 3.6 years after diagnosis.
Metastasis to lymph nodes should be dif-ferentiated from the presence of blue
naevus cells in the capsule of the node
{181,392,405,1357,1358}. This well-known pseudo-metastasizing phenome-non seems to be the result of migration
arrest during embryogenesis and is
characterized by monomorphous
melanocytes of blue naevus involving
only the capsule and the marginal sinus-es of the lymph node. In authentic metas-tases, nests of atypical melanocytes
replace most of the parenchyma of the
node, effacing its architecture.
Immunoprofile
Immunohistochemical studies in lesions
of melanoma associated with blue nae-vus have demonstrated a strongly posi-tive reaction of the neoplastic cells, both
of the benign and malignant compo-nents, for vimentin, S-100 protein, HMB-45 and NKI/C-3 {280,1708,1996}.
However, the number of silver positive
nucleolar organizer regions (AgNOR
score) {813,1826} and growth fraction as
measured by proliferating cell nuclear
antigen (PCNA) and Ki-67 (MIB-1) are
significantly lower in the benign compo-nent of blue naevus than in the nodule of
melanoma {1708,1826}.
Electron microscopy
Although some authors have interpreted
the neoplastic cells of melanoma associ-ated with blue naevus as being related
with Schwann cells {1588}, electron
microscopic studies have demonstrated
the presence of melanosomes in the
cells, as well as the lack of cytoplasmic
enclosures of unmyelinated axons, which
rule out the possibility of Schwann cell
differentiation. Although the melano-somes in many cells of the malignant
component are devoid of melanin {1014},
incubation with dopa demonstrates that
they are strongly dopa-positive {1625},
thus confirming their melanocytic nature.
Somatic genetics
Results of DNA flow cytometry studies in
melanoma associated with a blue naevus
are variable revealing diploid cell popu-lations in 4 cases {1574,1826} and aneu-ploid populations in 2 cases {1826}. A
molecular analysis failed to demonstrate
loss of heterozygosity on microdissected
samples in one case of melanoma asso-ciated with blue naevus, using a panel of
eight genes (MTS1, MXI1, CMM1, p53,
NF1, L-myc, hOGG1, and MCC), many of
which are commonly associated with
conventional melanomas {94}. These
findings suggest that melanoma associ-ated with blue naevus may represent a
distinct entity with a different molecular
pathway to tumourigenesis than that of
conventional melanomas. However, in a
comparative genomic hybridization
study comparing common blue naevi,
cellular blue naevi, and atypical cellular
blue naevi with melanoma associated
with a blue naevus, melanomas associat-ed with blue naevus showed chromoso-mal abnormalities similar to that of con-
82 Melanocytic tumours
ventional melanoma whereas cellular
and atypical cellular blue naevi exhibit
infrequent numerical chromosome aber-rations similar in character to that identi-fied in proliferative nodules found in con-genital melanocytic naevi {1490}.
Prognosis and predictive factors
Some authors have proposed that
melanoma associated with blue naevus
is a low-grade malignancy {1574}.
However, the literature review does not
support this opinion. For instance, in a
series of 12 cases, metastases devel-oped in 10, and 8 died of metastatic dis-ease {527}, and in another series of 10
cases, 4 patients developed metastases
and 3 of them died of disease {883}. Of
the 160 cases reported with follow up
data, 34% of patients have died due to
locally invasive or metastatic melanoma
20 months median, 41 months mean time
from diagnosis (range 2–240 months).
Therefore, melanoma arising in blue nae-vus is a highly aggressive tumour with
poor prognosis similar to that of thick
(>4.00 mm), AJCC stage IIB convention-al melanomas {392}. Indeed, the Breslow
thickness for this melanoma variant typi-cally is much greater than 4 mm with a
mean tumour thickness of 10 mm (range
2.8–45mm){64,640,813,883,1844}.
Possible prognostic factors indicative of
a poor outcome include the presence of
congenital melanocytosis, mixed mela-noma cell type (both spindle and epithe-lioid melanocytes), older age, high mean
mitotic count (>4/40 high power field),
and lymphocyte count (>100 per 20 high
power field) {2332}. These prognostic
factors were identified in a study of pri-mary orbital melanoma where 90% of the
patients had an associated blue naevus
and 47.5% had congenital melanocyto-sis (naevus of Ota or ocular melanocyto-sis). The role of sentinel lymph node dis-section and postoperative adjuvant ther-apy remains to be determined. Sentinel
lymph node dissection in the staging of
melanoma associated with a blue naevus
is advocated by some authors {2173}
and one patient with metastatic disease
to the lymph nodes was alive and without
evidence of disease two years after sur-gery followed by therapy with interferon
{640}.
Fig. 2.29 High Ki-67 labelling index in hyperchromatic spindle nuclei of the melanoma arising from blue nae-vus. The benign portion of the lesion (not shown) had a very low labelling index.
83Melanoma arising in giant congenital naevi
Definition
A proliferation of malignant melanocytes
arising either in the epidermal compo-nent or the dermal component of a giant
congenital naevus associated with risk of
metastasis and death.
ICD-O code 8761/3
Synonyms
Malignant melanoma arising in a gar-ment naevus;
malignant melanoma arising in a bathing
trunk naevus;
malignant melanoma arising in a giant
hairy naevus.
Epidemiology
About 1% of all infants have some kind of
a congenital pigmented skin lesion {568}.
The giant congenital naevus (GCN) is
estimated to occur in around 1 per
20,000 infants {67,411,1306}. The risk of
malignant transformation of a GCN has
been estimated at from 5-20% but more
recent studies based on statistical analy-ses suggest a figure of 6%. The GCN is
a direct precursor of melanoma {1197,
1207,1927,2218}. There is a bimodal dis-tribution to the occurrence of melanoma
in GCN. Most develop in childhood
before the age of 10 {1508} with a sec-ond peak of incidence in adult life.
Sites of involvement
Malignant melanoma can occur any-where in a giant congenital naevus. The
lesion most commonly arises in lesions
on the trunk but can appear in any area
even in congenital naevi of the meninges
{568,1306,1927}.
Clinical features
The definition of GCN varies and
includes a naevus with a diameter larger
than 20 cm. Frequently large areas of the
body (more than 2% of the body surface)
are covered in a garment-like fashion
{1306,1927}. The trunk and head and
neck are the most common sites for
these naevic lesions. The melanoma,
very rarely present at birth, usually
appears as a rather rapidly growing
asymmetrical nodule or plaque of blue-black, reddish or even rarely flesh
colouration {568,1009}. Melanoma can
occasionally present as a cystic lesion.
Therefore, any GCN that develops an
apparent subcutaneous cyst must be
biopsied. Melanoma is only one of many
benign and malignant tumours that may
occur in GCN {1009,1928}.
Macroscopy
The lesion usually appears either as a
firm nodule, or as a boggy discoloured
area, usually dark brown or black in the
midst of the naevus. If the lesion arises in
the dermis, the tumour can sometimes
only be seen on cut surface as a sepa-rate nonencapsulated nodule amidst the
otherwise tan or pale tan coloured nae-vus in the dermis or subcutis.
Histopathology
Histologically, the tumours are often
asymmetrical and sharply demarcated
from the adjacent congenital naevus. If
superficial, there is effacement of the rete
ridges of the epidermis and often ulcera-tion. The intraepidermal component usu-ally is composed of epithelioid cells with
pigmentation. Pagetoid spread is com-monly noted. The tumour cells of the der-mal component usually form expansile
Fig. 2.31  Melanoma arising from large congenital naevus.  A The melanoma is clearly separate from the naevus cells that are on the left.  B A protuberant nodule
shows the small dark naevus cells to the left and at the base of the melanoma that is composed of nests with dyscohesion.
BA
Fig. 2.30 Malignant melanoma presenting as a red-dish brown nodule in the midst of the congenital
naevus.
H. Kerl
C. Clemente
P.E. North
Melanoma arising in giant congenital
naevi
I Sanchez-Carpintero
M.C. Mihm
B.C. Bastian
84
R.L. BarnhillChildhood melanoma
Melanocytic tumours
nodules. They exhibit fully transformed
malignant characteristics with very irreg-ular chromatin patterns and prominent
nucleoli. There is variable pigmentation.
Both single cell and zonal necrosis may
be observed. The melanoma cells as
they abut or infiltrate as cords into the
adjacent naevus show no evidence of
maturation but maintain their fully malig-nant characteristics. Mitoses are com-mon and atypical forms are usually pres-ent. A lymphocytic host response is often
noted. Occasionally, a desmoplastic host
response may be observed as well as
focal mucinosis. In our experience, the
vertical growth phase dermal nodules
may exhibit prominent areas of different
cell types with different degrees of pig-mentation {568,703,1197,1928}.
Histologically, the presence of a residual
dermal naevic component with congeni-tal features may be quite difficult to find,
particularly, if present in the wall of a ves-sel.The differential diagnosis includes
the proliferative nodules that also arise in
large congenital naevi.
Somatic genetics
Comparative genomic hybridization
shows that melanomas arising in con-genital naevi show similar chromosomal
aberrations as melanoma arising inde-pendently {175}. By contrast, the prolifer-ative nodules arising in early life do not
show chromosomal aberration support-ing the view that they are benign {175}.
B CA
Fig. 2.32  Melanoma arising from large congenital naevus.  A There is a distinctive proliferation of malignant melanocytes invading the dermis. Note thinning of the
rete ridges with a proliferation of malignant melanocytes invading the dermis as spindle cells with an admixed population of melanophages.  B Reveals epithelioid
cells in nests invading the epidermis giving rise to spindle cells in the dermis.  C The malignant spindle cells show nuclear hyperchromasia and mitoses.
Definition
Melanomas developing in individuals
prior to the onset of puberty are child-hood melanomas and thereafter they are
designated as melanomas in adoles-cents with the age limitation of 18 to 20
years. Childhood melanomas can be fur-ther subcategorized as 1) congenital
melanoma (onset in utero to birth), 2)
infantile melanoma (birth to one-year of
age), and 3) childhood melanoma (one
year to onset of puberty).
Epidemiology
The incidence of melanoma is excep-tionally rare in prepubertal individuals
(estimated incidence approximately
0.4% among all melanomas) {269A,
1487A} and uncommon under the age of
20 years (incidence approximately 2%)
{123A}. The incidence of melanoma has
doubled in patients aged 15 to 19 years
over the past decade but has remained
unchanged in younger individuals
{204A,1037A}. Less than 80 well docu-mented cases of melanoma in children
younger than 10 years have been
recorded in the literature over a period of
30 years. As in adults, childhood mela-nomas have a predilection for Cauca-sians. Individuals with congenital naevi
especially large varieties, atypical naevi,
family history of melanoma, xeroderma
pigmentosum, and immunosuppression
are at increased risk for childhood
melanoma.
Localization
Melanomas developing in patients up to
16 years of age most commonly involve
the trunk (50%), followed by the lower
extremities (20%), head and neck
(15%), and upper limbs (15%).
Clinical features
Melanomas in individuals under the age
of 20, particularly in adolescents, show
fairly similar clinical features as com-pared to melanomas in adults
{123A,1916A}. However melanomas in
prepubertal individuals are so rare that
they are usually unsuspected. Features
suggesting melanoma in a pigmented
lesion such as a congenital naevus are
rapid increase in size, bleeding, devel-opment of a palpable nodule (e.g., in a
giant congenital naevus), colour change
of a nodular lesion, surface changes
such as ulceration, and loss of clearly
defined margins. Recognition of
melanoma appearing de novo requires a
high index of clinical suspicion, espe-cially for amelanotic lesions. Utilizing the
85Melanoma of childhood
conventional ABCDE criteria (Asymme-try, ill-defined Borders, irregular Colour,
and large Diameter, Elevation) the clini-cal detection of melanoma in adults, all
such suspicious lesions in children
should be evaluated for biopsy and
histopathological examination. Melano-ma in children also may be associated
with pain or pruritus {155,417A,530A,
1037A,1619A,1859A,1930A,1990A,
2003A,2089,2232}.
Histopathology
The same histopathological criteria
should be utilized for diagnosis as have
been developed for adult melanomas
{155,159A,417A,1990A,2232}. However,
clinical information must be strongly con-sidered, particularly age, since cuta-neous melanoma is almost nonexistent
under the age of two years and especial-ly in the neonatal period.
The important stimulants of melanoma
must be excluded: 1) atypical nodular
proliferations developing in congenital
naevi in infants and young children and
2) Spitz naevi.
Great attention should be given to avoid-ing over diagnosis melanoma and at the
same time to the under recognition of
atypical and borderline lesions that
require adequate surgery and follow-up
for disease recrudescence. Lesions not
clearly meeting sufficient criteria for
melanoma should be designated as bio-logically indeterminate. Features appear-ing to be most useful for the distinction of
melanomas from naevi are large size
(i.e., >7 mm), ulceration, high mitotic rate
(>4 mitoses/mm2), mitoses in the lower
third of the lesion, asymmetry, poorly
demarcated lateral borders, lack of mat-uration, finely-divided melanin, and
marked nuclear pleomorphism {155,
159A,2232}. Melanomas in children can
be (somewhat artificially) categorized
into three principal groups {155,
159A,2232}.
Conventional melanomas
About 40 to 50% of melanomas in chil-dren are similar histologically to those in
adults {159A,2232}.  The intraepidermal
components of such melanomas conse-quently may be pagetoid, lentiginous, or
nested. Melanomas of glabrous skin are
exceedingly rare in childhood {159A,
2232}. Solar (so-called lentigo maligna)
melanomas do not occur in childhood.
However, melanomas diagnosed in
patients with XP are histologically often
similar to solar melanomas except that
the actinic damage characteristic of
adult tumors is absent  {159A,2232}.
Small-cell melanomas
Small-cell melanomas are comprised of
monomorphous small cells, reminiscent
of small round cell malignancies such as
lymphoma, or a melanocytic naevus
{155,159A,2232}. These cells are often
arranged in sheets or in organoid config-urations. The melanocytes contain
basophilic round nuclei and condensed
chromatin. The high cellular density, lack
of maturation, and often prominent mitot-ic rate are features suggesting melano-ma. In children, small cell melanomas
may appear de novo or may develop in a
congenital naevus. Such melanomas
with small-cell phenotypes have often
been localized to the scalp, shown strik-ing Breslow thicknesses, and fatal out-come in most patients {159A}.
Melanomas simulating Spitz naevus
On occasion melanomas in both children
and adults may exhibit features strongly
suggesting a Spitz naevus. These fea-tures include both architectural and cyto-logical attributes such as epidermal
hyperplasia, wedge-shaped configura-tion, epidermal clefting about intraepi-dermal nests, large epithelioid cells and
spindle cells arranged in fascicles, etc.
{155,159A,2232}.
In addition to conventional melanomas
and typical Spitz naevi, there is also an
intermediate group of Spitz-like lesions
that demonstrate not only some features
of Spitz naevi but also varying degrees of
atypicality.
Differential diagnosis
Childhood melanomas must be distin-guished from congenital and other naevi
exhibiting pagetoid melanocytosis,
lentiginous melanocytic proliferation,
atypical nodular melanocytic prolifera-tion, and from Spitz naevi. Conventional
criteria such as age, clinical presenta-tion, size, asymmetry, circumscription,
degree of cellular density, maturation,
degree of cytological atypia, and mitotic
rate should facilitate this discrimination in
most cases.
Pagetoid melanocytosis and lentiginous
melanocytic proliferation and are fea-tures commonly observed in naevi devel-oping in children, particularly in glabrous
skin. These changes must not be overin-terpreted unless architectural disorder is
prominent and cytological abnormalities
are present throughout the breadth of the
lesion.
Virtually all atypical nodular melanocytic
proliferations developing in congenital
naevi are biologically benign.  Exami-nation of these atypical tumors with refer-ence to karyotype, expression of cell-sur-face antigens, growth in soft agar, chro-mosomal aberrations, and other parame-ters has shown that they have the prop-erties of an immature proliferative but
benign tumor {71A,175,1496A}.
Various authors have proposed criteria
for distinguishing Spitz naevi from
melanomas. Criteria favoring melanoma
include asymmetry, ulceration, deep
extension (particularly subcutaneous
fat), large size (>1 cm), prominent cellu-lar density, lack of maturation, deep
mitoses (i.e., more than 3 mitoses in the
lower third), high mitotic rate (i.e., >4 to
6/mm2), abnormal mitoses, and marked
nuclear atypia.
BA
Fig. 2.33  Small-cell melanoma from the scalp of a prepubertal individual.  A The lesion resembles a con-ventional melanocytic naevus at scanning magnification.   B  High magnification shows a highly cellular
dermal component without maturation.  There is a monomorphous population of small round melanocytes
with scant cytoplasms resembling the neoplastic cells in lymphoma or neuroendocrine carcinoma. The
nuclei are pleomorphic.
86 Melanocytic tumours
Definition
Naevoid melanoma is a subtype of
malignant melanoma of the skin that is
distinctive in that the primary lesion mim-ics many of the architectural features of a
common compound or intradermal nae-vus when composed of small melanoma
cells, or with Spitz naevus when com-posed of medium-sized to large
melanoma cells. These lesions are
defined not as atypical naevi but as
melanomas because they involve the
dermis and have the potential for metas-tasis.
ICD-O code 8720/3
Synonym
The term minimal deviation melanoma
has been used for some examples.
Epidemiology
Naevoid melanoma is uncommon, being
estimated to be approximately 1–2% or
less of melanomas {2096,2255}. Due to
the low incidence, the small size of series
of studies of these tumours, and the
slightly different definitions of the lesion,
the demographic profiles are not well-established. Naevoid melanomas can
occur at any age but often are in young
to middle-aged adults. Both men and
women are affected, but there is a slight
female predominance, perhaps due to
early detection in women. In combining
data from three similar studies with a total
of 65 patients, the distribution of lesions
was mostly on the trunk and proximal
extremities, specifically on the leg
(38.5%), trunk (26.1%), arm (18.5%),
head (12.3%), and neck (4.6%) {261,
262,1563,2092,2596}.
Clinical features
The lesions are generally small papular,
nodular, or verrucous, with tan to dark
brown colour. The colour may be uniform
or irregular. The borders of the lesion are
sharp and not very irregular. The lesions
often are approximately 5-10 mm in
diameter {568}. Clinically apparent
inflammation is uncommon. The patient
may report that there was a pre-existing
macular pigmentation, which became a
papule. The lesions are soft and non-ten-der. They are usually solitary lesions that
often are removed because of recent
growth or for cosmetic purposes.
Etiology
Unknown. The tumour may arise in clini-cally normal skin, or in a pre-existing
naevus that maintains a naevus pattern
of differentiation, or in a lentigo.
Histopathology
The microscopic features of naevoid
melanoma are at present restricted by an
arbitrary definition to lesions that do not
have much intraepidermal spread of
tumour cells (pagetoid upward migra-tion) and have a relatively symmetrical
profile at low magnification.
There is sharp lateral demarcation of the
lesion. Usually there are areas of sheet-like confluent melanocytic proliferation in
the dermis. Some lesions have only large
nests of cells in the dermis, often larger
in the deep portion of the lesion when
compared to the upper portion. Mitotic
B CA
Fig. 2.34  Naevoid melanoma. A Naevoid melanoma, papular lesion.  (A) At low magnification, note the lack of maturation and the lack of good naevus nest forma-tion in the dermis.   B Naevoid melanoma, papular lesion.  (B) At intermediate magnification, many of the cells are hyperchromatic and atypical.   C Naevoid
melanoma, papular lesion. Perivascular infiltration is at the base of the lesion.
Table 2.06
Sex and ages in series of patients with naevoid melanomas.
Reference  Number of subjects  M/F Ratio  Mean Age
Females Males
McNutt {1563}  5/16  11/16  2.2  M 47 (26-75); F 45 (44-57)
Schmoeckel {2092}  25/33  8/33  0.32  M 43 (22-52); F 49 (16-76)
Zembowicz {2596}  10/20  10/20  1  M 41 (19-61); F 44 (26-81)
Blessing 2000 {262}  10/14  4/14  0.4  48.6 (30-77) (small cell MM)
Blessing 1993 {261}  M>F   57 (verrucous MM)
N.S. McNutt
S. Kossard
.
Naevoid melanoma
87Naevoid melanoma
figures can be found in the dermis in
most lesions and often multiple mitoses
are noted. However, small lesions may
have very few mitoses. Naevoid
melanomas can occupy a portion of a
pre-existing intradermal or compound
naevus. The melanomas have a relative-ly uniform population of small cells with
hyperchromatic angulated nuclei or a
population of medium-sized to large
melanoma cells with more open nuclear
chromatin and pale cytoplasm.
Inflammatory reaction usually is slight
and may be absent. The lesions often are
dome-shaped, polypoid, or verrucous in
profile {261,568,1562,1563,2092,2543,
2596}.
Immunoprofile and other special stains
HMB-45 reactivity is variable and may be
negative or positive {265,1562,1563}.
When positive, aberrant patterns of reac-tivity are common. HMB-45 reactivity
may be uniform throughout the dermal
portion of the lesion even though there is
no junctional component. This reactivity
pattern can also be found in blue naevi,
some Spitz naevi, and in so-called deep
penetrating naevi, and combined naevi
{1563,2198}. HMB-45 antibody reacts
with the premelanosomal glycoprotein,
gp100, and indicates an immature status
of the cell with regard to melanin produc-tion. A103 antibody, which binds to the
antigen Melan-A, reacts with the
melanocytic cells throughout the lesion
{265}.
The reactivity of the tumour cells with the
antibody MIB-1 to detect the protein Ki-67 in cycling cells is positive in both the
upper and lower portions of the tumour.
In some lesions, the reactivity is slight but
greater in the deep portion than in the
superficial portion of the lesion. Under
controlled conditions, antibodies to
detect proliferating cell nuclear antigen
(PCNA) have been used to grade
melanomas {1160,1934}. In specimens
with varied fixation conditions, PCNA has
not been found to be reliable because it
is sensitive to underfixation and to over-fixation in formalin {1563}. Silver staining
of nucleolar organizing regions
(AgNORs) in 10 small cell melanomas
showed an average number of 5.83
(SD+/- 1.69) AgNORs per nucleus. This
provided some separation from benign
small dermal naevus cells, which had an
average of 2.71 (SD+/- 0.50) AgNORs
per nucleus. The comparison mean num-ber in 10 superficial spreading
melanomas was 8.49 (SD+/- 1.58)
AgNORs per nucleus {1316}.
Histogenesis
Naevoid melanomas may arise from the
dermal component of small compound or
intradermal naevi or from the junctional
component of melanocytes in normal
skin, or a pre-existing small naevus or
lentigo. It is possible that some naevoid
melanomas represent early nodular
melanomas lacking an evident junctional
component.
Prognosis and predictive factors
Predictive features of naevoid melanoma
prognosis are tumour thickness, mitotic
rate, and large cell type. From 3,500
melanomas, Schmoeckel et al. {2092}
selected naevoid melanomas with at
least 5 years of follow-up unless there
was earlier metastasis. Thirty-three
cases were selected: 18 were disease
free for at least 5 years. Fifteen had
developed metastases. Eight had died of
disseminated melanoma. The “most
Fig. 2.35  Naevoid melanoma.  A Verrucous type. Note the crowding of the cells in the dermal papillae.  B Naevoid melanoma, verrucous type.  Note the atypical
mitosis in the dermis.  C Naevoid melanoma, verrucous type. There is vascular invasion at the base of the lesion.  D Naevoid melanoma with spindle and epithelioid
cells. The diffuse dermal pattern with scattered atypical cells, without dermal maturation, shares some features with early desmoplastic melanomas.  E Naevoid
melanoma with spindle and epithelioid cells. Note the nuclear atypia.  F Naevoid melanoma with spindle and epithelioid cells. Note the lack of maturation of cells
in the base of the lesion.
FED
CBA
Table 2.07  Histological criteria for metastatic
spread of naevoid melanoma.
Metastases   Mean  Mean
thickness mitotic index
Without
(n=18) 2.24 mm 0.99/mm2
With
(n=15) 1.82 mm 2.96/mm2
88 Melanocytic tumours
important criterion was tumour thick-ness” (but mitoses also seem important
{1160}):
McNutt et al. {1562} studied 16 naevoid
melanomas and observed that 2 died of
melanoma (both large cell type), and one
was alive with metastases (10 years,
small cell type). Thirteen had wide exci-sions with no evidence of residual dis-ease or were lost to follow-up.
Zembowicz et al. {2596} selected 20
cases of naevoid melanomas from their
files. Three had died and 6 had metas-tases. There was a three-year follow-up
on 8 cases, with a mean follow-up period
of 2 years. They conclude: “Naevoid
melanoma, as currently defined in the lit-erature and in the present study, seems
to have a prognosis similar to that of clas-sical melanoma.”
Wong et al. {2543} studied 7 cases of
naevoid melanoma (two dome-shaped
and five verrucous types) and found
local recurrences in 3 and regional
metastasis in one patient after 2 years,
with a follow-up of 5 months to 5 years.
Lohmann et al. {1444} studied 10
patients with diagnostically controversial
lesions who underwent sentinel node
biopsy. The differential diagnosis was
between Spitz naevus and melanoma. In
5 of the 10 patients, there were sentinel
node deposits of tumour in the parenchy-ma. All patients were alive and free of
disease on follow-up of 10 to 54 months.
Variants and differential
diagnosis
Minimal deviation melanoma
In the writings of Dr Richard Reed et al.
{1911}, this category was analogous to
the minimal deviation hepatomas of
experimental liver carcinogenesis, which
were thought to deviate from the normal
cells by only a single enzyme defect, and
greatly resembled normal hepatocytes.
Initially the minimal-deviation melanomas
were characterized as having small cells,
without much cytologic atypia, but they
all had the architectural patterns of other
melanomas. As this concept evolved,
minimal deviation melanomas were divid-ed into the following types: blue naevus
type, Spitz naevus type, halo naevus
type, borderline melanoma, as well as
the ordinary minimal deviation
melanomas. This created considerable
confusion, particularly since the name
“minimal deviation” implies a better prog-nosis, which has not been a consistent
finding {2255}. Naevoid melanoma as
defined here was mixed into the various
types of minimal deviation melanoma
and was not recognized as a separate
category {1911}. The concept of minimal
deviation melanoma has become so
vague that the recommendation has
been made to stop use of that term.
However, there are attempts to clarify the
definition of minimal deviation melanoma
as distinct from naevoid melanoma
{568}.
Small cell melanoma
Melanomas composed of small cells
have been studied separately by
Kossard and Wilkinson in 1997 {1317}.
While some of them are naevoid
melanomas, many have the architectural
patterns of ordinary superficial spread-ing melanomas, lentigo maligna
melanomas, and acral-lentiginous
melanomas. In contrast, naevoid
melanomas closely resemble a benign
compound or intradermal naevus in
architecture. They are all included in the
original concept of minimal deviation
melanoma. Confusion in terminology
arises between small cell melanoma and
what we define as naevoid melanoma.
This confusion is due to the use of the
terms “small naevoid cell type” in small
cell melanomas, just on the basis of cell
size and without restrictions on the archi-tecture of the lesion. As defined above, a
diagnosis of naevoid melanoma requires
both architectural and cytological mimic-ry of a naevus.
Recently a subtype of small-cell naevoid
melanoma has been described that
develops predominantly in elderly indi-viduals with sun-damaged skin {1313}.
This variant has an atypical lentiginous
junctional melanocytic proliferation with a
nested pattern that may be mistaken for
a junctional naevus. This variant has a
male predominance and the melanomas
occur predominantly on the trunk. The
epidemiology suggests that these junc-tional lesions may be precursors of lenti-go maligna or superficial spreading
DC
Fig. 2.37 Naevoid melanoma.  A The melanocytes are arranged as a sheet rather than as discrete nests.
B The aggregates of melanocytes do not disperse very much at the base of the lesion, where there is a
dense lymphocytic infiltrate.  C Naevoid melanoma  and its recurrence. Atypical spindle and epithelioid cells
are at the base of the lesion.  D Mitotic figure among small and monotonous melanocytes.
BA
Fig. 2.36 Naevoid melanoma. The lesion has a ver-rucous profile, easily mistaken for papillomatous
naevus.
89Naevoid melanoma
melanoma in situ. This type of lesion
needs further studies as to whether it
represents a melanoma sui generis or a
lesion with a high propensity to develop
further mutations leading to melanoma. It
does not fit into the current restricted def-inition of naevoid melanoma since it has
a prominent junctional component and
does not involve the dermis in the early
stages.
Deep penetrating naevus
This type of naevus has a plexiform
growth pattern in the dermis, and despite
its name “deep penetrating” most of the
lesions are restricted to the upper and
middle reticular dermis, giving rise to the
concept of the “superficial form of deep
penetrating naevus” {2127}. The naevus
cells form cords in the dermis composed
of large spindled and epithelioid cells
resembling a combination of the cells in
a blue naevus with cells in a Spitz nae-vus. Mitotic figures are very rare and are
not atypical. They do not have much of
an epidermal component unless the
deep penetrating naevus component is
part of a combined naevus. They must
be distinguished from naevoid
melanoma, large cell type, which has
mitoses in the dermis. However, some
lesions given a diagnosis of deep pene-trating naevus (with mitoses) have
metastasized and may represent exam-ples of naevoid melanomas.
Spitzoid melanoma
This designation is used primarily for
melanomas that mimic a Spitz naevus.
The presence of a significant junctional
component and prominent pagetoid
upward migration of large atypical
melanocytes distinguish this tumour from
a naevoid melanoma. If the Spitzoid
melanoma is almost entirely intradermal,
it is a variant that would fit into the defini-tion of naevoid melanoma, large cell
type.
Metastasizing Spitz naevus
A small number of lesions given the initial
diagnosis of Spitz naevi have led to
metastases and even the death of
patients. Some cases have had only a
single lymph node metastasis removed
without further evidence of disease on
short-term follow-up. The cases with only
a single nodal metastasis have been
called metastasizing Spitz naevi. Some
of these lesions fit the restricted definition
of naevoid melanomas if they do not
have a significant junctional component.
Anecdotal reports indicate that some
cases classified as metastasizing Spitz
naevus by one institution go to another
institution years later with widespread
metastases leading to death. The criteria
to distinguish between Spitzoid
melanoma, melanoma arising in a Spitz
naevus, Spitzoid variant of naevoid
melanoma, and metastasizing Spitz nae-vus are controversial and require further
investigation. Examination of sentinel
lymph nodes in controversial cases of
Spitzoid tumours has found a significant
number of nodal implants of tumour
{1444}.
Proliferative nodules in a congenital
naevus
Benign proliferative nodules may arise in
the dermis in congenital naevi in some
very young patients and may be multiple.
Distinction from naevoid melanoma may
be difficult since mitotic figures are pres-ent in the dermal nodules of naevus
cells. Features of benign proliferative
nodules that have been emphasized are
multiplicity of nodules of similar sizes and
appearances, and a gradual blending of
the cells of the nodule with the surround-ing background congenital naevus cells
at the periphery of the nodules. Sharp
demarcation of the proliferative nodules
is more common in naevoid melanomas
arising in the dermal component of a
congenital naevus {568}.
Melanoma arising in the dermal
component of a large or “giant”
congenital naevus
In studies of melanomas arising in giant
congenital naevi, many arose from the
dermal component {254,1912,1928}. A
significant proportion of such
melanomas are composed of small,
hyperchromatic atypical cells and were
interpreted to be similar to melanoblasts,
leading to diagnosis of melanoblastoma.
These lesions were highly malignant.
They are a variant that fits the current
definition of naevoid melanoma since
they lack an epidermal component and
are composed of small epithelioid cells.
Early nodular melanoma
It is most likely that some naevoid
melanomas are an early stage in the evo-lution of nodular melanomas.
Desmoplastic/neurotropic melanoma
Although some of these lesions could fit
into the definition of naevoid melanoma,
it is conventional to separate them as a
distinct entity. Desmoplastic melanomas
generally have spindle-shaped cells and
naevoid melanomas, as defined here,
generally have more epithelioid cells.
Both tumours can present as predomi-nantly dermal lesions. Desmoplastic
melanomas can resemble desmoplastic
naevi, especially hypopigmented blue
naevi. Desmoplastic and neurotropic
melanomas are best separated from
naevoid melanomas since they can be
recognized as a distinct group of
tumours that has been characterized suf-ficiently for diagnosis.
Metastatic melanoma
The histologic features of naevoid
melanoma can be exactly reproduced in
satellite metastatic papules and nodules
of melanoma in the skin. The lack of an
intraepidermal component, confluent
growth patterns, sharp circumscription,
symmetry, and dermal mitotic figures can
all be found in metastatic melanoma. A
diagnosis of naevoid melanoma should
be made with great caution in an individ-ual with a known history of melanoma.
Misdiagnosis of primary naevoid
melanoma as metastatic melanoma can
lead to the clinical impression of a
metastatic melanoma for which a primary
lesion is never found. On the other hand,
individuals given a diagnosis of naevoid
melanoma, who subsequently rapidly
develop extensive metastases, may
actually represent patients with a
metastatic lesion that resembled a pri-mary naevoid melanoma. Multiplicity of
lesions resembling naevoid melanomas
simultaneously in the same patient points
toward metastatic disease. However mul-tiple naevoid melanomas have been
reported in an immunodeficient patient
{1804}.
90 Melanocytic tumours
Definition
Persistent melanoma is defined as the
persistent growth of residual, incom-pletely excised primary malignant
melanoma, of either the epidermal or the
invasive component, or both. It repre-sents one form of “local recurrence” of
melanoma, the other being local metas-tasis {30,1001}.
Synonym
Local recurrence of melanoma.
Epidemiology
The epidemiological characteristics are
those of the original primary melanoma.
Etiology
The etiological factors are those of the
primary melanoma.
Localization
Persistent melanoma may follow removal
of melanoma from any site of the body
although it seems more common on the
head and neck, probably due to the
higher incidence of poorly defined vari-ants of melanoma in this site. These
include lentigo maligna, in particular the
amelanotic variant, and desmoplastic
melanoma which is particularly suscepti-ble to incomplete excision because of its
poorly defined borders.
Clinical features
The most common clinical presentation
is the persistence or recurrence of a flat,
P.J. Heenan
J.C. Maize
M.G. Cook
P.E. LeBoit
Persistent melanoma and local
metastasis of melanoma
Table 2.08
Histological features of persistent melanoma and local metastases of melanoma.
Persistent melanoma Metastatic melanoma
Epidermal component Usually present, with or without a dermal component A. Absent in most cases.
. B. Epidermotropism uncommonly. The dermal component
usually extends beyond a zone of epidermotropism when
present. Sometimes the epidermotropic component is more
extensive, simulating primary melanoma {998}.
Dermal growth pattern The full range of patterns associated with  A. Single or multiple symmetrical dermal and/or
primary melanoma. subcutaneous nodules.
B. Diffuse small groups and strands of neoplastic
melanocytes (this pattern occurs in the smallest and
presumably earliest metastases).
Inflammation  Lymphocytic inflammation usually present.  Absent or sparse.
Vascular invasion  Sometimes present.  Present in many cases.
Mitotic rate  Variable  High (usually > than 6/mm2)
Cell type The full range of cell types seen in primary melanoma,  Usually monomorphic atypical melanocytic population of
frequently including a mixture of cell types.  epithelioid, spindle or small (naevoid) cells.
Associated naevus   Commonly present.  Rare (coincidental).
Necrosis  Uncommon  Often present in the centres of the nodules.
Epidermal collarette  Uncommon  Usually present, when nodules of metastatic melanoma are in
the superficial dermis.
Fibrosis  Frequently present in zones of regression and in  Little or no reactive fibrosis in the stroma of the tumour.
desmoplasia.
Scarring  Present in the dermis and often also in the subcutis.  Present when the metastasis occurs at the primary
excision site.
NOTE: 1. In cases of persistent melanoma, histological review of the primary excision confirms the presence of in-situ or invasive melanoma (or both) at a margin of excision.
2. The microscopic features of metastatic melanoma involving the scar of the primary excision are the same as those of metastatic melanoma at a site distant from the
scar, with the additional feature of the scar at the site of the completely excised primary melanoma {2573}.
91Persistent melanoma
variably pigmented patch adjacent to or
surrounding the scar of the primary exci-sion site. In some cases there may also
be nodule formation when there is per-sistent dermal invasion, especially of
desmoplastic melanoma.
Macroscopy
The lesion frequently is a variably pig-mented, often pale macule with poorly
defined borders. In many cases of per-sistent desmoplastic melanoma there is
no abnormal pigmentation in the epider-mis overlying a firm nodule.
Histopathology
In the uncommon event of incomplete
excision of both the epidermal and inva-sive components of one of the common
forms of cutaneous melanoma, the histo-logic appearances are those of the origi-nal tumour, frequently with pagetoid infil-tration of the epidermis overlying inva-sive atypical epithelioid melanocytes,
usually with little or no pigmentation,
forming an expansile growth pattern
adjacent to a zone of scarring. More
commonly, the persistent lesion consists
of in-situ melanoma with or without focal
dermal invasion. Persistence of incom-pletely excised desmoplastic melanoma
may present only sparse, subtle infiltra-tion of a sclerotic nodule in the dermis
and/or subcutis, containing atypical
spindle cells with hyperchromatic, vari-ably pleomorphic nuclei and sometimes
only sparse mitoses, distributed singly
and in strands between the collagen
bundles. As in the primary tumour, a
patchy lymphocytic infiltrate may provide
a clue to perineural invasion. Desmo-plastic melanoma may very closely simu-late a surgical scar in the primary lesion
and can be very poorly circumscribed
{1194}. However it can be distinguished
by its infiltrative pattern beyond the zone
usually expected to be involved with scarring following surgery. The features
of persistent desmoplastic/neurotropic
melanoma may be seen proximal or dis-tal to the scar at the primary excision site,
along the line of nerves.
In assessing locally recurrent melanoma
it should always be remembered that
melanoma metastases may be epider-motropic and simulate primary
melanoma {998}.
Differential diagnosis
Rarely, pigmentation of the epidermis or
growth of a nodule at the site of previous
excision of melanoma may be due to the
coincidental growth of an entirely new
and distinct tumour such as dermatofi-broma or pigmented basal cell carcino-ma. The most important differential diag-nosis, however, lies between true persist-ence of incompletely excised primary
melanoma and the other form of “local
recurrence” due to metastatic mela-noma. Metastatic melanoma in or adja-cent to the primary excision scar usually
presents as a rapidly growing papule or
nodule without pigmentation of the over-lying dermis, sometimes associated with
Fig. 2.38 Local melanoma metastasis. So-called
“local recurrence” of melanoma in the scar at the
excision site of a primary melanoma completely
excised with a margin of 25mm.
Fig. 2.39 Persistent melanoma.   A Melanoma in-situ at the lateral margin of the excision of a primary
melanoma.  B “Local recurrence”, at the excision site two years later, showing invasive melanoma, exten-sive adjacent melanoma in-situ and dermal scarring.
92 Melanocytic tumours
multiple similar, rapidly growing lesions
separate from the primary excision site.
Histologically, metastases involving the
scar present exactly the same features
as cutaneous metastases at a distance
from the scar {2573}
Histogenesis
Persistent melanoma occurs because a
primary melanoma was incompletely
excised. The histogenesis, therefore, is
essentially that of the original melanoma.
Somatic genetics
The genetic factors are those that apply
to the original melanoma.
Prognosis and predictive factors
The prognosis for persistent melanoma is
assessed in the same manner as for the
original tumour, tumour thickness still
being the most important single factor,
unlike local recurrence due to metastasis
which is a manifestation of systemic
metastasis and portends a poor progno-sis.
DC
Fig. 2.40  Metastatic melanoma.  A In this epidermotropic metastatic melanoma, a papule has formed large-ly due to the irregular epidermal hyperplasia.  B On the left side of the lesion, one can see sharp circum-scription, contributing to resemblance to a Spitz naevus.  C Metastatic melanoma simulating blue naevus.
D Irregular nests of melanoma cells are visible at the base of the lesion in the subcutis.
BA
93Congenital melanocytic naevi
Superficial type
Definition
Congenital melanocytic naevi (CMN) of
the superficial type are melanocytic pro-liferations present at birth. The term con-genital has been also applied to lesions
displaying clinical and histopathological
features of congenital melanocytic naevi
which may not be apparent at birth.
These lesions are designated as tardive
congenital melanocytic naevi.
ICD-O code 8761/0
Synonyms
Congenital pattern-like naevus; tardive
congenital naevus; congenital naevus-like naevus.
Clinical features
Congenital melanocytic naevi – superfi-cial type are frequently observed. They
can be found on any anatomic site and
belong to the group of small congenital
naevi with a diameter smaller than 1,5
cm.
On gross examination they vary from
macules and papules to plaques and
reveal different colours from light brown
to black. The lesions are usually round or
oval with a smooth or papillated surface.
They may be hairy or hairless.
Histopathology
In the superficial type of CMN, dense dif-fuse infiltrates of small monomorphous
melano-cytes are found in the upper part
of the dermis and the mid-portion of the
reticular dermis. The melanocytes are
frequently arranged in a band-like pat-tern and are disposed in single files
between collagen bundles (“splaying of
melanocytes“).
An important criterion for diagnosis is the
presence of melanocytes along epithelial
structures of adnexa and their angiocen-tric distribution. They may be found with-in sebaceous glands, vessels, nerves
and in smooth muscles {1168,1531}. In
the compound type of a congenital nae-vus – superficial type, nests of melano-cytes are present in the epidermis, most-ly at the dermo-epidermal junction.
Melanomas are very rare in newborn and
young infants (see chapter on childhood
melanoma). Congenital melanocytic
naevi, biopsied shortly after birth or in the
first years of life can display atypical
intraepidermal changes (pagetoid
melanocytes arranged as solitary units
and nests; single cells present in the
upper layers of the epidermis) similar to
those of melanoma in situ {1514}. This
finding is more commonly found in giant
congenital naevi than in small ones.
The clues for diagnosis of this unusual
change in a benign naevus are found in
the dermis where the large, pale
melanocytes merge with smaller ones
that have the characteristic features of a
congenital melanocytic naevus.
Somatic genetics
Like the majority of melanocytic naevi
except Spitz and blue naevi, congenital
melanocytic naevi have frequent BRAF
mutations and show no chromosomal
aberrations {173,1850}.
Prognosis and predictive factors
Recent studies revealed in a significant
number of malignant melanomas an
association with melanocytic naevi with a
congenital histopathologic pattern
{159,1245}. However, the pathogenetic
role of small congenital melanocytic
naevi as precursor lesions of melanoma
is controversial {1508, 2323}. Clinical fol-low-up of 3922 patients with small CMN
found no significant risk of melanoma
development {205}.
Proliferative nodules in
congenital melanocytic naevi
Definition
Proliferative nodules in congenital
melanocytic naevi are defined as atypi-cal melanocytic proliferations which
manifest predominantly in the neonatal
period within a pre-existing large (deep)
congenital melanocytic naevus.
ICD-O code 8762/1
Synonyms
Atypical proliferative nodules in giant
H. Kerl
D. Massi
P.E. LeBoit
B.C. Bastian
Congenital melanocytic naevus
B CA
Fig. 2.41  Congenital melanocytic naevus, superficial type. A Papule with brown to black colors and a mamillated surface.  B Band-like infiltrate of melanocytes in
the upper dermis. Adnexocentric arragement and “splaying” of melanocytes between bundles of collagen in the upper and mid-portion of the reticular dermis.
C Monomorphous melanocytes around and focally within an arrector pili muscle.
congenital naevi; dermal variant of mini-mal deviation melanoma in a giant con-genital naevus {1907}, dermal melano-cytic tumour of uncertain potential in a
giant congenital naevus.
Clinical features
There is usually a dark brown to black
plaque or nodule above a giant congen-ital melanocytic naevus. The lesions may
become lighter and show regression
after years. Occasionally a palpable
mass can be found deeply in the skin.
These nodular proliferations in congenital
melanocytic naevi behave in a benign
fashion.
Histopathology
The background congenital melanocytic
naevus reveals the characteristic fea-tures of a congenital melanocytic naevus
of the deep type. A dense diffuse infil-trate of small melanocytes involving the
entire dermis and often extending into
the septa of the subcutaneous fat can be
observed.
The “proliferative“ nodule, which is usual-ly found in the upper and mid dermis
consists of roundish epithelioid or spin-dled melanocytes. The cells are large
and appear to blend with the surround-ing smaller melanocytes (naevus cells).
Atypical nuclei and mitotic figures can be
observed.
Differential diagnosis
Proliferative nodules in congenital
melanocytic naevi can be misinterpreted
as a melanoma that developed in the
intradermal component of a congenital
naevus (see Melanoma arising in giant
congenital naevi) {1009}.
Somatic genetics
In a study of proliferative nodules using
comparative genomic hybridization
seven out of nine cases showed chromo-somal aberrations {175}. Six of the seven
cases with aberrations (86%) showed
numerical aberrations of whole chromo-somes exclusively. This pattern differs
significantly from the findings in
melanomas arising in congenital naevi or
melanoma in general in which the major-ity (96%) have aberrations involving only
partial chromosomes {173}. Loss of chro-mosome 7 was seen in three of the nine
proliferative nodules. Loss of chromo-some 7 was not observed in 132
melanomas that were not associated with
giant congenital naevi {173}. However,
one melanoma arising in a congenital
naevus in an eight-year-old boy showed
a similar loss of chromosome 7.
94 Melanocytic tumours
Fig. 2.42 Proliferative nodule in a large congenital
melanocytic naevus (garment type). A black plaque
above the sacrum representing the proliferative
nodule is recognizable.
Fig. 2.43 Proliferative nodule in a congenital melanocytic naevus. The congenital melanocytic naevus, with
small naevoid cells can be recognized on the left side of the picture. Melanophages are distributed in a uni-form fashion in the upper dermis. The profilerative nodule reveals cellularity with relatively monomorphous
large cells with prominent nucleoli.
A
Common blue naevus
Definition
Common blue naevus (BN) is a benign,
usually intradermal melanocytic lesion
characterized by pigmented dendritic
spindle-shaped melanocytes and, more
rarely, epithelioid melanocytes. The
melanocytes are usually separated by
thickened collagen bundles.
ICD-O code 8780/0
Epidemiology
BN is relatively frequent, has predilection
for females and presents mainly in young
adults between the second and fourth
decades. Although most tumours are
acquired, congenital examples have
been documented {1872}. Familial cases
may be seen and usually present with
multiple lesions {258,1292}.
Localization
The anatomical distribution is wide but
most lesions occur on the distal upper
limbs (particularly the dorsum of the
hand), followed by the lower limbs,
scalp, face and buttocks. Lesions have
also been documented in the vagina
{1002,2356}, cervix {2393}, prostate
{1414}, oral cavity (mainly the hard
palate) {327,328} and the capsule of
lymph nodes without a primary cuta-neous lesion {695,858,1497}.
Clinical features
The most common presentation consists
of a single asymptomatic, relatively well-circumscribed, dome-shaped blue or
blue-black papule less than 1 cm in
diameter. The characteristic blue colour
is produced by the Tyndall effect.
Tumours may rarely present as a plaque
{1025,2494}. Eruptive lesions have rarely
been documented. Exceptional clinical
presentations include a speckled variant
{1044}, hypopigmented lesions {278}, an
example with satellite lesions {1195} and
a case with widespread lesions.
Localized hypertrichosis has been
described in a single case {57}.
Histopathology
BN and cellular blue naevus show a wide
histological spectrum, frequently over-lapping with other melanocytic lesions
including deep penetrating naevus and
pigmented Spitz naevus {1637}.
BN is typically located in the reticular
dermis and only exceptionally extends
into the papillary dermis or subcutis. The
epidermis appears unremarkable,
except in the rare so-called compound
blue naevus, in which dendritic junction-al melanocytes are identified {733,
1190}. Low power examination reveals a
generally symmetric but often ill-defined
tumour of variable cellularity. Concen-tration around adnexa without adnexal
destruction is typical. Poorly cellular
lesions often display prominent sclerotic
stroma making the diagnosis difficult.
Lesions with very poor pigmentation are
rarely encountered {234,402}. Tumour
cells are bland and spindle-shaped or
dendritic and usually contain abundant
cytoplasmic coarse melanin pigment.
Nuclei are small, and an inconspicuous
basophilic nucleolus is sometimes pres-ent. Numerous melanophages are a rela-tively constant feature in the vicinity of
tumour cells. Extension of tumour cells
into nerves and, less frequently, blood
vessel walls, may be found. Mitotic fig-ures are exceptional. Rarely, a blue nae-vus may coexist with a trichoepithelioma
{48}.
In some instances, metastatic melanoma
may mimic common blue naevus {354}.
Blue naevus may co-exists with other
types of naevus (see combined naevus).
Immunoprofile
Tumour cells are usually diffusely positive
for melanocytic markers including S-100,
HMB45, melan A and microphthalmia
transcription factor (MITF-1). Unlike the
case in most other benign melanocytic
naevi and in melanomas, HMB45 strong-ly stains the entire lesion in blue naevi.
Somatic genetics
Mutations in the BRAF gene appear to be
rare in BN. Chromosomal aberrations are
uncommon {1490}.
95Blue naevi
E. Calonje
K. Blessing
E. Glusac
G. Strutton
Blue naevi
CA
Fig. 2.44 Common blue naevus.  A Typical clinical appearance of a common blue naevus.  B A more cellular example with hyalinization of dermal collagen.
C Melanocytes often extend into the perineurium of dermal nerves.
B
Prognosis and predictive factors
BN is benign, and malignant transforma-tion is exceptional {883} (see chapter
Melanoma arising from blue naevus).
Simple excision is curative and local
recurrence is very rare {973}.
Mongolian spot
Definition
Mongolian spot (MS) is a form of dermal
melanocytosis presenting on the lower
back and characterized by scattered
pigmented dendritic melanocytes in the
reticular dermis.
Epidemiology
MS presents at birth and has marked
predilection for Black and Oriental
patients with the same sex incidence
{1260,1261}. The incidence in Caucasian
children is approximately 9.5% {543}.
Localization
Most lesions occur on the lower posterior
trunk with predilection for the sacro-gluteal region. Lesions identical to MS
and naevus of Ito or naevus of Ota may
present rarely in other anatomical sites.
Clinical features
MS is characterized by a macular area of
blue-green or blue-grey discolouration
varying in size from a few to 10 or more
cm. Lesions fade gradually, usually dis-appearing completely when patients
reach adolescence.
Association with cleft lip {1096} and the
mucopolysaccharidoses, including Hur-ler and Hunter syndromes) {880, 2063}
has been documented. Lesions with the
clinical and histological features of MS
may rarely present at other body sites.
Histopathology
The epidermis and superficial dermis
appear unremarkable. Low power exam-ination reveals a mild increase in cellular-ity in the deep reticular dermis, consist-ing of few variably pigmented dendritic
melanocytes, which are usually, oriented
parallel to the epidermis. Melanophages
are occasionally seen.
Naevus of Ito and
Naevus of Ota
Definition
Naevus of Ito (NI) and naevus of Ota
(NO) are dermal melanocytoses with
identical histological features, which dif-fer in their characteristic clinical presen-tation. NI typically presents in the shoul-der region, following the distribution of
the lateral brachial and posterior supra-clavicular nerves. NO involves the skin
and mucosal surfaces (including the
conjunctiva), following the distribution of
the ophthalmic and maxillary branches of
the trigeminal nerve.
Synonyms
Naevus Ota: Oculodermal melanocyto-sis, Naevus fuscoceruleus ophthalmo-maxillaris.
Epidemiology
Both NI and NO are relatively rare, affect
mainly patients of Oriental or African ori-gin and have some predilection for
females {1027,1307,1626,2243}. Presen-tation is mainly at birth (up to 50%) or
during childhood and adolescence.
Adult onset is very rare {447}.
Localization
NI typically involves the supraclavicular,
deltoid and less commonly, the scapular
area. NO usually involves the sclera,
conjunctiva, and skin around the eye and
zygomatic and temporal areas. Rarely
the nasal and oral mucosa, optic tract
and the leptomeninges are involved.
Lesions identical to naevus of Ito or nae-vus of Ota may present rarely in other
anatomical sites. A limited form resem-bling naevus of Ota presenting in the
zygomatic area is called naevus of Sun.
Clinical features
Lesions are usually large, macular, ill
defined and have a blue or blue-grey
colour. A speckled appearance is seen
rarely. There is no tendency for sponta-neous regression. Bilateral involvement
has been documented rarely {1026}. Co-existence between NI and NO is a rare
occurrence {615,1026}. Glaucoma is a
rare complication of NO {1434}.
Histopathology
The histology of NI and NO is indistin-guishable. The epidermis appears unre-markable but may show increased
melanin in basal cells and a mild
increase in the number of basal melano-cytes. In the superficial and mid-dermis
there are scattered dendritic or spindle-shaped, often bipolar deeply pigmented
melanocytes. Melanophages are rare.
Prognosis and predictive factors
Malignant transformation is exceptional
and more common in NO {1783,2194,
2345,2414}. In the latter setting it may
occur in the skin, eye or meninges.
Cellular blue naevus
Definition
Cellular blue naevus (CBN) is an
acquired dermal/subcutaneous pigment-ed tumour with prominent cellularity and
an expansile growth pattern.
ICD-O code 8790/0
96 Melanocytic tumours
CA
Fig. 2.45 A Mongolian spot. Typical prominent macular blue/grey discolouration on lower back and buttocks.  B Naevus of Ota with involvement of the periorbital
skin and conjunctiva. The blue cast is typical.  C Naevus of Ota. Bipolar, deeply pigmented melanocytes in the reticular dermis.
B
Epidemiology
CBN tends to present between the sec-ond and fourth decades of life with
female predilection, and it is more com-mon in Caucasians. Congenital cases
are exceptional {1095}.
Localization
The anatomical distribution is wide, but
CBN have predilection for the buttocks
and sacral region (50% of cases), fol-lowed by the scalp, face, distal limbs and
other sites on the trunk {1957,2336}.
Lesions may also rarely occur on the
eyes, cervix, vagina, breast and sper-matic cord {266,1957,2336}. Aggregates
of tumour cells have been reported in the
capsules of regional lymph nodes drain-ing an area where an otherwise typical
benign cellular blue naevus is present
{287,1957,2261,2336}. This phenome-non is regarded as a benign occurrence
rather than an ominous finding.
Clinical features
Tumours are usually large, varying from 1
to several centimetres, and the colour
varies from light blue-brown to dark blue.
Lesions are asymptomatic and grow very
slowly, presenting as a non-ulcerated
firm nodule {1957,2336}. Exceptional
cases present as a large plaque {358}.
Rare tumours arising in the scalp have
been described with invasion of the
underlying bone {1596} and even the
brain {854}.
The epithelioid variant of blue naevus is
very rare and has mainly been described
in patients with Carney complex who
usually present with multiple lesions
{396,399}. Sporadic lesions are usually
solitary and may occur in genital skin
{1117,1646,1736}.
Macroscopy
The cut surface of a CBN characteristi-cally shows a dark brown to black, well-defined dermal and subcutaneous
tumour. In some cases there are areas of
haemorrhage and cystic degeneration.
Histopathology
Low-power examination reveals a fairly
characteristic picture with a dumbbell-shaped multinodular tumour occupying
the reticular dermis and often extending
into subcutaneous tissue. A junctional
component is not usually found. Areas of
pigmentation alternate with poorly pig-mented areas and, in a minority of cases,
pigment is very scanty {2595}. Cellular
areas tend to be more prominent towards
the centre of the tumour, and the cellular-ity may be most marked where the neo-plasm protrudes into the subcutis. The
cellular areas may alternate with sclerot-ic or hypocellular areas. In most cases
there are focal areas representing or sim-ulating a common blue naevus. High
power examination reveals bundles of
oval or spindle-shaped cells with pale
cytoplasm, alternating with bundles of
deeply pigmented spindle-shaped cells.
In addition, dendritic melanocytes and/or
round, somewhat epithelioid melano-cytes may be seen. Cytoplasmic melanin
is coarse and granular, and nuclei are
regular and vesicular, with a single small
inconspicuous basophilic nucleolus.
Maturation with depth is not a feature. A
frequent finding however, is the focal
presence of elongated slender melano-cytes resembling Schwann cells, indica-tive of neurotization as seen in ordinary
naevi. Some tumours exhibit a focal alve-olar growth pattern {1597} and desmo-plasia is occasionally prominent {1599}.
Degenerative changes including haem-orrhage, cystic change and fibrosis, are
seen in some cases. Focal mild or promi-nent myxoid oedematous change may
also be a feature {1598}, and balloon cell
change has been documented {1806}.
Occasional cases display a number of
unusual features including mitotic figures
(1/10 HPFs), focal necrosis, and/or
nuclear pleomorphism or hyperchroma-tism. Such cases show some overlap
with the malignant variant of CBN and
have been described as atypical CBN
{118,2371}.
The epithelioid blue naevus is composed
of large round epithelioid and short spin-dle-shaped deeply pigmented melano-97Blue naevi
Fig. 2.46 Cellular blue naevi on the upper back.
Fig. 2.47  Cellular blue naevus.  A Typical low-power appearance with a dumb-bell architecture.  B Bundles of bland spindle-shaped melanocytes alternating with
focally pigmented cells. Scattered melanophages are also seen.  C Typical small vesicular nuclei with a small basophilic nucleolus.
BA C
cytes. Some examples of this variant of
BN probably represent combined naevi
{903}.
Immunoprofile
Tumour cells in CBN are positive for S-100, melan-A and HMB45. In tumours
with prominent desmoplasia, and in
those with neurotization, staining for
melan-A and HMB45 tends to be patchy.
CD34 has been reported to be positive in
tumour cells in a group of congenital
CBN {2204}.
Genetics
Similar to other naevi, cellular blue naevi
do not show chromosomal aberrations
when analysed by CGH. In a small series
of atypical cellular blue naevi, three out
of eight cases showed single chromoso-mal losses with chromosome 3p being
affected in two of these cases {1490}.
Prognosis and predictive factors
Although limited case series have char-acterized these lesions as benign, some
cases with atypical features have result-ed in recurrences or death from systemic
metastasis. They may therefore be
regarded as having uncertain malignant
potential and treated with complete exci-sion if possible and perhaps long term
follow-up. Malignant transformation in
CBN is very rare {64,883}.
Deep penetrating naevus
Definition
Deep penetrating naevus (DPN) is a dis-tinctive deeply pigmented lesion show-ing overlapping features with blue nae-vus and Spitz naevus.
Synonym
Some cases have been described under
the heading of plexiform spindle cell
naevus {164}.
Epidemiology
DPN is an acquired lesion presenting
mainly between the second and third
decades of life with no sex predilection
{1953,2127}.
Localization
DPN has a wide anatomical distribution
with predilection for the face, upper trunk
and proximal limbs {164,537,1575,1953,
2127}.
Clinical features
The tumour presents as a solitary, well-circumscribed blue or dark brown/black
dome-shaped papule or nodule usually
less than 1 cm in diameter.
Histopathology
Low power examination typically reveals
a compound wedge-shaped deeply pig-mented dermal and, very rarely, superfi-cial subcutaneous tumour. The base of
the lesion parallels the epidermis. The
junctional component, which is usually
present and may be subtle, consists of
small round nests of ordinary naevus
cells. In fact, in most cases, a superficial
dermal component, representing an ordi-nary naevus, may be found and therefore
these lesions may be regarded as com-bined naevi {1953}. Much less common-ly, focal changes mimicking a Spitz nae-vus or a blue naevus are found {1953,
2127}. Tumour cells are arranged in
nests or bundles and have a short spin-dle-shaped or, less commonly, round
morphology. The cytoplasm contains
98 Melanocytic tumours
DC
Fig. 2.48 Hypopigmented cellular blue naevus.  A In some cases, melanin is almost completely absent.
B Myxoid change may be prominent in some cases.  C One of the melanocytes is much larger  than the oth-ers. Some refer to such cases as ‘atypical cellular blue naevus’.  D Large melanocytes are present, some
are multinucleated.
BA
Fig. 2.50  Deep penetrating naevus with a typical
wedge-shaped architecture.
Fig. 2.49 Cellular blue naevus.  A This lesion has a
central focus of cystic change.  B The edge of the
cystic area.
A
B
abundant melanin and nuclei are vesicu-lar with frequent intranuclear inclusions
and a single small basophilic nucleolus.
Hyperchromatism and variation in
nuclear size may be seen, but as a rule
mitotic activity is low or absent (usually
not more than 1 per section). The
melanocytes follow the path of adnexal
structures and blood vessels and there is
frequent perineural extension. Maturation
is not seen. Some tumours have the cyto-morphology of DPN but are superficial
and lack the deep penetrating compo-nent. Similar changes are seen in a com-mon form of combined naevus.
Prognosis and predictive factors
Local recurrence is exceptional, and only
a single case has been reported spread-ing to a regional lymph node {874}.
99Blue naevi
DC
Fig. 2.51 Deep penetrating naevus.  A A wedge shape and nests of cells around adnexal structures are char-acteristic findings.  B The large pale cells in a deep penetrating naevus are arranged as discrete nests.
C A thin rim of sustentacular cells is present around the edges of many nests.  D Toward the base of the
lesion nests of pale large cells are present near adnexal structures.
BA
100 Melanocytic tumours
Definition
A combined naevus or “melanocytic nae-vus with phenotypic heterogeneity” is a
melanocytic naevus either congenital or
acquired, containing two or more distinct
melanocytic naevus components.
Synonyms and historical annotation
Melanocytic naevus with phenotypic het-erogeneity; inverted type A naevus; nae-vus with focal dermal epithelioid compo-nent, and naevi with dermal nodules.
The term combined naevus was used ini-tially to describe the combination of a
conventional naevus and blue naevus
{61,653,702,1402,2331}. However, the
spectrum of combined naevus has been
subsequently extended to include com-ponents of any type of naevus (Table
2.09){135,156,520,1610}. There may be
poor concordance in the interpretation of
some cases, because of overlapping
features and the difficulty of defining the
morphological limits of blue naevi, Spitz
naevi, deep penetrating naevi, plexiform
pigmented spindle cell naevi, and naevi
with dermal epithelioid cell components.
Epidemiology
There are no population-based data
available as to the prevalence of com-bined naevi. However they appear to
constitute less than 1% of melanocytic
naevi sampled for histopathological
examination {2116}. These naevi occur in
all age groups (3 to 83 years in a recent
study) with a mean age of 30 years
{2116}. A slight predominance of women
has been consistently reported in sever-al studies {757,1864,1961,2116}.
The developmental biology of combined
naevi has not been delineated. Their
genesis may be related to more than one
pathway of melanocytic differentiation
occurring in a single naevus. It cannot be
excluded that there is focal neoplastic
progression in some proportion of these
lesions.
Localization
Scolyer et al. found a predilection for the
trunk (chest, back, abdomen) in 35.2% of
cases, the head and neck in 23.6%,
upper extremities in 22.0%, lower
extremities in 9.9%, and perineum and
buttocks in 4.4% {2116}. Naevi with a sig-nificant blue naevus component com-monly involve the face, back, and shoul-der {757}. Naevi with prominent compo-nents of Spitz naevus often occur on the
head and neck (face) or extremities as
do conventional Spitz naevi {1961}.
Clinical features
The gross morphological features of
combined naevi are probably related to
the types of and predominant cellular
populations present, e.g., focal dermal
pigmented components, blue naevus,
Spitz naevus, etc. Most of these naevi
measure less than 5 to 6 mm in greatest
diameter {156,757,1864,2116}, are rea-sonably symmetrical, are well-circum-scribed papular or dome-shaped
lesions, and exhibit dark brown, blue to
black colouration. Thus many such naevi
are often diagnosed clinically as blue
naevi or melanoma because of the pre-dominant dark colour. Some of these
naevi may also demonstrate a small well-circumscribed blue or blue-black focus,
e.g., often 1–3 mm in diameter, within an
otherwise ordinary flesh-coloured, tan, or
brown naevus (melanocytic naevi with
focal dermal pigmented components)
{135,156,520,757,2116}. Some naevi
may show irregular borders and pigment
patterns also raising concern for
melanoma.
Naevi with prominent Spitz components
are often diagnosed as an unusual nae-vus, Spitz naevus, dermatofibroma, or
possibly melanoma.
Histopathology
Combined naevi may potentially encom-pass the entire phenotypic repertoire of
melanocytic naevi. By definition two or
more distinct naevus components are
present. Any combination of naevus
components and percentage of the nae-vus components may occur. However
99% of combined naevi have only two
components {2116}. The two compo-nents are intimately admixed in 82% of
cases whereas they are adjacent in the
remainder. The most common pattern of
combined naevus is that of a common
acquired or congential naevus in combi-nation with discreet foci of pigmented
epithelioid and/or spindle cells (which
probably includes inverted type A nae-vus and melanocytic naevus with dermal
epithelioid cell components, dermal nod-ules, or a component of “deep penetrat-ing” or plexiform pigmented spindle cell
naevus) {158,164,537,2126}. The latter
cells are often enlarged, contain abun-dant granular melanin, and are disposed
in nests or fascicles in the superficial,
superficial and deep, or deep portions of
or beneath the ordinary naevus, some-times or commonly in plexiform arrange-ments. The sizes of the nests or fascicles
R.L. BarnhillCombined naevus
Common acquired naevi
– junctional
– compound
– dermal
Congenital naevi
– junctional
– compound
– dermal
Dysplastic naevi (naevi with architectural dis-order and cytological atypia)
– junctional
– compound
Blue naevi
– ordinary or common
– hypercellular
– cellular
– plaque
– epithelioid
Spitz naevi
– junctional
– compound
– dermal
– desmoplastic
Deep penetrating naevi
Plexiform pigmented spindle cell naevi
Naevi with dermal epithelioid cell components
(clonal naevus)
– inverted type A naevus
– naevus with dermal nodules
Other
Table 2.09  The naevus components potentially
occurring in combined naevus
101Combined naevus
may vary from being minuscule to large
lobular or digitate aggregates. The nuclei
are usually comparable in size to the sur-rounding conventional naevus cells, or
may be slightly enlarged round, oval, or
elongate and uniform. On occasion the
nuclei may show variable often slight to
moderate atypia. Melanophages are also
frequently associated with these pig-mented foci. This pattern of combined
naevus is also probably morphologically
identical to that of deep-penetrating nae-vus and plexiform pigmented spindle cell
naevus {158,164,537,2126}.
Another common pattern is that of an
ordinary naevus and blue naevus. The
ordinary naevus component may be
compound or dermal, often overlies or is
adjacent to the blue naevus component,
and commonly has a congenital pattern.
The blue naevus elements most often
consist of heavily-pigmented dendritic
melanocytes, melanophages, and vari-able fibrosis. Less commonly, the spindle
cells typical of cellular blue naevus may
also be present with or without dendritic
cells. The component of blue naevus
may extend deeply into the reticular der-mis as nests or fascicles, often in a plex-iform configuration. Despite the two or
more components, such naevi are usual-ly symmetric, well-circumscribed, order-ly, and display little or no cellular atypia.
Spitz naevi uncommonly are observed in
association with ordinary naevus ele-ments {1961}. The topographic relation-ships of these two components include
the Spitz naevus component being adja-cent to, beneath, or admixed with the
common naevus elements. Such naevi
also may have a desmoplastic stroma as
in desmoplastic Spitz naevi.
After the above relatively well-recognized
forms of combined naevus, almost any
combination of cell types is possible
{156,2116}. Thus, one may encounter
naevi containing various admixtures of
ordinary naevus cells, dendritic
melanocytes, Spitz naevus cells, and
perhaps other transitional cell types.
Atypical features may also be observed
such as disordered patterns of melano-cytes and cytological atypia of both the
intraepidermal and dermal components.
Somatic genetics
The conventional naevus component will
demonstrate frequent BRAF mutations in
contrast to their absence in blue or Spitz
naevus components.
Differential diagnosis
The differential diagnosis of combined
naevus is dependent on the particular
cellular populations present. The histo-logical feature often of most concern is
DC
BA
Fig 2.52 Combined naevus.  A Combined naevus (melanocytic naevus with phenotypic heterogeneity). The lesion is well-defined with central dark brown papule and
lighter brown annulus (Courtesy of Harold Rabinovitz, M.D.).  B There is a conventional compound naevus with small fairly discrete aggregates of heavily pigment-ed cells in the dermis.  C This field shows small nests of pigmented polygonal melanocytes and melanophages admixed with the background conventional naevus.
D The pigmented polygonal melanocytes have abundant cytoplasms and contain nuclei that resemble those in the surrounding small naevus cells.  The polygonal
cells show transition to the surrounding conventional cells.
102 Melanocytic tumours
an aberrant focus of cytologically
altered/atypical cells in an otherwise
ordinary naevus. Such a finding is of con-cern for early transformation to
melanoma or, even fully-evolved
melanoma. The latter histologic alteration
is present most commonly in the dermis.
However, the development of melanoma
in the dermal component of a naevus is
highly unusual. Therefore, such a diag-nosis must be carefully considered and
based on sufficient criteria of atypicality,
mitotic activity, nodular (confluent) prolif-eration, and usually the lack of transition
(maturation) to the surrounding naevus.
Although combined naevi are heteroge-nous, they are usually present in young
individuals (< 30 to 40 years), measure
less than 5 or 6 mm, and exhibit an over-all symmetry and regular appearance. A
focal aggregate of pigment-laden epithe-lioid/spindle cells is usually the feature of
concern. Although occasional aggre-gates of epithelioid cells are large, many
are small and well-circumscribed.
Cytologic atypia is usually low-grade or
insignificant compared to melanoma.
The surrounding naevus which common-ly is of ordinary type is generally unre-markable with reference to atypicality. An
occasional mitosis may be observed in
such a focus without undue concern;
however, the presence of 2 or more
mitoses per high power field should
prompt careful inspection for melanoma
{156}.
Prognosis and predictive factors
Combined naevi are by definition benign.
However it must be acknowledged that
as with cellular blue naevi and Spitz
naevi, there are unusual variants often
characterized by a number of abnormal
features. Such atypical lesions rarely
may result in metastases and require fur-ther study as to more definitive criteria for
malignancy. Thus such atypical variants
prospectively are best designated as
biologically indeterminate and require
complete excision and close clinical
monitoring.
Table 2.10
Comparison of combined naevus and melanoma
*Focus of epithelioid/spindle cells in ordinary naevus (as also observed in inverted type A and clonal naevi)
Mononuclear cell infiltrates Uncommon Frequent
Mitotic activity Absent or minimal (usually <
2/mm2
Frequent
Cytologic atypia Usually absent or low-grade High-grade
Focus, foci of altered cells* Present, transition (maturation)
to surrounding ordinary naevus
Variable
Lateral border Sharply defined Poorly-defined
Size < 6mm often > 1cm often
Symmetry Frequent Uncommon
Combined naevus Melanoma
103Melanotic macules, simple lentigo and lentiginous melanocytic naevus
Melanotic macules
Definition
Melanotic macules are pigmented
lesions that occur on skin, mucous mem-branes, and in nail units {2035}. The
lesions are characterized by hyperpig-mentation of the epidermal/epithelial
basal layer accompanied by a slight
increase in number of melanocytes.
There are several syndromes, which are
associated with multiple melanotic mac-ules/lentigines (Peutz-Jeghers, NAME,
LAMB, LEOPARD, Carney complex (See
Chapter 7).
Synonyms
Genital:  Genital melanosis/lentiginosis;
Vulvar melanotic macule; penile melanot-ic macule; penile lentigo.
Labial/oral:  Labial/oral melanosis; labial
melanotic macule; labial lentigo.
Volar: Volar melanosis.
Nail apparatus: Melanosis of the nail bed
and matrix; ungual melanosis.
Skin: Reticulated black solar lentigo; “ink
spot” lentigo.
Clinical features
Melanotic macule of vulvar and other
female genital sites
The condition occurs usually on the vulva
as a flat asymmetric macule with a dia-meter from less than 1–5 cm. Multiple
lesions are present in >50% of the cases.
The tan-brown to blue-black macules
mostly involve the labia minora. But they
can also occur on the labia majora, per-ineum, the introitus, vagina and cervix.
They may be difficult to distinguish from
melanoma {1400}.
Penile melanotic macule
This lesion usually presents in adult life
as a pigmented patch, uniform or varie-gated in colour with irregular borders, on
the glans penis or on the penile shaft.
Multiple macules can be observed.
Labial melanotic macule
The lesion occurs in about 3% of per-sons, mostly in women on the vermilion
border of the lower lip. The lesions can
be also present on the oral mucosa and
on the tongue. A single or multiple (oral
melanosis), brownish-black or black
macules with irregular sharply demarcat-ed borders can be observed {925}.
Variants
Volar melanotic macule
Clinically a brown, tan, or grey macule
(less than 5 mm in diameter) is located
on palms and soles usually in Black
patients.
Ungual melanotic macule
Pigmented bands (not thicker than 3
mm) are observed in the fingernails of
young individuals (longitudinal melano-nychia). The lesions are common in dark-skinned races and in the Japanese pop-ulation. In Laugier-Hunziker syndrome,
longitudinal melanonychia is accompa-nied with labial/oral melanotic macules.
Reticulated melanotic macule
These lesions appear on sun-exposed
areas of the trunk or shoulders as a dark-brown or black reticulated macule with
irregular borders.
Although the lesion has been named
“reticulated black solar lentigo” {277}, it
is different from the conventional solar
lentigo {1171}.
PUVA-lentigines
PUVA-lentigines are pigmented macules,
which develop as a direct response to
the effects of long-term therapy with
PUVA (psoralens + UVA).
Histopathology
Similar histopathologic changes can be
demonstrated in all types of melanotic
macules. There is usually no perceptible
or a slight increase in the number of
melanocytes, which are situated at the
dermo-epidermal junction in solitary
units. The melanocytes exhibit small and
monomorphous nuclei and delicate den-drites. Using Fontana-Masson silver
stain, the dendrites are better visible.
Atypia is not observed. The basal layer
reveals prominent hyperpigmentation.
Occasionally hyperplasia of the epider-mis can be seen. Melanophages and a
mild inflammatory infiltrate are often
present in the superficial dermis.
Reticulated melanotic macules show
marked hyperpigmentation of the epider-mis especially at the tips of the rete
ridges whereas the suprapapillary plates
are spared and nearly devoid of melanin.
A slightly increased number of finely
dendritic melanocytes can be observed
in the lower layers of the epidermis. In
contrast, solar lentigo represents an
evolving seborrhoeic keratosis revealing
small buds or nubbins of hyperpigment-ed keratinocytes.
PUVA-lentigines are characterized by an
increased number of melanocytes, which
are concentrated mostly in pigmented
rete ridges as solitary units. Some
melanocytes may show atypical nuclei.
H. Kerl
D. MassiMelanotic macules, simple lentigo and
lentiginous melanocytic naevus
BA
Fig. 2.53  Melanotic macule on the lip.  A Brown-black macule with irregular margins on the lower lip.
B Pigmentation of the epithelial basal layer and melanophages in the papillary dermis.
104 Melanocytic tumours
Differential diagnosis
Early stages of melanoma in situ must be
differentiated from melanotic macules.
Melanoma in situ (genital / labial areas)
can manifest as a sparsely cellular prolif-eration of melanocytes. Sometimes in a
partial biopsy the only clues are nuclear
hyperchromasia or irregularly shaped
dendrites. In more fully developed
cases, melanocytes are more regularly
distributed, can become confluent and
may also be situated above the junction.
Lesions with more than a slight increase
in melanocytes, even without atypia
should be carefully evaluated, with addi-tional sampling, over time if indicated. If
the problem cannot be resolved com-plete excision may be appropriate.
Simple lentigo – lentiginous
melanocytic naevus
Definition
Simple lentigo and lentiginous
melanocytic naevus are pigmented mac-ules representing the early stages in the
development of a melanocytic naevus. In
simple lentigo, melanocytes are
increased in number along the basal
layer; lentiginous junctional melanocytic
naevus shows in addition formation of
small junctional nests. In compound
lentiginous melanocytic naevi, small
round melanocytes are also present in
the papillary dermis.
Synonyms
Lentigo simplex, naevus incipiens.
Clinical features
Small flat roundish uniform brown or
black sharply circumscribed macules
usually less than 6 mm in diameter, which
are most frequently found on the trunk
and extremities of children and adults,
are observed.
Histopathology
Simple lentigo consists of an increased
number of melanocytes disposed as soli-tary units in the basal layer of variably
elongated and hyperpigmented rete
ridges. The melanocytes have small
round to oval and monomorphous nuclei.
They are positioned equidistant from one
another and are seen more pronounced
at the tips of the rete ridges. Pigment is
abundant and found throughout the epi-dermis including the stratum corneum.
Melanophages are usually present in the
papillary dermis. Giant melanosomes
can be present.
When one or more small nests of
melanocytes (i.e. three or more melano-cytes per congregation) in such a lesion
is observed, it is then called lentiginous
naevus (evolving junctional naevus).
The histology of naevus spilus (congeni-tal speckled lentiginous naevus) is indis-tinguishable from simple lentigo-lentigi-nous melanocytic junctional naevus.
Prognosis and predictive factors
Melanotic macules have been incorrectly
interpreted as premalignant lesions and
possible precursors of melanoma
{1757A,2394A}. Current evidence sup-ports the notion that melanotic macules,
irrespective of their location, should be
considered benign in their clinical
behaviour, since they tend to remain sta-ble and unchanged when followed over a
long period of time.
Simple lentigo and lentiginous melanocy-tic naevus are wholly benign melanocytic
proliferations which have no potential for
malignant transformation.
C
Fig. 2.54 Simple lentigo – Lentiginous melanocytic naevus.  A Small uniform brown macules; (stars) simple
lentigo. (arrows) lentiginous melanocytic naevus.  B Simple lentigo. Increase in the number of melanocytes
in single units along the basal layer – especially around elongated hyperpigmented rete ridges. Distinct
nests are absent.  C Lentiginous melanocytic naevus. Features of lentigo simplex can be recognized. The
aggregation of melanocytes in tiny nests indicates the transformation of this lentigo simplex into a lentigi-nous melanocytic naevus.
A
B
BA
Fig. 2.55  Lentiginous junctional melanocytic naevus.   A There are elongated rete ridges with increased
numbers of single melanocytes at their sides and bases, with some tiny junctional nests.  B  In this exam-ple, there are lymphocytic infiltrates and fibroplasia of the papillary dermis.
105Dysplastic naevus
Definition
Solitary or multiple naevi, variable in
colour, border, and size, with preferential
location on the upper trunk and extremi-ties. Dysplastic naevi (DN) occur as spo-radic lesions and in a familial setting.
They may progress to malignant
melanoma.
ICD-O code 8727/0
Synonyms
Atypical naevus {896} has been pro-posed as a synonym for clinically dys-plastic naevus. Other past designations
include naevus with architectural disor-der {1}, and melanocytic naevus with
architectural disorder and cytologic atyp-ia {1,2158}. The concept of Clark naevus
includes a large number of junctional
and superficial compound naevi of which
the dysplastic naevus is a subset.
Historical annotation
Originally, Wallace H. Clark and cowork-ers described patients with multiple atyp-ical naevi for which they proposed the
term “B-K mole syndrome”, using the first
initial of the surname of two probands
{496}. The authors photographically doc-umented two lesions that progressed
over time to malignant melanoma.
Therefore, the authors considered the “B-K mole” a precursor of melanoma. Soon
thereafter, in 1980, Elder et al found
lesions similar to those in “B-K mole”
patients with non-familial cutaneous
malignant melanoma {673}. Subse-quently, the “B-K Mole Syndrome” was
renamed to ‘Dysplastic Naevus Syn-drome’, with further sub-classification
into sporadic or familial types.
In 1992, a U.S. National Institutes of
Health Consensus Conference recom-mended “naevus with architectural disor-der” in order to avoid the negative con-notation associated with the word “dys-plasia” {1}. However, this term has failed
to gain wide acceptance {2153}.
In a recent survey by the American
Academy of Dermatology, 98% of
respondents recognized the dysplastic
naevus as a distinct entity {2373}.
Epidemiology
The estimated total number of individuals
affected by the familial form is approxi-mately 32 000 in the United States
{1320}.
Sporadic,  histologically dysplastic naevi
are seen in up to 50% of White adults,
depending on how the lesion is defined.
{535,571,1828}. The estimated preva-lences of dysplasia in a population
based series of naevi ranged from 7-32%
{1829}. The prevalence of  clinically
defined dysplastic naevi also varies
according to the criteria used, ranging
from 5–20%.
Etiology
Ultraviolet radiation has been implicated
in the genesis of dysplastic naevi and
melanoma. Noz et al found higher in vitro
sensitivity to DNA damage by ultraviolet
B radiation in melanocytic naevus cells
compared to foreskin melanocytes
{1732}. One recent study found an
increased relative risk for melanoma in a
dysplastic naevus group with poor in
vitro DNA repair capacity {1360}.
Localization
Dysplastic naevi can occur anywhere on
the body but are most commonly found
on the trunk {496}. In females, there may
be a considerable number on the legs
{5559}. A “quadrant” form of dysplastic
naevus distribution has been reported
where a 59-year-old man had numerous
aggregated pigmented lesions (common
acquired naevi and dysplastic naevi)
confined to the left upper quadrant of his
body. Within this quadrant, two malignant
melanomas at different stages of pro-gression developed from dysplastic
naevi {2266}. Hidden areas such as the
scalp and genitalia need thorough evalu-ation as dysplastic naevi may be seen in
these areas {731,2029}. In Greene’s orig-inal description, it was noted that unlike
ordinary moles, dysplastic naevi are
often found on the scalp, buttocks and
female breast {897}. Lesions on the
scalp, genitalia and upper back should
be considered for excision due to the dif-ficulty with patient self-examination of
these locations {749}, although careful
follow-up is a reasonable alternative.
Clinical features
Patients may have one, several or up to
hundreds of lesions. In one study,
patients who had DN outside the familial
melanoma setting had an average of 10
per person {157}. The clinical features
originally ascribed to DN included ill-defined or irregular border, irregularly
distributed pigmentation, background
erythema, and size greater than 5 mm
{496,2029}. Lesions often differ from one
another in the same individual and in
addition, they are often different between
individuals {778}. Some lesions may
have a central papular component with a
macular flare that blends into surround-ing tissue resulting in an ill-defined, fuzzy
periphery. The surface texture has been
described as “pebbly” {2476}. Other
lesions are macular or plaque-like with-out a central papule or nodule. Irregula-rities in pigment range from tan to dark
brown to black. There are often areas of
pink and some lesions are amelanotic.
Characteristically, lesions first appear
around the time of puberty and if they are
not apparent by age 20, it is unlikely that
an individual has the familial melanoma/
dysplastic naevi trait {897}.
Diagnostic criteria
The Dutch Working Group produced five
C.J. Cockerell
J. Grant-Kels
J.C. Cather
P. LeBoit
Dysplastic naevus
Fig. 2.56 Dysplastic naevus. A solitary leasion on
the abdomen. Note the variegated appearance.
106 Melanocytic tumours
criteria for the clinical diagnosis of dys-plastic naevi: 1) size greater than or
equal to 5mm in diameter, 2) vague bor-der, 3) asymmetric shape, 4) irregular
pigmentation , and 5) red hue {212}.
Additional diagnositic criteria have been
advocated by Newton et al. and consist
of a scoring system. One point was
awarded for the presence of one of five
parameters: 1) 100 or more naevi >
2mm, 2) > two atypical naevi, 3) > one
naevus on the scalp, 4) one naevus on
buttock or > 2 on dorsa of the feet, 5) >
one iris naevus. Individuals who have
three or more points are considered to
have the dysplastic naevus syndrome
phenotype {1700}.
Dermoscopy and imaging
Dermoscopy can be used to assist in dif-ferentiating a DN from other benign or
malignant lesions. A lesion that does not
demonstrate features of the predominant
type of naevus seen in that individual
should be considered atypical and
receive special attention {1043}. This is
analogous to the “ugly duckling” lesion
that refers to one that is distinct from oth-ers in a given patient. It has been recom-mended that such lesions be biopsied as
they are more likely to be the ones that
demonstrate features suggestive of
melanoma {900}.
Several studies have demonstrated the
usefulness of regular whole body photo-graphs {1474} and computerized imag-ing for melanoma surveillance {387,
1286,2440}.
Progression to malignant melanoma
Although melanomas in patients with
dysplastic naevi may arise within preex-isting dysplastic naevi, the vast majority
arise de novo. Histologic changes indis-tinguishable from those of dysplastic
naevi are often observed at the periph-eries of primary melanomas not associat-ed with naevi and such findings have
been interpreted as representing “pre-cursor” dysplastic naevi {672}.
Dysplastic naevi may have chromosomal
instability and poor repair mechanisms
after sunlight induced injury {1067,2128}.
Landi et al demonstrated an increased
relative risk for melanoma in a dysplastic
naevus group with poor in vitro DNA
repair capacity {1360}. Elder classified 6
stages of tumour progression via mono-clonal antibodies to melanoma cells or
their extracts on frozen tissue sections
{675A}.
Histopathology
Definition and description
The major histopathologic criteria
include architectural and cytologic fea-tures: size ≥4 mm, junctional component
often adjacent to a compound naevic
component, nested and single melano-cytes mainly near the tips and sides of
elongated rete ridges, stromal reactions
and mild to moderate cytologic atypia.
There is lack of consensus regarding the
histologic classification of dysplastic
naevi. Historically, some groups advo-cate that atypical architecture is all that is
required to establish the diagnosis
{1943,1980}, while others require cyto-logical abnormalities {1925}. Shea et al
recommend evaluating both cytology
and architecture in the diagnosis of DN
{2158}. More recent descriptions of fea-tures common in DN histology included a
central dermal naevocytic component
with a peripheral extension of a junction-al component, elongated epidermal rete
ridges, bridging of nests of melanocytes
at the dermo-epidermal junction, nests of
melanocytes at the sides of rete ridges
as well as at their bases, and concentric
eosinophilic papillary dermal lamellar
fibrosis {1943}. Ackerman and others
have placed emphasis on the “shoulder
phenomenon” which describes peripher-al extension of the junctional component
beyond the dermal component in dys-plastic naevi {18,1828}.
In general, histologic criteria involving
architecture used to describe dysplastic
naevi include: circumscription, symme-try, cohesion, suprabasalar melanocytes,
confluence and single cell proliferation.
Cytologic features include: nuclear
shape and staining, nuclear size, nucleo-lar prominence, and cell size {2158}.
One of the problems in the definition of
these lesions is that the histologic
changes are non-specific and may be
seen in a number of other naevi without
clinical features of “dysplastic” naevi
such as growing naevi in children and
naevi located on certain anatomic sites
such as the scalp and flexural areas.
Furthermore, the definitions used to
describe cytologic atypia are subjective
Table 2.12
Dermoscopy findings. From Steiner et al. {2259A}
Dermoscopy finding  Dysplastic naevi  Melanoma
Pigment network  Irregular discrete pigment  Irregular, prominent (darkly
network 55%  pigmented) in 81%
Overall pigment  Irregular 82%  Irregular (85%)
Brown globules  Irregularly arranged and of  Irregular arrangement and size
variable size (45%)   (35%)
Margin of pigment network  Irregular margin ends  Abrupt ending of an irregular
gradually (68%)   margin (63%)
Black dots   Present in 34% with irregular
arrangement at periphery in 26%
Radial streaming  1.7%  25%
Pseudopods 1.7%  31%
Depigmentation   Periphery (56%)
Table 2.11.
Clinical characteristics of dysplastic naevi
>Variable size (<5mm-over 1 cm): great
intralesional variation with respect to size
>Irregular colour: irregular browns, red papule
with brown halos, speckled
>Irregular contour: macular or macular with
central papular component
>Ill-defined border, often “fuzzy”
>Preferential location on the trunk
107Dysplastic naevus
as in no case are the atypical cytologic
features as frankly atypical as seen in
fully developed melanoma.
Immunoprofile
Mild to moderate staining of dysplastic
naevi is observed using antibody to
HMB45 antigen. This antibody also often
stains intradermal melanocytes within
melanomas but not as strongly in com-mon melanocytic naevi {2214}. S-100 is a
protein found in the central nervous sys-tem that is also present in melanocytes,
including melanoma. S-100 protein is
found at the dermo-epidermal junction
and at all levels of the dermis in dysplas-tic naevi {1792}. However, S-100 staining
is non-specific as it is seen in common
naevi, dysplastic naevi as well as malig-nant melanoma.
Growth fraction / MIB-1 index
Some authors assert that the presence of
the proliferation marker Ki-67 in dysplas-tic naevi indicates that these lesions are
precursors to melanoma {760}. The per-centage of cells that expressed Ki-67
was an independent prognostic factor
{1308}. Kanter et al found that percent-ages of MIB-1 immunoreactivity in the
intradermal portion of the lesions was
negligible for benign congenital and
acquired naevi, as well as in dysplastic
naevi compared to melanomas which
exhibited a markedly increased prolifera-tive activity, especially vertical phase
melanomas {1201}. At the current time, it
is not recommended that proliferation
markers be used as a reliable method for
distinguishing between naevi and
melanoma.
Electron microscopy
The melanosomes in epidermal
melanocytes in dyslastic naevi are
abnormal, with incompletely developed
lamellae and uneven melanization
{2476}. Abnormal spherical and partially
melanized melanosomes similar to those
observed in superficial spreading
melanoma have been observed by elec-tron microscopy {672,1363}. Based on
these transmission electron microscopy
findings, one group suggested that dys-plastic naevi lie on a continuum between
naevi and superficial spreading
melanoma. No correlation has been
shown prospectively between ultrastruc-tural findings and progression or
predilection to the development of MM.
Fig. 2.57 Dysplastic naevus.  A The naevus cell nests are confined predominantly to the tips of the rete pegs.  B Note the cytological atypia with nuclear hyper-chromasia.
BA
Fig. 2.58 Dysplastic naevus.  A The junctional component shows both architectural and cytological atypia. There is a mild, superficial perivascular lymphocytic infil-trate.  B Mild atypia of the junctional nests and dermal papillary fibroplasia.These is some melanin incontinence.
BA
108 Melanocytic tumours
Variants
Toussaint and Kamino observed
histopathologic changes of “dysplastic”
naevi in other types of naevi. They also
noted that some dysplastic naevi demon-strated features of other varieties of
naevi. 2,164 cases of compound
melanocytic naevi that fulfilled the
histopathologic criteria for the diagnosis
of compound dysplastic naevus were
reviewed. 87.6% had the histopathologic
characteristics of dysplastic naevus,
8.3% showed a dermal component with
a congenital pattern, 3.1% demonstrated
epidermal and dermal characteristics of
Spitz naevus, 0.3% had features of a
combined blue naevus, 0.6% had a halo
phenomenon and 0.1% showed intrader-mal naevus. The authors advocate
describing dysplastic melanocytic naevi
by categorizing them into six groups: 1)
dysplastic naevus; 2) dysplastic naevus
with a congenital pattern; 3) dysplastic
Spitz naevus; 4) dysplastic combined
blue naevus; 5) dysplastic halo naevus;
and 6) dysplastic neuronaevus {2370}.
Differential diagnosis
The clinical differential diagnosis of dys-plastic naevi includes congenital
melanocytic naevi, pigmented basal cell
carcinoma, Spitz naevus, common
acquired melanocytic naevi, melanoma
in situ, and superficial spreading malig-nant melanoma. The histologic differen-tial diagnosis includes melanoma, recur-rent naevus, halo naevus, congenital
naevus, a growing naevus in a child and
Spitz naevus.
Grading
Some authors emphasize cytologic crite-ria for grading dysplastic naevi {1925}. In
1993, Duncan et al advocated grading
dysplatic naevi into groups based on
cytology. Dysplastic naevi with slight,
moderate and severe cytologic atypia
were differentiated. However, concor-dance between experienced der-matopathologists ranged from 35% to
58%. Because of lack of reproducibility,
DeWit et al. did not recommend grading
atypia in dysplastic naevi {612}. An
analysis of 12 histologic parameters in
123 dysplastic naevi failed to identify
parameters useful in differentiating mild
from moderate dysplasia {1854}. Despite
these considerations, melanoma risk has
been associated with the degree of atyp-ia in dysplastic nevi {102}.
Somatic genetics
Cytogenetics and CGH
Jaspers et al performed cytogenetic
investigations on lymphocytes and
fibroblasts from 25 individuals with dys-plastic naevus syndrome and compared
the results with a a control population of
clinically normal relatives and unrelated
individuals. In five DNS patients,
increased frequencies of cells with ran-dom chromosomal rearrangements
including translocations and inversions
were observed. These abnormalities
were absent in the control population
{1134}.
Caporaso analyzed the karyotypes of
163 family members from 13 melanoma-prone families to investigate whether
chromosomal instability contributes to
familial melanoma. Cutaneous malignant
melanoma and dysplastic naevi syn-drome patients each had increased
structural and numerical abnormalities
compared with pooled controls {377}.
However, the criteria used to define
lesions as “dysplastic” naevi were sub-jective from the outset so the validity of
such studies remains in question.
Park and Vortmeyer examined the fre-quency of p16 and p53 deletion in nine
dysplastic naevi and 13 benign intrader-mal naevi with five microsatellite mark-ers. Hemizygous deletion was detected
in seven of nine dysplastic naevi at one
or more loci for p16. No loss of heterozy-gosity was detected in any of the benign
intradermal naevi {1775}.
Molecular genetic alterations
Greene performed an extensive review of
the genetics of malignant melanoma and
dysplastic naevi in 1998. Many studies
demonstrate an autosomal dominant
mode of inheritance and speculate
pleiotropic manifestations of a proposed
melanoma gene on chromosome 1
(1p36). CDKN2A, a tumour suppressor
gene localized on chromosome 9, is also
reported to be a melanoma gene. The
relationship of melanoma to mutation of
CDKN2A has been confirmed {895}.
Hussein evaluated skin tissue samples of
melanoma, dysplastic naevi and benign
melanocytic naevi for microsatellite insta-bility. Microsatellites are short single
sequence motifs repetitively scattered
throughout the human genome. The vari-ation in microsatellite pattern length
between tumourous and matching non-tumourous tissues is referred to as
microsatellite instability. Microsatellite
instability has been associated with other
familial and sporadic tumours. Hussein’s
results demonstrated MSI at 1p and 9p
chromosomal regions in dysplastic naevi
Fig. 2.59  Dysplastic naevus.  A Some naevus cell nests extend above the the tips of the rete pegs.  B Mild cytological atypia of the junctional nests.
BA
109Dysplastic naevus
and malignant melanoma but not in
benign naevi lending further support to
others that have speculated on the pres-ence of “melanoma genes” involving the
short arm of chromosomes 1 (1p36) and
9 (9p21) {1087}. In 2002, Tucker provid-ed 25-year prospective data regarding
33 families with familial melanoma and
dysplastic naevi. Seventeen members
were found to have mutations in
CDKN2A. Tucker found that the majority
of clinically diagnosed dysplastic naevi
remained stable or regressed over time.
The majority of melanomas detected
over the course of the study arose from
naevi although some arose de novo
{2384}.
Genetic susceptibility
As discussed above, Clark originally
described dysplastic naevi in relation to
a familial syndrome called the B-K mole
syndome {496}. Most dermatologists
agree that family members of patients
with dysplastic naevi need evaluation
{2373}. Familial dysplastic naevi and
melanomas have rarely been reported
with other systemic malignancies involv-ing the central nervous and digestive
system {129,213}.
Prognosis and predictive factors
The incidence of melanoma developing
in a given dysplastic naevus has been
estimated at 1:3000 per year. Therefore,
dysplastic naevi should not be consid-ered as high risk precursors of
melanoma, but rather as markers that
allow identification of individuals at
increased risk for melanoma.
Number of dysplastic naevi and family
history
Patients with greater numbers of naevi,
dysplastic or otherwise, are at greater
risk for melanoma {2386}. Dermatologists
acknowledge patients with multiple dys-plastic naevi, especially if there is a per-sonal or family history, are at greater risk
for developing melanoma {2373}. If
patients are from “melanoma-prone fam-ilies” and have clinically dysplastic naevi,
as defined by criteria that include lesion-al diameter, their individual risk for devel-oping a melanoma is several hundred
times that of the general population, with
a risk for lifetime incidence of melanoma
approaching 100% {744,846}. The signif-icance of a single histologically dysplas-tic naevus in this context has not been
determined. One study evaluated
patients with an established diagnosis of
melanoma (n=716) compared with nor-mal controls (n=1014) and found that
one clinically dysplastic naevus was
associated with a 2-fold risk, while 10 or
more conferred a 12-fold risk of
melanoma {2386}. In the same study,
patients who bore 100 or more clinically
non-dysplastic naevi had a relative risk of
3.4. Approximately 50% of dysplastic
naevi patients with a family history of MM
may have multiple primary melanomas
{1320}.
Histopathological criteria
There is evidence that histological atypia
does correlate with melanoma risk. A
recent study of more than 20,000 naevi
divided them microscopically into mild,
moderate, or severe categories of dys-plasia. A personal history of melanoma
was present in 5.7 of the patients with
mild, 8.1 with moderate and 19.7 with
severe atypia. It was concluded that the
risk of melanoma was greater for persons
who tend to make naevi with high-grade
histological atypia {102}.
Genetic predictive factors
Currently, there are no commercially
available genetic tests that would be pre-dictive of dysplastic naevi progression to
melanoma.
110 Melanocytic tumours
In some anatomic sites, naevi may have
atypical histological features. This chap-ter discusses three clinicopathologic
entities: acral, genital and Meyerson
naevi, but other site specific features
have been described, including naevi
occuring in flexures, umbilicus, ear and
scalp.
Acral naevus
Definition
Acral naevi (AN) are benign melanocytic
proliferations from the palms and soles.
Synonyms
AN or “naevi on volar skin” include histo-logic subtypes termed “Melanocytic
Acral Naevus with Intraepidermal Ascent
of Cells (MANIAC)” {1545} and “atypical
or acral lentiginous naevus” {501,1511}.
Epidemiology
Clinical studies which are unable to dis-tinguish lentigines from true naevi, record
discrete pigmented volar lesions in less
than 1{1763} to 92% {1416} of subjects,
with most studies suggesting a range of
3 – 41% of the population {63,519,574,
1338,2223,2418}. In a histologically con-firmed study, 3.9% of Caucasians had
AN {1473}. Darker patients tend to have
a greater percentage {519,1763} and
higher total of naevi on acral surfaces
{63,519,1553,2418}, though this is not
always found {574,1416}. Pigmented
acral lesions are generally more common
in the second and third decades
{63,1338,1415,2418}.
Localization
Plantar naevi are probably more common
than palmar naevi {63,574,1473,2418}.
AN may occur on both pressure-bearing
and pressure-spared surfaces {45,63,
1415}.
Clinical features
AN are usually less than 8 mm with a light
to dark brown striated macular compo-nent. Congenital AN can be particularly
difficult to clinically distinguish from
melanoma {289,1511,2013,2017,2018}.
On epiluminesence microscopy (ELM)
dermatoscopy), the pigmentation of AN
is accentuated in dermal glyphic furrows
and occasionally around eccrine ostia,
thereby creating reproducible patterns
{45,1232,2014,2015}. In acral melano-mas the pigment is distributed along the
dermatoglyphic ridges {45}.
Etiology
The origin of AN is hypothesized to
involve repeated trauma {701,2181,
2182}, foci of “unstable” melanocytes
{1416} and racially-correlated variations
in melanosome aggregation {1612}.
Histopathology
Distinction of acral naevi from melanoma
can be difficult because both may be
asymmetric, poorly circumscribed and
have intraepidermal ascent of cells {292,
701,984,1545,2181,2182}. Suprabasal
melanocytes in AN are relatively more
columnar, circumscript and less volumi-nous than in melanomas {1246}.
Signoretti et-al. have shown that symme-try, circumscription, the columnar organ-ization of ascending melanocytes and
organization of the junctional component
are all influenced by the histologic plane
of section; to wit, naevi sectioned per-pendicular to dermal glyphics are more
likely to have benign attributes {2017,
2018}. Subsequently, severe melanocytic
atypia and a dense lymphocytic infiltrate
have been found the most reliable fea-tures indicative of melanoma {493,707}.
Genital naevus
Definition
Melanocytic naevi on the perineum and
genitalia, hereafter “genital naevi (GN)”,
include different naevic types distin-guished and united by unusual, variably
present junctional features.
Synonyms
A subgroup of GN with “unusual histolog-ic features” {480,782} or “atypism” {1608}
have been dubbed “atypical melanocytic
naevus of the genital type (AMNGT)
{495}”.
Epidemiology
About 10% of men and women have pig-mented genital lesions {574,784,1955},
but many are lentigines {784,1955}.
Histologically confirmed GN occur in 2%
of women {267,480,1955}.
AMNGT comprise a minority of all GN
{267,480,1955}. They typically present
by the twenties {1608} and, in contrast to
vulvar melanoma, are seen exclusively in
premenopausal women {1608,2015}.
Dysplastic naevi may also occur on the
genitalia but they are usually observed in
people with dysplastic naevi elsewhere
on their bodies {267,1608}. Vulvar naevi
were said to have increased premalig-nant potential {1763}, though recent data
H. Kamino
D. WeedonSite specific and Meyerson naevi
BA
Fig. 2.60  Acral naevus.  A Epiluminesence microscopy of an acral naevus demonstrating linear hyperpig-mentation within the furrows of dermal glyphics.  B Intraepidermal melanocytes with  short dendrites are
seen along and above the basal layer.
111Site specific and Meyerson naevi
refutes this {1954}. Histological studies
suggest that from 1% {391} to 12% {495}
of vulvar melanomas are associated with
a naevus.
Localization
AMNGT are more commonly seen on the
labia minora and clitoris {495}. Although
infrequent, AMNGT may occur on male
genitalia {495}. Naevi with histologic fea-tures similar to AMNGT may be observed
on flexural sites and along the vestigal
“milk-line” from the axilla to the upper
thighs {1964}. Dysplastic naevi more
commonly occur on the labia majora and
perineum {495}
Clinical features
Common type GN are dome shaped,
evenly pigmented, tan to dark brown
papules less than 1 cm {1955}. Both
AMNGT and dysplastic GN can be poly-poid or flat {495}. They are usually tan-brown, often with some black areas
{495}. Clark et-al report a size range from
2 to 24 mm {495}. Despite a long history
of advice to the contrary, prophylactic
removal of all genital naevi is not recom-mended {480,784,1955}. AMNGT obser-ved from 1 to 16 years have not recurred
or metastasized; yet, their conservative
reexicision has been advised {495}.
Etiology
The genesis of GN is poorly understood.
Possible influences include repeated
superficial trauma, sex hormones, genet-ic determination and stroma type {391,
495,1964}.
Histopathology
AMNGT are typically “mushroom
shaped” with a base composed of matur-ing melanocytes similar to a common
naevus. Melanocytes at the dermal-epi-dermal junction are arranged in one of
three patterns: nests; dyshesive nests;
and crowded, ill-defined nests and sin-gle melanocytes. In about half of AMNGT
there are “skip areas” at the dermo-epi-dermal junction which lack melanocytes.
Thus, it is the junctional component in
AMNGT which is worrisome for
melanoma. Unlike dysplastic naevi,
AMNGT usually lack a lymphocytic infil-trate. The “ill-defined” stroma of AMNGT
is different from that typically seen in
melanomas or dysplastic naevi {495}.
The histopathologic features of dysplas-tic GN are similar to dysplastic naevi
elsewhere {267,495,1955}. Rarely, geni-tal naevi may be distorted by coexistent
lichen sclerosus et atrophicus, produc-ing histologic changes similar to those
seen in recurrent naevi {17,352,390}.
Unlike melanomas, vulvar naevi are said
to lack intraepidermal ascent of
melanocytes {17,24,391,782}, though
this has been disputed {984,1608}.
Regardless of subtype, GN differ from
melanoma by circumscription, matura-tion, and symmetry {17,24,391,782}.
Meyerson naevus
Definition
Meyerson naevus is a benign naevus of
junctional, compound or intradermal type
surrounded by an eczematous halo
{2478}.
Synonyms and historical annotation
“Spongiotic change in melanocytic naevi”
{2478}, halo dermatitis {352,2330}, halo
eczema {1329} and perinaevic eczema
{1816}.
The eponym “Meyerson naevus” (MN)
was suggested {1706} to honour the
1971 description of a spongiotic dermati-tis involving melanocytic naevi {1595}.
Epidemiology
MN typically occur in young adults
{1706} and children {2167}. Affected men
have been reported about three times
more frequently than women {1706}.
Localization
Eczema may involve one or several naevi
{1329,1706} and may spread beyond
naevi to previously normal skin {306,
729}. There are no clinical features to
suggest which naevi become dermatitic
{1329,1706}.
Clinical features
The change may involve one or more
naevi simultaneously. The naevus does
not usually undergo regression as a
result of this change although the trans-formation of a Meyerson naevus into a
halo naevus has been recorded once
{1884}. MN are characterized by a prurit-ic, raised erythematous, scaling and
crusted plaque which extends symmetri-cally 1–2 cm from the central naevus
{306, 1329,1595}. Upon resolution the
naevus persists unchanged {1595,2330},
though post-inflammatory hypopigmen-tation may occur {1595,2330}.
Etiology
The inflammation of MN has been likened
to pityriasis rosea {564,1595} and aller-gic contact dermatitis {2478}. One case
was triggered by interferon alpha {1328}.
Histopathology
MN are characterized by spongiosis,
Fig. 2.61 Genital naevus. This example contains features of a dysplastic naevus. Junctional melanocytes
are arranged as both nests and single units. There is bridging of rete ridges and lamellar fibroplasia. Dermal
melanocytes mature and melanocytes do not ascend above the basal layer.
Fig. 2.62  Meyerson naevus. Note the eczemetous
halo around a pigmented naevus.
112 Melanocytic tumours
microvesiculation, irregular acanthosis,
parakeratosis, focal crust and a superfi-cial perivascular infiltrate of lymphocytes
and eosinophils {306,676,1595,2478}.
There is no histologic regression nor
depigmentation {2478}.
There is a naevocellular naevus of junc-tional, compound or intradermal type
with an associated subacute spongiotic
dermatitis {1706}. There is variable epi-dermal acanthosis and a mild to moder-ate superficial perivascular and intersti-tial infiltrate of lymphocytes. Usually
there are a few eosinophils. There is
often mild exocytosis of lymphocytes into
the epidermis. There is no regression,
although one exception has been
recorded (see above). Rarely, dysplastic
naevi have been involved {676,1328}.
Immunoprofile
Lymphocytes in MN are predominately
CD4 positive {729,1816}. ICAM-1 has
been reported to be increased on ker-atinocytes and endothelium within MN
{717}.
Fig. 2.63  Meyerson naevus. Spongiosis, parakeratosis and irregular acanthosis characterize the epidermis.
113Persistent (recurrent) melanocytic naevus
Definition
Persistent melanocytic naevi are benign
compound or intradermal melanocytic
naevi that persist (recur) after incomplete
excision.
Synonym
Pseudomelanoma {1310}
Clinical features
Persistent melanocytic naevi are the
result of incomplete removal after super-ficial shave technics, dermabrasion or
laser treatment {271}. The lesions ‘recur’
usually after weeks or months after ther-apy. They are characterized by variably
pigmented macules, papules or plaques
with irregular borders. A scar from previ-ous surgery can be usually recognized.
Histopathology
Scanning magnification shows common-ly above a dermal melanocytic naevus a
scar with fibrosis. The intraepidermal
changes are characterized by sharp cir-cumscription and confluent nests of
melanocytes, that are not equidistant
and vary in sizes and shapes. The nests
are mostly situated at the dermo-epider-mal junction. Melanocytes are also
arranged as solitary units at the dermo-epidermal junction and sometimes
above it in upper layers of the epidermis
{1037}.
Assessment of the original specimen is
very important for an accurate diagnosis
to ensure that the lesion is really a per-sistent melanocytic naevus and not a
persistent melanoma.
Differential diagnosis
The features within the epidermis and in
epithelial structures of adnexa may simu-late a melanoma in situ.
However, the sharp circumscription of
the intraepidermal component, the pres-ence of melanocytes in nests and as sin-gle units mostly at the junction and the
typical naevoid cells of the preexisting
dermal melanocytic naevus beneath a
scar are helpful clues to the diagnosis of
persistence (recurrence). Furthermore in
persistent melanocytic naevi the melano-cytic proliferation within the epidermis is
confined to the area above the scar.
H. KerlPersistent (recurrent) melanocytic
naevus
BA
Fig. 2.64  Persistent (recurrent) melanocytic naevus.  A  Small irregular black macule. A scar surrounds the
lesion.  B Persistent (recurrent) melanocytic naevus. Melanocytes are arranged as solitary units along the
dermo-epidermal junction and also above it. Atypical nuclei can be observed. Note involvement of the fol-licle.
Fig. 2.65  Persistent (recurrent) melanocytic naevus. Trizonal arrangement: 1) Dermal melanocytic naevus.
2) Above the melanocytic naevus a scar revealing fibrosis. 3) Intraepidermal changes with nests of
melanocytes with irregular shapes and a tendency to confluence at the dermo-epidermal junction.
114
Definition
Spitz naevus is a benign proliferation of
large spindled, oval or large round
(epithelioid) melanocytes that begins in
the epidermis, and evolves into com-pound or intradermal stages. This distin-guishes it from some forms of blue nae-vus, in which the lesion is wholly intra-dermal from the outset.
ICD code 8770/0
Synonyms
Spindle and epithelioid cell naevus, nae-vus of spindled and/or epithelioid cells,
benign juvenile melanoma {2239}.
Pigmented spindle cell naevus (Reed) is
probably a distinctive variant of Spitz
naevus {158,162,2005}.
Epidemiology
Spitz naevus is most common in the first
two decades of life {1015,2155}.
Accurate population based studies on its
prevalence are not available, and are
coloured by the caution shown by pathol-ogists in making an outright diagnosis of
Spitz naevus in middle aged or older
adults, and in making a diagnosis of
Spitz naevus in young adults if there are
any unusual microscopic features.
Spitz naevi are mostly recorded in
Caucasian patients. However, they occur
in all racial groups, and their occurrence
in Asians and Africans may be underes-timated.
Localization
Spitz naevi can occur on any areas of the
body, although the face of children and
thighs of young women are stereotypical
associations.
Clinical findings
The earliest recognizable Spitz naevi are
about a mm. or so in diameter, and the
largest recorded are over 2 cm. While the
criterion of size has been popularized in
the differential diagnosis between Spitz
naevus and melanoma, many Spitz naevi
are over 1 cm. in diameter. There
appears to be an initial period of rapid
growth, followed by stabilization. This is
in contrast to melanoma, in which the
diameter of the lesion is seldom stable.
Most Spitz naevi are lightly pigmented.
The classic lesion is a pink to red papule,
with an even round border and a domed
shape. There is slight scale. The degree
of erythema is often such that the clini-cian considers the diagnosis of haeman-gioma. However, if one looks at the initial
description by Spitz, it is clear that there
is considerable heterogeneity, with tan
and medium or even dark brown lesions,
and verrucous ones also possible
{2239}. In dark skinned people, Spitz
naevi are usually darker than their normal
skin colour. There is usually a uniformity
of pigmentation, with the notable excep-tions of combined Spitz naevi and Spitz
naevi with a halo reaction.
Ulceration is practically never present in
Spitz naevi, except in children who trau-matize them in play or excoriate them.
The presence of an ulcer outside of these
settings merits reconsideration as
melanoma.
Most Spitz naevi are single lesions.
However, groups of Spitz naevi can
occur in a single area in agminated Spitz
naevus {44,2002}. In such cases, the epi-dermis in between the papules of Spitz
naevus can be normal in appearance, or
more commonly is lightly pigmented,
resembling a café au lait spot (when it
occurs in Caucasian patients). In erup-tive Spitz naevus, a patient may have
many papules of Spitz naevus appear on
a limb or even over the entire integument
within a few weeks or months. This obvi-ously distressing situation can be con-fused with metastasis of melanoma.
Etiology
The cause of Spitz naevus is unknown.
Sunburn and biopsy of a single Spitz
naevus have been linked to eruptive
lesions {597}.
Histopathology
Because the findings of Spitz naevus dif-fer significantly at various stages, we will
describe those in detail. Spitz naevus
begins as a proliferation of large oval
melanocytes at the dermal-epidermal
junction. This can occur along a front of
only a few mm., and is first recognizable
by single, large melanocytes with abun-dant eosinophilic cytoplasm and large
vesicular nuclei. There are often a large
number of cells with several nuclei, even
in small lesions. Cytoplasm is abundant,
and even though the nuclei may be
large, they are usually monomorphous.
Clefts demarcate the melanocytes from
adjacent keratinocytes. Even if single
cells are present in number above the
junction, they are evenly distributed
{355}. As these lesions enlarge, the epi-dermis above the proliferation thickens,
and nests begin to form. The epidermal
thickening is largely via hyperplasia of
the spinous layer, with squamatization of
the basal layer and pointed rete ridges.
Melanocytic tumours
P.E. LeBoit
B.C. Bastian
W.J. Mooi
Spitz naevus
BA
Fig. 2.66  Spitz naevus.  A A sharply circumscribed, dome-shaped lesion, which may be mistaken for hae-mangioma.  B Small brown papules form an agminated lesion. This configuration is often alarming.
115
There is corresponding hypergranulosis
and compact hyperkeratosis.
Within the junctional nests of a Spitz nae-vus are clefts, separating the melano-cytes from one another, and from the epi-dermis. The clefts tend to be prominent
over the apices of junctional nests. The
nests may appear to be embedded in the
epidermis, rather than lying at the bases
of rete ridges. The epidermal hyperplasia
of a well developed junctional Spitz nae-vus, and the nests of the naevus itself are
both well circumscribed {19,1636,
1638,1769,2479}. By the time that nests
are of substantial size, one may
encounter Kamino bodies in the epider-mis. Kamino bodies are dull pink staining
globules, up to the size of several ker-atinocytes, often with a scalloped border
and a periphery in which there are cres-cent shaped, compressed appearing
keratinocytes {1186}. Unlike dyskeratotic
cells, which are more brightly eosino-philic, their major ingredient is basement
membrane material. They stain with PAS-D and with immunoperoxidase stains for
basement membrane components, such
as laminin and type IV collagen {2499}.
Compound Spitz naevus forms when
junctional nests become incorporated
into the dermis. In early compound
lesions, one may see a dense lympho-cytic infiltrate, rather than the sparse
perivascular one that most authors
describe. The dermal nests tend to be
smaller than the junctional ones, and as
melanocytes descend into the reticular
dermis, one can discern a gradient from
large nests to smaller ones, and single
cells may predominate at the base.
Mitotic figures can be present in the
upper part of a compound Spitz naevus,
but tend to decrease in number toward
the base of the lesion. Maturation of
melanocytes is also a correlate, with
smaller cells that have less cytoplasm,
smaller nuclei, and smaller and less
eosinophilic nucleoli all findings that
reassure the pathologist. If a Spitz nae-vus is pigmented, the pigmentation
lessens in the lower half of the lesion.
Fully formed compound lesions often
have a domed surface and a wedge
shape. Unlike the case in early com-pound, or even junctional lesions, lym-phocytic infiltrates are usually sparse
and perivascular.
Intradermal Spitz naevi preserve the
domed/wedge shape noted above. The
epidermis is often slightly hyperplastic.
The nests of melanocytes are often pres-ent between thickened collagen bundles
in the lower part of the lesion. When this
is prominent, some apply the term
desmoplastic Spitz naevus. Unlike the
case in desmoplastic melanoma, there
are no markedly elongated fascicles of
cells. If the proliferation abuts the sub-cutis, one may see lymphoid nodules.
For both compound and intradermal
lesions, an important finding is that the
nests at each level of the lesion should
be similar in size, with the cells similar in
overall and nuclear size and in pigmen-tation.
There are many important variants of
Spitz naevus. On acral skin, one may see
many single melanocytes scattered
above the junction. A halo reaction may
be present, sometimes accompanied by
a clinical halo. The lymphocytes are
evenly dispersed throughout the lesion,
and some may be apposed to pyknotic
melanocytes . The stroma may be scle-rotic (hyalinizing Spitz naevus) or highly
vascular {2293} . Some nests may have
an empty appearing centre (tubular Spitz
naevus) {2228}. In combined Spitz nae-vus, other populations of melanocytes
(e.g. small round, bipolar-dendritic, bal-loon, etc.) may be present {1961}. This is
one of the most difficult variants to deal
with, as the large cells may not mature
and dense lymphocytic infiltrates (up to a
halo reaction) may be present {972}.
Another difficult variant is persistent Spitz
naevus. The great majority of Spitz naevi
do not recur at the biopsy site if the
lesion seems to be removed clinically,
but goes to a margin. Those that do can
show suprabasal scatter of melanocytes
(as in other recurrent naevi), a com-pound Spitz naevus over a scar, a nodule
next to a scar, or a picture resembling
desmoplastic Spitz naevus {969}.
Lastly, there is a “grey zone” of lesions in
which there are many findings of Spitz
naevus, but the diagnosis is less certain.
For lesions in which the diagnosis is Spitz
naevus, but there are a few findings that
are unusual, many use the term “atypical
Spitz naevus”, although this may be
attacked on semantic and functional
grounds. If one is not sure of the diagno-sis, a descriptive term, such as “prolifer-ation of large melanocytes involving the
epidermis and dermis” is preferable. This
should be accompanied by a note or
comment explaining the difficulties, dif-ferential diagnosis, including if appropri-ate, microstaging parameters that would
be appropriate if the lesion were regard-ed as melanoma, and advising reason-able management. The role, if any for
sentinel lymph node biopsy in difficult
cases is currently considered controver-sial {1444,2286}.
Among these “grey-zone” lesions is an
emerging, relatively homogeneous group
of lesions with a distinctive pattern, often
Spitz naevus
Fig. 2.67  Spitz naevus, junctional type, Clefts separate melanocytes from one another. Several large Kamino
bodies are present.
116
found from early childhood to young
adulthood in which there are some fea-tures of Spitz naevus and others of
melanoma. Common denominators
include a vertical orientation, extension
into the subcutis with no diminution in
cellularity and a blunt, multinodular inter-face, ulceration, a plasmacytic infiltrate
and deep mitotic figures. Such cases
have been described as “malignant Spitz
naevus” and also simply regarded as
melanomas {2205}. In the initial study of
“malignant Spitz naevus” there were 3/32
lesions in which palpable lymph node
enlargement had occurred, and another
3 in which lymph node involvement was
detected on elective dissection. Very
similar lesions have been described as
melanomas in children {1632}. Follow up
data has been presented to the effect
that systemic metastasis may not occur,
or may be much less frequent than in
adults with conventional melanomas
matched for thickness. Clearly, further
studies are needed to determine if these
lesions are fundamentally Spitz naevus,
melanoma, or neither.
Somatic genetics
While most cells in most Spitz naevi
seem to be diploid, there are a propor-tion of polyploid cells, at least in the
upper part of lesions as judged by image
analysis cytometry {1386}. True aneu-ploidy may be uncommon, as evaluated
by flow cytometry {2439}. In an analysis
using comparative genomic hybridiza-tion the majority of Spitz naevi did not
show chromosomal aberrations, whereas
25% showed an isolated gain of chromo-some 11p {174}. Preliminary studies indi-cate that the increased copy number of
chromosome 11p is due to the formation
of an isochromosome 11p {1494}. About
70% of the Spitz naevi with increased
copies of chromosome 11p have muta-tions in the HRAS gene which maps to
this location {172}. HRAS mutations have
been found only in a minority of cases (<
10%) with normal copy number of chro-mosome 11p. Preliminary studies indi-cate that mutations in BRAF occur infre-quently in Spitz naevi.
Melanocytic tumours
Fig. 2.68  Spitz naevus, compound type.  A Junctional portion of Spitz naevus with epidermal hyperplasia.  B The upper part of the lesion is highly cellular.  C Toward
the base single large oval melanocytes are interspersed between thick collagen bundles.
B CA
Fig. 2.69  Spitz naevus, desmoplastic type.  A Rete ridges are uniformly elongated but jagged above the upper part of the lesion.  B Thin spindle cells are present
between collagen bundles.
BA
117Pigmented spindle cell naevus (Reed)
Definition
Pigmented spindle cell naevus (Reed) is
a benign melanocytic naevus showing
dark pigmentation clinically, and a prolif-eration of spindled melanocytes histo-pathologically.
ICD-O code 8770/0
Synonyms and annotation
This melanocytic naevus has been
named eponymously after Richard Reed,
who described it in 1975 {1909}. It has
also been referred to as Reed naevus or
Reed tumour. While some authors regard
it as a subtype of the Spitz naevus, pig-mented spindle cell naevus (Reed) pres-ents with peculiar clinical and
histopathologic features, allowing a
reproducible diagnosis and classification
to be made.
Epidemiology
Pigmented spindle cell naevus (Reed) is
a melanocytic tumour found in children,
adults, and, rarely, older patients, with a
peak in the third decade. There is a pre-dominance for females.
Clinical features
The patients present with a darkly,
homogenously pigmented, flat or slightly
dome-shaped, sharply circumscribed
papule or plaque located usually on the
limbs, especially the thigh {158,2005,
2068}. Less common locations are the
trunk and the head and neck region. The
lesions are usually of recent onset and
smaller than 1 cm. Surface skin micro-scopy (dermatoscopy, dermoscopy)
reveals typically a “starburst” pattern
(characterized by the presence of pig-mented streaks disposed in a radial
arrangement at the edge of the lesion).
A clinical misdiagnosis of malignant
melanoma is not infrequent, due to the
dark pigmentation and recent onset of
the lesions.
Histopathology
Histologically, the tumours are symmetri-cal and show a sharp lateral circum-scription. Spindled, pigmented melano-cytes arranged in vertical nests at the
dermo-epidermal junction predominate
{158,2005,2068}. A few, and in some
instances many, melanocytes may be
seen above the dermal/epidermal junc-tion, as well as confluence of the nests.
The proliferation of melanocytes may be
confined to the epidermis, or may extend
into the papillary dermis. Occasional
mitoses may be found. Cytomor-phologically there is a uniform prolifera-tion of elongated, fusiform melanocytes,
usually without atypical features. The
nuclei are relatively small, with uniform,
delicate chromatin. Epithelioid melano-cytes are admixed in a minority of cases.
Commonly, the epidermis is slightly
hyperplastic and shows marked hyper-pigmentation of the basal keratinocytes.
Intraepidermal eosinophilic globules (so-called “Kamino bodies”) can be
observed in about half of the cases. An
inflammatory infiltrate composed of lym-phocytes and histiocytes with many
melanophages is found within the papil-lary dermis. A subset of cases shows a
considerable overlap with Spitz naevi.
Cases with some cytological atypia have
been termed “atypical pigmented spin-dle cell naevus – pigmented spindle cell
naevus with architectural and/or cytolog-ic atypia”, and may represent a source of
problem in differential diagnosis from
malignant melanoma {158}. A variant
described as “plexiform pigmented spin-dle cell naevus” probably represents a
pigmnented spindle cells naevus invol-ving the reticular dermis {158}.
Prognosis and predictive factors
Pigmented spindle cell naevus (Reed) is
a benign melanocytic proliferation with
no potential for distant metastases. Local
recurrences may be observed in tumours
that were incompletely excised.
L. CerroniPigmented spindle cell naevus (Reed)
DC
Fig. 2.70 Pigmented spindle cell naevus (Reed).  A Small, flat, dark papule.  B Dermoscopy shows the char-acteristic “starburst” pattern.  C Elongated nests at the dermoepidermal junction and in the papillary dermis;
note pigmentation of the basal keratinocytes and melanocytes, and the presence of numerous
melanophages in the papillary dermis.  D Fusiform melanocytes predominate. Note the mitosis in the upper
left corner.
BA
118 Melanocytic tumours
Definition
A halo naevus presents as a small cir-cumscribed symmetrical, usually papular
pigmented lesion with the appearance of
a common benign compound naevus,
surrounded by a symmetrical area of
depigmentation, representing the “halo”
{2469}. The lesion is defined histological-ly by the presence of a brisk lymphocyt-ic infiltrate among dermal naevus cells,
and by loss of pigment in the epidermis
adjacent to the naevus. Some naevi with
a lymphocytic response of the type seen
in halo naevi do not have an obvious clin-ical or histologic depigmented halo
{948}.
ICD-O code 8723/0
Synonyms
Sutton naevus; leukoderma acquisitum
centrifugum {2297}.
Clinical features
Halo naevi often present during the sum-mer, perhaps because the halo contrasts
better with tanned skin. They are most
common in teenagers and young adults.
In these cases, they are sometimes asso-ciated with dysplastic naevi, and are
sometimes multiple. Less often, a solitary
halo lesion develops in an older adult,
and in this circumstance the possibility of
melanoma should be ruled out histologi-cally, especially if the central pigmented
lesion is clinically atypical or if the halo is
eccentric or asymmetrical in contour.
Serial follow-up of halo naevi demon-strates a characteristic time sequence,
beginning with the appearance of the
halo around a compound naevus, fol-lowed by fading and disappearance of
the naevus. The halo then gradually re-pigments over a year or two, returning to
the appearance of normal skin. During
this period, especially in teenagers, other
similar lesions may develop.
Studies in patients with halo naevi have
demonstrated circulating antibodies that
are reactive with neoplastic melanocytes
including melanoma cells, and the infil-trating cells have been shown to be
mainly T lymphocytes {2090}. Antigen-presenting cells and CD8+ T cells have
been identified in the inflammatory infil-trates of halo naevi, implicating cytotoxic
mechanisms in destruction of naevus
cells {2581}. Affected individuals also
show activated lymphocytes in their
peripheral blood {148} as well as T cell
clonal expansion {1670} and anti-naevic
IgM antibody production {2359}. These
findings are consistent with the idea that
halo naevi represent immunologically -mediated rejection of a naevus. The halo
develops outside the naevus proper,
suggesting that there may be a cross-reaction with a “field” of melanocytes that
surrounded the naevus prior to the onset
of the intense inflammation in the dermal
component.
Histopathology
An early halo naevus presents as a small
circumscribed lesion, less then 4 mm in
diameter as a rule, composed of naevus
cells located in the papillary dermis and
usually also in the epidermis. The lesion
is symmetrical, and is composed of cells
that are uniform from side to side and
tend to become smaller (i.e., more
“mature”) from the top to the bottom of
the lesion. The epidermis may be hyper-keratotic with follicular plugging {2469}.
The feature that distinguishes a halo nae-vus from a banal naevus is the presence
of a striking dense lymphocytic infiltrate,
an appearance that may arouse a suspi-cion of melanoma in some cases. The
lymphocytes extend among the lesional
naevus cells, tending to obscure their
underlying nested pattern in some
cases. Melanin-laden histiocytes and
mast cells can be present as well as lym-phocytes {2090}. Occasional halo naevi
contain a few giant cells or there may be
a frankly granulomatous response. Over
the ensuing weeks or months, the dermal
naevus cells disappear and then the his-tologic differential diagnosis may include
lichenoid inflammatory dermatoses. Over
a period of a year or two, the inflammato-ry cells disappear and histologic exami-nation of the site of a completely resolved
halo naevus may disclose essentially
normal skin, with little or no evidence of
scarring or residual pigment {2469}. In
most halo naevi, there is little or no read-ily observable melanocytic abnormality
in the epidermis at the “shoulder” of the
lesion beyond the lateral border of the
dermal component, even though it is in
this region that the striking clinical halo is
located. However, DOPA stains for tyrosi-nase and immunohistochemical (e.g.
Melan-A) or argentaffin stains for
melanocytes reveal greatly reduced
numbers of them in the area of the halo
compared to the surrounding skin
{2469}.
D. E Elder
X. XuHalo naevus
Fig. 2.71 Halo naevus. There are two small naevi
surrounded by rims of depigmentation.
Fig. 2.72  Halo naevus. There is an apparently well circumscribed lesion which at first glance may be mis-taken for a lymphocytic infiltrate.
119Halo naevus
The lesional cells in most halo naevi are
unremarkable dermal naevus cells of the
large pigmented (type A) or small non-pigmented (type B) cytology. Pigment is
located in naevus cells and in melano-phages superficially, and is usually
coarse in texture. In some lesions, the
dermal cells have nuclei that are larger
than is usual in common naevi, and
sometimes there is hyperchromatism and
a degree of pleomorphism, with or with-out nucleoli, representing cytologic atyp-ia which is present in about 50% of halo
naevi and is usually mild or at worst mod-erate in degree {1640}. This cytologic
atypia may represent a form of “inflam-matory” or reactive atypia. Mitotic figures
are completely absent in most lesions.
However, a few lesions judged to be
benign halo naevi have shown one or two
mitotic figures {1909}. Such a finding
should provoke careful examination of
the lesion to rule out melanoma, with
deeper sections and embedding of any
residual gross tissue. Findings sugges-tive of melanoma in a lesion simulating a
halo naevus include the presence of a
separate population of cells with an
expansile pattern of growth, severe uni-form cytologic atypia, and/or the pres-ence of frequent mitoses, ulceration or
necrosis. The halo phenomenon may
occasionally involve other types of naevi,
including dysplastic naevi {2370}, Spitz
naevi {972} and congenital naevi {2359},
as well as melanomas {2090}, and there-fore careful inspection of the underlying
lesional architecture and cytology in mul-tiple sections may be required for defini-tive classification.
The halo region at the periphery of the
dermal component of the lesion may
contain a few lymphocytes at the dermal-epidermal interface, with a reduction or
an absence of identifiable melanocytes.
In comparison with adjacent normal epi-dermis, pigment may be visibly reduced,
and this contrast can be enhanced with a
melanin stain. In most lesions, there is no
intra-epidermal melanocytic proliferation
adjacent to the dermal component, but in
a few lesions an adjacent component of
melanocytic dysplasia may be observed.
If an in situ or microinvasive (“ radial
growth phase”) component diagnostic of
melanoma is present adjacent to a der-mal lesion simulating halo naevus, the
entire lesion is most likely to represent
melanoma.
Differential diagnosis
The distinction from common acquired or
most other types of naevi is usually easy
because of the dense lymphocytic infil-trate. The most important differential
diagnosis is with melanoma. Compared
to nodular melanoma or to the tumouri-genic (vertical growth phase) component
of superficial spreading melanoma, a
halo naevus is usually smaller (the cen-tral naevus is usually less than 4 mm in
diameter, while most melanomas are
larger than 6 mm, though these values
are by no means absolute). However, we
have rarely observed small melanomas
with naevoid characteristics but with dif-fuse cellular atypia combined with mitot-ic activity in which diffuse lymphoid infil-tration was a prominent pattern. When
pigment is present in a halo naevus, it is
usually in the form of coarsely divided
granules as is the case in most benign
naevi, and if there is a junctional compo-nent, its character is that of a naevus
rather than a melanoma. Thus, there is
usually a discontinuous rather than con-tinuous proliferation of predominantly
nested rather than predominantly single
naevus cells, and there is little or no ten-dency to single-cell upward (“pagetoid”)
intraepidermal spread of the junctional
cells.
Some halo naevi may be difficult to dis-tinguish from dysplastic naevi that have
an unusually brisk lymphocytic infiltrate.
Indeed, not only do halo naevi appear to
be common in patients with dysplastic
naevi but also a halo response may be
seen, clinically and histologically, in dys-plastic naevi themselves. If the charac-teristic patterns of dysplasia are seen at
the “shoulder” of the compound portion
of a lesion whose other features are con-sistent with a halo naevus, the diagnosis
of dysplastic naevus with halo reaction
can be made. Especially if there is a his-tory of other atypical naevi and/or a per-sonal or family history of melanoma, sur-veillance may be warranted for such indi-viduals.
When naevus cells are inconspicuous
among a dense infiltrate of lymphocytes,
inflammatory dermatoses such as
lichenoid keratoses may be simulated
{844}. In these circumstances, an S-100,
Melan-A or HMB45 stain may reveal the
hidden naevus cells. Care must be taken
in interpretation, since histiocytes may
weakly express S-100, whereas activat-ed melanocytes and melanoma cells
may express HMB45. Finally, there are
lesions that have an infiltrative lympho-cytic response similar to that of a halo
naevus but there is no clinical halo.
These lesions may be signed out
descriptively as “compound (or dermal)
naevi with halo reaction” {1909}.
Conversely, some naevi with a clinical
halo may lack a lymphocytic infiltrate of
the type seen in halo naevi {812}. These
may be termed “non-inflammatory halo
naevi”.
B CA
Fig. 2.73  Halo naevus.  A Infiltrating lymphocytes are intimately admixed with naevus cells, which will lead to apoptosis and ultimate disappearance of the naevus
cells. In later examples, naevus cells are more inconspicuous than they are in this field.  B Extending 1 to 2 mm beyond the lateral border of the dermal naevus com-ponent, the papillary dermis is widened with slight fibroplasia, there is a patchy lymphocytic infiltrate, and there is absence of pigment and of melanocytes in the
overlying epidermis. This region constitutes the clinical halo.  C Normal skin adjacent to the halo shows a normal papillary dermis, normal melanin pigment in basal
keratinocytes, and the presence of melanocytes, which can be demonstrated if desired with a Melan-A stain.
120
CHAPTER 3
Appendageal Tumours
Appendageal tumours are neoplasms whose differentiation is
toward one or more of the adnexal structures of the skin. While
mesenchymal tumours of various kinds are technically in this
category, conventionally, the term refers to those with origin
from, or differentiation toward epithelial adnexal neoplasms.
Depending on their presumed origin, adnexal tumours are
categorized into those with apocrine and eccrine, foliicular and
sebaceous differentiation. For most of these tumour types there
are benign and malignant counterparts. The histopathological-criteria for prognosis of biological behaviour are well estab-lished.
The WHO Working Group was aware of recent evidence indi-cating that basal cell carcinoma (BCC) should be included
under the adnexal neoplasms under the term trichoblastic car-cinoma. The inclusion of BCC in the chapter on keratinocytic
tumours reflects the traditional categorization but does not indi-cate that the Working Group denies their adnexal origin.
122 Appendageal tumours
WHO histological classification of appendageal tumours
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.
Tumours with apocrine and eccrine differentiation
Malignant tumours
Tubular carcinoma 8211/3
Microcystic adnexal carcinoma  8407/3
Porocarcinoma 8409/3
Spiradenocarcinoma 8403/3
Malignant mixed tumour 8940/3
Hidradenocarcinoma 8400/3
Mucinous carcinoma  8480/3
Digital papillary carcinoma 8408/3
Adenoid cystic carcinoma 8200/3
Apocrine carcinoma 8401/3
Paget disease of breast 8540/3
Extramammary Paget disease 8542/3
Benign tumours
Hidrocystoma 8404/0
Syringoma 8407/0
Poroma 8409/0
Syringofibroadenoma 8392/0
Hidradenoma 8402/0
Spiradenoma 8403/0
Cylindroma 8200/0
Tubular adenoma 8211/0
Tubular papillary adenoma 8263/0
Syringocystadenoma papilliferum  8406/0
Hidradenoma papilliferum 8405/0
Mixed tumour (chondroid syringoma)  8940/0
Tumours with follicular differentiation
Malignant tumours
Pilomatrical carcinoma 8110/3
Proliferating tricholemmal tumour  8103/1
Benign tumours
Trichoblastoma 8100/0
Pilomatricoma 8110/0
Tricholemmoma 8102/0
Multiple tricholemmomas 8102/0
Trichofolliculoma 8101/0
Fibrofolliculoma / trichodiscoma  8391/0
Tumours with sebaceous differentiation
Sebaceous carcinoma 8410/3
Sebaceous adenoma 8410/0
Sebaceoma 8410/0
Cystic sebaceous tumour 8410/0
__________
1
{894,2219}.
2
A help desk for specific questions about the TNM classification is available at http://www.uicc.org/index.php?id=508 .
TNM classification 1,2
T – Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour 2 cm or less in greatest dimension
T2 Tumour more than 2 cm but no more than 5 cm in greatest
dimension
T3 Tumour more than 5 cm in greatest dimension
T4 Tumour invades deep extradermal structures, i.e., cartilage,
skeletal muscle, or bone
Note: In the case of multiple simultaneous tumours, the tumour with the
highest T category is classified and the number of separate tumours is
indicated in parentheses, e.g., T2(5).
N – Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M – Distant metastasis
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Stage grouping
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2, T3 N0 M0
Stage III T4 N0 M0
Any T N1 M0
Stage IV Any T Any N  M1
TNM classification of skin appendageal carcinomas
Epidemiology
Most studies on adnexal neoplasms
have taken place in western countries
with Caucasian populations. Benign
adnexal neoplasms tend to occur in
younger patients than carcinomas do.
Adnexal carcinomas vary from those in
which actinic damage is the norm, such
as the common basal cell carcinoma
(which differentiates toward follicular
germ) to those that seem to have little
relationship to sun exposure (such as
spiradenocarcinoma).
Etiology
No known triggering event is evident in
the vast majority of adnexal neoplasms.
There are some cases in which the cause
is an autosomal dominant mutation in a
tumour suppressor gene.
Clinical signs and symptoms
Most benign adnexal neoplasms are
smooth surfaced, symmetrical papules
or nodules the same colour as the
patient’s skin or darker. Some, such as
sebaceous adenoma and syringocys-tadenoma papilliferum, have eroded sur-faces, but in general, ulceration is a sign
of malignancy. Most adnexal carcinomas
are irregularly shaped plaques, some-times ulcerated.
Tumour spread and staging
In general, low-grade carcinomas sel-dom metastasize; for some, e.g. micro-cystic adnexal carcinoma, metastasis
has not yet been recorded.
A haematogenous pattern seems the rule
for a few carcinomas, such as adenoid
cystic carcinoma, but most can spread
via either lymphatic or haematogenous
dissemination. Carcino-mas with eccrine
differentiation have a propensity to
metastasize to the skin.
Sentinel node biopsy
While a few sentinel node biopsies have
been performed for adnexal carcinomas,
not enough data have been collected to
validate this procedure {274}.
Pathology
Diagnostic criteria of adnexal
carcinomas
> Irregular borders, asymmetry at scan-ning magnification
> Horizontal orientation
> Markedly irrregular aggregates of
epithelial cells
> Necrosis en masse
> Infiltration of the dermis or subcutis
without the interposition of densely
fibrotic stroma
> Mitoses frequent, can be atypical
> Stroma irregular, often scant,
sometimes myxoid
> Nuclei pleomorphic. Some neoplasms
with monomorphous nuclei, e.g.
microcystic adnexal carcinoma, are
exceptions.
Diagnostic criteria of benign epithelial
adnexal neoplasms {28}:
> Symmetric and smooth bordered at
scanning magnification
>Vertically oriented with respect to the
surface of the skin
> Aggregates of epithelial cells uniform
> No necrosis en masse (with the exce-tion of poroma)
> Mitoses variable, but typical
> Densely fibrotic stroma, rich in fibro-cytes in the case of trichogenic
> Neoplasms forming a blunt, rounded
interface with the native dermis. An
exception is poroma, which has
vascular, myxoid stroma.
> Nuclei monomorphous; rare excep-tions include atypical squamous
nuclei in poromas.
Immunoprofile
Most adnexal neoplasms are accompa-nied by variably dense infiltrates of T-cells. These are intimately admixed with
the neoplasm (spiradenoma, cutaneous
lymphadenoma, adamantinoid tricho-blastoma) and lymphoepithelioma-like
carcinoma among malignancies are
examples. Syringocystadenoma papil-liferum has a complement of plasma
cells, many of which secrete IgA.
A complex array of keratins are
expressed in adnexal neoplasms. Those
with follicular germinative differentiation
express cytokeratins seen in follicular
germs in embryonic and neonatal life.
Those with ductular differentiation have
lumens that stain for carcinoembryonic
antigen (CEA), and express simple
epithelial keratins. Sebaceous differenti-ation is characterized by expression of
epithelial membrane antigen in a
microvacuolar pattern.
Precursor lesions
Benign adnexal neoplasms of various
sorts can arise in naevus sebaceous, a
malformation involving the epidermis,
dermis and adnexae. Otherwise, most
benign adnexal neoplasms arise de
novo. This is also the case for malignant
adnexal neoplasms. Rare apocrine carci-nomas arise in naevus sebaceous.
Rarely, porocarcinoma, spiradenocarci-noma or hidradenocarcinoma may arise
in a pre-existent poroma, spiradenoma,
or hidradenoma, respectively. The vast
majority of basal cell carcinomas arises
de novo. Rarely, basal cell carcinomas
occur in pre-existent trichoblastomas.
Histogenesis
The origin of most adnexal neoplasms is
unknown. It is better to speak of their dif-ferentiation. The most clear-cut evidence
of differentiation is in follicular neo-plasms, where such signs as follicular
papillae and germs (as in the trichoblas-tomas) or trichohyaline granules (as are
focally found in pilomatricoma and in
matrical carcinomas) can occur. Clear-cut apocrine differentiation, in which
decapitation secretion of columnar cells
that have brightly eosinophilic cytoplas-mic granules is also specific. However,
there is a marked similarity between
eccrine and apocrine ducts. Also, the
columnar cells of eccrine secretory coils
can resemble poorly differentiated apoc-rine secretory cells. Hence, neoplasms
with ductular differentiation often have
debatable histogenesis {1543}. To some
P.E. LeBoitAppendageal skin tumours:
Introduction
123Introduction
extent, the differentiation of neoplasms
probably reflects their distribution {1544}.
Genetics
Approximately one third of sweat gland
carcinomas contain TP53 mutations
{239A}. Otherwise, little is known about
the genetics of most epithelial neo-plasms, with the exception of those that
occur in multiplicity as part of autosomal
dominant syndromes (see Chapter 7).
The mutations found in the germlines of
patients with syndromes and multiple
tumour suppressor genes tend to be the
same as occur as somatic mutations in
sporadic adnexal neoplasms. Some
trichoblastomas have mutations in the
PTCH gene, as found in naevoid basal
cell carcinoma syndrome (Gorlin-Goltz
syndrome). Trichilemmomas have muta-tions in PTEN, the same gene as involved
in Cowden syndrome. Mutations in DNA
repair genes occur in the sebaceous
neoplasms of the Muir-Torre syndrome
and, to a lesser degree, in sporadic
sebaceous neoplasms.
Prognosis and predictive factors
In general, adnexal carcinomas of low
cytologic grade have a good prognosis,
especially if the lesion is relatively small
and completely excised. Those of high
cytologic grade may metastasize widely.
For many adnexal carcinomas, there are
simply insufficient numbers of reported
cases to develop much of an idea
regarding their prognosis.
124 Appendageal tumours
Tubular carcinoma
Definition
Tubular carcinoma is the malignant coun-terpart of tubular adenoma, featuring
apocrine differentiation with prominent
tubular structures.
ICD-O code 8211/3
Historical annotation
Probably the first reported examples of
tubular carcinoma were included in the
series of carcinomas of sweat glands
published by Stout and Cooley in 1951
{2274}.
Epidemiology
Tubular carcinoma seems to be slightly
more frequent in women. Most patients
are middle-aged adults.
Localization
The axilla is the most common location,
with rare bilateral involvement. Other
sites rich in apocrine glands may also be
involved {114,127,1705,1785,2274,2397,
2460,2569}.
Clinical features
Tubular carcinoma usually presents as a
firm erythematous nodule, which may be
ulcerated or adherent to deeper tissues.
Tubular carcinomas may arise in naevus
sebaceous {644}.
Histopathology
At scanning magnification, the neoplasm
is asymmetric, poorly circumscribed,
and infiltrative with prominent and crowd-ed tubular and ductal structures. The
lesion often involves the full-thickness of
the dermis and it may extend to the sub-cutaneous tissue. Neoplastic structures
show marked variation in size and shape,
but, in general, the size of the tubules
tends to decrease from superficial to
deeper areas. The more superficial larg-er tubules may show luminal papillations.
At higher magnification, epithelial cells
lining the tubules show abundant
eosinophilic or granular cytoplasm and
pleomorphic nuclei, some of them in
mitosis. Often the cytoplasm of these
cells exhibits signs of decapitation
secretion. Lumina are often filled with
homogenous eosinophilic material,
foamy histiocytes and necrotic debris.
Examples of tubular carcinoma may also
exhibit focally solid areas with a combi-nation of cribriform or adenoid cystic pat-terns as additional morphologic expres-sions. Areas of necrosis en masse are
also frequent, but in contrast with ade-noid cystic carcinoma, tubular carcino-ma shows no deposits of basement
membrane material within the aggrega-tions of neoplastic cells and perineural
involvement is usually absent. The stro-ma is sparse.
Before a diagnosis of primary tubular
carcinoma of the skin is established, the
possibility of cutaneous metastasis from
a visceral tubular carcinoma should be
ruled out.
Immunoprofile
Tubular carcinoma shows immunoreac-tivity with low molecular weight cytoker-atins and the luminal cells express EMA
and GCDFP-15. Expression of CEA is
variable {1785,2569}.
Histogenesis
The presence of decapitation secretion
and continuity between neoplastic
tubules and follicular infundibula are
signs of apocrine differentiation. This is
further supported by enzyme histochem-istry.
Prognosis and predictive factors
Tubular carcinoma of the skin behaves in
a highly malignant fashion. Of the 44
examples reported in the literature, neo-plasms from 21 patients metastasized
and at least 9 patients died as a result of
widespread metastatic disease {1705,
1785,2397,2569}.
Microcystic adnexal carcinoma
Definition
Microcystic adnexal carcinoma {861} is a
locally infiltrative and destructive low-125Malignant tumours with apocrine and eccrine differentiation
Fig. 3.01 Tubular carcinoma on the retroauricular
left region.
BA
Fig. 3.02 Tubular carcinoma.  A The neoplasm involves the full-thickness of the dermis and extends into sub-cutaneous tissue. The stroma is sparse and the epithelium predominates over the stroma.   B Some neo-plastic aggregations of this tubular carcinoma exhibit focally an adenoid cystic pattern.
L. Requena
H. Kutzner
M. A. Hurt
D. J. Santa Cruz
A.H. Mehregan
Malignant tumours with apocrine and
eccrine differentiation
Y.  M .  Mengesha
S. Kohler
Z B. Argenyi
J. McNiff
P. Rudolph
O. P. Sangüeza
grade adenocarcinoma differentiated
toward ducts. It has little capacity to
metastasize.
ICD-O code 8407/3
Synonyms
Sclerosing sweat duct carcinoma {541},
eccrine epithelioma, syringomatous car-cinoma.
Clinical features
The carcinoma occurs on the face of
adults, more commonly in women. It
affects commonly the face {469} and lip,
uncommonly other locations, and grows
slowly over a period of months to years.
It is similar usually to a depressed scar
and rarely causes ulceration.
Histopathology
The classical pattern is that of small,
superficial, solid to cystic structures that
are similar to small infundibular cysts and
ducts. In the middle depth, the lesion is
composed completely of small ducts,
often in very subtle patterns, frequently
with involvement of nerves and perineur-al spaces. In the deepest areas, “Indian”
filing and sclerosis are common findings.
Thus, there is a sense that the lesion is
stratified from superficial (tubules and
cysts) to deep (epithelial cords and scle-rosis).
Unusual examples contain sebocytic
zones {1862}, and others contain areas
similar to follicular sheath, thus suggest-ing differentiation toward the folliculo-sebaceous-apocrine unit. In other cases,
the lesions are exclusively ductal, caus-ing some authors to designate them as
“syringomatous carcinoma” or “scleros-ing sweat duct carcinoma” and suggest-ing that these examples could be
derived from eccrine ducts. Some MACs
have solid poromatous or clear cell cytol-ogy. Cytologically, the lesions are well
differentiated, lacking nuclear pleomor-phism or mitotic figures. In fact, the find-ing of nuclear pleomorphism should
cause one to reconsider whether the
diagnosis of microcystic adnexal carci-noma is correct.
Immunoprofile
There is cytoplasmic staining with
AE1/AE3, CK7, and bcl-2. EMA and Ber-EP4 stain in a membranous pattern
around ductal cells near the lumen.
Alpha SMA and S100 protein stain the
126 Appendageal tumours
Fig. 3.04 Microcystic adnexal carcinoma.  A There are a few cysts and solid nests, but no nuclear pleomorphism. The pattern of the lesion helps to recognize it as
carcinoma.  B Not only are there ducts; there are also strands and small nests of neoplastic cells.  C This example of microcystic adnexal carcinoma again illus-trates the zonation pattern, in this case with a few cysts superficially. Note the deep nests that are present in and around the sucutis; not every case will contain
compressed ducts exclusively in the deep zones.  D This example is similar to some poromas. There are solid nests of monomorphous cells as wells as nests of
cells with clear cytoplasm. Some authors have designated these lesions “syringomatous” carcinoma.  E Despite the striking structural patterns of these lesions,
most do not contain nuclear pleomorphism.  F Peripheral nerve, completely encircled by the neoplasm.  Note the ductal space.
FED
CBA
Fig. 3.03  Microcystic adnexal carcinoma. Scanning magnification of microcystic adnexal carcinoma illus-trates the zonal effect with solid nests and cysts superficially with complex glands deep.
tubules peripherally. P53 is positive in
less than 25% of the neoplastic cells.
There is a low proliferative index, as Ki-67 is positive in less than 5% of the neo-plastic cells. CK20, c-erb-2, and CD34
are negative {2207}.
Differential diagnosis
The principal differential diagnoses are
with superficial biopsies of columnar tri-choblastoma (desmoplastic trichoepithe-lioma) or morpheiform basal cell carcino-ma (trichoblastic carcinoma), all of which
are CK7 negative. Syringoma is a possi-ble consideration in some cases. Rare
examples of metastatic carcinoma to the
skin can also mimic it.
Genetics
There is a single report of a 6q deletion
{2538}. There is also a report of 2 micro-cystic adnexal carcinomas, one of which
was diploid, and the other, aneuploid,
when examined with DNA image cytom-etry {2437}.
Prognosis
Treatment is surgical, with microscopic
control of margins if possible {9}.
Radiotherapy has proven successful
rarely, but some reported cases have
taken on an even more virulent biology
after such treatment.
Malignant mixed tumour
Definition
Malignant mixed tumour (MMT) is an
exceedingly rare cutaneous adnexal car-cinoma with a significant risk for aggres-sive behaviour and a propensity for
metastasis. MMT is regarded as the
malignant counterpart of benign mixed
tumour {1919} albeit histological diagno-sis is foremost based on the biphasic
nature of the neoplasm rather than an
admixture of benign mixed tumour rem-nants with carcinomatous tissue {2515}.
ICD-O code 8940/3
Synonyms
Malignant apocrine mixed tumour.
Malignant chondroid syringoma.
Epidemiology
MMT represents an exceedingly rare
cutaneous adnexal neoplasm which
occurs in a wide age range (15 months
127Malignant tumours with apocrine and eccrine differentiation
Fig. 3.05  Malignant mixed tumour. Lobulated biphasic tumour consisting of epithelial and mucinous-mes-enchymal components. The former predominate at the periphery, while the latter predominate at the cen-ter.
Fig. 3.06 Malignant mixed tumour.  A Hyperchromatic tumour cells with mitoses.  B Note variations of cyto-logical differentiation and pleomorphism.  C Focal zone of tubule formation.  D Highly pleomorphic tumour
lobules with mitoses at the periphery of the tumour.  E Note the pseudo-sarcomatous pattern with hyper-chromatic spindle cells and many mitoses.  F Nests of plasmacytoid tumour cells amidst a myxoid stroma.
Plasmacytoid epithelial differentiation is a hallmark of myoepithelial differentiation.
FE
DC
A B
to 89 years; average 50 years) and is
twice more common in women than in
men {177,1919}.
Localization
In marked contrast to its benign counter-part MMT shows a predilection for the
trunk and the extremities, foremost the
hands and feet {177,961,1593,1903,
1919,2177,2377}.
Clinical features
MMT shares most clinical characteristics
with its benign counterpart, albeit
tumours of the former are much larger at
the time of presentation (2-15 cm in
diameter). Rarely, rapid growth, ulcera-tion, or pain in a previously indolent skin
tumour indicate carcinomatous growth.
Most MMT, however, present in a rather
bland way with a long history prior to
excision. These tumours are well circum-scribed and may appear cystic. They are
not painful, not ulcerated, and show no
distinctive clinical appearance.
Macroscopy
Grossly, most MMT are firm, circum-scribed, asymmetrical cutaneous or sub-cutaneous tumours with a diameter of up
to 15 cm. The tumour cut surface may
reveal gelatinous material in variable
amount {1919}. Because of the infiltrative
tumour growth enucleation is not possi-ble.
Histopathology
MMT originates within the dermis or
superficial subcutis, and presents as a
large, asymmetrical, poorly circum-scribed, lobulated biphasic tumour with
infiltrative tumour margins and adjacent
satellite tumour nodules. Juxtaposed
areas of benign and malignant mixed
tumour may rarely occur, but are not a
prerequisite for the diagnosis of MMT.
MMT is composed of both epithelial and
mesenchymal components, with epithe-lial components predominating at the
periphery and mesenchymal chondro-myxoid elements being more abundant
toward the centre {2100}. The chondro-myxoid tumour stroma is PAS-negative
and consists of hyaluronic acid and sul-phated acid mucopolysaccharides
{1112}. Stroma ossification is rare {961,
2177}. Epithelial tumour aggregations
present as confluent cords and nests of
variable size and shape, with inter-spersed zones of tubule formation.
Tubular structures may be either of the
elongated apocrine type lined by at least
two layers of epithelial cells, with luminal
cells exhibiting signs of apocrine secre-tion and abluminal cells showing plasma-cytoid / myoepithelial differentiation, or –
more rarely – of the eccrine type showing
small round structures lined by a single
layer of atypical epithelial cells {961,
1919}. Often, however, MMT consists
only of solid aggregations devoid of
tubules {928, 1919, 2471}. Epithelial
tumour cells may either have a decep-tively bland appearance {1112,2100} or
show distinctive atypia and pleomor-phism of nuclei with a high nuclear-cyto-plasmic ratio and numerous mitotic fig-ures {1919}. Zones of necrosis are com-mon. Characteristic epithelial tumour
cells are cuboidal with distinctive polyg-onal or plasmacytoid features {961,
1919}. The latter is considered an indica-tor of the myoepithelial/apocrine origin of
the neoplasm and may be seen as a clue
to the diagnosis of MMT {1919}.
Immunoprofile
Tumour cells may show a myoepithelial
immunophenotype with coexpression of
S100 and cytokeratin {177,976,1839,
2471} and actin expression in a minority
of cells {1488}. Spindle cells within the
myxoid stroma are vimentin-positive
{2117}.
Electron microscopy
Tumour cells exhibit ultrastructural fea-tures of myoepithelia with desmosomes
and abundant intracytoplasmic filaments
{177,1839,2471}. However, ultrastructur-al studies so far have not presented con-vincing evidence of either apocrine or
eccrine differentiation of MMT {1919}.
Variants
MMT may exhibit deceptively bland cyto-logical features {1112,2100} albeit asso-ciated with distinctive architectural crite-ria of malignancy, e.g. asymmetry, poor
circumscription, infiltrative tumour mar-gins, and satellite nodules.
The recently described malignant mixed
tumour of soft tissue {1062} shows over-lapping histologic criteria with MMT of
the skin. The former is considered to be
part of the morphological spectrum of
myoepithelial tumours of soft tissue.
Differential diagnosis
Extraskeletal myxoid chondrosarcoma
consists of non-cohesive elongated
tumour nests without ductal or tubular
structures. Tumour cells are cytokeratin
negative. Mucinous carcinoma and myx-opapillary ependymoma show distinct
PAS positivity of the extracellular myxoid
stroma. Cutaneous myoepithelial carci-noma favours monophasic differentiation
with a very discrete myxoid stroma
{1585}. MMT and cutaneous myoepithe-lial carcinoma may fall along a spectrum
of tumours with overlapping histologic
appearances {1585}.
Histogenesis
MMT probably does not originate in
association with its benign counterpart,
but develops de novo {1919}. A myoep-ithelial origin of MMT appears to be most
plausible {177,1585,2100}, and MMT
may be included in the spectrum of cuta-neous myoepithelial neoplasms {1585}.
Prognosis and predictive factors
MMT proliferates in an invasive and
destructive fashion, with a high rate of
local recurrences and metastases
(>50%) into regional lymph nodes, lung,
and bone {177,1593}. Death ensues in
>25% {177}. However, in >30% MMT nei-ther recurred nor metastasized (“atypical
mixed tumour of the skin”) {177}. In gen-eral, MMT is characterized by its pro-longed course {2467}. It is remarkable
that non-metastasizing MMTs showed
the same histological spectrum as those
of proven malignancy {1919}, ranging
from bland cytological appearance {961}
to marked nuclear pleomorphism and a
high mitotic count {2377}. Complete exci-sion before metastasis results in tumour
free survival {1919}.
Porocarcinoma
Definition
Eccrine porocarcinoma is a malignant
tumour related to the sweat gland duct,
showing both intraepidermal and dermal
components.
ICD-O code 8409/3
Synonyms and historical annotation
Epidermotropic eccrine carcinoma,
malignant eccrine poroma, malignant
hidroacanthoma simplex, malignant
intraepidermal eccrine poroma, poroep-ithelioma. The tumour was first described
128 Appendageal tumours
by Pinkus and Mehregan in 1963 as epi-dermotropic eccrine carcinoma {1837}.
Epidemiology
Eccrine porocarcinoma is a rare tumour,
predominantly observed in elderly
patients with an average age of 67 years
{1072}. Women and men are equally
affected. The incidence in one large
series was 18 per 450,000 cases
(0.004%) {1571}.
Etiology
Eccrine porocarcinomas may arise de
novo or as a malignant transformation in
a pre-existing poroma, hidroacanthoma
simplex, or in association with naevus
sebaceous {1571,2216,2604}. 18 to 50%
of eccrine porocarcinomas are associat-ed with pre-existing eccrine poromas.
Localization
Forty-four to 50% of eccrine porocarcino-mas arise on the legs, buttocks, or feet
{2216}. The trunk accounts for 24% of the
lesions and the head 18% of the lesions
with less frequent lesions located on the
upper extremities {1072}.
Clinical features
Eccrine porocarcinoma presents as a
verrucous nodulo-ulcerative plaque.
Clinically the lesions may resemble an
eccrine poroma, verruca vulgaris, sebor-rhoeic keratosis, melanocytic naevus,
fibroma, basal cell carcinoma, squamous
cell carcinoma, or pyogenic granuloma.
Diagnosis is made by skin biopsy.
Histopathology
Eccrine porocarcinoma forms intraepi-dermal and dermal nests and cords of
epithelial cells with pale cytoplasm. The
tumour masses form clearly demarcated
and frequently rounded nests of polygo-nal cells with pleomorphic and irregular-ly-shaped nuclei, prominent nucleoli, and
numerous mitotic figures. There is sharp
demarcation of the epithelial nests of
cells from the adjacent epidermal ker-atinocytes {1837}. The overlying epider-mis may be acanthotic. Both single
tumour cells and nests of cells may
involve the epidermis in a pagetoid fash-ion {1359}. Keratinization is usually
absent. Intercellular bridging between
the tumour cells is inconspicuous. The
tumour cells may contain glycogen
{2000}. Connection to the intradermal
eccrine ducts may be observed. Deep
dermal intralymphatic invasion may be
observed in up to 15% of the lesions
{1952}.
The differential diagnosis includes
eccrine poroma, hidroacanthoma sim-plex, and Paget disease {913}. Eccrine
poroma and hidroacanthoma simplex
may show focal atypia, but the lesions
are symmetrical and well circumscribed.
Eccrine porocarcinoma may be differen-tiated from Paget disease by its relative-ly sparse epidermal involvement and
greater dermal invasion, and the pres-ence of glycogen rather than mucin in
tumour cells {913}. In the absence of
residual eccrine poroma, it is very diffi-cult to differentiate eccrine porocarcino-ma from squamous cell carcinoma
{1571}.
Immunoprofile
The tumour nodules stain with antibodies
to pan-cytokeratin; tumour cells may
stain paler than adjacent epidermal ker-atinocytes {499,1072}. Ductal structures
within the tumour stain strongly positive
with CEA and EMA {1359,2216}.
Genetics
Mutation of the p53 gene with loss of its
suppressor function has been widely
noted with malignant transformation. P53
protein expression has been observed in
both eccrine poromas and eccrine poro-carcinoma {43,2327}. P16 staining is uni-formly negative {914}.
Prognosis and predictive factors
Approximately 20% of eccrine porocarci-nomas recur after excision {2216}.
Regional lymph node metastasis occurs
in 20% of patients, while 12% develop
distant metastases {2216}. Patients with
metastatic disease have a high mortality
rate {170}. Increased number of mitoses,
129Malignant tumours with apocrine and eccrine differentiation
Fig. 3.07 Porocarcinoma.  A Multinodular ulcerated
plaque.   B Closely arranged polygonal cells with
hyperchromasia.
A
B
Fig. 3.08 Porocarcinoma. There is a dermal component, partly in apposition with the epidermis, and a large
tumour nodule extending into the deep subcutaneous tissues. The lesion is remarkably well demarkated.
lymphovascular invasion and tumour
depth greater than 7 mm have all been
associated with a relatively poor progno-sis {1952}.
Spiradenocarcinoma
Definition
Spiradenocarcinoma is a malignant
adnexal neoplasm resulting from malig-nant transformation of a benign spirade-noma.
ICD-O code 8403/3
Synonym
Malignant spiradenoma
Epidemiology
Spiradenocarcinoma is an extremely rare
tumour. Approximately 50 well-docu-mented cases have been reported. The
tumour mainly affects middle age per-sons (mean age is 55 yr), and its inci-dence is similar in both sexes.
Localization
Spiradenocarcinoma can affect any
body site, but the most common loca-tions are the upper extremities, followed
by the lower extremities, trunk, and the
head and neck areas {725,884}.
Clinical features
Typically there is a history of a long-standing lesion that suddenly became
enlarged, ulcerated, tender, or changed
its colour. The size of the tumour ranges
from 0.8-10 cm. The mean duration of a
pre-existent lesion is about 20 years
before the diagnosis is made {725}. The
patient may also have multiple long-standing spiradenomas, which often
coexist with cylindromas {89}.
Histopathology
In all cases there are recognizable areas
of a benign spiradenoma with the usual
well-defined dermal nodules composed
of two cell types. Spiradenocarcinoma
arising from benign spiradenoma pres-ents two major histologic patterns {89,
725,884}. In one type, there are areas
showing gradual transition from benign
to a malignant neoplasm. In these lesions
the dual cell population of the benign
neoplasm imperceptibly merges with the
monomorphous cell population of the
carcinoma. The usual structural pattern
of spiradenoma disappears and is
replaced by poorly defined cell nests
and cords. Glandular and duct-like struc-tures, as well as hyaline globules, are
diminished or may be missing. These
changes can be very focal in early
lesions and can easily be missed without
adequate tissue sampling. In the second
type, the malignant changes are adja-cent to the spiradenoma without structur-al or cytological transition. These neo-plasms can present a wide spectrum of
histologic features including squamous,
bowenoid, adenomatous, ductal carcino-ma-like, and even histiocyte-like and car-cinosarcomatous changes with rhab-domyoblastic or osteosarcomatous dif-ferentiation {1391,1548,1958}. In advan-ced stages of both subtypes, necrosis,
haemorrhage, and infiltrative growth can
be observed.
Immunoprofile
Spiradenocarcinoma is positive for the
majority of cytokeratins, CEA, EMA, and
shows a spotty reaction for S-100 pro-tein. Over-expression of P53 has also
been reported {89,726,1555,2516}.
130 Appendageal tumours
C
Fig. 3.09 Spiradenocarcinoma.  A Transitional changes from benign to malignant. Note transitional area with
hypercellularity, hyperchromasia and diminished preservation of the usual histologic pattern of a spirade-noma.   B Spiradenocarcinoma with transitional changes from benign to malignant. Malignant area with
occasional residual duct-like structures with clear cell changes and prominent cytologic atypia.
C Spiradenocarcinoma with unusual cytodifferentiation, squamous “bowenoid” dysplasia.
A
B
Fig. 3.11 Hidradenocarcinoma involving the left
preauricular skin of an elderly male. Note the pres-ence of a retroauricular lymphadenopathy.
Fig. 3.10 Spiradenocarcinoma. Well-defined,
encapsulated mass with areas of solid and cystic
changes and haemorrhage.
Histogenesis
Theoretically, spiradenocarcinoma can
develop de novo. However, the tumour
lacks distinctive microscopic features,
therefore its histopathologic diagnosis
requires recognition of a spiradenoma in
association with the malignant changes.
Somatic genetics
TP53 mutations have been identified in
carcinomatous portion of spiradenocar-cinoma, whereas the spiradenoma part
lacked mutations {239A}.
Prognosis and predictive factors
Spiradenocarcinoma is an aggressive
neoplasm with multiple local recurrences
and eventual widespread metastases,
resulting in death. The metastases most
often involve lymph nodes, bones, and
lungs. Management is primarily surgical;
the role of radiation and chemotherapy is
still to be defined {1110,1594}.
Hidradenocarcinoma
Definition
Hidradenocarcinoma is the malignant
counterpart of hidradenoma.
ICD-O code 8400/3
Synonyms
Clear-cell papillary carcinoma {1436},
clear-cell hidradenocarcinoma {1249,
1470}, malignant clear-cell hidradenoma
{578,1237}, malignant clear-cell acro-spiroma {992}, malignant eccrine acro-spiroma {1741}, primary mucoepider-moid carcinoma of the skin {803, 2497},
nodular hidradenocarcinoma, clear-cell
eccrine carcinoma {2300}, mucoepider-moid hidradenocarcinoma {637}, and
malignant nodular clear-cell hidradeno-ma {204}.
Epidemiology
Hidradenocarcinoma seems to be slight-ly more frequent in women than in men,
with the mean age of 50 years, but cases
have been also recorded in children
{237,477}.
Etiology
Most cases of this carcinoma arise de
novo, but some cases are associated
with a hidradenoma {237,1013,1237,
1249,1427}.
Localization
This carcinoma may appear in any area.
Clinical features
The neoplasm does not have any distinc-tive clinical features and usually presents
as a slow growing solitary dermal or sub-cutaneous nodule.
Histopathology
Hidradenocarcinoma is composed of
one or several tumour nodules, which
vary in size and shape. Focal tubular and
ductal structures may be present. Areas
of necrosis en masse are common.
Usually there is no connection between
the epidermis and the tumour, but the
surface epithelium may be ulcerated.
The same cell types as seen in hidrade-noma are found in hidradenocarcinoma.
Atypical cells with pleomorphic nuclei
and mitotic figures may be focally promi-nent, but some tumours lack nuclear
atypia. Therefore, the diagnosis can be
established only on the basis of architec-tural characteristics.
Immunoprofile
Neoplastic cells express low molecular
weight cytokeratin CAM 5.2 and cytoker-atin 19. CEA and EMA decorate the lumi-nal border of ductal structures.
Histogenesis
Most neoplasms have apocrine differen-tiation, but some show eccrine features.
Prognosis and predictive factors
This carcinoma may metastasize widely
and cause death. Of the 76 patients with
this carcinoma described in the litera-ture, 22 developed metastases {204,485,
992,1013,1162, 2468}.
131Malignant tumours with apocrine and eccrine differentiation
Fig. 3.12 Hidradenocarcinoma.  A At scanning power the neoplasm appears as a well-circumscribed round nodule involving the full thickness of the dermis.
B Although the neoplasm is mostly a solid tumour, in some areas there is evidence of ductal differentiation in the form of cytoplasmic vacuoles and small round
ducts.
BA
Fig. 3.13 Mucinous carcinoma. Note typical “honey-comb pattern” with small epithelial strands floating
in lakes of mucin.
Mucinous carcinoma
Definition
Primary cutaneous mucinous carcinoma
(MC) is a rare epithelial neoplasm occur-ring mostly, but not exclusively, in mid-dle-aged and older patients. Although
MC is characterized by destructive local
growth and the potential of metastasizing
to regional lymph nodes and even be-yond them, it generally follows an indo-lent course with frequent local recurren-ces. Mucinous carcinoma metastatic to
skin from another organ, particularly the
breast and gastrointestinal tract, may be
histologically indistinguishable from MC.
ICD-O code 8480/3
Synonyms
Primary cutaneous mucinous carcinoma.
Colloid, gelatinous and adenocystic car-cinoma.
Epidemiology
MC is very rare and occurs mostly
between the fifth and seventh decades of
life, with an age range between 8 and 84
years. MC is slightly more common in
men than in women {1919}.
Localization
Most MC arise on the head, favouring
scalp and face with preference of the
eyelids {199,305,1212,2217,2319}. Rare
sites are axillae, trunk, lower extremities,
perianal area and vulva {1919}.
Clinical features
MC presents as a solitary, slowly grow-ing, painless nodular neoplasm. The
tumour has a tan, grey, or reddish colour,
a smooth surface, and a consistency
ranging from soft to firm. Positive trans-illumination may be a helpful diagnostic
tool.
Macroscopy
Grossly, most MC are well-circum-scribed, un-encapsulated tumours in the
dermis and the subcutaneous fat.
Tumour diameters range between 1 and
8 centimetres, albeit larger variants have
been reported {1231}. On excision, the
tumour appears fixed to the adjacent
dermis and does not “shell out” {1919}.
The cut surface of excised specimens is
gelatinous.
Histopathology
MC presents as an un-encapsulated
asymmetric dermal tumour that may
extend into the subcutis and even deep-er tissue planes {1919}. Tumour satellites
may occur at some distance from the
main tumour. MC is characterized by
large pools of basophilic mucin, which
are compartmentalized by delicate
fibrous septa, thereby creating a honey-comb pattern. Within the lakes of mucin
are small “floating” islands and bizarre
clusters of neoplastic epithelial cells,
sometimes exhibiting a cribriform
arrangement. The epithelial component
is denser at the periphery of the tumour.
Small glandular or tubular structures
containing mucin or showing signs of
apocrine secretion occur only rarely. The
small neoplastic cells are cuboidal,
round, or oval with abundant cytoplasm
that may be vacuolated. Nuclei are small
with very little atypia. Mitoses are rare.
The epithelial mucin is PAS-positive,
hyaluronidase and sialinase labile, and
consists of non-sulphated acid
mucopolysaccharides with sialic acid.
Immunoprofile
Neoplastic cells express low molecular
weight cytokeratins, CEA, EMA, GCDFP-15, alpha-lactalbumin, salivary amylase,
beta-2-microglobulin. S100 expression is
inconstant {199,404,664}. Nuclear
expression of oestrogen receptors may
be strong, but the pattern of progesteron
receptors is more variable {945}.
Cytokeratin 20 expression allows differ-entiation of mucinous gastrointestinal
carcinoma metastatic to the skin from
primary cytokeratin 20-negative cuta-neous MC {664}.
Variants
MC very rarely presents with focal neu-roendocrine differentiation {1876}, or with
a growth pattern imitating infiltrating car-cinoma of the breast {2557}.
Epidermotropism of neoplastic cells is
unusual.
Electron microscopy
There are less well-differentiated inner
pale cells and mucin-containing periph-eral dark cells {990}.
Differential diagnosis
Before a diagnosis of MC is established,
a primary carcinoma in a breast or anoth-er organ (salivary and lacrimal glands,
gastrointestinal tract, nose and
132 Appendageal tumours
Fig. 3.14 Mucinous carcinoma.  A Large mucin deposits clearly predominate over epithelial tumour components – in sharp contrast to cutaneous metastasis of muci-nous breast carcinoma where epithelial tumour cells predominate and delicate fibrous septa are scarce.  B Thin strands of epithelial tumour cells with little atypia
and very scarce mitoses. Note delicate fibrous septa and incipient tubule formation.
BA
paranasal sinuses, bronchi, ovary and
renal pelvis) should be specifically
sought and excluded as most cases of
mucinous carcinoma in the skin are
metastatic to it. Histological differentia-tion between primary cutaneous MC and
metastatic mucinous carcinoma to the
skin may be impossible, albeit the latter
exhibits subtle histological variations
{1919}: e.g. larger clusters of cohesive
neoplastic cells, less quantities of mucin,
a striking predominance of epithelium
over mucin, and the absence of delicate
fibrous septa that intersect the lakes of
mucin.
Malignant mixed tumour of the skin
exhibits tubular structures embedded in
a myxoid, chondroid, or osteoid stroma,
and distinctive polygonal and plasmacy-toid neoplastic epithelia. The character-istic honeycomb pattern of MC is not
present {1919}.
Histogenesis
Histogenesis of MC has not yet been elu-cidated, but there is strong morphologi-cal evidence that MC may be apocrine in
nature {1919}.
Prognosis and predictive factors
In contrast to most other sweat gland
carcinomas, MC is a low-grade malig-nant neoplasm with a tendency to persist
at the original site but with a low metasta-tic potential. 10% of the MC so far report-ed metastasized to regional lymph
nodes, but only 3% metastasized in a
more widespread fashion {1830}. While
multiple recurrences, due to the exis-tence of tumour satellites, are not unusu-al, death from MC is exceptional {1919}.
Digital papillary carcinoma
Definition
Digital papillary carcinoma is regarded
as an uncommon malignant adnexal
neoplasm with potential for both recur-rence and metastasis.
ICD-O code 8408/3
Synonyms
Aggressive digital papillary adenoma,
digital papillary adenocarcinoma
Historically, this group of lesions was
divided histologically into aggressive
digital papillary adenomas and digital
adenocarcinomas {1205}. However,
cases originally classified histologically
as adenoma developed metastases,
demonstrating that histologic parameters
do not accurately predict behaviour or
allow distinction between adenoma and
adenocarcinoma {655}. Therefore, the
term aggressive digital papillary adeno-ma has been abandoned in favour of
classification of all such lesions as digital
papillary carcinoma.
Epidemiology
Digital papillary carcinomas present
almost exclusively on the fingers, toes,
palms, and soles. Hands are involved
more frequently than feet. There is a male
predilection, and most affected individu-als are adults in the fifth and sixth
decades of life.
Clinical features
Most cases present as a slowly growing
deeply seated nodule on a digit. Lesions
may be several centimetres in diameter.
Pain is occasionally a presenting com-plaint, and may be related to tumour
extension into underlying bone, joint, or
nerve. Rarely, metastasis is the first man-ifestation of disease. Unless underlying
bone has been invaded, routine
roentgenographic examination may be
essentially unremarkable.
Histopathology
Typically, tumours are composed of
multi-nodular epithelial aggregates with
cystic spaces in the dermis. A cribriform
pattern of glands often fills the solid
areas of tumour, while papillary epithelial
projections are common within cystic
spaces. The papillary projections are
associated with fibrovascular cores in
some areas, while in other areas papillae
are formed by heaped up epithelium
without stromal support. The epithelium
is composed of low columnar or cuboidal
cells. Cytologic atypia is usually not
marked. Mitoses and necrosis are fre-quent findings. Cysts contain either
necrotic debris or eosinophilic secretory
material. Some tumours are well-circum-scribed, while others have an infiltrative
growth pattern.
Differential diagnosis
The differential diagnosis includes papil-lary eccrine adenoma, which is usually
well-circumscribed, and composed of
dilated ducts with a distinct two cell layer
and delicate papillae. Malignant adnexal
neoplasms such as malignant acrospiro-ma and malignant spiradenoma are also
in the differential, but typically lack the
pattern of papillary growth and/or back-to-back glands that characterize digital
papillary carcinoma. In addition, malig-nant spiradenoma usually retains its
characteristic two cell population (small
basaloid cells and large pale peripheral
cells) in at least some foci.
Histogenesis
The occurrence of digital papillary carci-noma on acral sites where eccrine
133Malignant tumours with apocrine and eccrine differentiation
Fig. 3.15 Digital papillary carcinoma. Within the tumour nodules, papillae are formed by heaped up epitheli-um without stromal cores.
glands are abundant suggests an
eccrine origin of this tumour. Although
some cases show decapitation secre-tion, as is common in apocrine lesions,
this phenomenon has also been
observed in eccrine tumours. In addition,
immunoreactivity for ferritin had led
investigators to favour that digital papil-lary carcinomas derive from eccrine
glands {417}.
Prognosis and predictive factors
Complete surgical excision with negative
margins is indicated, and sometimes
requires amputation. Tumour recurrence
is seen in up to 50% of patients, espe-cially in cases without adequate primary
excision {1205}. Metastatic disease has
been observed in 14% of cases {655}.
Metastases may accompany recurrent
disease or occur without evidence of
local recurrence. Lungs seem a favoured
site for metastases, suggesting the prob-ability of haematogenous spread of
tumour. Tumour recurrence and metasta-sis does not seem to correlate with
patient age, tumour size, or duration of
tumour. Similarly, histologic features such
as tumour differentiation, circumscrip-tion, or nuclear grade are not predictive
of behaviour {655}.
Adenoid cystic carcinoma
Definition
Primary cutaneous adenoid cystic carci-noma is a neoplasm of disputed histoge-nesis characterized by a cribriform pat-tern and frequent perineural involvement.
ICD-O code 8200/3
Epidemiology
Over 40 cases have been reported in the
literature. Adenoid cystic carcinoma
(ACC) affects middle-aged and older
individuals (mean age: 58.1) and has a
predilection for women {1219}.
Localization
This neoplasm is most common on the
scalp (35%) and chest and abdomen
(24%) {446,1219}.
Clinical features
Primary cutaneous adenoid cystic carci-noma has an indolent and progressive
course. The average duration of the
tumour prior to diagnosis is approximate-ly 9.8 years {1219}. The size of the
tumour ranges from 0.5-8 cm, with an
average size of 3.2 cm. Patients typically
present with slowly expanding, firm, skin
coloured nodules. Tenderness, ulcera-tion and bleeding are variable and
depend on the site of involvement. In the
scalp region, alopecia may be an associ-ated finding.
Histopathology
Primary cutaneous ACC is usually poorly
circumscribed and is composed of
islands, cords and strands of basaloid
cells with a glandular, cystic, cribriform
and tubular arrangement embedded in a
loose fibrous and sometimes mucinous
stroma. It typically occupies the mid and
deep dermis and may extend into the
subcutaneous fat {793}. The epithelial
cords have an infiltrative pattern and are
not connected to the overlying epider-mis. The tumour has a characteristic
basophilic appearance on low power
due to nuclear hyperchromatism and
crowding. Nuclear palisading is absent.
The tumour nests are surrounded by a
prominent eosinophilic hyaline basement
membrane-like material which is periodic
acid-Schiff-positive, and diastase-resist-ant. The cystic spaces often contain
abundant mucin {1812}. The mucin is
characteristically alcian blue (pH 2.5)
positive. The epithelium consists of fairly
uniform cells with darkly staining nuclei,
which sometimes contain conspicuous,
small, solitary nucleoli. Individual tumour
cells have a scant amphophilic cyto-plasm and an increased nuclear-cyto-plasmic ratio. Mitotic activity is usually
sparse with 1-2 division figures per high
power field (x40) {2514}. Perineural
extension, a characteristic feature of sali-vary gland adenoid cystic carcinoma
may be seen, however, not with the fre-quency seen in other organs.
Before the diagnosis of a primary cuta-neous ACC is made, the possibility of a
134 Appendageal tumours
CB
A
Fig. 3.16 Adenoid cystic carcinoma.   A Low power view of an adenoid cystic carcinoma demonstrating a
poorly circumscribed neoplasm which is composed of collections of basophilic cells arranged in a sieve-like pattern.  B This photograph highlights the sieve-like pattern with prominent mucin within the glandular
spaces.  Note also the irregularity of the size and shape of the cellular collections.  C Mild degree of pleo-morphism is seen within the neoplastic cells.
metastasis from other organs needs to
be ruled out on clinico-pathological
grounds. The adenoid cystic type of
basal cell carcinoma is differentiated by
the presence of palisading of the nuclei
and stromal retraction.
Immunoprofile
Primary cutaneous adenoid cystic carci-noma stain positively for epithelial mem-brane antigen (EMA), carcinoembryonic
antigen (CEA), broad-spectrum keratins,
and low-molecular-weight keratins (CAM
5.2). Focal staining with S-100 and
vimentin may be seen {210}. Epithelial
cells at the periphery of the tumour
islands may express actin.
Histogenesis
The eccrine or apocrine origin of this
tumour remains disputed. In the past, it
has been regarded as an eccrine tumour,
although some have been shown to arise
from modified apocrine glands {2407}.
Prognosis and predictive factors
An indolent but progressive course is the
major characteristic of this tumour. The
recurrence rate is high, ranging from 57-70% and therefore wide surgical excision
extending well beyond the clinical con-fines of the tumour is recommended.
Recurrences have been reported even
with 2 cm margins and may occur many
years after excision. For this reason
some people favour Mohs micrographic
surgery {462}. Only 4 cases have metas-tasized to the lymph nodes and lungs.
Apocrine carcinoma
Definition
Apocrine carcinoma (AC) is a malignant
sweat gland neoplasm with apocrine dif-ferentiation. Although an apocrine origin
has also been postulated for adenoid
cystic carcinoma, hidradenocarcinoma,
spiradenocarcinoma, malignant cylindro-ma, and microcystic adnexal carcinoma,
this remains unproven. These entities
shall, therefore, be presented separately.
ICD-O code 8401/3
Synonyms
Apocrine adenocarcinoma, apocrine
gland carcinoma
Epidemiology
AC is a rare tumour. Both genders are
almost equally affected, and there
appears to be no racial predilection.
{1785,2460}
Etiology
The etiology of AC is unknown. The fact
that all patients were over 25 years {824}
suggests that full maturity of the apocrine
glands is a prerequisite.
Localization
Most AC arise in the axilla and, to a less-er extent, in the anogenital region. Rare
locations include the scalp, face, chest,
and distal upper extremities. {536,988,
1785,2055,2460} Peculiar variants have
been described on the ear (ceruminous
gland carcinoma) and the eyelid (Moll
gland carcinoma) {2139,2172}.
Clinical features
Because reports are sporadic and may
have included a proportion of benign
lesions it is difficult to establish a precise
clinical profile for AC. Apparently, there
are no distinctive features that might
enable a confident clinical diagnosis of
AC. Most tumours are solitary, but a
patient with bilatelal axillary AC has been
reported. AC presents as single or multi-ple, firm or cystic nodules with a reddish
or purplish hue of the ovelying skin, siz-ing between 1.5 and 8 cm {2460}.
Ulceration and haemorrhage may be
present. The patients’ age at presenta-tion ranges from 25 to 91 years, with an
average age of 57.9 years {2460}. In
many cases, the lesions had been stand-ing for more than 10 years, and even up
to 30 years before diagnosis {1650}.
Some tumours have arisen within a nae-vus sebaceous {644}.
Histopathology
AC is typically centred on the deeper
dermis and tends to spread into the sub-cutaneous fatty tissue {1785,2460}.
Extension into the epidermis also occurs,
occasionally in the form of extramamma-ry Paget disease {1647}. The tumours are
usually poorly circumscribed with infil-trating borders. Neighbouring apocrine
glands occasionally show in situ carcino-ma. {988,2460}. The growth patterns of
AC are highly variable, including tubular,
135Malignant tumours with apocrine and eccrine differentiation
Fig. 3.17 Apocrine carcinoma.  A Well differentiated cutaneous apocrine carcinoma. Glandular structures with tubulopapillary growth pattern and apical decapita-tion secretion.  B Poorly differentiated cutaneous apocrine carcinoma. Micronodular and trabecular growth pattern with hardly any gland formation, hyaline stro-ma. The cells have scanty amphophilic cytoplasm and contain vesicular nuclei with prominent nucleoli and occasional mitotic figures.
BA
papillary, cystic, cribriform, micronodular,
and solid formations {1785,2460}. The
cells have abundant eosinophilic cyto-plasm and large, round to oval, mostly
vesicular nuclei that often contain a sin-gle prominent eosinophilic nucleolus
{1785}. Intacytoplasmic PAS-positive dia-stase-resistant granules are characteris-tic, and intracytoplasmic iron is some-times demonstrable {988,1785,2139}. A
key diagnostic criterion, decapitation
secretion in the form of apical snouts
{2460} is usually recognizable but may
be lacking in poorly differentiated
tumours. There is variable mitotic activity,
ranging from single mitotic figures in well
differentiated tumours and up to 4 mitot-ic figures per high power field in poorly
differentiated carcinomas {2460}. Long
standing tumours tend to show increas-ing anaplasia. The tumour stroma is usu-ally densely fibroblastic or hyaline and
may contain prominent lymphoplasma-cytic infiltrates.
AC may exhibit focal mucinous carcino-ma-like features {2556} or may be com-posed of signet ring cells {1126}. The lat-ter tumours are mostly located on the
eyelid but may occur in the axilla {1343}.
Signet ring cell AC show a striking predo-minance (10:1) in elderly males {1343}.
Immunoprofile
The cells of AC express low molecular
weight cytokeratin (CAM5.2), epithelial
membrane antigen, carcinoembryonic
antigen, cytokeratin15, gross cystic dis-ease fluid protein (GCDFP)-15 {1785}
and occasionally S-100 protein {1343,
1785}. Myoepithelial cells, detectable by
SMA or CK 5/6 immunostaining, are typi-cally absent {988,2460}.
Differential diagnosis
The main differential diagnosis is with
(tubular) apocrine adenoma, and the his-tologic features that distiguish these two
conditions are often subtle. Whilst vascu-lar and neural invasion are diagnostic of
carcinoma, stromal invasion is less so
and may be difficult to ascertain. Tumour
silhouette, cellular pleomorphism and
mitotic activity may provide clues to
malignancy. As focal squamous differen-tiation may occur in AC {1785} acan-tholytic squamous cell carcinoma may
have to be considered in the diagnostic
differential.
AC is otherwise indistinguishable from
apocrine mammary carcinoma metastat-ic to the skin or apocrine carcinomas
arising in ectopic breast tissue in the axil-la. Therefore, the diagnosis of primary
cutaneous AC rests on a meticulous clin-ico-pathologic correlation.
Histogenesis
AC is thought to arise from preexisting
apocrine (sweat) glands {988,1785,2139,
2459}. An interesting alternative origin
are the newly described mammary-like
sweat glands of the anogenital region,
which may also give rise to eccrine
tumours {2408}.
Prognosis and predictive factors
The majority of AC are slow growing
tumours with a tendency toward a pro-longed course. The overall mortality is
low, despite frequent recurrences (30%)
and metastases to regional lymph nodes
(50%) {536,1785,2460}. Wide dissemina-tion and tumour-related deaths have nev-ertheless been described {437,1785,
2172,2460}. As distant metastases may
be a late event in the course of AC a pro-longed follow-up is advisable. Reliable
predictive factors have not been estab-lished.
Paget disease and
extramammary Paget disease
Definition
Paget disease of the breast and extra-mammary Paget disease are intraepider-mal adenocarcinomas characterized by
large atypical and pale staining cells
scattered throughout the epidermis
either as single cells or in small clusters.
Mammary Paget disease (MPD) resem-bles an eczematous eruption of the nip-ple and areola, and in almost all cases
constitutes skin involvement by an
underlying in situ or invasive ductal car-cinoma of the breast.
Extramammary Paget disease (EMP) is a
scaly erythematous eruption affecting
apocrine gland bearing areas of the skin,
mainly the female and male genital
areas. The majority of cases represent an
apocrine adenocarcinoma in situ that
has a high recurrence rate and may
invade the dermis and then possesses
metastatic potential. In a subset of cases
EMP is the skin manifestation of an
underlying internal malignancy. The skin
manifestations of these cases are clini-cally and histologically indistinguishable
from cases not associated with internal
malignancy.
ICD-O codes
Paget disease of breast
8540/3
Extramammary Paget disease
8542/3
Historical annotation
In 1874 Sir James Paget first described
“about fifteen cases” of a chronic
eczematous eruption of the nipple and
areola and noted that mammary cancer
developed in all patients within two years
{1766}. George Thin described the
histopathologic features of this condition
in 1881. The term Paget disease was
coined in 1889 by Radcliffe Crocker
when he described a morphologically
and histologically similar eruption affect-ing the penis and scrotum {561}.
Epidemiology
MPD occurs almost exclusively in
women. Exceptional cases of men with
MPD have been reported {927}. One to
two percent of female patients with
breast carcinoma develop Paget disease
{1971}. Ten to 28% of cases of Paget dis-136 Appendageal tumours
Fig. 3.18 Mammary Paget disease (MPD). Sharply
circumscribed erythematous and scaly plaque
affecting the nipple and areola.
Fig. 3.19 MPD. Cytoplasmic melanin can accumu-late in Paget cells and does not indicate
melanocytic differentiation.
ease are detected only on histologic
examination of the nipple in a mastecto-my specimen, without a clinically appar-ent lesion {1971}.
No accurate epidemiologic data is avail-able for EMP. It is a rare condition that
comprises less than 2% of primary neo-plasms of the vulva. EMP occurring in
sites other than the vulva is even less
common. In genital EMP, women are
more commonly affected than men. Most
patients are above the age of 60.
Etiology
MPD is almost always associated with an
underlying carcinoma of the breast, and
the etiology is the same as for breast car-cinoma. The inciting factors for primary
EMP are unknown. Secondary EMP is an
expression of an underlying internal
malignancy and the etiology parallels
that of the underlying tumour.
Localization
MPD involves the nipple and areola and
in advanced cases may extend to the
adjacent skin.
EMP involves apocrine gland bearing
areas and is most common in the genital
area, groin, perineum or perianal region.
Axillae, eyelids and external auditory
canals rarely may be involved.
Clinical features
Patients who present with MPD initially
develop erythema of the nipple and are-ola. The lesion then progresses to scaly,
crusted thick plaques and ultimately to
areas of erosion and ulceration. Patches
and plaques are almost always unilateral
and sharply circumscribed, and some-times pruritic or painful. In approximately
half of the cases a breast mass is palpa-ble. Nipple retraction and serosan-guinous discharge may be features of
advanced cases with a large underlying
carcinoma. Not all patients with MPD
have clinical symptoms; 10-28% of
cases are detected only on histologic
examination in a mastectomy specimen
{1971}. The differential diagnosis
includes squamous cell carcinoma in situ
and eczema. Once a diagnosis of MPD is
established the patient needs to be eval-uated with imaging studies and other
procedures for breast carcinoma. If MPD
is associated with a palpable tumour
mass, the underlying carcinoma will be
invasive in more than 90% of cases. If no
tumour mass can be detected clinically,
less than 40% of women will have inva-sive carcinoma.
Patients with EMP most commonly pres-ent with pruritus or burning. The skin
shows well-demarcated erythematous
scaly patches and plaques, which may
be ulcerated. Following a diagnosis of
EMP the patient needs to undergo thor-ough examination to rule out an associat-ed internal malignancy.
Tumour spread and staging
MPD without invasive carcinoma on his-tologic examination is classified as carci-noma in situ (Tis). MPD with a contiguous
or non-contiguous invasive component
on histology is staged according to the
invasive component using the guidelines
for staging of breast carcinoma.
Primary EMP is staged either according
to the FIGO (Fédération Internationale de
Gynécologie et d’Obstétrique) or the
TNM system of the AJCC (American Joint
Committee on Cancer) for vulvar
tumours. After a long period of in situ
growth EMP can eventually invade the
dermis and acquire metastatic potential.
Typically, invasive carcinoma associated
with EMP first spreads to locoregional
lymph nodes and ultimately may develop
distant metastases. Secondary EMP is
staged according to the criteria for the
associated internal malignancy.
Histopathology
On histologic examination MPD and EMP
are characterized by neoplastic cells
with large nuclei, prominent nucleoli and
abundant pale to amphophilic cytoplasm
that are scattered throughout the entire
epidermal thickness. These cells occur
singly and in clusters and often are more
numerous in the basal layers of the epi-dermis. Acinus formation may be pres-ent. Paget cells can contain cytoplasmic
melanin pigment, a feature that should
137Malignant tumours with apocrine and eccrine differentia
Fig. 3.20 Mammary Paget disease (MPD). Paget cells with large nuclei, prominent nucleoli and abundant
pale cytoplasm permeate the entire epidermal thickness.
Fig. 3.21 Extramammary Paget disease (EMP).
Paget cells often have a propensity for tracking
along skin appendages.
not imply melanocytic differentiation. The
epidermis is often hyperkeratotic and
acanthotic, especially if the disease has
been chronic. Particularly in EMP, the
tumour cells have a propensity to track
along skin appendages. A dermal
perivascular lymphohistiocytic infiltrate
accompanies the epidermal changes.
Paget cells are positive with convention-al mucin histochemistry in 40-70% of
cases {1297}. In MPD the associated in
situ or invasive breast carcinoma is of
ductal differentiation in the majority of
cases. Lobular carcinoma only rarely
gives rise to MPD. Histologically, EMP
without an internal malignancy cannot be
differentiated from those cases with
associated neoplasm.
The histopathologic differential diagnosis
includes pagetoid squamous cell carci-noma in situ, superficial spreading malig-nant melanoma, pagetoid Spitz naevus,
clear cells of Toker, pagetoid dyskerato-sis, clear cell papulosis, sebaceous car-cinoma, intraepidermal Merkel cell carci-noma, eccrine porocarcinoma, cuta-neous T-cell lymphoma, Langerhans cell
histiocytosis and epidermotropic metas-tasis.
Immunoprofile
The immunophenotype of MPD closely
matches that of the underlying breast
carcinoma {511}. Paget cells are practi-cally always positive for low molecular
weight cytokeratins (detectable by spe-cific or broad spectrum cytokeratins
such as CK7, CAM5.2 and AE1/AE3) and
epithelial membrane antigen (EMA), vari-ably positive for polyclonal carcinoem-bryonic antigen (pCEA) and lack lym-phoid markers such as leukocyte com-mon antigen (LCA) and CD3
{1036,1461}. Gross cystic disease fluid
protein-15 (GCDFP-15) has been report-ed in approximately 50% of cases, simi-lar to that of breast carcinoma in general
{511}. As in breast carcinoma, reports of
S100 reactivity are quite variable, rang-ing from 0-26% {1757,2548}. Approxi-mately 5% of Paget cases are oestrogen
receptor (ER) and/or progesterone
receptor (PR) positive {511}.
The tumour cells in primary and second-ary EMP are positive for simple cytoker-atins (CAM5.2, AE1/AE3), EMA and CEA
{1004,1539,1757,2548}. Immunohisto-chemistry can also suggest the presence
of an associated internal malignancy,
because primary EMP has the staining
characteristics of an apocrine carcinoma
and is almost always CK7 positive and
gross-cystic disease fluid protein
(GCDFP) positive, while CK20 is com-monly negative whereas the opposite is
true for EMP with associated internal
malignancy. The cells in these latter
cases are also mostly CK7 positive, but
more often express CK20 and do not
stain for GCDFP {851,852,1298,1461}. In
EMP positive staining with CK20 and lack
of staining with GCDFP should prompt an
even more thorough evaluation for under-lying malignancy.
The most useful keratin markers for MPD
and EMP are CAM5.2 and CK7 because
they stain >90% of Paget cells but do not
react with epidermal or mucosal ker-atinocytes, a characteristic that makes
both antibodies very useful in the evalua-tion of surgical margins and invasion.
Histogenesis
MPD is almost always associated with an
underlying carcinoma of the breast either
in situ or invasive. MPD represents the
retrograde extension of an underlying
carcinoma into the epidermis, either in a
contiguous fashion, through spread
along the lactiferous ducts or through
intraepidermal metastasis. Cases without
underlying carcinoma exist but are
exceptional {1159}. The etiology of these
cases is speculative, but probably they
are analogous to primary EMP, repre-senting apocrine adenocarcinomas in
situ, derived from Toker cells. Toker cells
are cells with bland cytologic features
and clear cytoplasm that have been
identified by standard light microscopic
means in ~10% of normal nipples {1461}.
They are derived from lactiferous duct
lining cells and preferentially cluster in
the epidermis near lactiferous duct ostia.
Primary EMP is an apocrine adenocarci-noma in situ that most likely arises from
intraepidermal cells of apocrine gland
ducts. These cells, analogous to Toker
cells of the nipple, have been recently
demonstrated in the epidermis of vulvec-tomy specimens in association with
mammary-like glands {2531}. In second-ary EMP the disease represents migra-tion of an underlying internal malignancy
to the epidermis. Tumours associated
with EMP include rectal adenocarcino-ma, transitional cell carcinoma of the ure-thra and bladder, carcinoma of the
Bartholins glands, prostate carcinoma,
cutaneous adnexal carcinoma and carci-noma of the vagina and cervix.
Prognosis and predictive factors
The prognosis of MPD depends on the
size and characteristics of the underlying
breast carcinoma. Patients with MPD but
without a clinically detectable breast
mass have a much better prognosis. In a
recent study, 61 patients with MPD and
without palpable mass were treated with
a cone excision of the nipple-areola com-plex and radiation therapy. Histologic
examination revealed underlying DCIS in
93.3% of patients and Paget disease,
only, in 7%. The recurrence rate at a
median follow up of 6.4 years was 5.2%
(1 patient with DCIS and 3 patients with
invasive carcinoma) {242}.
The majority of cases of EMP are not
associated with another neoplasm and
show a recurrence rate of approximately
30% after surgery, but do not metasta-size. Around 10% of patients will develop
invasive adenocarcinoma that may
progress to metastatic disease {710}.
The rate of an associated internal malig-nancy varies from 15% to 33% and is
more common in perianal EMP than vul-var EMP {1024}. In these cases the asso-ciated tumour drives the clinical behav-iour, treatment and prognosis.
138 Appendageal tumours
139Benign tumours with aprocine and eccrine differentiation
Hidrocystoma
Definition
Hidrocystomas are cystic proliferations
of the sweat glands. They have either
apocrine or eccrine differentiation, with
the majority being of apocrine nature.
Apocrine hidrocystomas are cystic ade-nomas that arise from the apocrine
secretory coil, while eccrine hidrocys-tomas represent retention cysts of the
eccrine cyst duct {607,1919,2047,2188}.
ICD-O code 8404/0
Synonyms
Several and sometimes confusing terms
have been used to designate hidrocys-tomas, to wit: apocrine gland cyst, papil-lary apocrine gland cyst {1919}, apocrine
cystadenoma {1568}.
Epidemiology
Hidrocystomas are relatively rare and
account for approximately one per thou-sand of submitted cutaneous biopsies
{607}. They normally present as solitary
lesions, however patients with multiple
lesions have been observed. Hidro-cystomas usually affect middle-aged or
older individuals although rare examples
have been described in children and
adolescents; both sexes are equally
affected.
Localization
Hidrocystomas have a predilection for
the face and neck, mainly the periorbital
area, but may also affect other parts of
the body such as the perineum.
Clinical features
Hidrocystomas present as dome-shaped, cystic firm papules or nodules,
with a slightly blue colouration. In some
cases the content of the cyst is brown or
black.
Etiology
The exact cause of hidrocystomas is not
known. They have been reported to be
exacerbated with high temperatures and
to completely disappear with cold weath-er and atropine therapy {2236}. There is
an increased incidence of hidrocystomas
in hyperthyroid patients, perhaps related
to hyperhidrosis {1270,1673}.
Macroscopy
The lesions are of variable size ranging
from 0.5-1.0 cm, although lesions of up to
7.0 cm have been reported. Hidrocys-tomas are usually located in the dermis,
but in some cases they may be present
in the subcutaneous fat. The cut surface
reveals a well-circumscribed, unilocular
or multilocular cyst.
Histopathology
Hidrocystomas can be uni or multilocular
and are usually lined by a double layer of
epithelium. The inner layer contains large
columnar cells with eosinophilic cyto-plasm which has luminal decapitation
secretion, while the outer layer is flat and
composed of myoepithelial cells. The
term “papillary apocrine gland cyst” has
been applied for hidrocystomas with
papillary projections of epithelium into
the lumen {1919}. Occasionally, hidro-cystomas may show a single cystic cavi-ty lined by one or two layers of flattened
epithelium as a consequence of the
pressure exerted by the contents of the
cyst. In this circumstance, distinction
from eccrine hidrocystomas, which have
a similar lining, becomes impossible
{671}.
Benign tumours with apocrine and
eccrine differentiation
J. McNiff
T. H .  McCalmont
L. Requena
O. P. Sangüeza
C. Vassallo
R. Rosso
G. Borroni
E.J. Glusac
R.O. Pichardo
Fig. 3.22 Hidrocystoma presenting as small, dome-shaped lesion on the right side of the face, con-taining a clear fluid.
DC
Fig. 3.23 Hidrocystoma, papillary cystadenoma.  A Example of the so-called “papillary apocrine gland cyst”.
These lesions are characterized by the presence of papillary projections of epithelium into the lumen.
B The papillary projections contain a core of connective tissue and are lined by cuboidal epithelium.  C This
picture depicts a typical example of an apocrine hidrocystoma. The lesion is cystic and lined by a cuboidal
epithelium.  D At higher magnification the cyst is lined by a double layer of cuboidal cells with evidence of
decapitation and secretion.
BA
140 Appendageal tumours
Immunoprofile
Hidrocystomas express epithelial mem-brane antigen (EMA) and lysozyme in the
cells of the cyst wall; carcinoembryonic
antigen (CEA) decorates the luminal
cells {1217}. The pattern of cytokeratin
expression is variable {607,17444}; there
is expression of cytokeratins 7,8,18,19 in
the luminal cell layer and cytokeratins
1,5,10,14 in the basal and luminal cell
layers.
Smooth muscle actin (SMA) is present in
the basal layer {607}. Human milk fat
globulin 1 (HMFG) is expressed by the
apocrine sweat gland only {607}. S-100
protein is positive in the secretory portion
of normal eccrine glands and in the
myoepithelial cells of apocrine glands
{1678,2358}.
Prognosis and predictive factors
Complete excision is usually curative.
Topical atropine or scopolamine has also
been used {56,503,2236}. Avoidance of
a hot environment or other factors that
increase perspiration lessens the severi-ty of these lesions {1668}.
Syringoma
Definition
Syringomas are small benign adnexal
neoplasms that are almost always multi-ple. They are composed of sweat gland
epithelium (presumably eccrine) within
densely sclerotic stroma.
ICD-O code 8407/0
Synonyms
Eccrine syringoma, lymphangioma
tuberosum multiplex.
Epidemiology
Syringomas are common lesions, found
more often in women than men. They
appear more commonly in Asians than in
other races. Syringomas usually arise in
adolescence or early adulthood, but are
most often biopsied in the 4th decade.
Most are sporadic, though some eruptive
and disseminated forms may be familial.
Syringomas appear to be more common
in Down syndrome. A clear cell variant
has been associated with diabetes melli-tus in many instances {800,2474}.
Localization
By far, the most common sites of involve-ment are the lower eyelids. Involvement
of the upper cheeks is not uncommon.
Unusual sites of involvement include the
neck, chest, axillae, pubic area, perium-bilical region, penis, vulva, hands and
forehead. Unilateral linear lesions have
been described {552}. Eruptive syringo-mas are typically numerous, widespread
and may appear in crops {1388}.
Clinical features
The lesions are numerous, firm, smooth,
dome-shaped, skin coloured or slightly
yellowish papules, 1-3 mm in diameter,
usually situated in skin of the lower eye-lids. Syringomas are rarely solitary.
Histopathology
Syringomas are small lesions, restricted
to the upper reticular dermis. They are
composed of numerous small solid
nests, cords and tubules of epithelial
cells within a dense stroma of compactly
arranged bundles of collagen, accompa-nied by relatively few fibrocytes. The
epithelial aggregates are usually evenly
distributed throughout the lesion. The
epithelial cells of syringoma show small
nuclei, inconspicuous nucleoli and
absent mitotic figures. Cytoplasm ranges
from eosinophilic to clear.
The epithelial cells within tubular struc-tures show an inner layer of luminal cells
and one or two rows of more peripheral
cells. Tubular lumina may be distended,
causing flattening of the inner most lining
cells. Larger aggregates of cords and
nests of cells may exhibit a “comma-like”
or “tadpole-like” configuration. The
cords, nests and tubules of syringomas
branch and anastomose. Milia may be
present, and these may rupture produc-ing granulomatous inflammation and
subsequent calcification. Syringomas
may become confluent. Eruptive syringo-mas are similar to standard syringomas;
however, the stromal component is
sometimes less prominent.
In most conventional syringomas some
epithelial cells have pale cytoplasm. In
some lesions, these cells predominate,
and this pattern has been termed “clear-cell syringoma”; it has frequently been
associated with diabetes mellitus, but it
may be seen sporadically.
Differential diagnosis
Desmoplastic trichoepitheliomas differ
from syringomas by being larger, deeper,
and composed of epithelial elements that
show follicular differentiation. Superficial
biopsies of microcystic adnexal carcino-ma may greatly resemble syringoma.
Microcystic adnexal carcinomas are
larger, asymmetric and less circum-scribed than syringoma. Virtually all
microcystic adnexal carcinomas extend
into subcutaneous fat or skeletal muscle,
whereas syringomas are restricted to the
upper two thirds of the reticular dermis.
Fig. 3.24 Syringoma.  A Well circumscribed nodule within the upper dermis.  B Tubules and cords of uniform epithelial cells in sclerotic stroma.
BA
141Benign tumours with aprocine and eccrine differentiation
Prognosis
Syringomas are benign. Association with
or progression towards carcinoma has
not been described.
Poroma
Definition
Poromas are benign adnexal neoplasms
with terminal ductal differentiation.
Although historically considered a neo-plasm of eccrine differentiation, poromas
can show either eccrine or apocrine line-age.
ICD-O code 8409/0
Synonyms
Eccrine poroma, hidroacanthoma sim-plex, dermal duct tumour, syringoacan-thoma
Epidemiology
Poromas usually present as solitary
tumours on acral sites, although they can
be seen in virtually any cutaneous loca-tion. Most poromas arise in middle age
with no sex predilection. Uncommonly,
multiple poromas are seen, either limited
to palms and soles or in a widespread
distribution, for which the term poromato-sis has been applied.
Clinical features
Poromas typically manifest as dome-shaped cutaneous papules, nodules or
plaques, generally measuring less than 1
cm in diameter. Some lesions are highly
vascular and may show a tendency to
bleed, particularly on acral sites.
Uncommonly, poromas are pigmented.
Rapid growth has been reported during
pregnancy {920}. Multiple poromas have
developed after electron beam therapy
for mycosis fungoides {1348} and occur-rence in areas of chronic radiation der-matitis has been reported {1802}.
Occurrence of poroma within a naevus
sebaceous has been documented
{1133}.
Histopathology
Poromas are well-circumscribed tumours
composed of a proliferation of uniform
basaloid, cuboidal cells punctuated by
focal ducts and occasional cysts. The
epithelial cells of poromas typically
extend from the lower epidermis into the
dermis in broad columns. The epithelium
of poromas is sharply demarcated from
adjacent keratinocytes. Nuclei are small
and regular, and cytoplasm is modest in
amount. The cytoplasm often contains
glycogen. Most poromas contain ductal
structures lined by PAS positive diastase-resistant cuticles. Small areas of necrosis
as well as mitoses are seen in otherwise
banal poromas, and are of no prognostic
significance. Foci of sebaceous differen-tiation may be observed. The stroma sur-rounding poromas is often richly vascu-lar, and may contain granulation tissue.
Architecturally, poromas show a spec-trum of change from predominately
intraepidermal lesions (hidroacanthoma
simplex) to primarily dermal-based neo-plasms (dermal duct tumour). Another
rare variant has been termed syringoa-canthoma, representing a clonal pattern
of poroma within an acanthotic epidermis
with prominent surface keratinization.
Differential diagnosis
Histologically the differential diagnosis
includes seborrheic keratosis, which typ-ically shows keratinization with horn
cysts, a more sharply demarcated lower
border, and absence of ductal struc-tures. Basal cell carcinoma may some-times be considered histologically, but
shows more obvious peripheral palisad-ing, nuclear variability, and little or no
glycogen.
Histogenesis
Poromas may show evidence of either
eccrine or apocrine differentiation {970}.
Immunohistochemical studies reveal that
poroma cells express a cytokeratin phe-notype similar to basal cells of the
eccrine ducts in some cases {2466}. The
absence of myoepithelial cells also sug-gests differentiation toward the excretory
(ductal) component of sweat glands.
Occurrence of poromas within follicu-losebaceous lesions such as naevus
sebaceous, and presence of sebocytes
within poroma, implicates origin from
apocrine glands in some cases {662,
970}.
Genetics
Some cases of poromatosis have been
CB
A
Fig. 3.25 Poroma.  A Broad tongues of uniform epithelium extend into the dermis from the undersurface of
the epidermis.   B Pigmented poroma illustrating ductal structures and fibrovascular stroma.   C Clear cell
change may be prominent in some poromas.
Fig. 3.26 Intraepidermal variant of poroma. There
are discrete nests of bland basaloid and cuboidal
cells within the epidermis, associated with acrosy-ringium.
142 Appendageal tumours
associated with hidrotic ectodermal dys-plasia {2519}. Rare cases of poroma
have occurred in the setting of naevoid
basal cell carcinoma syndrome {904}.
Studies of p53 protein have shown high
expression in some poromas as well as
in some porocarcinomas, but staining is
not correlated with duration of tumours
{43}. Therefore, while p53 mutation may
be involved in progression of some poro-mas to porocarcinoma, other oncogenes
or factors are also likely play a role in
malignant transformation of poromas.
Prognosis
Poromas are benign and simple excision
is curative.
Syringofibroadenoma
Definition
Syringofibroadenoma is a rare benign
eccrine tumour with anastomosing
strands and fibrovascular stroma, first
described by Mascaro {1529}. Multiple
lesions of syringofibroadenoma are
referred to as eccrine syringofibroadeno-matosis {456,2189}.
ICD-O code 8392/0
Synonyms
Eccrine syringofibroadenoma {663},
eccrine syringofibroadenomatous hyper-plasia {1721}, eccrine syringofibroade-nomatosis {456,2189}, acrosyringeal
adenomatosis {950}.
Epidemiology
Syringofibroadenoma is rare, with about
75 reported cases. It occurs primarily in
older adults.
Localization
Most of syringofibroadenomas arise on
acral areas {498,685,769,2248,2313,
2344,2399}.
Clinical features
The most common clinical presentation
is solitary, often verrucous papules or
nodules {1529,2248,2313}. Unusual pre-sentations include large plaques, linear
lesions, and disseminated tumours
{1259,2189,2248}.
Etiology
Occasionally, syringofibroadenoma can
be associated with other entities, both
inflammatory and neoplastic, including
bullous pemphigoid {1720,1721}, lichen
planus {780}, ulcers {1092,2399}, squa-mous cell carcinoma {1399}, sebaceous
naevus {1719}, and chronic lymphoede-ma {806}. Based on the latter association
and the presence of fibrous stroma,
some authors consider syringofibroade-noma as a hyperplasia rather than a neo-plasia {779,780,806,1092,1399,1719,
1720}. It may be associated with Schöpf-Schultz-Passarge syndrome {2189}, an
autosomal dominant syndrome with pal-moplantar keratoderma, hypodontia, and
eyelid hidrocystomas, whose genetic
aberration has been localized to chromo-some 13q {1259}.
Histopathology
Syringofibroadenoma is characterized
by multiple anastomosing cords and
strands of monomorphous cuboidal cells
{26,1529}. The epithelial cords extend
usually into the mid-dermis, and are
embedded in a loose fibrovascular stro-ma. Rarely, a clear cell variant has been
observed {781,2415}.
Immunoprofile
Light microscopy usually leads to a spe-cific diagnosis. The tumour cells are usu-ally positive for both keratin 6 and 19 as
well as filaggrin {1108,1304,1742,1745,
2314}.
Prognosis and predictive factors
Syringofibroadenoma is a benign condi-tion, and solitary lesions are cured by
complete excision, while the treatment of
multiple lesions is dependent on the size
and location. Cases of syringofibroade-noma with foci of atypical squamous
cells have also been described {255,
1215}.
B CA
Fig. 3.27 Syringofibroadenoma. A Clinical features of the verrucous, solitary type of syringofibroadenoma; a nodule localized on left sole of a 75-years old female,
lasting for three years.   B Eccrine syringofibroadenoma (Mascaro). Presents in many cases as a verrucous plaque.   C Eccrine syringofibroadenoma (Mascaro).
There are branching cords of small keratinocytes attached in multiple foci to the undersurface of the epidermis
BA
Fig. 3.28 Hidradenoma.  A There is a multinodular solid and cystic proliferation of monomourphous adnexal
keratinocytes.  B Areas with cytoplasmic pallor are common (‘clear cell hidradenoma’).
143Benign tumours with apocrine and eccrine differentiation
Hidradenoma
Definition
Hidradenoma is a benign adnexal neo-plasm, closely related to poroma, that
displays a limited degree of ductal differ-entiation. While historically considered
eccrine, recent evidence suggests that
hidradenoma can be either apocrine or
eccrine {825,1543}.
ICD-O code 8402/0
Synonyms
Clear cell hidradenoma, nodular
hidradenoma, poroid hidradenoma,
acrospiroma, solid-cystic hidradenoma
{825,980,1374}.
Epidemiology
Hidradenomas are sporadic with no sex
predilection. Most develop in adults, but
childhood onset has been documented
{715,1652}. Hidradenoma can also arise
as a secondary neoplasm with naevus
sebaceous.
Localization
Hidradenomas commonly develop on
the scalp, trunk, and proximal extremi-ties, and rarely on the hands and feet.
Eyelid lesions have also been noted
{911}.
Clinical features
Hidradenomas lack any distinctive clini-cal features, presenting as skin-coloured
to red-brown nodules.
Histopathology
Hidradenoma is a mostly dermal neo-plasm with a nodular, circumscribed pat-tern at scanning magnification. Some-times an epidermal attachment can be
identified. The intervening stroma is often
sclerotic and may be highly vascular-ized, with ectatic vascular channels.
Hidradenoma is composed of several
types of cells:
Clear or pale cells, which contain abun-dant glycogen, and show distinct cell
membranes {578}. The number of clear
cells varies from lesion to lesion. When
these cells predominate, the name clear-cell hidradenoma is appropriate {2544}.
Squamoid cells are polygonal with a cen-tral vesicular nucleus and eosinophilic
cytoplasm, and often are arranged in
whorls {1774}.
Mucinous cells are the least common
component. They are large cells with fine
basophilic granular cytoplasm. Cuboidal
or columnar cells line the tubules and
show evidence of apocrine differentiation
{1427}.
Transition between different types of cells
is frequent. The cells are arranged in
sheets, punctuated by ducts and glan-dular areas which may show apocrine
differentiation. Hybrid lesions including
compact poroid cells with prominent
ductal differentiation have been referred
to as poroid hidradenomas.
Prognosis
Complete excision is curative.
Spiradenoma
Definition
Spiradenoma is a benign dermal neo-plasm that can show either eccrine or
apocrine differentiation, and significant
morphologic overlap with cylindroma.
Historical annotation
Chandeluz, in 1882, probably first
described this tumour {765}. Unna first
coined the term spiradenoma. In 1956
Kersting and Helwig published the clas-sic paper on spiradenoma in 136
patients {1250}. Additional series of spi-radenoma have since been published
{12,1496}.
ICD-O code 8403/0
Localization
Most spiradenomas appear on the face
Fig. 3.29 Spiradenoma.  A A pigmented and painful nodule on the posterior aspect of the arm.   B These aggregations of neoplastic cells show round shape and
smooth borders.  C At higher magnification, numerous lymphocytes are seen scattered within the nodules of neoplastic epithelial cells. There are two distinct pop-ulations of neoplastic epithelial cells, dark and pale. Dark cells are small, basaloid cells with hyperchromatic nuclei and pale cells are larger with vesicular nuclei
and ample pale cytoplasm.
BA C
144 Appendageal tumours
and upper trunk, but they can also affect
other sites.
Clinical features
Usually, spiradenoma appears as a soli-tary, well-circumscribed, firm nodule,
measuring usually less than 1 cm, but
giant variants {546} and multiple lesions
have also been described {1725}.
Unusual cases show multiple spiradeno-mas arranged in a zosteriform linear pat-tern {926,2162}. Spiradenoma appears
in adult life, although there are also
reports of congenital cases {2091}, and
in one patient spiradenoma developed
within a naevus sebaceous of Jadassohn
{2154}. Pain is one of the main clinical
characteristics of spiradenoma {926,
2091,2154}. The mechanism of pain or
tenderness in spiradenoma is not clear.
Histopathology
At low power magnification, spiradeno-ma appears as a solid neoplasm com-posed of a single or few nodules of basa-loid cells. These aggregations are round
with smooth borders and involve the full
thickness of the dermis, sometimes
extending into the subcutaneous fat.
Often, the intervening stroma is oedema-tous with ectatic vessels {546}. Dilated
vessels rimmed by sclerosis have been
interpreted as “ancient” changes due to
long-standing lesions {2229}.
Another characteristic finding is the pres-ence of abundant lymphocytes scattered
within the tumour nodules. At higher
magnification, two distinct populations of
neoplastic epithelial cells can be seen,
dark and pale. Dark cells are small,
basaloid cells with hyperchromatic nuclei
located at the periphery, whereas pale
cells, which are larger with vesicular
nuclei and ample pale cytoplasm, tend to
be near the centre of the clusters.
Tubules lined by two rows of epithelial
cells may be found within the tumour
nodules. A characteristic feature is the
presence of eosinophilic PAS positive
globules throughout the entire neoplasm,
sometimes surrounded by neoplastic
cells in pseudorosette fashion. These
globules are composed of basement
membrane material. Sometimes the stro-ma shows striking oedema.
Spiradenoma in children may show a dif-ferent histopathologic pattern. The neo-plastic cells appear more immature,
making the distinction between clear and
dark neoplastic epithelial cells difficult,
and the neoplasm may be misinterpreted
as a mesenchymal neoplasm {1206}.
Spiradenoma and cylindroma show sig-nificant morphological overlap. In some
patients with multiple lesions, some
tumours show features of spiradenoma,
and others features of cylindroma. This
supports the notion that spiradenoma
and cylindroma are closely related, prob-ably representing two morphologic
expressions of the same basic neoplas-tic process {846,2280}.
Immunoprofile
The tumour cells express cytokeratins,
and the tubular structures are CEA posi-tive {1801,2465}. Inflammatory cells scat-tered within the neoplastic aggregations
have been identified as abundant T lym-phocytes and Langerhans cells.
Histogenesis
The histochemical and immunohisto-chemical studies have not clarified the
histogenesis of spiradenoma. The fre-quent association of spiradenoma and
cylindroma, a likely apocrine neoplasm,
and the sporadic association of spirade-noma with neoplasms with follicular dif-ferentiation such as trichoepithelioma
{2500}, support an apocrine line of differ-entiation for spiradenoma on the basis of
the common embryologic origin for the
three elements of the folliculo-seba-ceous-apocrine unit. This is furthermore
supported by some examples of spirade-noma that show decapitation secretion in
the cells lining the luminal border of the
tubular structures. Therefore, the qualify-ing term of “eccrine” that almost invari-ably is applied to spiradenoma is inac-curate.
Prognosis and predictive factors
Spiradenoma is a benign neoplasm.
Because of the sharp demarcation of the
tumour from the surrounding stroma,
excision is easily accomplished. Several
examples of carcinomas arising in long-standing spiradenomas have been
described. In those instances, enlarge-ment of a nodule that had been stable for
many years seems to be the sign of
malignant transformation {89,240,539,
699,884,2602}. It appears to be accom-panied by increased expression of p53
protein {239}.
Fig. 3.30 Cylindroma.  A There is a puzzle-like array of basaloid cells with relatively sharp circumscription of individual nodules. The larger nodules on the left show
trabecular internal structure, suggesting overlap with spiradenoma.  B The nests are outlined by a thick rim of PAS-positive and diastase-resistant basement mem-brane material.
BA
145Benign tumours with apocrine and eccrine differentiation
Cylindroma
Definition
Cylindroma is a relatively undifferentiated
benign adnexal neoplasm with a mosaic
microscopical pattern. Cylindroma com-monly occurs as a hybrid with spirade-noma, an event that has been referred to
as cylindrospiradenoma or spiradeno-cylindroma {301,846,1543,1600}.
ICD-O code 8200/0
Synonyms
Cylindrospiradenoma {301}, spiradeno-cylindroma {1600}
Epidemiology
Cylindromas may be solitary or multiple,
arising on a sporadic basis or as part of
Brooke-Spiegler syndrome. There is no
sex predilection.
Etiology
The etiology is unknown. A link to chro-mosome 9 seems likely for multiple spi-radenomas and cylindromas in the con-text of the Brooke-Spiegler syndrome, as
the gene has been mapped to 9p21
{951,1538}.
Localization
The vast majority of cylindromas occur
on the scalp or face, especially in the
vicinity of the ear. Uncommonly, cylindro-mas develop on the trunk or proximal
extremity.
Clinical features
Cylindromas are typically smooth, dome-shaped hairless red-brown papules and
nodules. Extensive scalp involvement
can create clinical morphology resem-bling a headpiece (“turban tumour”).
Cylindroma can rarely be found as a sec-ondary neoplasm within naevus seba-ceous.
Histopathology
Cylindroma is a mostly dermal and
sometimes subcutaneous neoplasm with
a multinodular, circumscribed pattern at
scanning magnification. Individual nod-ules are composed of mosaic nests of
undifferentiated basaloid cells with small
darkly-staining nuclei and scant cyto-plasm; individual nests fit tightly and
neatly within larger nodules in a pattern
that has been likened to that of a jigsaw
puzzle. The nests of cylindroma are com-monly surrounded by a rim of densely
eosinophilic PAS-positive basement
membrane material, and the nests are
also punctuated by small round
“droplets” with similar staining qualities.
Hybrid lesions with areas of cylindroma
and spiradenoma in juxtaposition are not
uncommon {301,846,1543,1600}.
Immunoprofile and histogenesis
Refer to the previous chapter on spirade-noma.
Prognosis and predictive factors
Simple excision is usually curative.
Malignant transformation is extremely
uncommon.
Tubular and tubular papillary
adenoma
Definition
Tubular apocrine adenoma is a benign
dermal adnexal neoplasm demonstrating
apocrine differentiation that typically
occurs in a broad age group of women
on the scalp region.
ICD-O code
Tubular adenoma 8211/0
Tubular papillary adenoma
8263/0
Synonyms
Apocrine adenoma, tubular adenoma,
tubulopapillary hidradenoma, papillary
tubular adenoma
Epidemiology
Tubular apocrine adenomas occur spo-radically with a female predilection
{1361}. A broad age group may be
affected {1361}. Some neoplasms may
occur in association with a syringocys-tadenoma papilliferum {76,489,1111,
2364} and can also arise within an
organoid naevus {1111,1361,2394}.
Localization
Tubular apocrine adenomas commonly
occur on the scalp and less often at other
sites including the leg, trunk, axillary and
anogenital areas {1361}.
Clinical features
Tubular apocrine adenomas present as
asymptomatic solitary nodules that are
skin-coloured to pink-red in appearance
with either a smooth or irregular appear-ance {1361}. Most tumours range in over-all dimension between 1 to 2 cm but
rarely may be as large as 7 cm {1361}.
Histopathology
Tubular apocrine adenomas are well-cir-cumscribed dermal neoplasms that may
extend into the subcutis. They have an
overall lobular architecture and are typi-cally encased by a fibrous stroma. The
lobules consist of multiple irregularly
shaped tubular structures that have a
double to several layered epithelial lin-B CA
Fig. 3.31 Tubular adenoma.  A A skin-coloured smooth surfaced nodule on the left parietal scalp.  B Multiple irregularly shaped tubular glandular structures within
a partly sclerosed stroma.  C Banal appearing tubular glandular elements lined by a double layer of epithelial cells within a sclerosed stroma. The peripheral layer
is cuboidal in appearance and the luminal layer demonstrates decapitation secretion. The lumina are filled with cellular debris and granular eosinophilic material.
146 Appendageal tumours
ing. The peripheral epithelial layer con-sists of cuboidal to flattened cells
(myoepithelial) and the luminal layer of
columnar cells that demonstrate decapi-tation secretion. In some tubules papil-lary cellular extensions that are devoid of
stroma project into the lumina. Addi-tionally, cellular debris and eosinophilic
granular material are identified within
some lumina {1361}. The neoplasm lacks
cytologic atypia and mitotic activity.
Overlying epidermal hyperplasia may be
present. In those neoplasms that occur in
conjunction with syringocystadenoma
papilliferum {76,489,2364}, the tubular
adenoma component is typically present
underlying the syringocystadenoma
component. The differential diagnosis
includes apocrine adenocarcinoma and
papillary eccrine adenoma. In contrast to
apocrine adenocarcinoma tubular apoc-rine adenomas lack cytologic atypia, are
well circumscribed and possess a
peripheral myoepithelial layer {1751}.
Tubular apocrine adenomas resemble
papillary eccrine adenomas in many
respects and previously these were
believed to be related neoplasms {489}.
However on the basis of morphologic cri-teria (papillary eccrine adenomas lack
decapitation secretion) and enzyme his-tochemistry and ultrastructural analysis
demonstrating differences in differentia-tion (apocrine versus eccrine) they are
now believed to represent distinct neo-plasms. In some instances both eccrine
and apocrine differentiation may be
observed making a distinction between
these neoplasms impossible {771}. The
terms tubulopapillary hidradenoma {705}
and papillary tubular adenoma {2335}
have been suggested for cases with
apocrine and eccrine differentiation.
Histogenesis
Enzyme histochemistry {1361} and ultra-structural analysis {1361,2394} have
demonstrated tubular apocrine adeno-mas to be of apocrine differentiation.
Prognosis
Tubular apocrine adenomas are benign
slow-growing neoplasms. Simple exci-sion is curative.
Syringocystadenoma
papilliferum
Definition
Syringocystadenoma papilliferum is a
benign adnexal neoplasm that occurs in
association with an organoid naevus
such as naevus sebaceous in at least
one-third of cases.
ICD-O code 8406/0
Synonmys
Syringoadenoma
Epidemiology
Syringocystadenoma papilliferum occurs
with equal frequency in both sexes. It is a
tumour of childhood or adolescence,
with many examples noted at birth.
These lesions tend to increase in size at
puberty, and sometimes multiply in num-ber as well as becoming more papillo-matous over time.
Clinical features
The majority of syringocystadenomas
affect the head and neck area, typically
as one or more warty papules, some-times in a linear array, or as a solitary
grey or red plaque. Scalp and neck are
favoured sites; those on the scalp are
typically alopecic. Syringocystadenomas
may develop during puberty in a pre-existing naevus sebaceous, and at least
one-third are associated with an underly-ing organoid naevus.
Histopathology
Histologically, endophytic invaginations
of epithelium extend from the epithelial
surface into the dermis. Typically squa-mous epithelium is present at the surface
of the invaginations, and is contiguous
with a double layer of cuboidal and
columnar epithelium in the deeper por-tions of the lesion. Within the dermis,
broad villous projections protrude into
cystic spaces. Columnar epithelium is
present toward the lumen of the spaces,
and simple cuboidal epithelium can be
seen at the periphery. Decapitation
secretion of luminal cells is a frequent
finding. Plasma cells are consistently
numerous within the stroma, and are a
highly reproducible finding in the stroma
of syringocystadenomas.
The differential diagnosis includes
hidradenoma papilliferum, which differs
clinically by location in the perineal
region, and histologically by dermal nod-ules showing a more complex papillary
growth pattern, and absence of plasma
cells in the stroma. The epithelial lining of
the two lesions shows histologic overlap,
however.
Precursor lesions
Approximately one-third of cases arise in
organoid naevi.
Histogenesis
Syringocystadenomas show differentia-tion that is predominantly apocrine in
pattern, but eccrine origin has been sug-gested in some cases, as exemplified by
immunohistochemical labelling with
eccrine marker IKH-4 {1109}. An intrigu-ing finding is the presence of IgA and
secretory component within the epithelial
cells in syringocystadenomas, and IgA
and well as IgG within the plasma cells
{2420}. This observation suggests that
plasma cells are attracted to tumour
epithelium via a mechanism similar to
that used by glands of the normal secre-tory immune system.
Somatic genetics
Allelic deletions of the patched gene
9q22 and loss of heterozygosity at 9p21
BA
Fig. 3.32 Syringocystadenoma papilliferum.  A Keratinizing squamous epithelium at the surface merges with
columnar epithelium in the deeper portions of the tumour.   B  Papillary projections are lined by pseudos-tratified columnar epithelium, and plasma cells are typically noted in the stroma.
147Benign tumours with apocrine and eccrine differentiation
(p16) have been reported in syringocys-tadenoma papilliferum {281}.
Prognosis and predictive factors
Syringocystadenonas are benign and
simple excision is curative.
Hidradenoma papilliferum
Definition
Hidradenoma papilliferum is a benign
cystic and papillary neoplasm that
almost always develops in the vulval and
perianal regions of middle-aged women.
ICD-O code 8405/0
Epidemiology
Most cases appear in women, although
there are also reports in males {588,
1441,1697,2421}. The neoplasm is rare
in Black patients. The age of presenta-tion ranges from 20-90 years {2428,
2435}.
Localization
The skin of the vulva and perianal
regions are the most frequently involved
areas {588,1106,1441,1565,1568,1697,
2324,2421}, although rare examples of
extra-genital or ectopic hidradenoma
papilliferum have been reported on
postauricular skin {247}, eyelids {1106,
1697,2056,2421}, external auditory canal
{1718}, face {1106,1697} scalp {845},
axilla {1106,2421}, upper limb {2421},
back {727,1106} and thigh {2421}.
Clinical features
The lesion appears as a slow-growing
cystic dermal nodule, usually asympto-matic, although it sometimes ulcerates
and bleeds. The neoplasm is a unilateral
skin-coloured nodule, papule or polypoid
exophytic lesion, most commonly locat-ed on the labius majus.
Histopathology
At scanning magnification, hidradenoma
papilliferum consists of a cystic neo-plasm composed of elongated tubules
and large papillary structures with a
frond-like pattern. The papillae are com-posed of a central axis of connective tis-sue lined by two layers of epithelial cells.
The basal layer is composed of pale-staining cuboidal myoepithelial cells and
the luminal layer is made up by columnar
cells with decapitation secretion. The
cystic cavity and the lumina of the tubu-lar structures contain apocrine secre-tions in the form of eosinophilic homoge-neous material.
The epithelial cells at the periphery are
flattened, and decapitation secretion is
less evident, as a consequence of the
pressure exerted by the cyst contents.
The stroma surrounding the cystic cavity
is composed of compressed fibrous tis-sue that is separated from the normal
adjacent dermis by clefts. These clefts
are responsible for the tendency of the
neoplasm to shell out easily after incision
of the epidermis.
In contrast with syringocystadenoma
papilliferum, hidradenoma papilliferum is
not connected with follicular infundibula
and there are not plasma cells in the axis
of connective tissue of the papillations.
Sometimes, neutrophils are scattered
within the connective tissue framework.
Immunoprofile
Immunohistochemical studies demon-strated that epithelial cells lining the
papillations express low-molecular
weight cytokeratins. The luminal border
of the cells lining tubular structures is
also decorated by carcinoembryonic
antigen, epithelial membrane antigen
and gross cystic disease fluid protein-15.
Immunostains for S-100 protein and
high-molecular-weight keratins are nega-tive {2257}. Neoplastic epithelial cells lin-ing tubules and papillations also express
strong immunoreactivity for androgen
and oestrogen receptors {1739}.
Histogenesis
Both the histopathologic and ultrastruc-tural characteristics of hidradenoma
papilliferum support an apocrine line of
differentiation, although some authors
have postulated the possibility of origin
from Wolffian ducts or accessory mam-mary glands {576,1633}.
Prognosis and predictive features
Hidradenoma papilliferum is a benign
neoplasm cured by simple excision.
Malignant transformation is a very
uncommon event {588,1730,2274,2460}.
A case of adenosquamous carcinoma of
the vulva developing from a pre-existing
hidradenoma papilliferum has also been
reported {142}.
Mixed tumour
(chondroid syringoma)
Definition
Cutaneous mixed tumours are benign
adnexal tumours of skin composed of
epithelial and stromal elements with a
wide spectrum of patterns. These
tumours are histologically analogous to
mixed tumours of the salivary gland, but
lack the tendency for local recurrence
seen in the latter lesions.
ICD-O code 8940/0
Synonyms
Chondroid syringoma, mixed tumour of
skin.
Epidemiology
Mixed tumours most often occur as soli-tary slowly growing nodules on the head
B CA
Fig. 3.33 Hidradenoma papilliferum.  A Hidradenoma papilliferum of the vulva. A polypoid exophytic lesion involving the left labius majus of an elderly woman.  B The
neoplasm shows a prominent papillary pattern.  C Columnar cells shows evidence of decapitation secretion in their luminal border.
148 Appendageal tumours
and neck of adults, although other sites
may be affected. There is a male
predilection. Most lesions are between 1-3 cm in diameter, although examples as
large as 6 cm have been reported
{1182}.
Clinical features
Cutaneous mixed tumours present as
asymptomatic dermal nodules, with no
specific distinguishing clinical character-istics.
Histopathology
At low power, cutaneous mixed tumours
are well-circumscribed lesions located in
the dermis and/or subcutis. A biphasic
growth pattern can be readily detected,
with epithelial elements embedded with-in a myxoid, chondroid, or fibrous stro-ma. The epithelium often shows a pattern
of branching tubules, sometimes with
decapitation secretion suggesting apoc-rine differentiation. Solid cords and
islands of epithelium as well as single
cells may also be present. In some
cases, the epithelial elements are com-posed of small non-branching tubules
that may contain eosinophilic cuticles.
Follicular differentiation occurs in some
mixed tumours, in the form of follicular
germinative cells, shadow cells, or sebo-cytes. Mixed tumours may exhibit clear
cell change within the epithelial cells. In
an estimated 40% of cases, mixed
tumours contain hyaline cells character-ized by an ovoid shape, dense ground-glass or hyaline-like cytoplasm, and an
eccentric nucleus {85}. The cells resem-ble plasma cells, and have been called
plasmacytoid cells. In some cases, hya-line cells are the predominant cell type,
leading to the term hyaline-cell rich
chondroid syringoma {735}. The pres-ence of hyaline cells appears to be of no
prognostic significance, although such
cells may present a diagnostic challenge
to the unsuspecting pathologist {735}.
Immunoprofile
Immunohistochemical studies reveal
staining of the inner layer of epithelial
cells with cytokeratin, CEA, and EMA,
and staining of the outer cellular layer
with S100 and vimentin {2559}.
The stroma of mixed tumours usually
comprises at least half of the lesion, and
may show variable patterns of differenti-ation, including myxoid, fibroblastic,
fibrocartilagenous, chondroid, and even
osteoid components. Combinations of
matrix components are the rule. Despite
the name chondroid syringoma, chon-droid areas may be absent in the stroma.
The stroma stains strongly for alcian blue
with hyaluronidase resistance.
Differential diagnosis
In mixed tumours where stroma predom-inates, the differential diagnosis includes
entities such as myxoma. In other lesions
with abundant epithelial elements, the
differential diagnosis includes benign
adnexal tumours such as hidradenoma
and syringoma, depending on the pat-tern of epithelial growth.
Histogenesis
It is generally accepted that there are
both apocrine and eccrine variants of
mixed tumours. Ultrastructural studies
confirm that myoepithelial cells surround
the epithelial cells, and appear to pro-duce the stromal components of the
lesions {2423}. The stroma of mixed
tumours contains matrix components
such as types II and IV collagen,
tenascin, fibronectin, and laminin {773}.
Ultrastructural and immunohistochemical
studies of hyaline cells in mixed tumours
suggest these cells derive from both the
epithelial and stromal components of the
lesions, possibly representing a regres-sive process {85}.
Prognosis
Cutaneous mixed tumours are benign
lesions cured by simple excision.
Fig. 3.34 Mixed tumour (chondroid syringoma).   A Well-circumscribed mixed tumour with branching tubules and myxochondroid stroma.   B Mixed tumour with
epithelial tubules embedded in a myxoid and hyaline stroma.  C Predominately ductal epithelial pattern of mixed tumour.
BA C
149Malignant tumours with follicular differentiation
Pilomatrical carcinoma
Definition
Pilomatrical carcinoma is the malignant
counterpart of pilomatricoma.
ICD-O code 8110/3
Synonyms
Pilomatrix carcinoma, matrical carcino-ma, invasive pilomatrixoma, malignant
pilomatrixoma, matrix carcinoma.
Epidemiology
Pilomatrical carcinoma is an extremely
rare tumour. Most cases present in adults
with a broad age range {28,804,954,
2064}. The mean age at the time of diag-nosis is about 48 years. The male to
female ratio is 2:1.
Etiology
The majority of pilomatrical carcinomas
develop de novo, although malignant
transformation from a pre-existing pilo-matricoma has been reported {2064}. It
is conceivable that proliferating pilomatri-coma, a variant of pilomatricoma that
occurs mainly in middle aged and elder-ly individuals, may represent an interme-diate precursor lesion.
Localization
Pilomatrical carcinomas mostly occur in
the head and neck, upper extremities
and buttocks. Rare tumours have been
reported in the axilla and inguinal
regions.
Clinical features
The clinical appearance of pilomatrical
carcinoma is generally not distinctive.
Patients show solitary, occasionally
ulcerated or fungating nodules ranging
in size from 1-10 cm in diameter. Skin
nodules are often of long duration rang-ing from several months to years before
diagnosis, although occasional cases of
recent onset and a history of rapid
growth have been reported.
Histopathology
The tumour is a large, asymmetrical,
poorly circumscribed dermal or dermal-subcutaneous mass composed of sever-al, irregularly shaped and variously sized
aggregations of basaloid cells (matrical
and supramatrical cells) {28,804,954,
2064}. Foci of cornified material contain-ing shadow cells are characteristically
observed within the basaloid cell aggre-gations. Some neoplasms show a vari-able desmoplastic stroma surrounding
the basaloid cell aggregations. Focal
connections of basaloid cell aggrega-tions to the overlying epidermis and/or
ulceration are often noted. Basaloid cells
exhibit hyperchromatic nuclei, with one
or more prominent nucleoli and ill-defined cytoplasmic margins as well as
variable numbers of occasionally atypi-cal mitotic figures (up to 10 mitoses per
high-power field). Foci of geographical
necrosis, calcification and ossification
are observed. Mitotic activity is not a reli-able indicator of malignancy, because
mitoses are common in pilomatricoma.
Other parameters, such as an infiltrative
growth pattern, as well as angiolymphat-ic, perineural, and bone invasion, are
more reliable features {804,2064}.
Immunoprofile
Immunohistological studies have previ-Fig. 3.35  Pilomatrical carcinoma.  A The neoplastic cells are present in apposition to the epidermis.  B A large mass of shadow (ghost) cells is present. The clear
cells have more nuclear pleomorphism than in the pilomatricoma.
Malignant tumours with follicular
differentiation
S. Kaddu
L. Requena
A B
150 Appendageal tumours
ously revealed keratin staining in both
basaloid and shadow cells {556}.
Prognosis and predictive factors
Treatment of choice is by surgical exci-sion with adequate margins. Mohs micro-graphic surgery technique may be useful
in treating some patients. Pilomatrical
carcinoma is a mainly locally aggressive
tumour which often recurs if not com-pletely removed but very rarely shows
distant metastases. Metastatic spread is
evidenced by involvement of regional
lymph nodes, lungs and/or bone.
Proliferating tricholemmal
tumour
Definition
Proliferating tricholemmal tumour is a
solid-cystic neoplasm that shows tric-holemmal differentiation similar to that of
the isthmus of the hair follicle.
ICD-O code 8103/1
Synonyms and historical annotation
Epidermoid carcinoma in sebaceous
cyst {252,416} subepidermal acanthoma
{1458}, proliferating epidermoid cyst
{1152}, invasive hair matrix tumour of the
scalp {1910}, trichochlamydocarcinoma
{1053}, giant hair matrix tumour {583},
proliferating tricholemmal cyst {321}, pro-liferating pilar cyst {68,92}, proliferating
follicular cystic neoplasm {23}, proliferat-ing tricholemmal cystic squamous cell
carcinoma {1631}, proliferating isthmic
cystic carcinoma. These different names
reflect the distinct histogenetic and bio-logic interpretations for this neoplasm
among different authors.
Epidemiology
The neoplasm is more frequent in women
than in men and most patients are elder-ly {2069}.
Localization
More than 90% of the lesions are situated
on the scalp. Other described locations,
in decreasing order of frequency, include
face, trunk, back and forehead {2069}.
Clinical features
The tumour is a solitary, multilobular,
large, exophytic mass, which may devel-op within a naevus sebaceous {866,
1874}. Multiple lesions are very rare. The
size ranges from 2-10 cm in diameter,
although lesions up to 25 cm in diameter
have been described {407}. Alopecia
and ulceration can be found.
Macroscopy
The lesions often show a multilobular
appearance. The cystic structures often
contain compact keratin and calcified
material.
Histopathology
Proliferating tricholemmal tumour occurs
on a morphologic continuum. On one
end of the spectrum, it consists of a well-circumscribed solid and cystic neoplasm
which involves the dermis and some-times extends to the subcutaneous tis-Fig. 3.36 Proliferating tricholemmal tumour. A large
tumour on the scalp of an elderly woman.
Fig. 3.38  Proliferating tricholemmal tumour. At scanning power the neoplasm appeares as a well-circum-scribed cystic neoplasm involving deeper dermis and subcutaneous tissue of the scalp.
Fig. 3.37 Proliferating tricholemmal tumour. The
lobules of the neoplastic epithelium show tricho-lemmal keratinization, characterized by peripheral
palisading of small basaloid cells and large ker-atinocytes with ample eosinophilic cytoplasm that
develop abrupt keratinization without previous
granular layer, resulting in compact orthokeratotic
eosinophilic keratin. This type of keratinization is
similar to that of the outer sheath at the level of the
isthmus of the hair follicle.
151Malignant tumours with follicular differentiation
sue. In addition to the typical features of
a tricholemmal (pilar) cyst, this tumour
shows prominent epithelial infoldings into
the cyst lumen. The epithelium shows
peripheral palisading of small basaloid
cells arranged along a thick vitreous
membrane, differentiating towards large
keratinocytes with ample eosinophilic
cytoplasm and abrupt keratinization with-out a granular layer. Often, areas of cal-cification and abundant cholesterol crys-tals are seen within the compact
eosinophilic keratin. The neoplastic cells
are monomorphous without significant
cytologic atypia and with only rare
mitoses {1135,1724}.
On the other end of the morphologic
spectrum are neoplasms with malignant
features such as invasive growth extend-ing beyond the confines of the cyst wall
coupled with nuclear pleomorphism and
high mitotic activity. These areas may be
indistinguishable from squamous cell
carcinoma. Additional findings include
shadow cells as an expression of focal
matrical differentiation similar to that of
pilomatricoma {1726}, areas of seba-ceous and apocrine differentiation
{2021}, and spindle cells {1649}.
Differential diagnosis includes tricholem-mal cyst, which lacks the multilobular
architecture, as well as proliferating epi-dermoid (infundibular) cyst {2069}. The
latter occurs most commonly in the
anogenital region of male patients and
shows a cystic cavity lined by stratified
squamous epithelium with infundibular
keratinization. Up to 20% of the lesions
may undergo malignant transformation
into squamous cell carcinoma {2069}.
Differentiation between proliferating tric-holemmal tumour and proliferating
infundibular cyst is straightforward,
because the former shows tricholemmal
keratinization, whereas the latter has
mainly infundibular keratinization.
Tricholemmal carcinoma should also be
considered.
Immunoprofile
Proliferating tricholemmal tumour
expresses fetal hair root cytokeratin, as
well as cytokeratin 7 {933}.
Histogenesis
The pathogenesis remains unknown. In
some cases, human papillomavirus has
been implicated in the etiology {23}. It is
unclear if proliferating tricholemmal
tumours arise de novo or from pre-exist-ing tricholemmal cysts {1631,1847}.
Prognosis and predictive factors
Proliferating tricholemmal tumours with-out atypical features generally behave in
a benign fashion {762}. Yet, complete
excision is recommended to avoid recur-rences, and to allow for complete
histopathological evaluation. Tumours
with an invasive growth pattern or cyto-logic atypia have an unpredictable
course. They may be locally aggressive,
recur, or metastasize {68,178,982,1017,
1537,1572,1727,1728,1773,2311,2486}.
For this reason, it has been suggested
that even the classical benign lesions are
squamous cell carcinoma {1631}.
152 Appendageal tumours
Trichoblastoma
Definition
Trichoblastoma is a benign neoplasm dif-ferentiated toward the trichoblast, i.e.,
the folliculo-sebaceous-apocrine germ,
or follicular germ, for short. In many
cases, advanced follicular differentiation
can be present also {28,989,1083}.
ICD-O code 8100/0
Synonyms
Trichoepithelioma, trichoblastic fibroma,
trichogenic trichoblastoma, lymphadeno-ma (adamantinoid trichoblastoma), tri-chogerminoma, sclerosing epithelial
hamartoma, Brooke-Fordyce disease,
Brooke-Spiegler disease.
Clinical features
Trichoblastomas, as a rule, are solitary,
small papules that occur on any hair fol-licle-bearing location (usually head and
neck), at any age, and can affect either
sex. They can also present as multiple
centrofacial papules or nodules, particu-larly in the diseases of Brooke-Fordyce
and Brooke-Spiegler. The size of an indi-vidual neoplasm can vary from a few mil-limetres to several centimetres, but most
are less than 1 cm in diameter. Most are
skin-coloured and ulcerated only rarely.
The differential diagnosis is non-specific
for solitary lesions, but includes the
“angiofibroma” of tuberous sclerosis
when multiple.
Histopathology
Trichoblastic epithelial components
associated with stereotyped stroma,
chiefly the follicular papilla, must be
present to establish the diagnosis with
surety. There are five patterns; these can
be mixed in any given neoplasm.
Large and small nodular trichoblastomas
are usually circumscribed, sometimes
subcutaneous, and contain a uniform
distribution of solid trichoblasts with fol-licular papillae. In some cases, the follic-ular “papillae” are not papillary in that
they fail to invaginate into the epithelial
components of the germ. The epithelial
cells are deeply basophilic, uniform, and
overlap each other usually. Melanocytes
can be prominent within the epithelial
areas in some cases. Some cases have
nodules that are lymphocyte-rich, a pat-tern termed originally lymphadenoma
{1561,2053}.
It should be noted that, rarely, lesions
with a pattern similar to nodular tri-choblastoma are really trichoblastic
(basal cell) carcinomas that mimic tri-choblastoma. While it is not completely
understood what are all the factors that
differentiate these lesion from trichoblas-toma, one seems to be that the carcino-mas infiltrate through skeletal muscle or
other deep structures while there is a
conspicuous absence of the usual stro-ma present in a classic nodular tri-choblastoma. Rare examples with this
pattern have metastasized {1960}.
Retiform trichoblastomas are reticulated,
with large fenestrations containing follic-ular stroma.
Cribriform trichoblastoma is the most
common pattern when the neoplasms
are multiple, characteristic of Brook-Fordyce disease. The trichoblasts are
usually fenestrated, but with small fenes-trations compared to the retiform pattern.
Racemiform trichoblastoma contains
epithelial nests that simulate “clusters of
grapes”. This results in stromal compo-nents that connect with the surrounding
stroma rather than being isolated from it
in fenestrations.
Columnar trichoblastoma (desmoplastic
“trichoepithelioma”) occurs most com-monly as a solitary depression on the
face of a young woman. As a rule, these
neoplasms are confined to the superficial
dermis. They contain stereotyped, thin
strands of epithelium compressed by
dense stroma. Small trichoblasts can be
seen in some cases, but are less com-mon compared to conventional forms of
Benign tumours with follicular
differentiation
M. A. Hurt
S. Kaddu
H. Kutzner
Fig. 3.39 Trichoblastoma.  A Large nodular trichoblastoma. Note the circumscription. Melanin pigmentation is present in this lesion.  B Cribriform trichoblastoma. At
scanning magnification, there are small groupings of basophilic cells containing small fenestrations of stroma.
BA
B. Cribier
T. Schulz
W. Hartschuh
153Benign tumours with follicular differentiation
trichoblastoma. The differential diagnosis
includes morpheiform basal cell carcino-ma, microcystic adnexal carcinoma, and,
rarely, metastatic carcinoma from breast.
Thus, superficial biopsies of such lesions
should be investigated thoroughly, and
additional biopsy or excision should be
requested for cases in which the diagno-sis is uncertain.
Immunoprofile
Trichoblastomas, as a rule, cannot be dif-ferentiated from basal cell (trichoblastic)
carcinoma based solely on specific
expression of cytokeratins. The presence
of presumed Merkel cells within a neo-plasm, however, does seem to favour tri-choblastoma over basal cell carcinoma
{1349}. Some trichoblastomas can con-tain zones of ductal differentiation; when
this occurs, markers, such as CEA will
highlight those areas {2398} but they will
not aid in establishing the diagnosis.
Uncommonly, excessive pigmentation is
seen in nodular trichoblastoma, and
these lesions contain markers for
melanocytes {1199}, but they are non-specific for the diagnosis, as basal cell
(trichoblastic) carcinoma can have simi-lar findings.
Desmoplastic trichoepithelioma contains
AE14, EMA, and Leu-M1 (CD15) focally,
but is negative for CEA and S100 {2511}.
CK 5, 8, 14 and 15 have been identified
in some cases {2555}. It can be differen-tiated from morpheiform basal cell carci-noma and microcystic adnexal carcino-ma, in most cases, by applying CK20,
which marks neuroendocrine cells in
desmoplastic trichoepithelioma, but not
in basal cell carcinoma or microcystic
adnexal carcinoma {13}. Furthermore,
CK7 is usually positive in breast carcino-ma metastatic to skin and in microcystic
adnexal carcinoma, but not in desmo-plastic trichoepithelioma. Stromelysin 3
has also been identified in the stroma of
morpheiform basal cell carcinoma, but
not in the stoma of desmoplastic tri-choepithelioma {2346}.
Somatic genetics
Multiple trichoblastomas (Brooke-Fordyce disease) are transmitted as an
autosomal dominant trait linked to chro-mosome 9p21 {6,951}. Solitary (spo-radic) trichoblastomas have been linked,
in some cases, to 9q22.3 {1538}, the
same locus for the naevoid basal cell
carcinoma syndrome {4}. Familial multi-ple trichoblastomas and cylindromas
(Brooke-Spiegler disease) have been
linked to chromosome 16q12-q13
{5,722}.
Prognosis and predictive factors
Because these are benign neoplasms,
no treatment is required, in most cases, if
the diagnosis is established with certain-ty. Because some trichoblastomas may
occur, rarely, in association with basal
cell (trichoblastic) carcinoma, and
because of the difficulty in establishing
the diagnosis in superficial biopsies, in
some cases, additional biopsy or exci-sion should be considered if there is
uncertainty about the diagnosis.
Pilomatricoma
Definition
Pilomatricoma is a relatively common
benign cutaneous adnexal neoplasm
with differentiation towards the matrix
and inner sheath of a normal hair follicle
as well as hair cortex {28,1169}.
ICD-O code 8110/0
Synonyms
Pilomatrixoma, calcifying epithelioma of
Malherbe, benign calcifying epithelioma
Epidemiology
Pilomatricoma accounts for up to 0.2% of
all routine dermatopathologic specimens
Fig. 3.40 Trichoblastoma.  A This trichoblast has a typical follicular “papilla” that does not extend cleanly into an invaginated epithelial component of the follicular
germ.  B Compared to the usual types of trichoblasts seen in nodular trichoblastoma, this trichoblastic carcinoma has diminished mesenchymal stroma, specifical-ly diminished mesenchyme of the follicular papilla.  C Trichoblast containing a superficial follicular papilla that protrudes into an invaginated follicular germ.  This
is a fundamental finding in trichoblastomas of any pattern.  D Retiform trichblastoma. This reticulated pattern is seen often in large, solitary lesions.  E This sieve-like pattern is commonly present in the small centrofacial lesions of Brooke-Fordyce disease and is the pattern known classically “trichoepitheliom”.  F Groupings
of follicular germinative cells that branch out, mimicking a “cluster of grapes”. Absence of sieve-like areas seen in the cribrifom pattern.
FED
CBA
154 Appendageal tumours
in certain centres. The tumour occurs in
all age groups {1169}. About 30-50% of
cases present in young individuals less
than 30 years of age. Previous studies
have shown a female predominance.
Localization
Pilomatricomas favour hair-bearing
areas, with the majority of cases arising
in the head and neck region as well as
upper extremities.
Clinical features
Patients present with solitary, asympto-matic, slowly growing, cystic or firm nod-ules measuring 0.5-3 cm in diameter
{28,1169,1170}. Lesions are commonly
skin-coloured, but may show a bluish-purple to reddish hue or pigmentation.
Unusual presentations include rapidly
growing or giant tumours (measuring up
to 15 cm in diameter), lesions with over-lying striae or anetodermic changes, and
multiple tumours. Multiple pilomatrico-mas are quite rare. They are a marker for
myotonic dystrophy, and may rarely be
associated with a number of different
conditions including Rubinstein-Taybi
syndrome, Turner syndrome, Goldenhar
syndrome, sternal cleft defects, coagula-tive defects, and sarcoidosis. Piloma-tricoma-like features are an occasional
finding in cutaneous cysts removed from
patients with Gardner syndrome.
Macroscopy
Grossly, pilomatricomas occur mostly as
lobulated masses with variable amounts
of chalky white or yellow keratinous
material on their cut surfaces. Foci with
bone may be observed.
Histopathology
There is usually a relatively well-circum-scribed, deep dermal or dermal-subcu-taneous, cystic neoplasm surrounded by
a variable connective tissue stroma {28,
1169}. A spectrum of histopathologic
features reflecting mainly different stages
of development is observed in individual
lesions. Early and well-developed pilo-matricomas are characterized by small
to large-sized, cystic lesions lined focally
by aggregations of basaloid cells (matri-cal and supramatrical cells) and few
squamoid cells and filled centrally with
large masses of eosinophilic cornified
material (faulty hair matrix) containing
shadow (ghost) cells as well as a few
keratin filaments. A transition zone of
retained nuclei from basaloid cells to
eosinophilic cornified material containing
shadow cells is focally observed.
Basaloid cells exhibit deeply basophilic
oval or round nuclei and a variable num-ber of mitotic figures. Inflamed or
regressing pilomatricomas are relatively
large cystic tumours with prominent
areas of shadow cells and foci of basa-loid and/or squamoid cells surrounded
by a variable, often dense inflammatory
infiltrate with histiocytic giant cells, and
occasionally siderophages and/or mela-nophages. Areas of granulation tissue
may be present. Occasional lesions dis-Fig. 3.42 Tricholemmoma.   A Exo-endophytic tumour with wart-like silhouette and focal desmoplastic stroma.   B Peripheral epithelia are arranged in a palisade.
Small central follicular microcyst.
BA
Fig. 3.41 Pilomatricoma. There is a growth component of basolid cells with transition to pilar ‘shadow cells’.
155Benign tumours with follicular differentiation
play features of transepidermal elimina-tion of shadow cells (perforating piloma-tricoma) or a keratoacanthoma-like pat-tern. Old pilomatricoma lesions reveal no
epithelial components but show irregu-larly shaped, partially confluent, focally
calcified or metaplastically ossified
shadow cell areas embedded in a
desmoplastic stroma, with little or no
inflammatory infiltrate. Extramedullary
haematopoiesis has been observed in
some regressing and old pilomatricoma
lesions.
A subset of pilomatricomas, also termed
“proliferating pilomatricoma”, is charac-terized by the presence of relatively
large, solid or solid-cystic basaloid cell
areas with small foci of shadow cells
{1170}. This variant presents mainly in
middle aged and elderly individuals.
“Matricoma” represents another unusual
pilomatricoma variant characterized by
discrete, small, solid aggregations of
basaloid cells with several connections
to pre-existing infundibula at different
points {28}.
Molecular and cytogenetics
Derivation of pilomatricomas from the
hair matrix has been underlined by
recent biochemical studies demonstrat-ing prominent staining of tumour cells
with antibodies directed against LEF-1, a
marker for hair matrix cells. Mutations in
the gene CTNNB1 have been detected in
up to 75% of pilomatricomas studied
implicating beta-catenin/LEF misregula-tion as a possible cause of hair matrix
cell tumourigenesis {438}. In another
study, all 10 pilomatricomas examined
were found to display strong bcl-2
immunostaining, a proto-oncogene well
known to help in suppressing apoptosis
in benign and malignant tumours {712}.
This finding supports a role for faulty sup-pression of apoptosis in the pathogene-sis of pilomatricomas.
Prognosis and predictive factors
Treatment is recommended mainly to
avoid a foreign body reaction and inflam-mation with eventual scarring. Surgical
excision is usually curative, but occa-sional recurrences may be observed.
Spontaneous regression has been
reported in a few cases. Malignant trans-formation has only been suspected in a
single case of pilomatrical carcinoma
{2064}.
Tricholemmoma
Definition
Tricholemmoma (TL) is a benign folliculo-infundibular proliferation occurring fre-quently but not exclusively on the face of
adults. Multiple tricholemmomas may be
associated with Cowden disease.
ICD-O code
Tricholemmoma 8102/0
Multiple tricholemmomas 8102/0
Synonyms
Trichilemmoma
Epidemiology
TL is a relatively common cutaneous pro-liferation that occurs mostly in adults and
affects both sexes equally {323}. Multiple
TLs, often in conjunction with acral ker-atoses, palmar pits, and oral fibromas,
are a cutaneous marker of Cowden dis-ease (multiple hamartoma and neoplasia
syndrome) {322,325,681,2025,2247,
2249-2251}.
Localization
TL arises on the head and neck, almost
exclusively on the face, favouring the
centrofacial area. Rarely, TL may occur in
naevus sebaceous {410,1979}.
Clinical features
Patients usually present with a solitary
asymptomatic exophytic centrofacial
lesion which is either wart-like with verru-cous and keratotic features or dome
shaped with a smooth surface. Individual
lesions are small, varying in diameter
between 3 and 8 mm {28}. Multiple facial
TLs are almost invariably associated with
Cowden disease {2247,2249-2251}.
Histopathology
Most cases of TL present as a sharply
circumscribed superficial exo-endophyt-ic proliferation with a papillated surface.
There is marked parakeratosis, hyperker-atosis, and wedge-shaped hypergranu-losis of the infundibula, in conjunction
with a collarette of embracing adnexal
epithelium {28,323}. TL does not involve
the interfollicular epidermis. The domi-nating histological pattern of TL is that of
a bulbous infundibular hyperplasia with
tricholemmal differentiation, akin to the
outer root sheath of the hair follicle {28}.
There are one or more bulbous lobules,
always in continuity with the epidermis.
These lobules consist of numerous pale
and clear isomorphic epithelia, most of
which are PAS positive. At the periphery,
pale columnar cells are arranged in a
palisade, bordered by a prominent PAS-DC
Fig. 3.43 Tricholemmoma.  A Thick PAS-positive basement membrane.  B Focal necrosis within bulbous fol-licular hyperplasia. Thickened basement membrane.  C Desmoplastic stroma with entrapped bizarre epithe-lial strands (“pseudoinvasive interface”).  D PAS-positive desmoplastic stroma and basement membrane.
BA
156 Appendageal tumours
and type IV collagen-positive basement
membrane. Central foci of epidermal /
infundibular keratinization, occasional
small and inconspicuous squamous
eddies, and keratinous microcysts in
larger lesions are occasional findings
{28}. There are no mitoses.
Desmoplastic tricholemmoma is a variant
of TL characterized by a highly desmo-plastic stroma with broad zones of scle-rosis and distinctive artifactual clefts.
Instead of “pushing” smooth lobular con-tours there may be a pseudoinvasive
interface akin to pseudocarcinomatous
epithelial hyperplasia, simulating carci-nomatous growth {1079,2333}.
Differential diagnosis
Warts, basal cell carcinomas, squamous
cell carcinomas, trichoblastomas, sebor-rhoeic keratoses, and keratosis follicu-laris inversa may contain areas of tric-holemmal differentiation {31,1931}. The
tumour of the follicular infundibulum
exhibits a plate-like pattern with inter-connecting horizontally oriented epithe-lial strands. Inverted follicular keratosis
consists of basaloid and squamous
epithelia, associated with large numbers
of squamous eddies (i.e. concentric lay-ers of squamous cells in a whorled pat-tern, sometimes keratinized).
Histogenesis
According to strict topographical anato-mical criteria, TL arises from the follicular
infundibulum and differentiates toward
the outer [tricholemmal] root sheath {28}.
Its superficial folliculo-infundibular loca-tion militates against the classification of
TL as a neoplasm of the lower portion of
the hair follicle (i.e. the [outer] tricholem-mal sheath).
However, it is still a matter of debate
whether TL is of hamartomatous/neo-plastic {318,991,1906,1931} or of viral
origin {15,28,31}. The detection of HPV
DNA in tricholemmomas by PCR {2688}
favours the latter view of TL as a resolv-ing verruca vulgaris with tricholemmal
differentiation {15,28, 31}.
Prognosis and predictive factors
TL is an entirely benign cutaneous neo-plasm. Multiple TLs are a hallmark of
Cowden disease and should prompt a
search for internal malignancy.
Trichofolliculoma
Definition
Trichofolliculoma (TF) is a follicularly dif-ferentiated hamartoma generally appear-ing during adult life.
ICD-O code 8101/0
Epidemiology
TF represents a rare hamartoma mostly
occurring during adulthood (with a wide
range of ages between 11 and 77 years
{28}) without sex predilection {887}.
Localization
TF favours the head and neck region,
foremost the face. Most lesions are situ-ated around the nose {887}.
Clinical features
TF presents as a solitary asymptomatic
dome-shaped lesion with a smooth sur-face and a widely dilated central ostium
from which a small tuft of delicate white
hairs emerges. Lesions are small, rang-ing between 0.5 and 1.0 cm in diameter
{28}.
Histopathology
The main histological features of TF are
reflected by its “Caput Medusae” pattern
{28}: embedded in a highly fibrocytic
stroma, large numbers of vellus follicles
with upper and lower segments like
those of normal follicles radiate from the
perimeter of a dilated infundibulum.
TF is a symmetrical, well-circumscribed,
vertically oriented lesion composed of
three components: infundibulo-cystic,
follicular, and stromal {28}. The centre of
the lesion is occupied by one or more
widely dilated infundibulo-cystic struc-tures that are continuous with the epider-mis and open to the surface of the skin
through an ostium. The cystic lumina
may be filled with innumerable corneo-cytes and vellus hairs. From the epithelial
walls of the infundibular cystic spaces
smaller infundibula radiate, to which are
attached vellus follicles in various num-bers. These vellus follicles are not asso-ciated with muscles of hair erection or
with sebaceous ducts, albeit sebaceous
cells arranged as solitary units or in lob-ules may occur within the lining epitheli-um of the central infundibulo-cystic
structure.
The morphology of the individual vellus
follicles may vary from normal to striking-ly aberrant {28}. Normal vellus follicles
may exhibit all stages of the follicular
cycle {2106}. The whole lesion is embed-ded in a cellular connective tissue
sheath, which is separated from the adja-cent normal dermis by prominent shrink-age clefts. The highly fibrocytic stroma
C
Fig. 3.44 Trichofolliculoma.  A Note reticulate pattern of vellus follicles in devolution.  B Detail. Reticulate
epithelial strands, sebaceous lobules and few vellus follicles.  C Note sebaceous lobules and dense fibrot-ic stroma. Vellus follicles in different stages of devolution.
A
B
157Benign tumours with follicular differentiation
which surrounds the individual vellus fol-licle resembles perifollicular sheath {28}.
The existence of considerable numbers
of Merkel cells in all trichofolliculomas
underlines their classification as hamar-tomas with follicular differentiation {967}.
Variants
TF is a complex lesion with protean fea-tures {28}. Some of these are caused by
the evolutionary and devolutionary alter-ation of the vellus hair follicles in their
regular biological cycles {2106}. In this
context, folliculo-sebaceous cystic
hamartoma {1275,2187} may be inter-preted as a TF at its very late stage with
nearly complete regression of the tran-sient follicular epithelium, but with con-current growth and maturation of seba-ceous elements {2105}. Sebaceous tri-chofolliculoma {1846} exhibits distinct
sebaceous lobules at its outer circumfer-ence, but lacks vellus follicles that radi-ate from the epithelial lining of the dilated
infundibulum. The latter criterion militates
against the classification of sebaceous
trichofolliculoma as a true TF {28}. Hair
follicle naevus is regarded as a TF that
was histologically sampled at its periph-ery {28}. There is a striking predomi-nance of mature vellus follicles and the
central infundibular lumen may be quite
inconspicuous.
Prognosis and predictive factors
TF represents an entirely benign cuta-neous hamartoma with no reports of
tumour progression or aggressive clini-cal course.
Pilar sheath acanthoma
Definition
Pilar sheath acanthoma is a follicular
neoplasm differentiated toward the per-manent part of the hair follicle, to wit, the
infundibulum and the isthmus. [The
infundibulum is an extension of epider-mis to meet the isthmus, but both func-tion as part of the follicular sheath].
Synonyms
Infundibuloisthmicoma
Clinical features
Pilar sheath acanthomas affect adults of
either sex, and are identified usually on
the face. They are small, solitary papules
up to 5 mm in diameter, with a central 1-2 mm punctum, lacking hair filaments,
and will express corneocytes if
squeezed. There are no known associat-ed syndromes and no known genetic
abnormalities within the neoplasms {29,
232,473,1570,2212,2402}.
Histopathology
The classical example consists of a pat-ulous infundibulum that connects with
lobules of epithelium differentiated
toward both the infundibulum and the
isthmus. This differentiation results in
blue-gray (infundibular) and pink (isth-mic) corneocytes that fill the follicular
canal. There can be a minor component
of stem or bulb (or both) differentiation in
some examples. Consequently there is,
as a rule, no evidence of hair filaments in
these neoplasms.
Differential diagnosis
Pilar sheath acanthoma should be differ-entiated from dilated pore (Winer), tri-chofolliculoma, and fibrofolliculoma/tri-chodiscoma. Dilated pore is an
infundibular cyst that has proliferated
minimally, but lacks isthmic differentia-tion.
Trichofolliculoma is a hamartoma and
contains fully formed vellus hair follicles
that radiate around a centrally positioned
cyst. Fibrofolliculoma/trichodiscoma is
also a hamartoma found characteristical-ly in the Birt-Hogg-Dubé syndrome and
that contains thin strands of infundibular
epithelium connected so that fenestra-tions of delicate fibrous stroma are found
within. Additionally, considerable stroma,
lacking epithelium, is often identified (tri-chodiscoma).
Fig. 3.45  Pilar sheath acanthoma. A The characteristic infundibular and isthmic differentiation is stereo-typed.  Note the lack of a hair filament or inner root sheath.  B The lobule contains red-pink corneocytes,
characteristic of the isthmus.  C This pilar sheath acanthoma does not have the obvious widened ostium,
but it does contain the lobules of isthmic epithelium.  D The lobules have a nearly syncytial pattern.  E This
lobule has clear-cell changes and syncytial, pink cell changes. Note the lack of inner sheath or hair fila-ment.  F The small, partly cornified cyst seen here contains no hair filament. Parts of the transient portion
of the follicle are rarely seen in pilar sheath acanthoma.
FE
DC
A B
158 Appendageal tumours
Prognosis and predictive factors
The neoplasm is benign; no treatment is
necessary.
Tumour of the follicular
infundibulum
Definition
Tumour of the follicular infundibulum (TFI)
is a benign epithelial neoplasm of follicu-lar origin.
Synonym
Infundibular tumour.
Epidemiology
TFI is an uncommon tumour occurring in
adults, mainly after the age of 50. In two
studies, TFI accounted for less than 10
per 100,000 skin samples. They can be
observed on the face of patients with
Cowden syndrome or on the surface of
naevus sebaceous.
Localization and clinical features
Solitary TFI is mainly localized on the
face and presents as a small flesh-coloured nodule, resembling basal cell
carcinoma. Multiple or eruptive TFI pres-ent as hundreds of symmetrically distrib-uted hypopigmented geometric macules
localized on the face, neck, trunk, or on
the periocular area. Sun exposure
increases the contrast between normal
skin and the tumours.
Histopathology
TFI is a plate-like horizontal proliferation
of pale keratinocytes, which is localized
in the papillary dermis and shows multi-ple connections with the overlying epi-dermis or with the infundibulum. The
cells are paler and larger than normal
keratinocytes and their cytoplasm stains
with PAS. The tumour is sharply circum-scribed and limited by a dense network
of elastic fibres easily demonstrated by
orcein staining. Desmoplastic and seba-ceous variants have been described
{557,1485}.
Histogenesis
TFI derives from the normal follicular
infundibulum. The occurrence of multiple
TFI suggests a possible genetic basis,
which remains to be established.
Prognosis and predictive factors
The prognosis is good, except in rare
patients with multiple TFI who may devel-op basal cell carcinomas.
Fibrofolliculoma /
trichodiscoma
Definition
Fibrofolliculoma and trichodiscoma are
different developmental stages in the life
of one single benign appendageal
hamartomatous tumour, which differenti-ates towards the mantle of the hair follicle
{27}. Fibrofolliculoma represents the
early and trichodiscoma the late stage in
the development of this lesion {27}.
ICD-O code 8391/0
Synonyms
Trichodiscoma first was erroneously
thought to arise from or to differentiate
toward the hair disk (Haarscheibe) and
therefore bears this name {1836}.
Fibrofolliculoma was often used for peri-follicular fibroma in the past. Neuro-follicular hamartoma and trichodiscoma
are the same {2048}. ”Mantleoma” was
used as the overall term for both fibrofol-liculoma and trichodiscoma {27}.
Epidemiology
Fibrofolliculomas/trichodiscomas are
rare appendageal tumours, occurring
equally in males and females, usually not
before the third decade of life.
Etiology
The etiology of the solitary lesions is
unknown. The BHD gene was mapped to
17p11.2 {1256}.
Localization
The preferred sites of location are the
face, neck and chest.
Clinical features
Fibrofolliculomas and trichodiscomas
cannot be distinguished clinically {248}.
The onset of the lesions is mostly in the
third to fourth decade of life. They are
skin coloured, smooth, dome-shaped
papules, measuring 2-4 mm in diameter
{248}. The lesions are asymptomatic.
Histopathology
There is a histomorphological continuum
between fibrofolliculoma and trichodis-coma. However, most of these presented
cases were actually fibrofolliculomas
which were merely prepared histological-ly in an unusual sectioning technique,
resulting in misinterpretation as perifollic-ular fibroma {2107}.
Fibrofolliculoma
The fibrofolliculoma is composed of sim-ilar amounts of epithelial as well as mes-enchymal elements. At scanning magni-fication there are one or several adjacent
small, vertically oriented infundibulocys-tic structures, surrounded by a prominent
stroma, which is well demarcated from
the surrounding normal reticular dermis
by clefts. Anastomosing cords and
strands of epithelium arise from the dilat-ed infundibulum. Often, cells with seba-ceous differentiation are apparent in
these epithelial cords. The surrounding
Fig. 3.46 Histopathology of a typical tumour of the follicular infundibulum, with horizontal proliferation of pale
keratinocytes in the papillary dermis. Note the connection with the overlying epidermis.
prominent stroma is made up of fine, fib-rillary ribbon-like bundles of collagen,
often arranged parallel to one another
and perpendicular to the epithelial cords.
The stroma contains numerous spindled
fibrocytes and many venules and capil-laries. Elastic fibres are markedly
reduced. The stroma is often mucinous,
comparable to the stroma of the follicular
mantle-region.
Trichodiscoma
Trichodiscoma is a horizontally oriented
dome-shaped tumour composed of more
mesenchymal tissue than epithelial ele-ments. A prominent tumour stroma of
elliptical shape is seen, possessing the
same cellular characteristics as in fibro-folliculoma. In peripheral zones of this
prominent stroma, small groups of seba-ceous lobules may be found. Mantle-like
epithelial structures are uncommon.
Plaque-like variants of fibrofolliculomas/
trichodiscomas with confluence of single
lesions and a resulting extension up to
several cm in diameter have been
described {2103}.
The differential diagnosis of fibrofolliculo-ma includes trichofolliculoma at a late
stage {2105}. Fatty tissue is a typical
finding in late stages of trichofolliculoma
but not in fibrofolliculoma. Perifollicular
fibroma/fibrous papule is also similar to
fibrofolliculoma. However, it is usually
devoid of mucin and shows no mantle-like epithelial proliferations {27}. Tricho-discomas have to be differentiated from
neurofibromas and cutaneous myxomas
{521}. However, the latter tumours lack
the sebaceous epithelial component,
typical of trichodiscoma.
Immunoprofile
The epithelial and mesenchymal parts of
the lesions show the common reactivities
to cytokeratins and vimentin. The tumour
stroma is strongly reactive with antibod-ies to CD34, reflecting its differentiation
towards the follicular mantle region.
Histogenesis
Histologic and immunohistologic data
suggest that fibrofolliculoma/trichodisco-ma is derived from/differentiated to the
mantle region of the hair follicle {27,521}.
The mantle region is a specialized
epithelial-mesenchymal structure, locat-ed at the lower end of the follicular
infundibulum {606} and is the source and
starting point for the development of the
sebaceous glands {27}. Fibrofolliculoma/
trichodiscoma is considered to be a
hamartomatous lesion. Its mesenchymal
part may be responsible for the origin
and growth of the whole lesion, leading
to the distinctive mesenchymal- epithelial
proliferation, reminiscent of a deformed
mantle region {2103}. The postulated cell
of origin therefore might be a specialized
dermal dendritic spindle cell, normally
situated in the mantle region {521,2103}.
Genetic susceptibility
Multiple fibrofolliculomas/trichodiscomas
are part of the Birt-Hogg-Dubé syndrome
(BHD), an autosomal inherited syn-drome, also affecting the lung and kid-ney {248,2579}. The BHD gene is located
at 17p11.2 {806} and encodes folliculin
whose function is unknown. The patients
may have multiple, often bilateral renal
carcinomas, frequently representing
unusual histological subtypes. They also
have an increased frequency of sponta-neous pneumothoraces.
Prognosis and predictive factors
Fibrofolliculoma/trichodiscoma is a
benign lesion, excised primarily for cos-metic reasons. However, it is an impor-tant marker for Birt-Hogg-Dubé syn-drome and its associated complications.
159Benign tumours with follicular differentiation
160 Appendageal tumours
Sebaceous carcinoma
Definition
Sebaceous carcinoma (SC) is a cytolog-ically- and/or architecturally- malignant
neoplasm demonstrating exclusive sebo-cytic differentiation.
ICD-O code 8410/3
Historical annotation
Historically, SCs have been subcatego-rized into ocular and extraocular sub-types {1510A, 1696A, 1827A, 1856A,
2511A,2609A}, although there is no
inherent biological difference between
such lesions.
Epidemiology
SC usually arises in adults, with an aver-age patient age of 62 yrs. and a female
predominance, by a factor of roughly 2:1.
Tumours of the eyelids are preferentially
seen in Asian patients, and also may rep-resent a complication of prior radiothera-py {1067A}.
Clinical features
All SCs present as painless masses,
which can be multifocal. In the ocular
adnexae, they may be mistaken clinical-ly for chalazions, blepharitis, cicatricial
pemphigoid, or conjunctivitis {642,839,
2542}. In extraocular sites, sebaceous
malignancies are commonly confused
with basal cell carcinomas and squa-mous cell carcinomas.
Most extraocular SCs are encountered in
the skin of the head and neck, followed
by the trunk, genitals, and extremities.
Rare cases may also be seen in the
mouth, salivary glands, lungs, and
breasts.
Macroscopy
SCs are nodules that typically enlarge
slowly but may occasionally grow rapid-ly; some become ulcerated. A minority of
individuals with this tumour have the
Muir-Torre syndrome {2227}.
Histopathology
Sebocytic differentiation, typified by mul-tivesicular and vacuolated clear cyto-plasm, is the sine qua non for sebaceous
neoplasms including SC. It must be sep-arated from simple cytoplasmic clarity, a
microscopic change that is relatively
common in cutaneous neoplasms of
many other lineages {2294}. SCs are
organoid proliferations comprising der-mal lobules of variably-atypical polygo-nal cells, with a fibrovascular stroma that
typically lacks desmoplasia. Central por-tions of the tumour cell nests may be
necrotic, yielding a “comedo” growth
pattern. The cells of well-differentiated
neoplasms show abundant cytoplasm
and oval vesicular nuclei with distinct
nucleoli; mitotic figures are variable in
number. On the other hand, more poorly-differentiated SCs show high nuclear-to-cytoplasmic ratios, nuclear pleomor-Tumours with sebaceous
differentiation
A. Rütten
M.R. Wick
O. P. Sangüeza
C. Wallace
CB
A
Fig. 3.47 Sebaceous carcinoma.  A Sebaceous carcinoma, represented by a lobular proliferation of atypical
epithelioid cells in the dermis. Multivesicular cytoplasmic vesiculation is present.  B Extensive in-situ
involvement of the surface epithelium is present in this example of sebaceous carcinoma.  C “Bubbly” cyto-plasmic vacuolization is apparent in sebaceous carcinoma.
161Tumours with sebaceous differentiation
phism, prominent nucleoli, brisk mitotic
activity – sometimes with pathologically-shaped forms – and amphophilic or
basophilic cytoplasm. Intracellular vac-uoles are sometimes not seen easily in
those lesions, and may require the use of
special histochemical stains, such as the
oil-red-O or Sudan IV methods, to detect
them {2540}.
The grading of SCs – into grades I
through III – is based on growth patterns
rather than on their cytological features
{1892}. Tumours that are constituted by
well-demarcated, roughly equally-sized
cellular lobules are graded as I; those
with an admixture of well-defined nests
with infiltrative profiles or confluent cell
groups are grade II lesions; and grade III
SCs exhibit highly-invasive growth or a
medullary sheet-like pattern.
All SCs have the potential for an associa-tion with overlying carcinoma in-situ
(CIS), or extramammary Paget disease
(EPD) of the sebaceous type, or both, in
the surface epithelium and in other epi-dermal appendages (especially pilose-baceous units) {448,1702}. The latter
lesions are probably marker lesions that
represent a cutaneous “field” defect,
rather than being direct precursors of, or
extensions from, underlying SC. This
premise has support from occasional
cases in which only intraepithelial seba-ceous carcinoma is present, in the
absence of an invasive component in the
dermis {1510}. In pragmatic terms, how-ever, one should always consider the
possibility of infiltrative SC whenever
EPD or carcinoma in-situ is seen in a
superficial biopsy.
Variants
Selected microscopic variants of SC
deserve special comment because they
may engender interpretative confusion
with other cutaneous tumours {2540,
2542}.
Basaloid SC comprises small cells with
scant cytoplasm, and may often show
nuclear palisading at the periphery of
cellular nests. It commonly manifests a
grade III growth pattern, and overtly-sebocytic elements are sparse and diffi-cult to identify as such.
Squamoid SC shows prominent squa-mous metaplasia, often with keratin pearl
formation; some examples may also
demonstrate spindle-cell areas, equating
with a sarcomatoid image.
Still other examples of SC may demon-strate pseudo-neuroendocrine organoid
growth, focally resembling the pattern of
“carcinoid” tumours {1235}. Based on
these brief descriptions, one could easi-ly predict that basal cell carcinoma,
squamous cell carcinoma, neuroen-docrine tumours, epithelial malignancies
with potential spindle-cell differentiation,
and a variety of clear-cell neoplasms in
the skin may enter differential diagnostic
consideration in selected cases of SC.
Immunoprofile
SC shows immunoreactivity for several
generic epithelial markers such as
pankeratin, epithelial membrane antigen
(EMA), CD15, CU18, CA15.3, and
Thomsen-Friedenreich antigen {75}. EMA
labeling may enhance the cytoplasmic
“bubbliness” of the tumour cells in this
neoplasm. That pattern is distinctive, but
it is not observed in all examples of SC.
Reactivity for androgen receptor protein
and human milk fat globule protein-2 also
has been reported in SC {182,2191}.
However, it is not yet know whether the
latter markers are diagnostically helpful
in excluding other clear-cell tumours.
Genetic susceptibility
Immunoreactivity in SC for various DNA-mismatch repair gene products, espe-cially for MSH-2, has been correlated
with a relationship to the Muir-Torre com-plex {1468,1536}. However, virtually no
systematic data are available on the
detailed genetic profiles of either spo-radic or syndromic SC.
Prognosis and predicitive factors
Both ocular and extraocular SCs have a
30-40% risk for local tumour recurrence,
20-25% for distant metastases, and 10-20% for tumour-related mortality {1645}.
Some reports appear to support the
premise that immunoreactivity for mutant
p53 protein at a level of >10%, and for
proliferating cell nuclear antigen at a
level of >25% may be linked to an
adverse outcome {977}. A similar com-ment may apply to those lesions that
overexpress the c-erbB-2/HER-2/neu
protein {472,977}.
Sebaceous adenoma
Definition
Sebaceous adenoma is a small tumour
composed of basaloid cells and fully dif-ferentiated sebocytes.
Fig. 3.48 Sebaceous adenoma.  A Well circumscribed lobulated sebaceous tumour. Fully differentiated sebocytes predominate and epidermis is replaced by the
tumour.  B High magnification of the periphery of the lobule.
BA
162 Appendageal tumours
ICD-O code 8410/0
Epidemiology
Sebaceous adenomas occur mostly as
solitary lesions in persons older than
forty years {1993}. Lesions are located
usually on sun-damaged skin of the head
and neck area. Rarely patients have mul-tiple lesions {2258}, then the possibility of
Muir-Torre syndrome should be consid-ered.
Clinical features
Sebaceous adenomas are relatively
small yellowish tumours often covered by
a scale or crust {2353}.
Histopathology
This well-circumscribed tumour is made
up of small lobular aggregations of sebo-cytes with a rim of basaloid cells at the
periphery, recapitulating the maturation
of sebocytes from the periphery to the
centre comparable to normal sebaceous
glands {1542}. Lobules are composed of
vacuolated fully differentiated sebocytes
and these cells predominate markedly
over the basaloid sebocytes. Sebaceous
adenoma is often connected to the over-lying epidermis, and may be covered by
a thick plug of keratin and disintegrated
sebocytes. Ductal structures are rare, as
are mitotic figures.
Sebaceous adenoma has to be differen-tiated from sebaceous hyperplasia,
where the sebaceous lobules are
arranged around a central placed follicu-lar infundibulum that is connected to the
epidermis. In sebaceous hyperplasia the
epidermis may show changes mimicking
seborrhoeic keratosis.
Sebaceomas are nodular lesions of
basaloid undifferentiated sebocytes and
only a few small groups of vacuolated
sebocytes. There may be morphological
overlaps between sebaceous adenoma
and sebaceoma. The term sebomatrico-ma was introduced as an attempt to sim-plify the nomenclature of the different
benign sebaceous adnexal tumours and
to summarize them under one name
{2003}.
Genetics
Little is known about the genetics of
sebaceous adenoma. Most of the
tumours occur as solitary lesions but a
few examples of SA are part of the spec-trum of different sebaceous tumours in
MTS. By immunohistochemistry it is pos-sible to look for a loss of MSH-2, MLH-1
repair proteins. Tumours related to a mis-match repair gene defect show a micro-satellite instability in a high percentage
{1334}.
Prognosis and predictive factors
Sebaceous adenomas are benign
tumours. If the patient has Muir-Torre syn-drome, the prognosis depends on the
associated internal malignancies.
Sebaceoma
Definition
Sebaceoma is a benign, adnexal neo-plasm with sebaceous differentiation. It is
characterized by multiple, smooth-bor-dered lobules and cystic spaces com-posed primarily of immature sebaceous
cells admixed with randomly scattered
mature sebocytes.
ICD-O code 8410/0
Synonyms
Sebaceous epithelioma, basal cell
epithelioma with sebaceous differentia-tion, and sebomatricoma.
Epidemiology
Sebaceomas are rare sebaceous neo-plasms that may be associated with the
Muir-Torre syndrome {1624,2114}. They
typically arise in late adulthood with the
mean age of diagnosis being at approxi-mately 70 years of age, but may be seen
in early adulthood {2378}. The tumours
have a predilection for females.
Localization
Sebaceomas occur mainly on the face
and scalp, with rare cases reported on
the trunk {226,636,1710,1749,1922,
2258,2378}.
Clinical features
Clinically, sebaceomas present as yellow
to orange solitary papules on the head
and neck {636,2258,2378}. Those
lesions associated with the Muir-Torre
syndrome may be multiple {347,1624,
2114}. They are slow-growing neoplasms
and do not recur after excision {636,
2258,2378}.
Histopathology
Architecturally sebaceoma is composed
of multiple well-circumscribed lobules of
various size centred on the dermis. The
lobules often contain ducts and cystic
Fig. 3.49 Sebaceoma.  A Low power view demonstrating a neoplasm with multiple well-circumscribed nod-ules of different sizes.  B Example of a reticulated sebaceoma. The neoplasm is composed predominantly
of uniform basaloid cells distributed in a reticulated pattern. Please note the presence of cells with seba-ceous differentiation at the base of the lesion.  C Cytologically the basaloid cells are uniform and present
between collagen bundles.
A C
B
163Tumours with sebaceous differentiation
areas containing holocrine secretion and
only rarely do they connect with the over-lying epidermis. A brightly eosinophilic
cuticular material lines both the ducts
and cysts, similar to what is seen in the
normal sebaceous ducts.
Cytologically the neoplasm is comprised
predominantly of small, uniform basaloid
cells with bland nuclear features
admixed with haphazardly distributed
mature-appearing sebaceous cells. The
mature sebaceous cells have abundant
vacuolated cytoplasm and ovoid nuclei,
which often have a scalloped nuclear
membrane. Rare typical mitoses may be
seen, however, atypical mitosis and
necrosis are not features of sebaceoma.
The surrounding stroma is dense,
eosinophilic connective tissue. There is
no cleft seen between the neoplasm and
the stroma, as is the case with basal cell
carcinoma.
A wide variety of patterns have been
described for sebaceoma, sometimes
even within the same neoplasm. These
include reticulated, cribriform and glan-dular {634,1710}. There have been
reports of a variant with eccrine differen-tiation, a pigmented variant and a
sebaceoma that arose in a seborrhoeic
keratosis {226,1749,1922}. Those lesions
that arise in Muir-Torre syndrome may
have a keratoacanthoma-like architec-ture {347}.
Immunoprofile
Immunohistochemistry demonstrates
positivity with high-molecular weight ker-atin. EMA stains most mature sebocytes,
and thus will only show positivity of the
mature vacuolated sebaceous cells scat-tered amongst the tumour, while the
basaloid cell compartment will be nega-tive {1710}. Several reports have demon-strated loss of heterozygosity as well as
microsatellite instability in a marker gene
located near hMSH2 in patients with
sebaceoma and Muir-Torre syndrome
{1332,1536}. By immunohistochemistry it
is possible to look for a loss of MSH-2,
MLH-1 repair proteins {1334}.
Prognosis and predictive factors
Sebaceoma is a benign neoplasm that
does not recur after treatment or metas-tasize. It may be a marker of Muir-Torre
syndrome, in which case the patient has
a high risk of internal malignancies.
Cystic sebaceous tumour
Definition
Cystic sebaceous tumour is a large dis-tinctive tumour with is almost always
associated with Muir-Torre syndrome
(MTS) {1999}.
ICD-O code 8410/0
Epidemiology
Cystic sebaceous tumours occur nearly
exclusively in MTS, which is a phenotyp-ical variant of the hereditary non polypo-sis colon cancer syndrome (HNPCC).
MTS is inherited in an autosomal-domi-nant fashion and is caused by genetic
alterations within the DNA mismatch
repair system. Patients often have a fam-ily history of malignancies and most are
affected with a variety of internal malig-nancies such as colon cancer, urothelial
cancer, endometrial cancer and others.
MTS patients develop a broad spectrum
of different sebaceous skin tumours,
which may be difficult to classify {347,
1624}, and keratoacanthomas. Among
the sebaceous tumours, CSTs are unique
because they serve as diagnostic mark-ers for the syndrome. MTS has a male
preponderance and is clinically diag-nosed mostly in adults older than 40
years.
Localization
The upper trunk is the most common
location.
Clinical features
CSTs are usually solitary, but rarely can
be multiple. They resemble hair follicle
cysts and present as dermal nodules. In
patients diagnosed with internal malig-nancies CST is often excised in order to
rule out a metastatic skin lesion.
Histopathology
CST are large, well circumscribed der-mal tumours which may connect to the
upper dermis, and usually extend into
the subcutis. The outer surface of the
neoplasm may be obscured in cases
with an accompanying granulomatous
inflammation due to the ruptured cyst
wall. Well-differentiated CST show a cys-tic growth pattern with a small line of
basaloid undifferentiated sebaceous
matrix cells at the periphery and a broad
zone of fully differentiated vacuolated
sebocytes towards the centre of the cys-tic tumour. Well-differentiated CST do not
show cytological atypia, and have only
few mitoses. Ductal structures may be
seen in the cyst wall. Proliferation of
tumour cells produces infoldings of the
cyst wall in some CST. The more solid
variants are predominantly composed of
undifferentiated sebaceous cells with
mitotic figures and variable cytologic
atypia.
Genetics
Germline mutations of the DNA mismatch
repair genes are responsible for MTS. In
the vast majority of cases the associated
tumours show a complete loss of the cor-responding mismatch repair protein
(MSH2 or MLH1). This can be demon-strated immunohistochemically by anti-bodies directed against MSH2 and
MLH1 protein {1469,1536,2227}. A loss
of the nuclear staining for one of these
antibodies within the tumour cells
accompanied by a positive staining of
nuclei in the surrounding tissue strongly
suggests loss of the corresponding DNA
mismatch repair protein. Typically, these
tumours show high microsatellite instabil-ity {1332, 1469, 1999}.
Prognosis and predictive factors
Some authors interpret cystic sebaceous
adenoma as a variant of sebaceous car-cinoma {1733}. So far there is no clinical
evidence that these tumours in any case
represent malignant sebaceous tumours
{872,1624,1999}. Because of these con-flicting views, complete excision is rec-ommended.
The prognosis in MTS is determined by
the nature of the associated internal
malignancies. In most cases CST devel-ops after the first internal malignancy, but
in up to 25% of cases they represent the
first clinical sign of MTS. Even in a patient
with a solitary CST who does not fulfil the
clinical criteria for MTS, a molecular
genetic analysis may show a germline
mutation in a mismatch repair gene
{1333}. Because of the specific marker
function of CST it is possible to detect
patients and families with an inherited
DNA mismatch repair defect predispos-ing to various types of internal cancer.
CHAPTER 4
Haematolymphoid Tumours
Lymphoma may involve the skin as the primary and only site of
involvement, or may spread to the skin as a secondary site of
disease.  Some cutaneous lymphomas morphologically resem-ble their counterparts in lymph node, but differ in terms of phe-notype, genotype, and clinical behaviour, suggesting that they
represent an independent entity. Cutaneous follicular lym-phoma demonstrates such fundamental differences from nodal
follicular lymphoma. Some lymphomas present only in the skin,
but never primarily in lymph nodes or other extranodal sites.
Mycosis fungoides is one such example. Finally, some cuta-neous lymphomas exhibit a different clinical behaviour from
their nodal counterparts, despite apparent phenotypic and
genotypic similarities.
The members of the WHO Working Group, together with their
colleagues from EORTC, were able to formulate a classification
that respects the many unique features of skin lymphomas but
avoids a terminology restricted to primary cutaneous lym-phomas. We are confident that this proposal will be used by
pathologists and dermatologists world-wide for years to come.
WHO / EORTC classification of cutaneous lymphomas1
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of  Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.
* Extracutaneous lymphomas frequently involving the skin as a secondary site are printed in italics.
** Definition is restricted to lymphomas of alpha/ beta T-cell origin
*** Recent evidence suggests an origin from a dendritic cell precursor. In recognition of uncertain histogenesis, the term CD4+/CD56+ haematodermic neoplasm” is preferred.
Mature T-cell and NK-cell neoplasms
Mycosis fungoides 9700/3
Pagetoid reticulosis (localized disease)
Follicular, syringotropic, granulomatous variants
Granulomatous slack skin
Sezary syndrome 9701/3
CD30+ T-cell lymphoproliferative disorders of the skin
Lymphomatoid papulosis  9718/1
Primary cutaneous anaplastic large cell lymphoma 9718/3
Subcutaneous panniculitis-like T-cell lymphoma** 9708/3
Primary cutaneous peripheral T-cell lymphoma
(PTL), unspecified 9709/3
Subtypes of PTL (provisional)
Primary cutaneous aggressive epidermotropic
CD8-positive cytotoxic T-cell lymphoma
Cutaneous gamma/delta-positive T-cell lymphoma
Primary cutaneous small/medium CD4+
T-cell lymphoma
Extranodal NK/T-cell lymphoma, nasal type 9719/3
Hydroa vacciniformia-like lymphoma (variant)
Adult T-cell leukaemia/lymphoma*
9827/3
Angioimmunoblastic T-cell lymphoma* 9705/3
Mature B-Cell neoplasms
Cutaneous marginal zone B-cell lymphoma (MALT-type) 9699/3
Cutaneous follicle centre lymphoma 9690/3
Cutaneous diffuse large B-cell lymphoma 9680/3
Intravascular large B-cell lymphoma* 9680/3
Lymphomatoid granulomatosis* 9766/1
Chronic lymphocytic leukaemia* 9823/3
Mantle cell lymphoma* 9673/3
Burkitt lymphoma* 9687/3
Immature haematopoietic malignancies
Blastic NK-cell lymphoma *** / 9727/3
CD4+/CD56+ haematodermic neoplasm
Precursor lymphoblastic leukaemia/lymphoma
T-lymphoblasic leukaemia* 9837/3
T-lymphoblastic lymphoma* 9729/3
B-lymphoblastic leukaemia* 9836/3
B-lymphoblastic lymphoma* 9728/3
Myeloid and monocytic leukaemias*
Hodgkin lymphoma*
166 Haematolymphoid tumours
167WHO/EORTC and TNM classification
Stage T  N  M
Ia  T1 Limited lesions covering <10% of the  N0 no palpable lymph nodes, M0 no involvement of
skin surface  pathology negative for CTCL  visceral organs
Ib  T2 generalized lesions covering 10%  N0 no palpable lymph nodes,  N0 no involvement of
and more of the skin surface  pathology negative for CTCL  visceral organs
IIa  T1 Limited lesions covering <10%  of the N1 palpable peripheral lymph nodes M0 no involvement of
skin surface,or T2 generalized lesions  pathology negative for CTCL visceral organs
covering 10% and more of the skin surface
IIb  T3 tumours, one or more N0: no palpable lymph nodes,  M0 no involvement of
pathology negative for CTCL or, visceral organs
N1 palpable peripheral lymph nodes,
pathology negative for CTCL
III T4 generalized erythroderma N0:  no palpable lymph nodes,  M0 no involvement of
pathology negative for CTCL or visceral organs
N1 palpable peripheral lymph nodes,
pathology negative for CTCL
IVa  T1-4  N2:no palpable peripheral lymph nodes,  M0 no involvement of
pathology positive for CTCL or visceral organs
N3:palpable peripheral lymph nodes,
pathology positive for CTCL
IVb  T1-4  N0-3  M1 involvement of visceral organs
__________
Modified, from Refs. {333,344,2537}.
TNM classification of cutaneous T-cell lymphomas (CTCL)
168 Haematolymphoid tumours
The skin is the second most common site
of extranodal lymphoma, following the
gastrointestinal tract {340}.  Lymphoma
may involve the skin as the primary and
only site of involvement, or may spread to
the skin as a secondary site of disease.
Because the clinical implications of pri-mary and secondary cutaneous lym-phoma are different, the dermatologist
and pathologist should be familiar with
both types of neoplasms. For this reason
it also is problematic to use a classifica-tion system restricted to primary cuta-neous lymphomas {2523}. It is important
for dermatologists, haematooncologists,
and pathologists to use a unified system
for the diagnosis and treatment of cuta-neous lymphoma {1858}.
Nevertheless, cutaneous lymphomas
present some unique clinical aspects.
There are some diseases that present
only in the skin, and are never primary in
lymph nodes or other extranodal sites.
Mycosis fungoides is one such example.
Some cutaneous lymphomas morpholog-ically resemble their counterparts in
lymph node, but differ in terms of pheno-type, genotype, and clinical behaviour,
suggesting that they represent an inde-pendent entity.  Cutaneous follicular lym-phoma demonstrates such fundamental
differences from nodal follicular lym-phoma.  Finally, some cutaneous lym-phomas exhibit a different clinical behav-iour from their nodal counterparts,
despite apparent phenotypic and geno-typic similarities. These differences may
be related to stage or tumour burden, or
more fundamental biological differences.
For example, some lymphomas com-posed of large centrocytes and centrob-lasts have an indolent clinical course
when presenting as a localized cuta-neous tumour, but a similar cytological
process in lymph node would be consid-ered aggressive, i.e. diffuse large B-cell
lymphoma.
Dermatologists, haematooncologists,
and pathologists must use a common
language. In this spirit we utilize the
WHO classification of lymphoid neo-plasms {1121}, but we expand upon the
unique features of many cutaneous lym-phomas to emphasize their distinctive
clinical and biological characteristics
{336A,2522}. Additional clinical and mor-phological variants have been added,
where appropriate, in order to compre-hensively cover the many manifestations
of cutaneous lymphoma. Atypical reac-tive lesions that may represent precur-sors of cutaneous lymphoma are dis-cussed where relevant {336A,2522}.
Cutaneous lymphoproliferative
disorders (CLD)
These include reactive lymphoid hyper-plasias (so called cutaneous “pseudo-lymphomas”), prelymphomatous condi-tions and definite malignant lymphoma of
low grade or of high grade malignancy.
According to their biologic behaviour,
CLD can be subgrouped into prognostic
categories which are not reflected in the
classifications, which however are of
special interest for the patient and for the
treating physician.
When diagnosing a cutaneous lympho-proliferative disorder, both the clinico-pathologic classification and the biologic
category should be considered. The
advantage of such an approach is to pro-vide the diagnosis according to the cur-rent WHO-classification of lymphomas,
and in addition, to include essential infor-mation about the biologic behaviour,
which may be significantly different than
that of the nodal counterpart. These data
are crucial for the clinician involved in
counseling and treatment of the patient.
Reactive lymphoid hyperplasias (RLH)
(pseudolymphomas)
These are reactive benign lymphoprolif-erative processes, localized or dissemi-nated, which heal either spontaneously
after elimination of the causative factor
(e.g. drugs) or after treatment with non-aggressive (no severe side effects to be
expected after long term application)
modalities, and which do not recur after
removal of the causative agent.
Prelymphomatous (“abortive”) disorders
(PLD)
PLD show a chronic long-standing
course, no spontaneous regression in
most cases, and no extracutaneous
spread with involvement of visceral
organs. In some cases, clonality of the
infiltrate can be demonstrated. However,
in most cases the neoplastic cell clone
never overcomes host control mecha-nisms and cannot expand and therefore
does not convert into definite malignant
lymphoma. Survival time is not affected.
Definite malignant lymphoma of low-grade malignancy (LLM). This category
includes cutaneous lymphomas that
show a slowly progressive course with
systemic spread in later stages and have
the potential for transformation into more
aggressive high-grade malignant lym-phomas. Survival time usually is greater
than 5 years.
Definite malignant lymphoma of high-grade malignancy (LHM)
These diseases are characterized by a
more rapid course than the low-grade
lymphomas and usually exhibit a bad
prognosis with survival times less than 5
years.
WHO / EORTC Classification
of cutaneous lymphomas
J.L. Diaz-Perez
L. Duncan
N.L. Harris
H. Kerl
R. Knobler
M. Kurrer
C. Meijer
N. Pimpinelli
G. Burg
E.S. Jaffe
W. Kempf
E. Berti
L. Cerroni
S. Chimenti
R. Dummer
E. Ralfkiaer
C. Sander
M. Santucci
W. Sterry
S.H. Swerdlow
J. Wechsler
S. Whittaker
R. Willemze
169Mycosis fungoides (MF)
Definition
Mycosis fungoides (MF)  is the prototype
of cutaneous T-cell lymphomas (CTCL)
and can be defined as a peripheral, epi-dermotropic non-Hodgkin T-cell lym-phoma of low grade malignancy initially
presenting in the skin and showing step-wise clinical progression from patches to
plaques and tumours, and distinct histo-logical (except in early stages), pheno-typic and genotypic features.
ICD-O code 9700/3
Synonyms and historical annotation
In 1806 Jean-Louis Alibert (1768-1837)
{58} presented an extraordinary skin dis-ease which he described in detail under
the name of “Pian fungoides” in 1814 and
as “Mycosis fungoides” in 1832 {58}. At
his time the etiology of the disease was
completely unclear. It is worth noting that
Alibert in 1832 copied part of the text
from Bontius {283}. Ernest Bazin (1807-1878) published  three different stages
{184}:
Période érythemateuse (erythematous
stage: red colored patches)
Période lichénoide (the lichenoid stage:
itching and different plaques with small
papules).
Période fongoïdique, mycositique (fungal
stage:mushroom-like tumours of different
size).
Epidemiology
The incidence of MF from 1973 through
1992 in the USA was 0.36/ 100’000 per-sons per year {2445}.
Most frequently MF affects adults, usual-ly in their 5th-6th decade, with a male to
female ratio of approximately 2:1 and a
preponderance of black (1.7) vs white
populations.
The increase of frequency paralleled by
a decrease of mortality rates between
1979 and 1991 {2485} most probably is
due to changing criteria resulting in over-diagnosing MF by including non-neo-plastic conditions  into this group.
Data collected by the Surveillance,
Epidemiology and End Results Program
(SEER) of the US National Cancer Insti-tute indicate that the relative survival
changed little after 11 years, at which
point it was 66% {2485}.
Etiology
The etiology of MF is unknown. The role
of environmental antigens, viruses or
bacteria is controversial {2605}.
Localization
All parts of the skin may be involved with-out any predilection site.
Clinical features
Clinically MF is characterised by a step-wise evolution with sequential appear-ance of patches, plaques and tumours.
Patches are circumscribed lesions with
discolouration and sometimes little scal-ing, without palpable infiltration of the
skin. Plaques usually evolve out of
patches and present with palpable infil-tration of various degree (thin and thick
plaques).  Tumours exhibit an exophytic
growth in most of the cases and tend to
ulcerate.  In advanced stages of the dis-ease there may be spread into the
peripheral blood, involvement of lymph
nodes, bone marrow and internal organs.
Besides physical examination, including
mapping of skin lesions and photodocu-mentation, a skin biopsy for paraffin
embedding and for cryo-preservation
should be taken, preferentially at multiple
sites. Additional investigations include
blood cell counts with PAS staining for
Sézary cells, chest x-ray and CT-scan of
abdomen and of peripheral lymph
nodes. There is no need for taking a
bone marrow biopsy in early patch and
plaque stages of MF without atypical
cells in the peripheral blood. Biopsy of
enlarged lymph nodes is mandatory.
The current TNM-staging System for
CTCL takes into account body surface
involved less (T1) or more (T2) than 10%,
quality of skin manifestation, i.e. patch-es/plaques or tumours (T3) or erythroder-ma (T4) in conjunction with presence or
absence of lymph node (N0-N3) or vis-ceral organ involvement (M0-M1) {334}.
Tumour spread and staging
MF, like other cutaneous lymphomas, is a
systemic disease with preferential hom-ing and proliferation of neoplastic lym-phocytes into the skin. Therefore skin
lesions may spread all over the body sur-Mycosis fungoides  G. Burg
W. Kempf
B. Smoller
E. Ralfkiaer
D.V. Kazakov
C. Sander
J. Feit
Ph. LeBoit
B CA
Fig. 4.1 Mycosis fungoides.  A Large patches involving hip and abdomen.  B Plaque-stage MF affecting the left arm.  C Medium-sized hyperconvoluted cerebriform
cells with prominent cytoplasmic halos in the epidermis, aligned within the basal layer.
170 Haematolymphoid tumours
face. Spread to extracutaneous compart-ments occurs in advanced stages of the
disease, due to change or loss of  hom-ing receptors, These changes are usual-ly accompanied by a change of  cyto-morphology of the tumour cells from
small cerebriform to medium-sized pleo-morphic or large blast-like cells.
Histopathology
The histologic diagnosis of MF is based
on numerous subtle changes, most of
which may be present to some degree in
many inflammatory and neoplastic cuta-neous conditions. The most significant
criteria, which however in early lesions
often are missing or are only present in
part, are Pautrier microabscesses, exo-cytosis of lymphocytes, disproportionate
epidermotropism. The presence of cells
with hyperconvoluted cerebriform nuclei
in the epidermis larger than dermal lym-phocytes, or lymphocytes in clusters in
the dermis, and lymphocytes aligned
within the basal layer without or with only
little spongiosis and without prominent
vacuolisation in the dermo-epidermal
junction are typical but not specific fea-tures. Haloed lymphocytes  have proved
to be the most robust discriminator of MF
from non-MF.
Patch stage
The diagnosis is usually based on a com-bination of specific histologic criteria,
without the necessity of confirmatory
immunophenotyping {2058,2059,2213}.
Whereas in very early “prelymphoma-tous” patch stages the histological pic-ture often is non-specific, the histological
findings become diagnostic in the thin
plaque stage, when a denser infiltrate
with lymphocytes lining up in the basal
layer, especially at the tips of the rete
ridges with epidermotropism of single
cells is present. The majority of cells are
small, differentiated lymphocytes with
round or only slightly cerebriform nuclei.
Haloed cells may predominate in the epi-dermis in early patch lesions of patients
with otherwise advanced disease. In
addition, there can be mild acanthosis,
hyperkeratosis, signs of basal layer dam-age (pigment incontinence), edema or
fibrosis of the papillary dermis. There is
proliferation of postcapillary venules with
prominent endothelial cells, simulating
giant cells The infiltrate may contain an
admixture of eosinophils, plasma cells,
macrophages, and dermal dendritic
cells {922,2156}.
Thick plaque stage
This is typified by a dense, subepider-mal, usually band-like infiltrate contain-ing a high number of cerebriform cells.
Epidermotropism is more prominent with
small intraepidermal clusters (2-3 cells)
of lymphocytes. Typical Pautrier micro-abscesses are seen only in approximate-ly one-third of cases. Subcorneal, intra-epidermal and subepidermal bullous for-mation may result from confluence of
Pautrier microabscesses {1460}.
Progression to tumour stage
With progression from plaque stage to
tumour stage the dermal infiltrates
become more diffuse, and epidermotro-pism may be lost. The proportion of
tumour cells increase both in number
and size, and may include cells with
small, medium-sized and large cerebri-form nuclei, blast cells with prominent
nuclei and intermediate forms. There is a
concomitant decrease in the numbers of
reactive T-cells and dendritic cells. In
approximately 25% of advanced cases,
transformation to a CD30 positive or neg-ative large T-cell lymphoma defined by
B CA
Fig. 4.3 A Plaque-stage mycosis fungoides (MF).  B Thick plaque with haemorrhage in MF.  C Histopathology of plaque-stage MF. Intra-epidermal and dermal infil-trate.
DC
Fig. 4.2 Mycosis fungoides (MF).  A Typical Pautrier abscesses. The neoplastic cells are strongly positive
for B CD3 and  C CD4, while  D CD8 is negative.
BA
171Mycosis fungoides
the presence of more than 25% blast
cells may be observed.
Immunoprofile
The immunophenotypical prototype of
MF is CD2+, CD3+, CD4+, CD5+,
CD45RO+,CD8, TCR-beta +, CD30-.
During progression of the disease loss of
CD7, 2 and 5 can occur. Helpful in the
diagnosis is the loss of CD7, CD2, CD5,
or CD4 in the epidermotropic cerebriform
cells. During progression of the disease
especially when transformation is pres-ent CD4 positive epidermotropic cells
can have a cytotoxic phenotype (TIA-1,
Granzyme B). In the transformed stage
the blast cells can express CD30.
Besides the CD4 prototype, a small num-ber of MF cases have a CD8 positive
cytotoxic phenotype (TIA-1 and gran-zyme B). These cases have the same
clinical behaviour as the CD4 positive
cases.
Prelymphomatous precursor lesions
The term “parapsoriasis” is confusing
and requires explanation. It encompass-es a number of different pathologic
states clinically manifested by chronic
recalcitrant erythematous scaling lesions
{311,312,1375}.
Two groups of parapsoriasis can be dif-ferentiated {337}. The benign form ‘para-psoriasis en plaques’ (Brocq disease),
never evolve into malignant lymphoma.
The large plaque forms (LPP) with poik-iloderma (prereticulotic poikiloderma,
parapsoriasis en grandes plaques poik-ilodermiques, poikiloderma vasculare
atrophicans, parapsoriasis lichenoides,
parakeratosis variegata) or without poik-iloderma (parapsoriasis en plaques, pre-malignant type, parapsoriasis en
grandes plaques simples), may after
several decades evolve into mycosis fun-goides or CTCL in up to 10-50% of
cases. Few large (more than 5 cm in
diameter) patches show pityriasiform
scaling with (poikilodermatous variant) or
without telangiectasia and netlike pig-mentation. There is no palpable infiltra-tion.
Histologically lesions in large plaque
parapsoriasis (LPP) are different from MF
or other CTCL. Under patchy parakerato-sis there is slight atrophy of the epider-mis, due to loss of rete ridges. The
subepidermal zone is free of lympho-cytes, which accumulate in a band-like
arrangement in the upper dermis, spar-Fig. 4.4 Tumour-stage mycosis fungoides (MF).  A Patches, plaques and tumours.  B Ulcerating tumours in the face.  C ‘Fungoid’ tumours on the hands.
BA C
B CA
Fig. 4.5 Histopathology of transformed mycosis fungoides(MF).  A Large-cell pleomorphic transformation.  B Large cell anaplastic transformation.  C Immunohisto-chemistry reveals CD30 positive tumour-cells.
172 Haematolymphoid tumours
ing the papillary region. There is no sig-nificant epidermotropism as usually seen
in early stages of mycosis fungoides. The
poikilodermatous variant of the diseases
in addition shows dilated blood vessels
in the upper dermis. T-cell receptor
gamma gene rearrangement, which is
clonal in about half of the patients with
LPP, is without any prognostic signifi-cance {2186}. There is no significant dif-ference between the observed and
expected survivals in patients with LPP.
Histogenesis
Mature skin homing T cells that express
the cutaneous lymphocyte antigen (CLA)
enabel them to specifically home into the
skin. Functionally, the neoplastic cells in
MF express TH2 phenotype, which
accounts for many systemic changes
associated with MF due to the production
of a TH2-specific cytokine pattern (IL-4,
IL-5, IL-10) leading to fever, oedema,
eosinophilia, increase of IgE or IgA, and
impaired delayed type reactivity
{656,2445}.
Somatic genetics
There have been a few reports on famil-ial occurence of MF or CTCL  {2160} and
on a possible association of HLA-DR5
with MF {2004}.  HLA class II susceptibil-ity alleles, i.e. HLA-DRB1*11, HLA-DQB1*03 and HLA-DRB1*1104 are
more prevalent among patients with MF
and are likely to be important in the
pathogenesis of MF  {1039,1118}. T-cell
receptor beta and gamma chain genes
are clonally rearranged. In advanced
cases with extracutaneous involvement,
the same clone is usually detected in the
skin and in the extracutaneous lesions. In
transformed cases the same clone is
present in the pre-existing lesions and
the high-grade lymphoma {207}.
In advanced stage, the rate of chromo-somal aberrations, especially  of chromo-somes 1, 6 and 11, increase with the
activity of the disease and has prognos-tic significance in patients with MF.
Aberrations of chromosomes 8 and 17
are especially associated with active or
progressive disease.
Chromosomal abnormality possibly
results in increased genetic instability as
a basic prerequisite for the development
of CTCL. In G-banding studies, numeri-cal aberrations of chromosomes 6, 13,
15, and 17, marker chromosomes, and
structural aberrations of chromosomes 3,
9, and 13 were increased in MF {1209}.
In contrast to nodal lymphomas, the
large cell transformation in cutaneous T-cell lymphoma (CTCL) is not associated
with t(2;5)(p23;q35) chromosomal trans-location {613,1420}.
Increased expression of C-myc, p62,
TP53 and proliferation markers (PCNA)
has been found in advanced stages of
MF as compared to early stages of MF
suggesting a relationship between levels
of these proteins and aggressiveness of
CTCL {1192}.
Prognosis and predictive factors
The majority of MF patients show an
indolent clinical course over years or
decades. The prognosis of the disease is
defined by its stage. Patients with early
B CA
Fig. 4.6 A Plaque in mono-lesional mycosis fungoides (MF).  B Symptomatic mucinosis follicularis in MF.  C Hypo-pigmented lesions in MF.
Fig. 4.7 Mycosis fungoides (MF).  A Bullous variant of MF.  B Immunohistochemistry shows CD8 positive tumour-cells lining up in the basal layer.
BA
stages, i.e. with patches or thin plaques,
without involvement of lymph nodes,
peripheral blood or other extracutaneous
compartment have an excellent progno-sis with survival similar to that of an age,
sex, and race-matched population
{2575}.
Advanced stage and age above 60
years of age indicate a poor prognosis.
When extracutaneous involvement or
transformation into high-grade lym-phoma occurs, expected survival is usu-ally less than one year {2367,2412}.
Variants
Apart from the classical form of MF, there
are several variants of this disease with
unusual or atypical clinical and/or
histopathological features. These com-prise follicular, bullous, dyshidrotic, gran-ulomatous, hypopigmented, poikiloder-mic, hyperpigmented, pigmented purpu-ra-like, unilesional, palmoplantar, hyperk-eratotic/verrucous, vegetating/papillo-matous, ichthyosiform, pustular and
other forms {1234}.
Pagetoid reticulosis, syringotropic MF,
folliculotropic (pilotropic) and granulo-matous MF also are variants and
deserve special emphasis.
Pagetoid reticulosis
Pagetoid reticulosis, in its localized form
also referred to as Woringer-Kolopp dis-ease (WKD) {302,2550} clinically pres-ents as a solitary, slowly growing psori-asiform crusty or hyperkeratotic patch or
plaque, typically on a distal limb.
The histological hallmark is the sponge-like disaggregation of the epidermis by
small to medium-sized lymphoid cells
(pagetoid) which immunophenotypically
correspond to those found in MF in most
of the cases {336}. However, the neo-plastic cells in WKD often demonstrate a
higher proliferation rate (>30%) in com-parison to lymphocytes in patch or
plaque stage MF (<10%), and in some
cases infiltrates in WKD may contain high
numbers of CD30+ cells {937}. CD8+
{792} variants have also been reported.
There exists a disseminated form featur-ing the same distinct pagetoid pattern of
the infiltrate {1252}, which is now regard-ed as a separate disease, primary cuta-neous aggressive epidermotropic CD8+
cytotoxic T-cell lymphoma.
Syringotropic MF
Syringotropic MF represents a rare vari-ant of MF {2586} showing a solitary well
circumscribed red-brown plaque with
hair loss in the affected area. Histology
reveals predominant involvement of
irregularly proliferating eccrine sweat
glands by small cerebriform lympho-cytes {343,2586}.
Folliculotropic MF
Follicular  MF, also referred to as pilotrop-ic MF {776} is a rare variant, histopatho-logically characterized by infiltrates of
atypical T lymphocytes around and with-in the epithelium of the hair follicles with
sparing of interfollicular skin. The follicles
may show cystic dilatation and/or corni-fied plugging. There may or may not be
mucinosis. When present, mucinous
degeneration of the follicular epithelium
varies from focal spots of mucin deposi-tion to complete destruction of follicles
with mucin lakes. The folliculotropism is
173Mycosis fungoides
Fig. 4.9  Pagetoid reticulosis. A Solitary psoriasi-form lesion on the foot.   B Pagetoid reticulosis
showing sponge-like disaggregation of the epider-mis by invading haloed lymphoid cells.
A
B
B CA
Fig. 4.10 Syringotropic cutaneous T-cell lymphoma (CTCL).  A Cutaneous patch with hair-loss.  B Infiltration of a sweat gland.  C EM showing the convoluted nucle-us of a neoplastic cell between acinar cells.
Fig. 4.8 Mucinous follicular variant of MF.
possibly due to  an increased expression
of skin-selective homing receptors and
adhesion molecules in the follicular
epithelium {1805}. A recent study has
demonstrated that follicular MF shows a
more aggressive behaviour and a worse
prognosis than classical MF {829,2411}.
Granulomatous MF
Granulomatous MF is characterized by
the histological presence of a granulo-matous reaction {584}, sometimes featur-ing a sarcoidal or granuloma annulare-like pattern. Multinucleated giant cells
may be present {1387}.
The prognostic and clinical significance
of a granulomatous reaction in MF
remains uncertain {454}.
174 Haematolymphoid tumours
Fig. 4.11 Pilotropic lymphoid infiltrate in follicular
mycosis fungoides (MF).
Fig. 4.12  Granulomatous MF. Granulomatous
plaques with ulceration on the leg.
Fig. 4.13 Granulomatous mycosis fungoides (MF) with sarcoidal infiltrate pattern.
175Sézary syndrome
Definition
Sézary syndrome (SS) is a rare variant of
cutaneous T-cell lymphoma (CTCL),
characterized by erythroderma, blood
involvement and a poor prognosis.
Neoplastic lymphocytes are typically
mature T-helper cells with cerebriform
nuclei. Criteria for the diagnosis of SS
include the demonstration of a peripher-al blood T-cell clone by molecular or
cytogenetic methods; an expanded
CD4+ population resulting in a CD4:CD8
ratio > 10, and immunophenotypic ab-normalities such as absent expression of
T-cell antigens (CD2, CD3. CD4 and/or
CD5). Sézary syndrome (SS) is part of a
broader disease spectrum, erythroder-mic CTCL. The presence of a clonal T-cell population in the peripheral blood
distinguishes SS from reactive disorders
that exhibit erythroderma and circulating
cells with cerebriform nuclei (pseudo-SS)
{777}.
ICD-O code 9701 / 3
Epidemiology
Sézary syndrome accounts for less than
5% of all cutaneous T-cell lymphomas
{2523}. It occurs almost exclusively in
adults, characteristically presents over
the age of 60 and has a male predomi-nance {2523}.
Etiology
SS is of unknown etiology. However, a
syndrome clinically indistinguishable
from SS is occasionally seen in HTLV-1
associated lymphoma/leukaemia.
Clinical features
SS comprises a clinical triad of pruritus,
erythroderma and lymphadenopathy.
The pruritus is commonly intractable and
sufficiently severe to prevent the patient
sleeping or pursuing a normal life.
Additional clinical features include alope-cia, ectropion, nail dystrophy, palmo-plantar keratoderma and leonine facies.
Bacterial skin infection is common in
Sézary patients and may lead to a
marked deterioration in their cutaneous
disease. An increased prevalence of
secondary malignancies, both cuta-neous and systemic, has been reported
in SS and attributed to the immunopare-sis associated with loss of normal circu-lating CD4 cells {2075}.
Tumour spread and staging
Haematological involvement was defined
in the TNM classification of MF as more
than 5% atypical circulating lymphocytes
(B1), but was not included as part of the
Bunn-Lamberg staging system {1356}.
Sézary patients are all T4/B1 (erythroder-ma with blood involvement) but staging
will vary from stage III if there is no lymph
node involvement to IVB if there is bone
marrow involvement. In practice, most
cases of SS are staged as IVA. In 1988,
the definition of B1 was increased from 5
to 20%, by the NCI, but was still not
included as part of the staging system
{2071}.
The problem is that erythrodermic CTCL
represents a spectrum and that any
attempt to distinguish SS from cases that
show a lesser degree of haematological
involvement is necessarily arbritary. An
alternative approach is to develop a
staging system that incorporates both
lymph node status and haematological
stage. A haematological staging system
Fig. 4.14 Erythroderma and scaling of the face in
Sézary syndrome.
Sézary syndrome  R. Russell-Jones
M. Bernengo
G. Burg
L. Laroche
S. Michaelis
E. Ralfkiaer
E. Vonderheid
S. Whittaker
Fig. 4.15 Palmar hyperkeratosis and onychodystro-phy in Sézary syndrome.
Fig. 4.16 Sézary syndrome. Note erythroderma,
oedema of the skin, and swelling of lymph nodes.
176 Haematolymphoid tumours
comprising five categories (H0-H4) was
proposed by Russell-Jones and
Whittaker {1998}, and subsequent data
showed an increase in disease-specific
death rates for each category with the
most significant change occurring at H2,
defined by 5% Sézary cells with a T cell
clone demonstrated by PCR, or a T cell
clone demonstrated by Southern blot
analysis only {2077}. The need for a
haematological staging system has also
been recognised by the International
Society for Cutaneous Lymphoma ISCL
{2444}. Currently this is being tested in a
larger, multi-centre study under the aus-pices of the ISCL.
Histopathology
Despite minor differences {1099}, the
range of histological changes in SS are
not dissimilar to those seen in patients
with mycosis fungoides {2135}.
Epidermotropism is a variable feature,
and the size of Sézary cells varies in the
skin as it does in blood. Only 2/3 of the
skin biopsies and 73% of patients had
diagnostic changes in the skin biopsies
Other causes of erythroderma need to
be differentiated from SS, particularly
drug induced erythroderma and chronic
actinic reticuloid, both of which may
show a high proportion of activated lym-phocytes with cerebriform nuclei {2135}.
In cases with a non-specific histology,
the differential diagnosis would include
other causes of erythroderma such as
eczema or psoriasis.
Immunoprofile
A typical Sézary cell is a mature helper T
cell with a memory phenotype. A classic
immunoprofile is CD2, CD3, CD4, CD5,
CD45RO positive and CD8 negative
{1368,2526}. The majority of Sézary cells
are also CLA positive {1827} and CD7
negative, and this latter feature has been
proposed as a method of distinguishing
Sézary cells from normal lymphocytes
{957}. However, further studies have
shown that the neoplastic cell population
is present in both the CD7 positive and
CD7 negative subset in the same patient
{657}. More recently, Bernengo et al have
demonstrated that CD4 positive Sézary
cells typically loose the CD26 marker
and that a diagnosis of SS or MF with
haematological involvement can be
made if the CD26 negative subset
exceeds 30% of the CD4 positive cells
{215}.
Complete loss of T cell antigens such as
CD2, CD3, CD4, or CD5 is present in
approximately 2/3 of patients with SS
{957}. An alternative approach would be
the identification of a tumour-specific
antigen {669}. Recently two differentia-tion antigens P140 and SCS have been
reported in circulating Sézary cells and
P140 was also found in skin-infiltrating
cells of patients with SS {1715}.
BA
Fig. 4.17 Morphology of Sézary cells.   A  Blood  film and   B Ultrastructure showing a typical convoluted
nucleus.
BA
Fig. 4.18 Sézary syndrome.   A Band-like infiltrate in the epidermis without epidermotropism.   B Intraepi-dermal Pautrier micoabscesses.
Fig. 4.19 Sézary syndrome transforming into blast-stage.  A Multiple nodules and tumours.  B Large atypi-cal cells in blastic transformation of Sézary syndrome.
BA
Histogenesis
The postulated cell of origin is a mature
peripheral T cell which has skin-homing
properties and exhibits a helper-cell phe-notype.
Somatic genetics
Recurrent chromosomal translocations
have not been detected in Sézary syn-drome, but complex clonal numerical
and structural chromosomal abnormali-ties are common and associated with a
poor prognosis {1505,2343}.  M-FISH
techniques have shown a high rate of
unbalanced translocations and associat-ed deletions often involving chromo-somes 1p, 10q, 14 and 15 {1505}. CGH
studies have identified a consistent pat-tern of chromosomal gains/deletions (1p,
10q, 13q, 19, 17p losses and 4/4q, 17q
and 18 gains) which, with the exception
of 17q gains in Sézary syndrome, are
identical to mycosis fungoides suggest-ing a similar pathogenesis {1210,1504}.
Allelic losses on 1p, 9p, 10q and 17p
have been confirmed by LOH studies
and a high rate of microsatellite instabili-ty (MSI) has also been detected {2079,
2080}. These findings suggest that dys-regulated genes at these chromosomal
loci are involved in the pathogenesis
{1554,2078}. There is a high rate of
genomic instability as indicated by the
presence of chromosomal instability
{1505}. Constitutive activation of Stat 3
and chromosomal amplification of JUNB,
a member of the AP-1 transcription factor
complex, have been identified in Sézary
syndrome  {1089,1506}. A recent cDNA
array study in Sézary syndrome has con-firmed the presence of JunB over-expression and has also revealed over-expression of other genes associated
with a TH2 phenotype such as Gata-3
and RhoB {1211}. These array findings
appear to allow the identification of a
poor prognostic group {1211}.
Prognosis and predictive factors
Sézary syndrome has a poor prognosis
with a median survival of 2 to 4 years
depending on the exact definition used
{777,1271,2044,2523}. Absolute Sézary
cell count and lymph node involvement
are independent prognostic factors. In
addition, large cell transformation and
the development of skin tumours on a
background of erythroderma are poor
prognostic signs.
177Sézary syndrome
Fig. 4.20 Diagnostic pathways for the differential diagnosis of erythroderma. Algorithm for the evaluation
and diagnosis of erythroderma due to cutaneous T-cell lymphoma (E-CTCL) vs. ‘reactive’ causes of ery-throderma. TCR, T-cell receptor. *A CD4/CD8 ratio > 10 or an absolute Sézary cell count of 1   109 L 1 have
been proposed as diagnostic criteria for Sézary syndrome (SS), but this algorithm requires additional
immunophenotypic or genotypic data. Even so, a Sézary cell count > 1   109 L 1 or a CD4/CD8 ratio > 10
increases the probability of neoplasia, and separates SS from E-CTCL with a lesser degree of blood involve-ment. **Abnormal T-cell immunophenotype = an increased population of CD4+ cells that are CD26  (> 30%)
or p140+. CD7 is less reliable. Aberrant T-cell immunophenotype = loss of pan T-cell markers such as CD2,
CD3 or CD5, and/or double-negative T cells (CD4  and CD8 ). In skin, the loss of CD7 from epidermal lym-phocytes is CTCL specific.
From: R. Russell-Jones {1997}.
178 Haematolymphoid tumours
Definition
Granulomatous slack skin (GSS) is clini-cally characterized by the development
of bulky skin lesions in the major skin
folds and histologically by a granuloma-tous infiltrate composed of small lympho-cytes and scattered multinucleated giant
cells containing nuclei arranged in a
wreath-like fashion.
Synonyms
Progressive atrophying chronic granulo-matous dermohypodermitis
Epidemiology
GSS is a rare form of primary cutaneous
T-cell lymphoma. GSS usually appears in
the third or fourth decade, but can also
affect children {373}. GSS occurs almost
exclusively in Whites. The male to female
ratio is 2:1 to 3:1 {490}.
Clinical features
GSS begins with slightly infiltrated, poik-ilodermatous sharply demarcated patch-es and plaques. Predilection sites are the
intertriginous areas, especially the axil-lary and inguinal folds. After years,
pathognomonic bulky pendulous skin
folds develop as a result of progressive
destruction of elastic fibres. The lesions
then resemble cutis laxa. Occassionally
ulceration occurs. Regional lymph-adenopathy may be present. In contrast
to granulomatous MF, GSS is in almost all
cases confined to intertriginous areas,
and runs a more benign course than
classic MF {1387}.
Histopathology
Early lesions of GSS display a bandlike
infiltrate of small lymphocytes without
significant nuclear atypia {1379}. More
advanced lesions show a dense lympho-cytic infiltrate throughout the entire der-mis. Nuclear atypia of lymphocytes is
less pronounced than in granulomatous
MF. The diagnostic hallmark is numerous
multinucleated histiocytic giant cells,
which are scattered throughout the back-ground of the dense lymphocytic infil-trate. These giant cells contain 20-30
nuclei located at the periphery of the
cytoplasm. Elastophagocytosis and
emperipolesis (phagocytosis of lymphoid
cells by giant cells) are present. Elastic
stains demonstrate the loss of elastic
fibres at the sites of the infiltrates in all
dermal layers. On occasion, involvement
of large vessels occurs. Ultrastructurally,
the lymphocytes show hyperchromatic
cerebriform nuclei similar to those seen
in mycosis fungoides and Sézary syn-drome {490}. Specific infiltration of
regional lymph nodes or internal organs
exhibiting similar features as in the skin
has been observed in rare cases.
Immunoprofile
The lymphoid tumour cells display a T
helper phenotype with expression of
CD3, CD4 and CD45RO. There may be
loss of other T-cell markers like CD5 or
CD7. In rare cases, the tumour cells
express CD30.
Genetics
Clonal rearrangement of TCR genes can
be found in most cases and is a useful
diagnostic tool in early stages of the dis-ease {1382}. Trisomy 8 has been report-ed in two cases {136,2442}.
Histogenesis
The tumour cells represent skin-homing
T-helper cells.
Prognosis and predictive factors
The disease has a long natural history
with a slowly progressive course over
decades. Occasionally involvement of
regional lymph nodes is found, but does
not seem to affect survival. Although life
expectancy is not reduced by GSS  per
se, other cutaneous and nodal lym-phomas such as mycosis fungoides,
Hodgkin lymphoma and peripheral T-cell
lymphomas occur in approximately 20 –
50% of the patients, often years or even
decades after the manifestation of GSS
{202,490,1729,2413}.
Fig. 4.21  Granulomatous slack skin (GSS). Large
slightly infiltrated plaque in the groin.
Fig. 4.22 GSS showing characteristic multinucleat-ed giant cells with emperipolesis of lymphocytes.
Granulomatous slack skin W. Kempf
D.V. Kazakov
S. Michaelis
G. Burg
P. LeBoit
179CD30+ T-cell lymphoproliferative disorders
CD30-positive T-cell lymphoproliferative
disorders (LPD) of the skin (CD30+LPD)
represent a distinctive group of primary
cutaneous T-cell lymphoma. The spec-trum of CD30+ LPD includes lymphoma-toid papulosis (LyP), primary cutaneous
anaplastic lymphoma (C-ALCL) and bor-derline cases which differ in their clinical
and histological presentations  {191,
1174,1225,1795,2520}.
A feature common to all is the expression
of CD30, a cytokine receptor belonging
to the tumour necrosis factor receptor
superfamily.
The term ‘borderline lesions’ has been
applied to lesions that show clinical pres-entation of one entity (e.g. C-ALCL) but
histological features of another one (e.g.
LyP). This discrepancy may result in diffi-culties to assign such lesions to a distinct
entity. Clinical presentation plays a cru-cial role in such discordant cases.
Lymphomatoid papulosis (LyP)
Definition
LyP is a chronic recurrent lymphoprolifer-ative skin disease with self-regressing
papulo-nodular skin lesions and atypical
lymphoid cells in a polymorphous inflam-matory background {1466}.
ICD-O code 9718/1
Epidemiology
LyP is a rare disease with an estimated
prevalence of 0.1 to 0.2 cases per 100
000 and a male to female ratio of 1.5:1
{2456}. Mostly people in the third and
fifth decades are affected, but children
can also be involved.
Localization
Although no definite predilection site has
been identified, LyP lesions more often
arise on the trunk, especially the but-tocks, and extremities.
Etiology
The cause of the disease is unknown.
Endogenous retroviral elements have
been identified in LyP lesions {1242}.
Interaction of CD30 and CD30L as well
as TGF-beta and its receptor play an
important role in growth regulation,
including regression of tumoural lesions
{1177,1648}.
Clinical features
LyP is characterized by grouped or dis-seminated asymptomatic papules and/or
nodules, which regress spontaneously
after a few weeks sometimes leaving
behind varioliform scars {1174}. Often
new lesions develop concurrently in the
same or another body region. Larger
nodules up to 2 cm can develop and per-sist for months {2524}. Clinicopathologic
variants of LyP include regional follicular
and pustular forms {2076}.
Histopathology
The histological features of LyP are vari-able and depend on the stage of the
lesions and disease. Three histologic
subtypes (types A, B and C) have been
delineated {2524} which represent a
spectrum with overlapping features
{2148}. In fully developed LyP lesions,
there is a wedge-shaped diffuse dermal
infiltrate which contains medium-sized to
large pleomorphic or anaplastic lym-phoid cells with irregular nuclei, sparse
chromatin and mitotic activity. Some of
the large atypical lymphoid cells resem-ble Reed-Sternberg cells. Ulceration
may be present. In type A lesions, scat-Fig. 4.23 Lymphomatoid papulosis with papules and
ulcerating nodules.
Fig. 4.24 Lymphomatoid papulosis. Wedge-shaped infiltrate with superficial ulceration and crust formation.
CD30+ T-cell lymphoproliferative
disorders
W. Kempf
R. Willemze
E.S. Jaffe
G. Burg
M.E. Kadin
180 Haematolymphoid tumours
tered tumour cells are intermingled with
numerous inflammatory cells such as
neutrophils, eosinophils and histiocytes.
Type C lesions show cohesive sheets of
large atypical lymphoid cells with only a
few intermingled reactive inflammatory
cells. The rare type B is characterized by
an epidermotropic infiltrate of small atyp-ical lymphoid cells with cerebriform
nuclei and histologically resembles
mycosis fungoides. Various histologic
types may be present in individual
patients at the same time.
Due to an overlap of histologic features
between LyP and primary as well as sec-ondary cutaneous ALCL, final diagnosis
depends on correlation of clinical pres-entation and histologic findings.
Immunohistochemistry
A hallmark of the large atypical lymphoid
cells is their positivity for CD30 {1173,
1227}. The large atypical lymphoid cells
in LyP are of T-cell origin with a CD3+,
CD4+, CD8-. In 10% of the cases tumour
cells express CD56+ {193}. Usually CD2
and CD5 are expressed, whereas often
CD7 and sometimes CD3 are absent. In
addition, expression of activation mark-ers such as HLA-DR and CD25 (inter-leukin 2-receptor) is found. Cytotoxic
molecules such as TIA-1 and granzyme
B are expressed in 70% of the cases
{1342}. CD56 is generally negative {968}.
CD15, a marker for Reed-Sternberg cells
in Hodgkin lymphoma, is usually not
expressed in LyP. In contrast to the
tumour cells expressing CD30 as in LyP
type A and type C, the small atypical
lymphocytes present in LyP type B are
usually negative for CD30.
Genetics
Clonal rearrangement of T cell receptor
genes can be found in at least 40% of
LyP lesions. Cytogenetic studies have
demonstrated chromosomal deletions
and rearrangements of chromosomes 1,
7, 9 and 10 {1813}. The t(2;5)(p23;q35)
translocation is not detected in LyP
{613}.
Histogenesis
LyP represents a proliferation of activat-ed skin-homing T-cells with a unique
cytotoxic phenotype (TIA-1+).
Prognosis and predictive factors
LyP exhibits a favorable prognosis with
5-year-survival rates of 100% {191,1795}.
So far, there are no data indicating that
any kind of therapeutic intervention in
LyP alters the natural history of the dis-ease or prevents progression to other
malignant lymphomas {650}. Other cuta-neous and nodal lymphomas such as
mycosis fungoides, Hodgkin lymphoma
and systemic or cutaneous CD30+ large
T-cell lymphoma (LTCL) develop in 5-20% of patients with LyP {191,1174}.
Long-term follow-up is therefore recom-mended. These lymphomas are usually
referred to as LyP-associated malignant
lymphomas. They can develop prior to,
concurrent with, or after the manifesta-tion of LyP {1175} and result in a fatal out-come in 2% of patients {191}. No risk fac-tors have been identified which definitely
indicate likely progression to associated
lymphomas in LyP patients. So far, only
fascin expression is found at a signifi-cantly higher rate in LyP cases associat-ed with systemic lymphomas {1243}.
Primary cutaneous anaplastic
large-cell lymphoma
Definition
Primary cutaneous anaplastic lymphoma
(C-ALCL) is a neoplasm composed of
large atypical lymphocytes of either pleo-morphic, anaplastic or immunoblastic
cytomorphology and expression of the
CD30 antigen by the majority, i.e. more
than 75% of tumour cells. Primary cuta-neous and primary nodal CD30+ ALCL
are distinct clinical entities that can have
similar morphologic features and some
overlap in immunophenotype, but differ
in age of onset, genetic features, etiology
and prognosis {600,2259,2493}.
ICD-O-code 9718/3
Synonyms
Regressing atypical histiocytosis ,
EORTC: Primary cutaneous large cell T
cell lymphoma CD30+
Epidemiology
C-ALCL is the second most common
form of cutaneous T-cell lymphoma with
an incidence of 0.1-0.2 patients per
100’000. This form of lymphoma affects
B CA
Fig. 4.25  Lymphomatoid papulosis.   A  Grouped and scattered CD30+ lymphocytes of various sizes.   B Mixed infiltrate consisting of large atypical lymphocytes,
eosinophils and neutrophils (LyP, type A).  C 1325. Cohesive sheets of large atypical lymphocytes with only few neutrophils (LyP, type C).
Fig. 4.26 Primary cutaneous anaplastic CD30+
large-cell lymphoma. Solitary large ulcerated nod-ule on the leg.
181CD30+ T-cell lymphoproliferative disorders
mainly people in their sixth decade with a
male to female ratio of 2-3:1 {191,1226},
but it can also occur in childhood. C-ALCL is a common form of cutaneous T-cell lymphoma in HIV-infected individuals
{1248}.
Localization
The extremities and head are predilec-tion sites {196,1228}.
Clinical features
ALCL usually presents as an asympto-matic, solitary firm nodule which rapidly
grows and often ulcerates {1174}.
Approximately 20% of the patients have
multifocal disease, i.e. two or more
lesions at multiple anatomic sites {191}.
Involvement of regional lymph nodes can
occur. Other extra-cutaneous spread is
rare. If there is no therapeutic interven-tion, spontaneous regression occurs in
10-40% of the tumour lesions {191,1226}.
Histopathology
There is a dense nodular infiltrate
extending through all levels of the dermis
into the subcutis. Epidermotropism may
be found. The infiltrate consists of cohe-sive sheets of large, cells with irregularly
shaped nuclei and one or multiple nucle-oli and an abundant, clear or eosinophilic
cytoplasm. Mitoses are frequent.
Clusters of small reactive lymphocytes
are found within and around the tumour.
Eosinophils, plasma cells, and accesso-ry  dendritic cells usually are not promi-nent in C-ALCL. Variants of C-ALCL
include neutrophil-rich or pyogenic
CD30+ ALCL presenting histologically
with small aggregations or scattered
CD30+ medium to large pleomorphic
lymphoid cells within an extensive infil-trate of neutrophils {341,1549}.
Immunohistochemistry
C-ALCL displays an activated T-cell phe-notype with expression of T-cell associat-ed antigens CD2, CD3, CD4 and
CD45RO, activation markers such as
CD25 (IL-2R), CD30, CD71 and HLA-DR,
and frequent expression of cytotoxic mol-ecules such as TIA-1, granzyme B and
perforin {290,1342}. CD30 must be
expressed by at least 75% of the large
pleomorphic or anaplastic lymphoid
cells. Variable loss of T cell antigens
(CD2, CD3, CD5 and CD7) can be found
{1228}. In contrast to systemic (nodal)
ALCL, C-ALCL does not express EMA,
but may express the cutaneous lympho-cyte antigen (CLA, HECA-452) and
homeobox gene HOXC5 {243}. C-ALCL
is consistently negative for the anaplastic
lymphoma related tyrosine kinase (ALK).
Genetics
Clonal rearrangement of T cell receptor
genes is detected by Southern blot and
PCR in most cases (over 90%) of C-ALCL
{1467}. The translocation t(2;5) (p23;q35)
resulting in expression of npm-alk protein
(p80), which is a characteristic feature of
systemic anaplastic large cell lym-phomas, is rarely if ever found in C-ALCL
{228,613}. Systemic ALCL may present
with cutaneous disease, and the identifi-cation of ALK-expression is helpful in this
distinction.
Histogenesis
Activated skin-homing T-cell.
Prognosis and predictive factors
C-ALCL has a favourable prognosis with
5 year-survival rates of 90% {191,1795}.
Up to 40% of C-ALCL show spontaneous
regression {198}. Regional lymph nodes
may be involved, but the survival rate is
similar to patients with skin lesions only
{191}. Other extracutaneous spread
occurs in 10% of the patients, especially
in those with multiple grouped or multifo-cal tumour lesions with a fatal outcome in
only a minority of the patients {191}.
Spontaneous regression and age less
than 60 years are associated with a bet-ter prognosis, while extracutaneous dis-ease and higher age tend to have a
worse outcome. Cytomorphology (ana-plastic or pleomorphic and immunoblas-tic) seems not to be a prognostic factor
{191,1795}.
DC
Fig. 4.27  CD30+ Primary cutaneous anaplastic large-cell lymphoma.  A Large cells in a background of his-tiocytes, plasma cells and small lymphocytes.   B Large atypical cells in CD30+ anaplastic large-cell lym-phoma.  C Scattered tumour cells expressing CD30.  D Expression of CD30 by almost all tumour cells.
BA
182 Haematolymphoid tumours
Definition
Subcutaneous panniculitis-like T-cell lym-phoma (SPTCL) is a T-cell lymphoma
with preferential infiltration of subcuta-neous tissue by atypical lymphoid cells
of varying size, often with marked tumour
necrosis and karyorrhexis.
ICD-O code 9708/3
Historical annotation
In the historical literature, most cases of
SPTCL were probably diagnosed as his-tiocytic cytophagic panniculitis {562,
1527}.
Epidemiology
Subcutaneous panniculitis-like T-cell lym-phoma is a rare form of lymphoma, rep-resenting less than 1% of all non-Hodgkin lymphomas. It occurs in males
and females equally, and has a broad
age range. Cases have been reported in
children under the age of two years. Most
cases occur in adults {1060,1341,2026,
2480}.
Etiology
Unknown. In most patients the disease
presents sporadically.
Localization
Patients present with multiple subcuta-neous nodules, usually in the absence of
other sites of disease. The most common
sites of localization are the extremities
and trunk.
Clinical features
Clinical symptoms are primarily related to
the subcutaneous nodules. The nodules
range in size from 0.5 cm to several cm.
in diameter. Larger nodules may become
necrotic, but ulceration of cutaneous
lesions is rare. Systemic symptoms, most
commonly fever, are variable but usually
present. Some patients may present with
a haemophagocytic syndrome with pan-cytopenias, fever, and hepatospleno-megaly {338,863,2480}. Lymphadeno-pathy is usually absent.
Histopathology
The infiltrate extends diffusely through
the subcutaneous tissue, usually without
sparing of septae. The overlying dermis
and epidermis are typically uninvolved.
The neoplastic cells range in size from
small cells with round nuclei and incon-spicuous nucleoli to larger transformed
cells with hyperchromatic nuclei. The
lymphoid cells have a moderate amount
of pale-staining cytoplasm. A helpful
diagnostic feature is the rimming of the
neoplastic cells surrounding individual
fat cells {1341}. Admixed reactive histio-cytes are frequently present, particularly
in areas of fat infiltration and destruction.
The histiocytes are frequently vacuolat-ed, due to ingested lipid material.
Vascular invasion may be seen in some
cases, and necrosis and karyorrhexis are
common. However, the infiltrates usually
are confined to the subcutaneous tissue,
with sparing of the dermis. This feature is
helpful in the differential diagnosis from
other lymphomas involving skin and sub-cutaneous tissue. The necrosis is prima-rily apoptotic in nature, possibly related
to the release of cytotoxic molecules
{1341,2133}. Cutaneous  γδ T-cell lym-phomas can have a panniculitis-like
component, but commonly show both
dermal and epidermal involvement in
addition to subcutaneous disease {1060,
1341,2026,2366}. Plasma cells and reac-tive lymphoid follicles are generally
absent, in contrast to lupus profundus
pannicultis, and other forms of lobular
panniculitis.
In some cases of SPTCL the infiltrates in
initial phases may appear deceptively
benign, and the differential diagnosis
with benign panniculitis may be difficult
{338,863}.
Immunoprofile
SPTCL is derived from  αß cells, T-cells
with a cytotoxic profile.The cells are usu-Subcutaneous panniculitis-like
T-cell lymphoma
E.S. Jaffe
G. Burg
Fig. 4.28 Subcutaneous panniculitis-like T-cell lymphoma (SPLTCL).  A Erythematous plaques and nodules on the leg with ulceration.  B Diffuse infiltration of sub-cutaneous tissue simulating lobular panniculitis. Large atypical cells rimming around fat lobules.
BA
183Subcutaneous panniculitis-like T-cell lymphoma
ally CD8-positive, with expression of
cytotoxic molecules including granzyme
B, perforin, and T-cell intracellular anti-gen (TIA-1) {1341,2026}. However, in
contrast to other cytotoxic TCLs related
to the innate immune system (enteropa-thy-type T-cell lymphoma, extranodal
NK/T-cell lymphoma), the cells are nega-tive for granzyme M (metase) {694,
1122,1325,2564}. The neoplastic cells
are capable of producing a number of
cytokines and chemokines, a feature that
is related to development of systemic
symptoms and the haemopha-gocytic
syndrome {338,2340}. Cutaneous  γδ T-cell lymphomas {119,338,1341,2026} are
distinguished from SPTCL, even if a pan-niculitis-like component is present.
Histogenesis
Mature cytotoxic T-cell of the adaptive
immune system.
Precursor lesions
Oligoclonal T-cell populations may be
found in some cases of lobular pan-nicultis, suggesting the potential for clon-al evolution in rare cases {1484}.
However, progression from cytophagic
panniculitis without monoclonality to
SPTCL rarely if ever occurs {1527}.
Somatic genetics
The neoplastic cells show rearrangement
of T-cell receptor genes, and are nega-tive for Epstein Barr sequences.
Prognosis and predictive factors
Dissemination to lymph nodes and other
organs is uncommon and usually occurs
late in the clinical course. The natural his-tory is often aggressive {694,863,917,
1300,2026}. A haemophagocytic syn-drome is a frequent complication in  αβ
cases and usually precipitates a fulmi-nant downhill clinical course. However, if
therapy for the underlying lymphoma is
instituted and is successful, the
haemophagocytic syndrome may remit.
Fig. 4.29 Subcutaneous panniculitis-like T-cell lym-phoma (SPLTCL). Subcutaneous erythematous
plaques and nodules on the legs.
Fig. 4.30 Subcutaneous panniculitis-like T-cell lymphoma (SPLTCL) Lobular panniculitis-like infiltrate of neo-plastic lymphoid cells.
184 Haematolymphoid tumours
Definition
A heterogeneous group of cutaneous T-cell lymphomas that do not fit into one of
the well-defined subtypes of T-cell lym-phoma/leukaemia. Three provisional enti-ties have been separated: Cutaneous γδ
T-cell lymphoma, primary cutaneous
aggressive epidermotropic CD8+ cyto-toxic T-cell lymphoma and primary cuta-neous small-medium CD4+ T-cell lym-phoma.
ICD-O code 9709/3
Synonyms and historical annotation
The category of the peripheral T-cell lym-phomas, unspecified (PTL) was intro-duced in the REAL classification {960}
and was maintained in the WHO classifi-cation {1369}. It encompasses per defini-tion all T-cell neoplasms that do not fit
into any of the better defined subtypes of
T-cell lymphoma/leukaemia. As such it
constitutes a heterogeneous group of
diseases. These conditions are most fre-quently systemic {1121}. Primary cuta-neous PTL are rare and constitute less
than 10% of all cutaneous T-cell lym-phomas (CTCL) in large series {195}.
They correspond to the CD30-negative
CTCL in the EORTC classification and
show an aggressive behaviour in most
cases {195,2523}. Therefore, distinction
between “primary” and “secondary” cuta-neous involvement seems less important
for this category.
Although it is still controversial how these
tumours can be grouped into separate
diseases, recent investigations have
suggested that some disorders within
this broad group of neoplasms can now
be separated out as provisional entities.
For the remaining diseases that do not fit
into either of these provisional entities
(Table 4.1), the designation PTL, unspec-ified, is maintained.
Cutaneous γδ T-cell lymphoma
Definition
Cutaneous  γδ T-cell lymphoma (CGD-TCL) is a lymphoma composed of a clon-al proliferation of mature, activated gd  T-cells expressing a cytotoxic phenotype.
This group includes cases of subcuta-neous panniculitis-like T-cell lymphoma
(SPTCL) with a gamma/delta phenotype.
In the WHO classification 2001, these
were grouped together with SPTCL of αβ
origin {1121}, but they show distinctive
features and seem to be more closely
related to other CGD-TCL {192,1060,
1533,2026,2366}. A similar and possibly
related condition may present primarily in
mucosal sites {98}. Whether cutaneous
and mucosal γδ TCLs are all part of a sin-gle disease, i.e. muco-cutaneous γδ TCL,
is not yet clear {1122,2539}.
Epidemiology
CGD-TCLs are rare, with approximately
50 cases reported {1533,1665,2366}. In
one series they represented <5% of cuta-neous T-cell lymphomas {1879}. Most
cases occur in adults. There is no report-ed sex predilection.
Table 4.1
Characteristic features of three provisional cutaneous T-cell lymphomas.
Skin lesion  Pattern of   Cytology  Phenotype  EBV  Behaviour
infiltration
γδ-TCL  Patches, plaques,  E, D, S Medium-large,  TCRd1+, CD3+,  – A
tumours, disseminated pleomorphic CD4-, CD8-,
CyAg+, CD56 +/-AECD8+ Eruptive nodules,  E  Medium-large bF1+, CD3+, CD4-, – A
hyperkeratotic paches/ pleomorphic CD8+, CyAg+
plaques, disseminated ,
PTL,  Solitary nodules, D, S Small-medium bF1+, CD3+,  – I
CD4+ tumours pleomorphic CD4+, CD8-Abbreviations:  γδ-TCL= gamma delta-T-cell lymphoma; AECD8+= aggressive, epidermotopic, CD8+ cytotoxic T-cell
lymphoma; E=epidermal; D=dermal; S=subcutaneous; CyAg= cytotoxic antigens (TIA-1, granzyme B, perforin); EBV=
Epstein-Barr Virus; A =aggressive; I=indolent.
Primary cutaneous peripheral
T-cell lymphoma, unspecified
E. Ralfkiaer
R. Willemze
C.J.L.M. Meijer
R. Dummer
E.S. Jaffe
S.H. Swerdlow
E. Berti
W Kempf
G. Burg
L. Cerroni
Fig. 4.31 Cutaneous γδ T-cell lymphoma presenting with skin tumours.
185Primary cutaneous peripheral T-cell lymphoma, unspecified
Etiology
The distribution of disease reflects the
localization of normal  γδ T cells, which
are believed to play a role in host mucos-al and epithelial immune responses
{268}. Impaired immune function associ-ated with chronic antigen stimulation
may predispose to the development of
mucosal and CGD-TCLs {98,2539}.
Epstein-Barr virus (EBV) is generally
negative in CGD-TCLs, but may be posi-tive in primary  γδ TCL in mucosal sites
{98,1191,2366,2539}.
Clinical features
The clinical presentation is variable. The
disease may be predominantly epider-motropic and present with patches/
plaques, or it may be predominantly
deep dermal/subcutaneous with necrotic
tumours or nodules, resembling subcuta-neous panniculitis-like T-cell lymphoma
(SPTCL) of αβ type {192,221,1060,1533,
1665,1879,2026,2366}. The lesions are
often mainly present on the extremities
{2366}, but other sites may be affected
as well {1533,2365}. Patients with CGD-TCL usually lack involvement of lymph
nodes, spleen, and bone marrow, but the
disease may disseminate to extran-odal/mucosal sites. A haemophagocytic
syndrome may occur in patients with
panniculitis-like tumours {119,2365}.
Histopathology
The neoplastic cells are generally medi-um to large in size with coarsely clumped
chromatin {2366}. Large blastic cells with
vesicular nuclei and prominent nucleoli
are infrequent. Apoptosis and necrosis
are common, often with angioinvasion
{1533}. Three major histologic patterns of
involvement are present: epidermotropic,
dermal, and subcutaneous. However,
usually more than one histologic pattern
is present in the same patient in different
biopsy specimens or within a single
biopsy specimen {2366}. Epidermal infil-tration may occur as mild epidermotro-pism to marked pagetoid reticulosis-like
infiltrates {221,1665,1879}. Subcuta-neous nodules may be pannicultis-like or
more solid in appearance and may show
rimming of fat cells, similar to SPTCL of
alpha/beta origin {1533}. Dermal and
epidermal involvement often coexists
with subcutaneous disease, in contrast
to SPTCL of αβ origin, which is mainly or
exclusively subcutaneous in distribution
{192,1060,2026}.
Immunoprofile
The cells are CD3+, CD2+, CD7 +/-, but
usually negative for CD5 {2539}. Most
CGD-TCLs lack both CD4 and CD8, but
some are CD8+ {2366}. The cells are
positive for TCR-δ, but lack βF1 of the αβ
T-cell receptor. The absence of βF1 may
be used to infer a γδ origin under appro-priate circumstances {1151,2026,2365}.
The cells are positive for TIA-1 and the
cytotoxic proteins granzyme B, gran-zyme M, and perforin. {1325,1341,
1533}. CD56 is frequently expressed
{1533}.
Histogenesis
Functionally mature and activated cyto-toxic γδ T-cells of the innate immune sys-tem.
Somatic genetics
The cells show clonal rearrangement of
the TCR gamma gene. TCR beta may be
rearranged or deleted, but is not ex-pressed. Cases with predominant subcu-taneous involvement express Vδ2, but
this has not been studied in other CGD-TCL {1860,2026}. EBV is generally nega-tive in primary CGD-TCL {98,119}.
Prognosis and predictive factors
Patients have aggressive disease resist-ant to multiagent chemotherapy and/or
radiation {1665,2366}. In a recent series
of 33 patients, 22 (66%) died within 5
years of diagnosis, and in the same
study TCRδ1 expression was an inde-pendent predictor of survival {2366}.
Among 33 patients with CGD-TCL, there
was a trend for decreased survival for
patients who had subcutaneous fat
involvement in comparison with patients
who had epidermotropic or dermal dis-ease only. Age, sex, and lymphadenopa-thy did not have any discernible prog-nostic impact {2366}.
Primary cutaneous aggressive
epidermotropic CD8+ cytotoxic
T-cell lymphoma
Definition
A cutaneous T-cell lymphoma character-ized by epidermotropic infiltrates of CD8-positive, cytotoxic T-cells of  αβ origin.
The behaviour is aggressive in most
cases {223}.
Epidemiology
This disease occurs mainly in adults and
is rare with approximately 30 cases pub-lished worldwide {36,192,223,1533,
2062}.
Clinical features
The clinical presentation is characterized
by sudden eruptions of localized or dis-seminated papules, nodules and
tumours, often with central ulceration and
necrosis. Superficial, hyperkeratotic
patches and plaques may also be pres-ent {36,223}. The disease may resemble
epidermotropic variants of other cuta-neous T-cell lymphomas and is similar, if
not identical to cases described as gen-eralized pagetoid reticulosis of the
Ketron-Goodman type {1252,1533}.
Classical MF, which may express CD8 in
rare cases {1456,1880, 2062,2510}, usu-B CA
Fig. 4.32 Cutaneous γδ T-cell lymphoma.  A The infiltrates may be epidemotropic,  B dermal  C subcutaneous or combined.
186 Haematolymphoid tumours
ally does not show overt destruction and
necrosis and has a more protracted
behaviour with progression over years
from patches to plaques and tumours.
The disease may disseminate to other
visceral sites (lung, testis, central nerv-ous system, oral mucosa), but lymph
nodes are often spared {223}.
Histopathology
The histological and cytological appear-ance is very variable ranging from a
lichenoid pattern with marked, pagetoid
epidermotropism and subepidermal
edema to deeper, more nodular infil-trates. The epidermis may be acanthotic
or atrophic, often with necrosis, ulcera-tion and blister formation {36,223}.
Invasion and destruction of adnexal skin
structures are commonly seen {1533}.
Angiocentricity and angioinvasion may
be present {1533}. Tumour cells are
small-medium or medium-large with
pleomorphic or blastic nuclei {223}.
Immunoprofile
The tumour cell have a  βF1+, CD3+,
CD8+, Granzyme B+, perforin+, TIA-1+,
CD2-, CD4-, CD5-, CD7-/+ phenotype
{36,223,2062}. EBV is generally negative
{192,1533}.
Histogenesis
Skin homing, CD8-positive, cytotoxic T-cells of αβ type.
Somatic genetics
The neoplastic T-cells show clonal TCR
gene rearrangements. Specific genetic
abnormalities have not been described.
Prognosis
These lymphomas have an aggressive
clinical course with a median survival of
32 months {36,223,1533,2062}.
Primary cutaneous small-medium CD4+ T-cell lymphoma
Definition
A cutaneous T-cell lymphoma character-ized by a predominance of small to
medium-sized CD4-positive pleomorphic
T-cells with clinical features different from
MF. Most cases have a favourable clini-cal course {195,878}.
Epidemiology
A rare disease, accounting for 5-10% of
cutaneous lymphomas in large series
{195,878}.
Clinical features
Characteristically, these lymphomas
present with a solitary plaque or tumour,
generally on the face, the neck or the
upper trunk {195}. Less commonly, they
present with one or several papules,
nodules or tumours, but always without
patches typical of mycosis fungoides
{195,783,2267}.
Histopathology
These lymphomas show dense, diffuse
or nodular infiltrates within the dermis
with tendency to infiltrate the subcutis.
Epidermotropism may be present focally.
There is a predominance of small/medi-um-sized pleomorphic T cells {195,783,
2267}. A small proportion (<30%) of
large pleomorphic cells may be present
{195}. A considerable admixture with
small reactive lymphocytes and histio-cytes may sometimes be observed
{2074}.
Immunoprofile
By definition these lymphomas have a
CD3+, CD4+, CD8-, CD30- phenotype
sometimes with loss of pan T-cell mar-kers {195,783}. Cytotoxic proteins are
generally not expressed {195}.
Histogenesis
Skin homing, CD4-positive T-cell.
Somatic genetics
The TCR genes are clonally rearranged
{783,878}. Demonstration of clonality is a
useful criterion for distinction from pseu-do-T-cell lymphomas, which may also
present with a solitary plaque or nodule.
No consistent cytogenetic abnormalities
have yet been identified.
Prognosis and predictive factors
These lymphomas have a rather
favourable prognosis with an estimated
5-year survival of 60-80% {195,783,
878,2267}. Cases presenting with soli-tary or localized skin lesions seem to
have an especially favourable prognosis
{195,878}.
Primary cutaneous PTL,
unspecified
Definition
The designation PTL, unspecified is
maintained for cutaneous T-cell lym-Fig. 4.33 Primary cutaneous aggressive epider-motropic CD8+ cytotoxic T-cell lymphoma present-ing with an ulcerated skin tumour
B CA
Fig. 4.34 Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma.  A The neoplastic infiltrate is markedly epidermotropic and pleomorphic
and is  B positive for CD3 and  C for CD8.
187Primary cutaneous peripheral T-cell lymphoma, unspecified
phomas that originate from mature, trans-formed T-lymphocytes and that do not fit
into any of the better defined subtypes of
mature cutaneous T-cell neoplasms.
Hence, other categories of T-cell lym-phoma must be excluded. These include
the 3 provisional entities described
above. Furthermore, given the wide vari-ety of histologic appearances of tumour
stage mycosis fungoides (MF), a diagno-sis of MF should always be ruled out by
complete clinical examination and an
accurate clinical history.
Epidemiology
These tumours account for 5 to 10% of all
primary cutaneous T cell or NK cell lym-phomas {195}. All ages may be affected,
but the disease is most common in
adults.
Clinical features
Most lymphomas in this category present
with rapidly growing tumours or nodules
that may be multiple or (more rarely) soli-tary or localized {195,197,878,2523}. No
sites of predilection have been recorded.
Histopathology
Skin infiltrates are most often diffuse, but
nodular or band-like patterns can be
seen. Epidermotropism is mild or absent
in most cases. The tumour cells are
medium to large, usually with markedly
pleomorphic nuclei. Rare cases may
show a predominance of cells that are
more immunoblastic in appearance
{197,2523}. Small reactive lymphocytes,
eosinophils and plasma cells may be
present {195}, but the inflammatory
background is usually not as pro-nounced as it can be in nodal malignan-cies.
Immunoprofile
The tumour cells express T-cell associat-ed antigens (CD2, CD3, CD5), but usual-ly lack CD7; most cases are CD4+, but
rare tumours may be CD8+ or positive
(or negative) for both CD4 and CD8
{195}. Cytotoxic antigens (TIA-1+,
granzyme B) are usually not expressed
{195}. Occasional tumour cells may be
CD30-positive.
Histogenesis
Skin homing T-cells.
Precursor lesion
There are no known precursor lesions. As
mentioned, cases of transformed MF
may closely resemble peripheral T cell
lymphoma unspecified and can only be
distinguished on clinical grounds.
Somatic genetics
The TCR genes are clonally rearranged.
No consistent cytogenetic abnormalities
have yet been identified.
Prognosis and predictive factors
The prognosis is poor with 5-year sur-vival rates of less than 20% {195,878}.
Cases with immunoblastic morphology
may have an even more aggressive
behaviour {197,2523}. Cases with soli-tary/localized lesions seem to behave
just as aggressivelys as those with multi-ple lesions {195}.
Fig. 4.36  Cutaneous small-medium pleomorphic T-cell lymphoma.  A Small-medium lymphocytes with pleo-morphic nuclei predominating.  B Staining for CD3 confirms the T-cell lineage of the lymphocytes.
A
B
BA
Fig. 4.35 Primary cutaneous small-medium T-cell lymphoma.  A Small-medium CD4+ T-cell lymphoma with
a solitary skin nodule on the face.   B Nodular infiltrates of lymphocytes involving the entire dermis and
superficial part of subcutaneous tissues.
188 Haematolymphoid tumours
DC
BA
Fig. 4.37 Primary cutaneous peripheral T-cell lymphoma, unspecified.  A Grouped and B disseminated skin lesions.  C The dermal neoplastic infiltrate is dense and
D consists of large, pleomorphic cells with irregular nuclei and numerous mitoses.
189
Definition
Adult T cell leukaemia / lymphoma
(ATLL) is a malignancy of mature CD4+ T
cells caused by the human T-cell
leukaemia virus type I (HTLV-1).
ICD-O code 9827/3
Synonyms
Adult T-cell leukaemia (ATL)
Epidemiology
ATLL is endemic in some regions of the
world, especially in southwest Japan, the
Caribbean islands, South America, and
parts of Central Africa {1848,2392}.
Etiology
ATLL develops in 1% to 5% of individuals
infected with HTLV-1 after more than 2
decades of viral persistence. In most
patients viral exposure occurs early in
life, and incidence figures are related to
the place of birth, not residence.
HTLV-1 proviral DNA is monoclonally
integrated in the malignant T cell. HTLV-1
encodes the transcriptional activator Tax,
which can transform T cells by increas-ing the expression of a unique set of cel-lular genes involved in T cell proliferation
{1589}.
Localization
Based on organ involvement and severi-ty, ATLL is divided into four clinical cate-gories: acute, chronic, lymphoma, and
smoldering types {2171}. Cutaneous
involvement is seen in up to 50% of
patients. Lymph nodes, liver and spleen
are frequently involved.
Clinical features
Patients with ATLL exhibit various cuta-neous manifestations. The most frequent
manifestation is nodules/tumours
(33.9%), followed by red papules
(22.6%), erythematous plaques (19.4%)
and macules (6.5%) {2142}. Nodules/
tumours usually occur as solitary or sev-eral lesions on limited sites, whereas
multiple papules tend to be distributed
over large areas of the body. Sub-cutaneous tumours (4.8%), erythroderma
(3.5%), and purpura (1.6%) are less fre-quent, and alopecia, folliculitis, erythema
multiforme, and prurigo are rarely seen.
In addition to the four clinical types, the
cutaneous type of ATLL has been pro-posed to indicate skin-limited lesions
without lymph node involvement or
leukaemic involvement {1144}. ATLL lim-ited to the skin may be considered part
of the smouldering type.  Two patterns of
skin involvement are seen; i.e., tumoural
and erythematopapular. The tumoural
subtype has been reported to have a
worse prognosis than the erythe-matopapular one.
Histopathology
Individual skin lesions of ATLL exhibit
varying degrees of tumour cell infiltration
from the epidermis to subcutaneous tis-sue. Epidermotropism of the malignant T-cells is present in the majority of cases,
Cutaneous adult T-cell leukaemia/lymphoma
Fig. 4.38 Adult T-cell leukaemia/lymphoma (ATLL)  A A large tumour on the right cheek.  B Multiple erythematous plaques on the trunk.  C Multiple papules on the
hand and forearm.
BA C
Cutaneous adult T-cell
leukaemia / lymphoma
Y. Tokura
E.S. Jaffe
C. A. Sander
190
and even Pautrier microabscesses,
indistinguishable from those of mycosis
fungoides and Sézary syndrome, are
often seen. The cells have medium- to
large-sized pleomorphic nuclei, and
occasionally show mitoses. Nuclear
irregularity may be marked, with polylo-bated flower cells often seen in the blood
and tissues. Eosinophils may be inter-mingled with lymphocytes. In some
cases, the tumour cells infiltrate mainly in
the subcutaneous tissue {2142,2171}.
Immunohistochemistry
In general, the malignant T cells are pos-itive for CD3, CD4, CD25, and CD45RO
but negative for CD7. CD8, CD19, and
CD20 {2171}. CD30 expression may be
seen in larger transformed cells.
Prognosis and prognostic factors
The prognosis of ATLL patients with skin
lesions is dependent on clinical and his-tological factors, and relates to the four
main clinical subtypes. It has been sug-gested that cases of the smoldering type
of ATLL have a poorer prognosis if there
are deep dermal cutaneous infiltrates, as
compared to cases in which skin mani-festations are absent, or only present as
superficial infiltration {2142}.
Haematolymphoid tumours
Fig. 4.39 Adult T-cell leukaemia/lymphoma (ATLL).  A Erythematous macule, showing infiltration of atypical
lymphocytes in the upper dermis with Pautrier microabscess.  B Tumour, massive infiltration of pleomorphic
lymphocytes in the dermis.
B
A
191
Definition
Extranodal NK/T-cell lymphoma, nasal-type, is an EBV+, nearly always extrano-dal lymphoma of small, medium or large
cells usually with an NK-cell, or more
rarely cytotoxic T-cell phenotype. The
skin is the second most common site of
involvement after the nasal cavity/
nasopharynx, and skin involvement may
be a primary or secondary manifestation
of the disease.
ICD-O code: 9719/3
Synonyms
REAL: angiocentric T-cell lymphoma;
EORTC used to include in CTCL, large
cell, CD30- and CTCL, pleomorphic,
small/medium-sized
Epidemiology
Extranodal NK/T-cell lymphoma is a rare
disease occurring in adults, with a male
predominance. This lymphoma is more
prevalent in Asia, Central America and
South America.
Etiology
It is universally associated with EBV, and
genetic factors play a role in susceptibil-ity to the disease {443,1689}.
Localization
The majority of patients present with skin
lesions affecting more than one anatom-ic region, most commonly the trunk and
extremities {443,1660}.
Clinical features
Cutaneous involvement consists of
tumour nodules and plaques. Systemic
symptoms such as fever, malaise and
weight loss are common. Some cases
are accompanied by a haemophagocyt-ic syndrome. The disease is closely relat-ed to aggressive NK-cell leukaemia,
which also may have cutaneous manifes-tations, and is also EBV-associated.
Histopathology
A dense dermal infiltrate is often centred
on the skin appendages and blood ves-sels resulting in a column-like low power
appearance {1689}. Prominent angio-centricity and angiodestruction are often
accompanied by extensive necrosis
{443,1689}. Extension into the subcutis is
common. Approximately 30% of cases
show at least focal epidermotropism
{1689}. The mitotic rate is high and apop-totic bodies are numerous. NK/T-cell lym-phoma has a broad cytologic spectrum
ranging from small to large cells, with
most cases consisting of medium sized
cells. The cells often exhibit irregular
nuclear foldings, moderately dense chro-matin, and pale cytoplasm.
Immunoprofile
The most common immunophenotype is:
CD2+, CD56+, surface CD3-, cytoplas-mic CD3ε+, CD43+ and cytotoxic gran-ules + (TIA-1, granzyme B, perforin)
{1325}. Occasional cases are CD56-, but
then require EBV positivity or presence of
cytotoxic granules for diagnosis;other-wise they should be classified as periph-eral T-cell lymphoma, unspecified. LMP-1
is inconsistently expressed, with EBER in
situ hybridization preferred for diagnosis.
Genetics
The T-cell receptor is usually in germline
configuration.
Prognosis and predictive factors
Extranodal NK/T-cell lymphoma present-ing in the skin is a highly aggressive
tumour with a median survival of less
than 15 months {443,1660}. The most
Extranodal NK/T-cell lymphoma, nasal-type
Extranodal NK/T-cell lymphoma,
nasal-type
S. Kohler
K. Iwatsuki
E.S. Jaffe
J.K.C. Chan
Fig. 4.40 Extranodal NK/T-cell lymphoma, nasal-type. Clinical appearance with violaceous tumour
nodules.
DC
Fig. 4.41 Extranodal NK/T-cell lymphoma, nasal-type.  A Angiocentricity and angiodestruction.  B Involve-ment of the subcutis.  C Focal epidermotropism, present in approx. 30% of cases.  D Cytologic detail show-ing medium sized cells with irregular nuclear foldings.
BA
192
important factor predicting poor outcome
is the presence of extracutaneous
involvement at presentation {1660}.
Preliminary data indicate that co-expres-sion of CD56 and CD30 may be associ-ated with a better prognosis {1660,1690}.
Hydroa vacciniforme-like
cutaneous T-cell lymphoma
Definition
Hydroa-vacciniforme-like cutaneous T-cell lymphoma is a rare EBV-associated
lymphoma of cytotoxic T-cell or NK-cell
origin that affects children, characterized
by a vesiculopapular skin eruption that
clinically resembles hydroa vaccini-forme.
Synonym
Angiocentric cutaneous T-cell lymphoma
of childhood
Epidemiology
Hydroa vacciniforme-like CTCL affects
children and teenagers, with almost all
reported cases being from Latin America
(such as Peru, Bolivia, Mexico) {166,
1479,1991} and Asia (such as Korea and
Japan). Boys and girls are affected in an
equal ratio {471,765}.
Etiology
The strong association with EBV sug-gests a pathogenetic role of the virus and
genetic predisposition, as in extranodal
NK/T-cell lymphoma. The anatomic distri-bution of the skin lesions suggests sun
exposure as a risk factor although tests
for minimal erythema doses are usually
within normal limits.
Localization
The lesions occur predominantly in sun-exposed areas, particularly the face and
limbs.
Clinical features
Patients present with facial and hand
oedema and a papulovesicular eruption
that affects sun-exposed and to a lesser
extent sun-protected areas. Individual
lesions start with oedema and erythema
and then progress to vesicles, necrosis,
ulceration, crusts, and heal as varicelli-form scars. Fever, wasting, hepato-splenomegaly, lymphadenopathy and
hypersensitivity to insect bites are com-mon. Some cases are accompanied by a
haemophagocytic syndrome. The dis-ease may progress to lymph node and
visceral involvement.
Histopathology
The infiltrate consists of medium-sized
atypical lymphoid cells set in an inflam-matory background. The depth of the
infiltrate seems related to the age of the
lesion {166}. A fully developed lesion
shows a dense dermal infiltrate with epi-dermotropism and extension into the fat
in a lobular fashion. Ulceration is com-mon. The infiltrate is often angiotropic/
angioinvasive and in addition may dis-play a periadnexal and perineural growth
pattern.
Immunoprofile
The tumour cells are cytotoxic T-cells,
that have often lost expression of some
pan T-cell markers. The most common
phenotype is: CD2+, CD3+, CD8+,
CD43+, CD45RO+, TIA-1+, Granzyme
B+; CD4-,  CD5-, CD7-. CD56 is variably
positive, but CD57 is negative. CD30
reactivity can be seen in a subset of cells
(<30%).
Somatic genetics
The T-cell receptor gene is clonally
rearranged {166,1479}, although in
cases of NK-cell derivation, T-cell recep-tor genes are germline.
Prognosis
The prognosis is poor, with a 2-year sur-vival rate of 36% {166}.
Haematolymphoid tumours
Fig. 4.42 Nasal type NK/T-cell lymphoma (EBV+),
immunostained for CD56. Almost all cells are CD56
positive.
Fig. 4.44 A Subcutaneous infiltrate of tumour cells
with prominent cytophagocytosis.  B In situ hybridi-sation showing EBER+ tumour cells
A
BFig. 4.43 Hydroa vacciniforme-like cutaneous T-cell
lymphoma.   A Infiltrate on the sun-exposed ear-lobe.  B Papules, vesicles and crusted erosions on
face of young boy.
A
B
193Cutaneous involvement in primary extracutaneous T-cell lymphoma
Systemic peripheral T-cell lymphoma
(PTL), unspecified, involves the skin in
approximately 20-30% of the cases {836,
1453}. Skin lesions may be present at
diagnosis or can develop during disease
progression. Lesions are most often
tumours or nodules that may be solitary
or multiple. No sites of predilection have
been recorded. The histological and
phenotypic features are identical to the
systemic disease. The prognosis is very
poor {104,690,836,1453}.
Systemic anaplastic large cell
lymphoma (ALCL)
Primary systemic anaplastic large cell
lymphoma affects lymph nodes and
extranodal sites, including in 20% of the
cases the skin. The skin lesions may be
present at diagnosis or can develop at
relapse or during disease progression.
The skin lesions are usually tumours or
nodules that can be solitary or multiple.
No sites of predilection have been
recorded. The histological, phenotypic
and genotypic features are identical in
lymph nodes and the skin. The tumour
cells are most often large with abundant
cytoplasm and characteristic so-called
hallmark cells with eccentric, horseshoe-or kidney-shaped nuclei often with an
eosinophilic region near the nucleus. The
principal morphological variants are the
small cell variant and the histiocyte rich
variant {809}. It is important to distinguish
these lesions from primary cutaneous
ALCL. The histological appearance of
systemic cases is usually more
monomorphic with infrequent tumour
giant cells. The tumour cells in systemic
ALCL express a cytotoxic phenotype
and are positive for CD30 and EMA. CD3
is negative in more than 75% of cases
{191, 1121}. CD5 and CD7 are often neg-ative. CD2, CD4 and CD43 are more use-ful and are expressed in a significant pro-portion of cases. ALK expression and
t(2;5) or variant translocations involving
ALK and fusion partners other than NPM
are present in the majority of cases {706,
809}. The natural history is aggressive
but long term complete remissions can
be obtained in most patients with ALK-positive disease {191}.
Angioimmunoblastic T-cell
lymphoma (AITL)
ICD-O code 9705/3
Skin lesions in angioimmunoblastic T-cell
lymphoma (AITL) occur in half of the
cases, usually as a generalized macu-lopapular eruption simulating  viral exan-them or drug eruption, or as urticaria,
purpura, erythemato-squamous plaques,
prurigo-like lesions, erythroderma, ero-sions and necrotic lesions. The disease
occurs mostly in middle-aged or elderly
people without gender preponderance
{787}. Other findings are fever, weight
loss, night sweats, lymphadenopathy,
hepato- and splenomegaly, anaemia, an
elevated sedimentation rate, leukocyto-sis, neutropaenia or thrombocytopaenia,
as well as polyclonal hypergammaglobu-linemia. AITL exhibits an aggressive
course with a median survival ranging
from 11 to 30 months and a fatal outcome
in  50 to 70% of patients.
Histologically, the skin lesions are charac-terized by nonspecific subtle superficial
perivascular infiltrates composed of
eosinophils and lymphocytes without
atypia accompanied by hyperplasia of
capillaries. Admixed plasma cells and
histiocytes can be found {2087}. Clonal T
cell receptor rearrangement has been
reported in some cases {1522}. However,
it is not clear whether the cutaneous man-ifestations are generally due to tumour
cell involvement or a secondary phenom-enon related to cytokine production.
Cutaneous involvement in primary
extracutaneous T-cell lymphoma
W. Kempf
E. Ralfkiaer
D.V. Kazakov
E.S. Jaffe
Fig. 4.45 Cutaneous involvement in AITL. A poly-morphous perivascular infiltrate is present in the
superficial dermis
194 Haematolymphoid tumours
Definition
Primary cutaneous marginal zone B-cell
lymphoma (MZL) is an indolent lym-phoma composed of small B cells includ-ing marginal zone (centrocyte-like) or
monocytoid cells, lymphoplasmacytoid
cells and plasma cells. It is considered
part of the broad group of extranodal
marginal zone B-cell lymphomas com-monly involving mucosal sites (mucosa
associated lymphoid tissue, MALT).
Primary cutaneous immunocytoma, pri-mary cutaneous plasmacytoma and
cutaneous follicular lymphoid hyperpla-sia with monotypic plasma cells are con-sidered variants of MZL.
ICD-O code 9699/3
Synonyms
EORTC (1997): Primary cutaneous
immunocytoma / marginal zone B-cell
lymphoma
Epidemiology
MZL most commonly affects adults aged
over 40 years. There is no clear gender
preponderance {132,2141}.
Etiology
In Europe, Borrelia burgdorferi DNA has
been identified in some cases of MZL
suggesting that it may play an etiological
role. {433}. However, no association of
Borrelia with CBCL has been found in the
United States and Asia {2547}.
Localization
MZL is predominantly localized on the
upper extremitites, and less often head
and trunk.
Clinical features
In most cases, cutaneous MZL presents
with red to violaceous plaques or nod-ules with an erythematous border {2141}.
Ulceration and visceral dissemination are
uncommon. MZL with secondary spread
to the skin is often multifocal {1418}.
Histopathology
The infiltrate is characterized by residual
reactive lymphoid follicles surrounded by
pale staining cuffs of tumour cells.
Reactive germinal centres with distinct
mantle zones are commonly found in
early lesions but may become colonized
by tumour cells as the disease progress-es. The interfollicular infiltrate is com-posed of small to medium-sized, centro-cyte-like or monocytoid cells with slightly
irregular nuclei, moderately dispersed
chromatin, inconspicuous nucleoli and a
rim of pale cytoplasm {2234,2362}.
Variable numbers of lymphoplasmacy-toid cells and plasma cells are typically
present at the periphery of the infiltrates
or in the subepidermal area. Intranuclear
PAS positive pseudoinclusions (Dutcher
bodies), are commonly found, particular-ly in plasma cell rich forms of MZL.
Diffuse infiltrates almost completely con-sisting of monocytoid cells, lympho-epithelial lesions with infiltration of sweat
glands and the presence of very imma-ture plasma cells should raise suspicion
of secondary cutaneous involvement.
Immunoprofile
The neoplastic cells express CD19+,
CD20+, CD22+, CD79a+, but are nega-tive for CD5-, CD10-, bcl-6, CD23-. CD43
may be positive {132}. In contrast to FL,
the tumour cells are bcl-2+, but negative
for bcl-6 and CD10 {603,1418}. Reactive
Cutaneous marginal zone
B-cell lymphoma
W. Kempf
E. Ralfkiaer
L. Duncan
G. Burg
R. Willemze
S.H. Swerdlow
E.S. Jaffe
Fig. 4.46 Cutaneous marginal zone B-cell lym-phoma. Infiltrate extends through dermis to subcu-taneous tissue.
Fig. 4.47 Cutaneous marginal zone B-cell lym-phoma. Neoplastic cells surround a residual germi-nal centre.
Fig. 4.48 Marginal-zone lymphoma. Firm nodules on
the forehead.
195Cutaneous marginal zone B-cell lymphoma
germinal centres are bcl-6+ and bcl-2-.
Anti-CD21 staining often reveals regular
and irregular networks of follicular den-dritic cells (FDC) in reactive follicles, but
not associated with tumour cells. The
lymphoplasmacytoid cells and the plas-ma cells show monotypic expression of
immunoglobulin light chains. There are
numerous admixed reactive T-cells.
Precursor lesion
Cutaneous lymphoid hyperplasia due to
Borrelia infection may mimic MZL and
has been postulated to represent a pre-cursor lesion in some circumstances.
Histogenesis
Post germinal centre B-lymphocyte with
plasmacytic differentiation and gene
expression pattern {2273}.
Somatic genetics
IgH genes are clonally rearranged. The
most common translocation in gastric
MZL, the t(11;18) involving the API2/MLT
genes, has not been demonstrated in pri-mary cutaneous MZL {1418,2141,2279}.
However, the t(14;18)(q32;q21) involving
IGH and MALT1 was reported in approx-imately one third of cases in a small
series. Fas gene mutations are present in
a minority of cases, similar to MZL of
other extranodal sites. Abnormalities of
BCL10 are absent {906}.
Prognosis
MZL shows a protracted clinical course
with a tendency for recurrences.
However, the prognosis is favourable
with 5-year-survival rates between 90
and 100%. Transformation into diffuse
large B cell lymphoma occurs infrequent-ly {2141}.
DC
BA
Fig. 4.49 Plasmacytoid cells in cutaneous marginal zone B-cell lymphoma.  A Monoclonal plasma cells are admixed with cells with monocytoid features.  B In a sub-sequent biopsy from the same patient, all of the cells have a plasmacytic morphology and express monoclonal Ig light chains.  C Kappa.  D Lambda.
196 Haematolymphoid tumours
Definition
Primary cutaneous follicle centre lym-phoma (PCFCL) is defined as a tumour of
neoplastic follicle centre cells (FCC),
usually a mixture of small and large
cleaved cells (centrocytes) and, to a
lesser extent, large noncleaved cells
(centroblasts) with prominent nucleoli.
The growth pattern varies from follicular
to follicular and diffuse to diffuse.
ICD-O Code 9690/3
Synonyms
Kiel: centroblastic-centrocytic (follicular,
follicular and diffuse), centroblastic.
Working formulation: follicular, follicular
and diffuse (predominantly small clea-ved, mixed small cleaved and large cell,
predominantly large cell).
WHO: follicular lymphoma, diffuse follicle
centre lymphoma, diffuse large B-cell
lymphoma.
EORTC (1997): follicular centre cell lym-phoma.
Reticulohistiocytoma of the dorsum
(Crosti disease): {220}.
Epidemiology
Primary cutaneous B cell lymphoma
(CBCL) in Europe account for up to 25%
of cutaneous lymphomas, manifesting
predominantly in middle aged adults,
with no gender predominance {2523},
and having an incidence rate of 0.1-0.2
per 100,000 persons per year {1831}.
Among primary CBCL, marginal zone B
cell lymphoma and FCL are by far the
most common subtypes {744,1281,
2576}.
Etiology
The etiology of primary cutaneous FCL is
unknown.
Localization
Most patients have local or regional dis-ease. Trunk and head and neck regions
are by far the most frequent localizations
{429,744,2061,2523}. Presentation with
multifocal skin lesions is observed in a
small minority of patients.
Clinical features
The clinical presentation consists of firm
erythematous to violaceous plaques,
nodules or tumours of variable size.
Larger nodules may be surrounded by
small papules and slightly infiltrated,
sometimes figurate plaques. The skin
surface is smooth. Lesions may be pres-ent for months to many years {220,
2061,2523}.
Histopathology
The infiltrates show a spectrum of growth
patterns, with a morphologic continuum
from follicular to follicular and diffuse to
diffuse. The lesions are by definition
composed of a mixture of centrocytes
(which may be small and/or large) and
centroblasts in varying proportion. Small
centrocytes and a predominantly follicu-lar growth pattern are more frequently
found in small, early lesions. A predomi-nance of large neoplastic cells, particu-larly large centrocytes or multilobated
cells and less frequently centroblasts
(not in confluent sheets), are generally
found in more advanced lesions (large
nodules or tumours) {2523}. When mor-phologically identifiable, follicles are
often ill-defined and show a monotonous
population of FCC, lack starry sky histio-cytes, and generally have an attenuated
or absent mantle zone, different from
cutaneous follicular hyperplasias {425,
429,603,864,1397}. The infiltrates are
found primarily in the dermis, with exten-sion into subcutaneous tissue seen in
larger nodules. The overlying epidermis
is generally unaffected.
Immunoprofile
The cells express B-cell markers includ-ing CD19, CD20, and CD22, and may
show (more often in cryostat sections)
Cutaneous follicle centre lymphoma N. Pimpinelli
E. Berti
G. Burg
L. Duncan
N. L. Harris
E.S. Jaffe
H. Kerl
M. Kurrer
W. Kempf
C.J.L.M. Meijer
M. Santucci
S.H. Swerdlow
R. Willemze
Fig. 4.50 Cutaneous follicle centre lymphoma. Firm
nodules on the trunk.
Fig. 4.51 Primary cutaneous follicle centre lymphoma. Neoplastic bcl6+ cells surround and infiltrate a reac-tive follicle with bcl6+ germinal center.
197Cutaneous follicle centre lymphoma
monotypic staining for surface immu-noglobulins (sIg). However, absence of
detectable sIg staining is common in
tumours showing a diffuse population of
large FCC. In PCFCL, neoplastic cells
consistently express Bcl-6 protein, while
CD10 is variably expressed (often posi-tive in follicular cases and more fequent-ly negative in lesions with diffuse pattern
of growth) {425,429,823,1042,1832,
2061}. Bcl-2 protein is usually not
expressed but may be faintly positive,
less than reactive T-cells {38, 209, 425,
603, 774, 1042,1 622}.  The follicles are
associated with follicular dendritic cells,
positive for CD21, CD23, and CD35.
Residual, scattered FDC may be some-times found in diffuse large cell infiltrates.
Neopastic cells are constantly CD5- and
CD43-negative. Admixed T-cells may be
abundant and sometimes predominant,
particularly in small, early lesions.
Histogenesis
Mature germinal centre derived B-lym-phocyte {2273,2523}.
Somatic genetics
Clonally rearranged immunoglobulin
genes are present. Bcl-2 gene
rearrangement and t(14;18) chromoso-mal translocation are absent in most
cases {209,430,467,1622,1820,2523}.
Inactivation of p15 and p16 tumour sup-pressor genes by promotor hypermethy-lation has been reported in about 10%
and 30% of PCFCL, respectively {468}.
Chromosomal imbalances have been
identified by comparative genomic
hybridization (CGH) analysis in a minori-ty of PCFCL, but a consistent pattern has
not been emerged {942,1503}.
Prognosis and predictive factors
Primary cutaneous FCL have an excel-lent prognosis (>95% 5-year survival).
Local recurrences, most often near the
initial site of cutaneous presentation, may
develop but will not influence clinical out-come. Cytologic grade or growth pattern
(follicular or diffuse) do not appear to
have an impact on prognosis in patients
with primary cutaneous disease. Locally
directed forms of therapy, most common-ly radiation or surgical excision (small,
isolated lesions), are generally effec-tive {194, 429, 1283, 1824, 1825, 1938,
2060, 2061, 2202, 2523}.
Secondary cutaneous follicular
lymphoma (FL)
Patients more often present with multiple
lesions in non-contiguous skin sites
{429,2060}. Unlike PCFCL, neoplastic
cells strongly express CD10 and Bcl2,
and show t(14:18) translocation in most
cases. These secondary cutaneous
forms are managed like a systemic lym-phoma. Whether cutaneous involvement
by FCL has an impact on prognosis is
presently unknown.
Fig. 4.52 Cutaneous follicle centre lymphoma, follicular growth pattern.   A Small and large follicle centre
cells.  B Detail of large follicle centre cells
B
A
198 Haematolymphoid tumours
Definition
Primary cutaneous diffuse large B-cell
lymphomas (DLBCLs) are neoplastic
proliferations showing a completely dif-fuse growth pattern consisting of large
transformed B-cells without significant
admixture of centrocytes.
The most common variant, DLBCL, leg-type, usually occurs on the leg and less
frequently at other sites. Other variants
are referred to as DLBCL, other and com-prise T-cell/histiocyte-rich LBCL, plas-mablastic lymphoma and lesions that do
not fulfill the criteria for a DLBCL, leg type.
ICD-O code 9680/3
Diffuse large B-cell lymphoma
(DLBCL), leg-type
Epidemiology
Approximately 5-10% of cutaneous B-cell lymphomas are classified as DLBCL,
leg type. The median age is around 70
years, and the tumours are more com-mon in females than males {2432}.
DLBCL of the skin is rare in children
{1005}.
Clinical features
DLBCL, leg type occurs primarily in eld-erly females who present with rapidly
developing multiple tumours, most com-monly on the leg but sometimes at other
localizations. Therefore analogous to the
“nasal-type” designation for a distinct
extranodal variant of NK/T-cell lym-phomas, the term “DLBCL, leg-type” is
chosen for all cutaneous diffuse large B-cell lymphomas with the designated
cytological and immunophenotypic fea-tures. Clinically multiple disseminated or
aggregated dome shaped red tumours
with a firm consistency and a shiny sur-face without scaling are seen. Ulceration
may occur in advanced stages.
Histopathology
The tumour cells diffusely infiltrate the
dermis with a destructive growth pattern,
often obliterating adnexal structures. The
infiltrate may extend into subcutaneous
tissue. The epidermis is often spared,
with a Grenz zone. The infiltrate is com-posed of medium to large sized B cells,
which are usually monomorphic in
appearance. Cells may resemble immu-noblasts, and less commonly centrob-lasts. There is usually a minimal inflam-matory component and little stromal
reaction.
Immunohistochemistry
The tumour cells are positive for CD20
and CD79a, negative for CD10 and
CD138, have variable BCL-6 expression
and are usually strongly positive for BCL-2 protein and MUM-1/IRF-4 {1797}.
These features have been shown in
nodal DLBCL to correlate with an activat-ed B-cell gene expression profile, which
is usually predictive of a more aggressive
clinical course {1041, 1977}.
Histogenesis
Transformed peripheral B cell of proba-ble post germinal centre origin {816}.
Somatic genetics
The immunoglobulin genes are clonally
rearranged. The BCL-2/JH translocation
is absent {814,905,2472}. Recent studies
using gene expression profiling have
identified increased expression of genes
associated with cellular proliferation. The
gene expression profile of the leg-type of
tumour resembles that of activated B-cell
type of nodal or systemic DLBCL {1041}
Significant differences have not been
identified among tumours of the leg-type
arising in different sites {814,1797}.
The primary cutaneous large B-cell lym-phoma of the leg-type can be seen in a
variety of anatomic locations and is not
restricted to the leg {1797}.
Prognosis and Predictive factors
In multivariate analysis, BCL-2 expres-sion, multiple skin lesions, and age
remained independent prognostic fac-tors. The 5-year disease-specific survival
rates in BCL-2–positive and BCL-2–neg-ative patients were 41% and 89%,
respectively (P < .0001). 11,12 13 Thus,
these studies support the identification of
DLBCL leg type, as a clinically and bio-logically distinctive group.
Diffuse large B-cell
lymphoma, other
Cutaneous diffuse large B-cell
lymphoma
G. Burg
E.S. Jaffe
R. Willemze
C. Dommann-Scherrer
S.H. Swerdlow
W. Kempf
M Kurrer
H Kutzner
J. Wechsler
N.L. Harris
B CA
Fig. 4.53 Diffuse large B-cell lymphoma.  A Dome-shaped nodules and tumours without ulceration on the trunk and in the face.  B Soft tumour surrounded by an ery-thematous infiltrate on the back.  C Aggregation of non-ulcerated nodules and tumours confined to a limited area of the lower leg.
199Primary cutaneous diffuse large B-cell lymphoma (DLBCL)
Definition
The term DLBCL, other, refers to diffuse
lymphomas composed of large trans-formed B-cells that lack the typical fea-tures of DLBCL, leg-type, and do not
conform to the definition of primary cuta-neous follicle centre lymphoma. These
tumours may be comprised of a mono-morphic population of centroblast-like
cells, but with a mixed inflammatory
background.
BCL-2 protein may be negative, whereas
BCL-6 will usually be expressed. The
presence of multiple lesions is a poor
prognostic indicator; such cases must
be distinguished from secondary
involvement by DLBCL.
There are some primary cutaneous folli-cle centre lymphomas in which the
majority of tumour cells are centroblasts.
Previously these lesions have been cate-gorized as DLBCL by most observers
{864,877,879,1263}. These lymphomas
invariably contain a population of centro-cytes as well as some reactive cells. A
focal follicular growth pattern may be
seen. Despite the predominance of cen-troblasts, clinical studies have suggest-ed that these lymphomas have an benign
clinical course, and may usually be treat-ed in a conservative manner. Based on
the clinical behaviour and the spectrum
of cytological composition, these
tumours are classified under the single
heading of cutaneous follicle centre lym-phoma.
T-cell / histiocyte-rich large
B-cell lymphoma
T-cell / histiocyte-rich large B-cell lym-phoma is an unusual morphological vari-ant of “diffuse” LBCL {1886} that rarely
occurs primarily in the skin {645,1423}. It
is characterized by a small number of
large neoplastic B-cells (<10%), scat-tered within an abundant background of
small reactive T-lymphocytes with or with-out histiocytes. Some T-cell/histiocyte-rich large B-cell lymphomas may repre-sent progression from a more indolent B-cell lymphoma {645,2042}.
Plasmablastic lymphoma
Plasmablastic lymphomas rarely may
present as a primary cutaneous lym-phoma. The tumour cells can be positive
for Epstein Barr virus (EBV), and have a
phenotype that reflects terminal stages
of B-cell differentiation (CD20-, MUM-1+,
CD138+, EMA+). Plasmablastic lym-phomas are usually a heterogenous
group of disease entities {524} and can
be encountered in settings of immunode-ficiency, HIV-associated, or iatrogenic
{617,985}.
Secondary skin involvement
by diffuse large B-cell
lymphoma
Secondary skin involvement most com-monly shows localisation of the disease
on the trunk and the extremities {1263}.
The prognosis is worse than in primary
DLBCL, which can be controlled by local
treatment modalities, particularly if one is
dealing with a single lesion.
Fig. 4.54 Diffuse large B-cell lymphoma (DLBCL) leg type. Lymphoid cells in the dermis; no infiltration of the
epidermis. Left insert: lymphoid cells with strong immunoreactivity for BCL-2. Right insert: large, densely
packed lymphoid cells.
Fig. 4.57 Plasmablastic lymphoma. Tumour displays
a spectrum of immunoblasts, plasmablasts, and
plasma cells between collagen bundles.
Fig. 4.55 Diffuse large B-cell lymphoma (DLBCL),
leg type. BCL-2 staining of atypical lymphoid cells.
Fig. 4.56 T-cell/histiocyte-rich large B-cell lym-phoma. CD20 staining highlights the few neoplastic
B-cells intermingled in a dense infiltrate of reactive
T-cells.
200 Haematolymphoid tumours
Definition
Intravascular large B-cell lymphoma (IL)
is a rare disease with multiorgan involve-ment, which also affects the skin. This
extranodal subtype of diffuse large B-cell
lymphoma (DLBCL) is characterized by
the presence of large lymphoid cells
within the lumina of small to medium-sized blood vessels, particularly capillar-ies and postcapillary venules. Skin is a
common site of presentation, but most
patients have systemic disease at time of
diagnosis {696,2523}.
ICD-O code 9680/3
Synonyms
Intravascular lymphomatosis; intravascu-lar lymphoma; angioendotheliomatosis
proliferans systematisata; malignant
angioendotheliomatosis; angiotropic
large cell lymphoma (Lukes-Collins), dif-fuse large B-cell lymphoma (REAL)
intravascular large B-cell lymphoma
(WHO).
Epidemiology
IL is rare and can occur at any age, but
most patients are in their 6th – 9th
decade of life. Male to female ratio is 0.8
(range 0.7 – 5.0) {2566}.
Localization
Dermatological manifestations are pres-ent in up to one third of patients. Sites of
predilection are the lower extremities, but
lesions may involve all parts of the
integument. A wide range of organ
involvement has been described: central
nervous system, skin, adrenal glands,
thyroid, gastrointestinal system, kidneys,
lungs, genitourinary tract, and eye {275}.
At autopsy, involvement of the majority of
organs is seen despite the absence of
prior clinical manifestations or mass
lesions {1257}.
Clinical features
The clinical manifestations are predomi-nantly neurologic (85%) {214} and der-matologic {633} and are attributed to
vascular occlusion. There is a notable
absence of lymphadenopathy, spleno-megaly or circulating lymphoma cells in
the majority of cases {631,684, 837,
1257,2387}.
There is a plethora of different skin
lesions including tender, indurated nod-ules, livedo-like reticulate erythema, lin-ear erythematous streaks, and painful
indurated telangiectasias. Lesions may
imitate phlebitis, panniculitis, or vasculi-tis {1809}.
Histopathology
The angiotropic lymphoid infiltrate often
spares the dermis, requiring deep biop-sies including parts of the subcutaneous
fat. The large neoplastic lymphoid cells
are usually confined to the lumina of cap-illaries and postcapillary venules {1809,
2513}, albeit extravascular involvement
may occur {1257}. Tumour cells are large
with vesicular nuclei, prominent nucleoli,
and frequent mitoses. Fibrin thrombi in
the upper and deep dermal plexus, with
partial occlusion of the vascular lumina,
and few entrapped hyperchromatic lym-phocytes are typical of IL presenting with
reticulate and livedoid erythema.
Immunoprofile
Tumour cells usually express B-cell asso-ciated antigens and may coexpress
CD10 or CD5. {406,697,953,1193,1253,
2566}. Although most IL present with
overexpression of theBCL-2 protein
{1257} they lack BCL-2 gene rearrange-ment {1193,2566}. These cases have to
be distinguished from other intravascular
lymphomas of different lineages {112,
113,633,697,736,1355,2138,2143}.
The precise mechanisms of lymphoid-endothelial interaction leading to vascu-lar occlusion and thrombotic events are
Intravascular large B-cell lymphoma H. Kutzner
E.S. Jaffe
Fig. 4.58 Intravascular large B-cell lymphoma.  A Involvement of the cutis with livedoid palpable erythema.  B Dilated dermal vessels filled with densely packed neo-plastic lymphoid cells.
BA
201Intravascular large B-cell lymphoma
not clear. The intravascular trapping of
lymphoid tumour cells might be the result
of a defect in homing receptors and
adhesion molecules on the neoplastic
cells and the endothelial cells {737,
1852}.
Histogenesis
The postulated cell of origin is a post fol-licle centre transformed peripheral B-cell.
B CA
Fig. 4.59  Intravascular large B-cell lymphoma.   A Tortuous dermal venules with fibrin thrombi and entrapped neoplastic lymphoid cells.   B Dilated postcapillary
venules with intraluminal pleomorphic lymphoid cells.  C Neoplastic lymphoid cells within lumina of subcutaneous postcapillary venules. Extravascular lymphocytes
are distinctly smaller, lacking pleomorphism and mitoses.
202 Haematolymphoid tumours
Definition
Lymphomatoid granulomatosis (LYG) is
an angiocentric and angiodestructive
lymphoproliferative disease involving
extranodal sites, composed of Epstein
Barr virus (EBV)-positive B-cells,
admixed with numerically predominant T-cells. The skin is the most common
extrapulmonary site of involvement.
ICD-0 code 9766/1
Synonyms
Angiocentric immunoproliferative lesion
{1432}, angiocentric lymphoma.
Epidemiology
LYG is rare, usually presenting in adult
life. It affects males more often than
females (at least 2:1) {1223}.
Etiology
Patients with underlying congenital or
acquired immunodeficiency are at
increased risk for LYG {921,949}.
Predisposing conditions include allo-geneic organ transplantation, Wiskott-Aldrich syndrome, human immunodefi-ciency virus infection, and X-linked lym-phoproliferative syndrome.
In patients without evidence of underly-ing immunodeficiency, reduced immune
function can usually be demonstrated
upon careful clinical or laboratory analy-sis {2534}.
Localization
Skin is the most common site of involve-ment outside the lung (25-50%), but
cutaneous involvement is rarely seen
without pulmonary disease. Extremities
and trunk are the most frequent localiza-tions {185,393,1047,1124,1223,1560}.
Clinical features
Patients usually present with signs and
symptoms related to the respiratory tract
{1124,1223,1426}. Skin lesions consist of
multiple erythematous dermal papules
and/or subcutaneous nodules {185}.
Necrosis and ulceration are generally
associated with larger nodules. Indu-rated plaques, lichen sclerosus et
atrophicus-like lesions, and alopecia are
less commonly seen {185,1129}. Cuta-neous lesions rarely precede pulmonary
disease, and are seen either at diagnosis
(30%) or later in the course {185}. Other
sites of involvement include brain (26%),
kidney (32%), liver (29%) {1124}. Lymph
nodes and spleen are spared.
Histopathology
LYG is characterized by an angiocentric
and angiodestructive lymphohistiocytic
infiltrate. Most cutaneous lesions show
infiltration of subcutaneous fat, with or
without dermal involvement. Lympho-cytic vasculitis is frequent, and fibrinoid
necrosis may be present {2339}. Well-formed granulomas are usually absent,
but a granulomatous reaction may be
seen secondary to fat necrosis.
Immunohistochemistry
While EBV-positive B-cells are readily
found in the lung, they are generally rare
in skin, with the predominant cell being a
CD3+, CD4+ lymphocyte {185}.
Histogenesis
Mature B lymphocyte, transformed by
EBV.
Somatic genetics
The ability to detect clonal immunoglob-Lymphomatoid granulomatosis E.S. Jaffe
J. Toro
W.H. Wilson
BA
Fig. 4.60 Lymphomatoid granulomatosis.  A The most common manifestations of LYG in the skin are papules
which may grow into nodules.  B Larger nodules may ulcerate superficially. From M.W. Beaty et al. {185}.
Fig. 4.61 Cutaneous lymphomatoid granulomatosis.
Atypical EBV-positive large B-cells represent a
minority of infiltrating cells.
Fig. 4.62 Lymphomatoid granulomatosis. Histolo-gical features include perivascular dermal infil-trate.
203Lymphomatoid granulomatosis
ulin heavy chain gene rearrangement is
related to grade, with clonal B-cell popu-lations usually found only in grade 2-3
lesions. Southern blot , polymerase chain
reaction (PCR), and in situ hybridization
techniques can be used to detect EBV
sequences {921,1224,1560}.
Prognosis and predictive factors
The natural history of LYG is variable
{714,1223}. In some patients it may fol-low a waxing and waning clinical course,
with spontaneous remissions without
therapy. However, in most patients the
disease is more aggressive, with a medi-an survival of less than two years.
Histological grade and clinical aggres-siveness relate to the proportion of EBV+
B-cells, but even grade 3 lesions may
show spontaneous regression {2534}.
The most common cause of death is pro-gressive pulmonary involvement. Skin
lesions may appear, without evidence of
relapse at other sites {185,2534}.
204 Haematolymphoid tumours
Mantle cell lymphoma
Definition
Mantle cell lymphoma is a B-cell lym-phoma that almost always overexpresses
cyclin D1 and is composed either of
small lymphocytes bearing some resem-blance to centrocytes or, in the blastoid
variant, by cells resembling lym-phoblasts or large B-cells. Neither clas-sic centroblasts nor paraimmunoblasts
are present.
ICD-O code 9673/3
Epidemiology
MCL occurs in middle aged to older indi-viduals with a male predominance and
accounts for up to 10% of all non-Hodgkin lymphomas {2301}.
Clinical features
Most patients present with adenopathy
and stage III/IV disease. Hepato-splenomegaly and bone marrow involve-ment are common and peripheral blood
involvement is seen in about 25% of
patients. Gastrointestinal disease is also
common but often subtle {2254}.
Cutaneous MCL
Skin involvement is rare (2-6% of cases)
{2030} but when it occurs, is usually, but
not always, seen at initial presentation
and associated with extracutaneous dis-ease {654,2132}. Rare cases that appear
to be primary are described. Lesions are
most common on the thorax and extrem-ities and usually occur as multiple ery-thematous macules, papules, plaques or
nodules {654,2132}.
Histopathology
MCL are usually composed of relatively
small lymphocytes with slightly irregular
to very clefted nuclei and somewhat dis-persed chromatin. In the blastoid variant,
which may be relatively more common in
cutaneous lesions, the cells either have
very dispersed chromatin with inconspic-uous nucleoli resembling lymphoblasts,
or are larger and more pleomorphic,
sometimes with very prominent nucleoli,
resembling cells of a diffuse large B-cell
lymphoma.
MCL infiltrates in the skin occur in the
dermis sometimes with extension to the
subcutaneous tissue. A grenz-zone
should be present. The infiltrate may be
relatively scanty and perivascular/peri-appendageal, form nodules or be very
dense and diffuse. A mantle zone growth
pattern with MCL growing around reac-tive germinal centres may occur
{219,654}. Admixed inflammatory cells
may be present {654}.
Immunohistochemistry
MCL are distinguished in most cases
from other non-Hodgkin lymphomas by
their frequent but not invariable CD5+,
CD10-, CD23-, cyclin D1+,BCL-6-,
CD20+ light chain class restricted phe-notype {376,2301,2303}. Cyclin D1 stain-ing can be problematic and CD5 not
always positive. With one interesting
exception, the cases are negative for the
cutaneous lymphocyte-associated anti-gen {2132}.
Histogenesis
Mature B-cell, probably of the inner man-tle zone, usually but not always with
unmutated immunoglobulin heavy chain
genes.
Somatic genetics
Immunoglobulin genes show clonal
rearrangement in all cases and in many,
but not all, cases they lack somatic
hypermutation {1756,2451}. The vast
majority of MCL have a t(11;14)(q13;q32)
translocation involving the CCND1
(cyclin D1) and immunoglobulin heavy
chain genes with subsequent CCND1/
cyclin D1 overexpression {376, 2303}.
The most sensitive technique to docu-ment the translocation in diagnostic
specimens is cytogenetic fluorescence
in situ hybridization (FISH) analysis
Cutaneous involvement in primary
extracutaneous B-cell lymphoma
S. H. Swerdlow
M. Kurrer
M. Bernengo
S. Büchner
Fig. 4.63 Mantle cell lymphoma.  A Nodular perivascular and periappendageal infiltrates in all layers of the dermis. A subepidermal grenz-zone is present.  B Tumour
cells show nuclear immunoreactivity for cyclin D1.
BA
205Cutaneous involvement in primary extracutaneous B-cell lymphoma
{654,1422}. Gene profiling has suggest-ed the presence of a small subset of
cases that lack cyclin D1 abnormalities
{1978}. Other primary and mostly sec-ondary abnormalities are also described
{376,1045,2303}.
Prognosis and predictive factors
MCL has a median survival of 3-5 years
with those having “non-nodal” disease
doing better {376,1756,2301,2303}.
Adverse prognostic indicators include a
high proliferative fraction, probably blas-toid morphology, secondary genotypic
abnormalities and blood involvement (at
least in patients with nodal disease).
Whether skin involvement in particular is
an independent prognostic indicator is
uncertain.
Burkitt lymphoma
Definition
Burkitt lymphoma is a mature B-cell neo-plasm composed of relatively uniform
medium sized transformed B-cells with a
C-MYC translocation {630}.
ICD-O code 9687/3
Epidemiology
BL occurs in children in equatorial Africa
(endemic), primarily in children and
young adults elsewhere (sporadic) and
in immunodeficient patients. There is a
male predominance.
Etiology
Endemic BL and a minority of sporadic
BL are Epstein-Barr virus positive.
Clinical features
BL usually presents as an extranodal
mass often in the abdomen or, in endem-ic cases, in jaw or other facial bones.
Other patients have a leukaemic presen-tation. Cutaneous involvement in BL
appears to be extremely rare and at least
usually is associated with disease at
other sites {123,141,349,700}. It has
rarely been described as occurring with
ulceration from direct invasion from
underlying bony lesions {349}, as distinct
cutaneous lesions at relapse {123} and in
12% of autopsied cases of American BL
(2 cases) {141}.
Histopathology
Histologic sections show a diffuse prolif-eration of medium sized transformed
lymphocytes with relatively round nuclei
with several nucleoli and a narrow rim of
very amphophilic/basophilic cytoplasm.
There are many apoptotic bodies and tin-gible body macrophages creating a star-ry  sky appearance. Skin involvement
demonstrates a diffuse but sometimes
patchy dermal and subcutaneous infil-trate with a Grenz zone {123,700}.
Immunohistochemistry
Immunophenotypic studies demonstrate
CD5-, CD10+,BCL-2-, CD20+ mature B-cells with surface immunoglobulin
expression.
Histogenesis
Germinal centre/post germinal centre B-cell
Somatic genetics
All cases have clonal immunoglobulin
gene rearrangements and a C-MYC
translocation, most often with a
t(8;14)(q24;q32) {1483}. Many, if not all,
cases also have C-MYC mutations {230,
1483}.
Prognosis and predictive factors
BL is an aggressive but curable neo-plasm with a 5 year overall survival of
44% {3}.
Chronic lymphocytic
leukaemia / small lymphocytic
lymphoma
Definition
Chronic lymphocytic leukaemia/small
lymphocytic lymphoma (CLL/SLL) is a
mature B-cell neoplasm composed of
small, usually CD5+, CD23+, cyclin D1-B-cells with relatively round nuclei having
clumped chromatin {1662}. Especially in
lymph nodes, there is often an associat-ed minor population of prolymphocytes
and paraimmunoblasts that form prolifer-ation centres.
ICD-O code
Chronic lymphocytic leukaemia
9823/3
Small lymphocytic lymphoma
9670/3
Epidemiology
CLL is the most common type of
leukaemia in the West and SLL are
reported to account for 6.7% of non-Hodgkin lymphomas {3,1064}.
Fig. 4.64 Mantle cell lymphoma.   A Perivascular infiltrate of small atypical lymphoid cells.   B Densly packed small atypical lymphoid cells showing polygonal or
indented nuclei and homogeneous chromatin staining.
BA
206 Haematolymphoid tumours
Clinical features
CLL/SLL is seen most commonly in mid-dle aged and older adults with a male
predominance. It usually presents with
blood and marrow involvement, frequent
adenopathy and sometimes hepato-splenomegaly. Skin involvement is
reported in 2% of patients without a
marked predilection for any region of the
body and occurs in patients who also
have blood involvement {273,1167}. The
face and scalp are frequent sites of
involvement. It may be present either at
the time of diagnosis or, much more fre-quently, develops subsequently {431}.
Lesions may be single or multiple erythe-matous macules, papules, violaceous
plaques, nodules or tumours either
occurring in a limited or less frequently
more generalized area {431,1167}.
Atypical presentations include chronic
paronychia, papulovesicular eruption
and finger clubbing. Skin involvement
may occur at sites of previous viral (eg,
herpes zoster, herpes simplex) or
Borrelia burgdorferi infection {427} and
at sites of epithelial neoplasms {2215}.
Spontaneous regression of CLL infiltrates
at least at sites of prior herpetic infection
may occur {2449}. In contrast to the
absence of virus in at least most of the
lesions in viral scars, B. burgdorferi DNA
is found in at least some cutaneous CLL
lesions {427}.
Histopathology
Histologic sections demonstrate a diffuse
proliferation of small relatively round lym-phocytes with condensed chromatin with
lymph node biopsies typically demon-strating paler (pseudofollicular) prolifera-tion centres where the cells have more
abundant pale cytoplasm, more dis-persed chromatin and sometimes promi-nent central nucleoli. The latter cells rep-resent paraimmunoblasts and some of
the former cells prolymphocytes.
Cutaneous lesions show a patchy
perivascular, nodular, more diffuse or
rarely band-like dermal infiltrate of small,
usually but not always round, lympho-cytes with occasional single lympho-cytes in the epidermis and frequent
extension into the subcutaneous tissue
{431}. Patients with more than one biop-sy can demonstrate more than one
growth pattern. There may be overlying
epidermal changes infrequently includ-ing ulceration. Proliferation centres are
seen only in a minority of cases although
there may be scattered larger cells in
other cases {427}. A minority of cases
have admixed eosinophils, neutrophils,
and/or histiocytes. A granulomatous
reaction may be present especially in
some of the lesions arising in scars fol-lowing prior viral infection {432}.
Cutaneous CLL associated with granulo-ma annulare-like changes has also been
reported {797}.
Immunoprofile
Immunophenotypic studies demonstrate
a characteristic CD5+, CD43+, CD10-,
CD23+, FMC7-, cyclin D1-, weakly
CD20+ monoclonal B-cell population
with weak surface immunoglobulin
expression {1662}. In the cutaneous
lesions, the admixed T-cells present are
mostly of CD4+ type {431}.
Histogenesis
Mature B-cell most likely of memory type
(including cases with either mutated or
unmutated immunoglobulin heavy chain
genes) {586,1288,1976}.
Somatic genetics
All cases have clonal immunoglobulin
gene rearrangement although oligoclon-al bands suggesting admixed reactive B-cells may also be present in the cuta-neous lesions {431}. In some cases the
immunoglobulin genes show somatic
hypermutation and in others they do not
{586,943,1288,1976}. There are no chro-mosomal abnormalities specific for
CLL/SLL; however, the most commonly
described abnormalities include 13q and
11q deletions, trisomy 12 and 17q dele-tion {643}.
Genetic susceptibility
There is an inherited susceptibility to
CLL; however, the critical genes remain
to be determined {1064}.
Prognosis and predictive factors
CLL/SLL is one of the indolent lymphoid
neoplasms. Clinically advanced stage,
17q deletions, unmutated immunoglobu-lin genes, CD38 and ZAP-70 expression
include some of the more important
adverse prognostic indicators {553,643,
943,1662,1760,2518}. Most do not be-lieve that skin involvement portends an
adverse outcome; however, it has been
reported that cases with >5% medium
and large-sized B-cells, admixed reac-tive cells and epidermal changes did
worse than those without these features
and there are reports in the literature sug-gesting a poor outcome following any
cutaneous involvement {427,432,1167}.
Transformation to a large cell lymphoma
(Richter syndrome), Hodgkin lymphoma
or prolymphocytic leukaemia is also
associated with an aggressive course
{826}. Richter syndrome can present as
cutaneous lesions {427,2578}.
207Hodgkin lymphoma
Definition
Hodgkin lymphoma (HL) is a neoplasm
characterized by large tumour cells of B-cell lineage in a characteristic inflamma-tory background. It encompasses two
entities distinguishable by their morphol-ogy and phenotype, namely nodular lym-phocyte predominant Hodgkin lym-phoma (NLPHL) and classical Hodgkin
lymphoma (cHL). Cutaneous involve-ment by NLPHL has not been reported,
and is rare in cHL. For details see the
WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues
{1121}.
ICD-O code
Nodular lymphocyte predominant
Hodgkin lymphoma  9659/3
Classical Hodgkin lymphoma
9650/3
Synonym
Hodgkin disease
Epidemiology
Cutaneous involvement by cHL is rare
and is seen in <5 % of cases, and <1% of
cases at presentation {1076,1457,
2326,2505}. The incidence appears
slightly increased in patients infected with
the human immunodeficiency virus (HIV)
{2094,2157}. cHL has also been reported
to occur with increased frequency in
patients with mycosis fungoides and
cutaneous CD30+ T-cell lymphoprolifera-tive disease (CD30+ LPD), but is usually
nodal in localization without cutaneous
spread {1123,1176,1324, 2190}.
Etiology
The etiology of cHL is not established.
However, an association with the Epstein
Barr virus has been suggested, especial-ly in cutaneous cases {1340}.
Localization and Clinical features
Three mechanisms of cutaneous involve-ment have been implicated: 1) retro-grade lymphatic spread from regional
lymph nodes; 2) direct extension, usually
from a mass lesion; and 3) haematoge-nous dissemination {2326,2505}. The
distribution of cHL lesions relates to the
manner of spread. Direct extension is
most common in patients with massive
mediastinal disease, with involvement of
the skin of the chest wall. The lesions are
manifested as erythematous papules or
nodules. Rare cases of HL presenting as
primary disease in the skin have been
reported 12 {2195}.
Histopathology, immunoprofile and
genotype
The histological features resemble those
of cHL in other sites. Classical Reed-Sternberg (RS) cells and variants are
seen in an inflammatory background.
The immunophenotype also is character-istic of cHL, with the neoplastic cells
expressing CD30 and CD15 {426,1340}.
However, while most cases of cHL are of
B-cell lineage {1340}, cases of cHL with
cutaneous involvement may express a T-cell phenotype {595,1176,2527}. Such
cases are usually associated with con-comitant CD30+ LPD. Common clonal T-cell gene rearrangement has been iden-tified in the atypical cells of CD30+ LPD
and cHL involving lymph nodes.
Because RS-like cells may be seen in
CD30+ LPD, the differential diagnosis
between these disorders is often difficult.
Prognostic factors
In patients with cutaneous involvement
secondary to haematogenous spread,
the prognosis is poor. However, other
patterns of cutaneous involvement are
not necessarely associated with a poor
prognosis {415,1023,1457,1651,1987,
2326,2505}.
Hodgkin lymphoma E. S. Jaffe
M. Kadin
H. Kerl
Fig. 4.65 Hodgkin lymphoma.  A Secondary involvement of the skin often occurs by direct extension, as in this large cutaneous nodule with ulceration.  B cHL, skin.
Classical Reed Sternberg cells are present in a background of reactive lymphocytes.
BA
208 Haematolymphoid tumours
Definition
Blastic NK-cell lymphoma is a clinically
aggressive lymphoma, with a high inci-dence of cutaneous involvement and risk
of leukaemic dissemination. The blastic
appearance and CD56 expression initial-ly suggested an NK-precursor origin
{632}. More recent studies suggest deri-vation from a dendritic cell precursor, as
reflected in the designation CD4+,
CD56+ haematodermic neoplasm.
ICD-O code 9727/3
Synonyms
CD4+, CD56+ agranular haematodermic
neoplasm, blastoid NK-cell lymphoma,
monomorphic NK-cell lymphoma
Epidemiology
Blastic NK-cell lymphoma is a rare lym-phoma. Currently, there are no reports
showing any racial or ethnic predilection.
Most patients are middle-aged or elderly
{632,739,1817}. However, every age can
be affected.
Localization
Blastic NK-cell lymphoma has a
predilection for skin. At presentation
there may be a single tumour, nodule or
plaque {632,1817}. Lymph node, soft tis-sue, peripheral blood or bone marrow
can be simultaneously involved. Central
nervous system involvement can devel-op during the course of the disease.
Clinical features
Blastic NK-cell lymphoma frequently
involves the skin at presentation with a
single tumour, or tumours and plaques.
Additionally, lymph nodes, soft tissue,
peripheral blood or bone marrow can be
simultaneously involved. Most cases of
blastic NK-cell lymphoma presenting in
the skin progress quickly to develop
lymph node, bone marrow, and central
nervous system involvement {450,739}.
The clinical course is aggressive. There
may be initial responses to multiagent
chemotherapy, but a high risk of relapse.
Regimens for both aggressive lym-phomas and acute myeloid or lymphoid
leukaemias have been utilized.
Histopathology
The dermis contains a dense, monoto-nous infiltrate of medium-sized cells with
finely clumped chromatin, and absent or
indistinct nucleoli resembling lym-phoblasts or myeloblasts {632,1121,
1817}. The cells have sparse cytoplasm.
Mitotic figures are frequent. The overly-ing epidermis is spared, with a distinct
grenz zone. Inflammatory cells are
absent. There is generally no necrosis or
angioinvasion.
Immunoprofile
The tumour cells usually express CD4,
CD56, and CD43. Expression of CD7,
CD2 is variable, whereas surface and
cytoplasmic CD3 are negative {632,
1817,2391}. Cytotoxic molecules are
generally absent. In some cases TdT
and/or CD34 can be positive {313,1681,
2159}. CD68 can be weakly positive,
showing focal staining in the Golgi
region. Since lymphoblastic and
myeloblastic neoplasms can also be
positive for CD56, stains for myeloperox-idase, and CD3 should always be per-formed in order to exclude these entities
{2118,2299}. The cells express CD123
and TCL1, both of which support a rela-tionship to dendritic cells {450,1012}.
Blastic malignancies of precursor NK-Fig. 4.66 Hodgkin lymphoma.  A Subcutaneous nodule from primary cutaneous cHL. This patient presented with multiple nodules on the right and left arms. Two
years later, she developed a mixed cellularity cHL subtype involving lymph nodes and bone marrow.  B Reed-Sternberg cells in a background of reactive lympho-cytes.  C Reed-Sternberg cells were strongly CD30-positive, and were positive for CD15 and EBV by in situ hybridization (not shown).
BA C
Blastic NK-cell lymphoma C.A. Sander
E.S. Jaffe
M.J. Flaig
R. Dummer
D.V. Kazakov
W. Kempf
G. Burg
Blastic NK-cell lymphoma
cell origin also exist, and may be difficult
to distinguish in the absence of special-ized techniques {1012,1681,2302}. There
has been one report showing expression
of KIR receptors {1293}.
Histogenesis
Based on the expression of CD56, an
NK-cell derivation was initially proposed.
However, the tumour was considered to
be of uncertain lineage in the WHO clas-sification. Recently studies have sug-gested a derivation from plasmacytoid
dendritic cells based on gene expres-sion studies and cytokine production.
The cells express high levels of inter-leukin-3 receptor alpha chain (IL-3R-alpha).
Genetics
T-cell receptor genes are in germline
configuration. Tumour cells are negative
for EBV.
Prognosis and predictive factors
Blastic NK-cell lymphoma is an aggres-sive disease with a poor prognosis
{311,739}. While close to 80% of patients
obtained an initial complete remission,
the majority of patients relapsed within
two years. Patients with single isolated
skin lesions appear to have a better
prognosis {525}.
Fig. 4.68 Blastic CD4+ CD56+. NK-cell lymphoma. Diffuse infiltration of the trunk and upper extremities.Fig. 4.67 Blastic CD4+ CD56+. NK-cell lymphoma.
Brownish haemorrhagic plaques and infiltrates.
From D.V. Kazakov et al {1236}.
CB
A
Fig. 4.69 Blastic CD4+ CD56+  NK-cell lymphoma.  A Tumour cells diffusely infiltrate the dermis, but not epi-dermis. Note the finely distibuted chromatin and inconspicuous nucleoli.   B Tumour cells are positive for
CD4 and  C CD56.
210 Haematolymphoid tumours
Definition
Precursor lymphoblastic leukaemia/ lym-phoma is a malignancy derived from pre-cursor cells of either T-cell or B-cell line-age. There is overlap in the clinical pres-entation, and patients may present with
disease primarily in the bone marrow and
peripheral blood (leukaemia) or in solid
tissues (lymphoma). Because of similari-ties in stage of differentiation, and man-ner of presentation, precursor T-cell and
B-cell malignancies will be discussed
together.
ICD-O code
Precursor T-lymphoblastic leukaemia
9837/3
Precursor T-lymphoblastic lymphoma
9729/3
Precursor B-lymphoblastic leukaemia
9836/3
Precursor B-lymphoblastic lymphoma
9728/3
Synonyms
Acute lymphoblastic leukaemia
Lymphoblastic lymphoma
Epidemiology
Lymphoblastic leukaemia/lymphoma is
rare. Approximately 3.5% to 7% of all
malignant lymphomas of the skin are of
the lymphoblastic type {339,2041}. Most
cases are diagnosed in children and
young adults. However, every age can
be affected. Precursor B-cell malignan-cies are more common in skin than those
of precursor T-cell origin {470,1431,1489,
2043}.
Clinical features
Lymphoblastic lymphoma/leukaemia
may initially present in cutaneous or
other extranodal sites as a single nodule
or tumour {1429,2041}. Frequent sites
are the head and neck region, especially
for patients with precursor B-cell disease
{2043}. However, there is a high likeli-hood of occult disease in the bone mar-row, and patients should be regarded as
having systemic disease for therapeutic
purposes.
Morphology
The dermis contains a monotonous infil-trate composed of small to medium sized
cells with fine chromatin and scant cyto-plasm, characteristic of lymphoblasts.
Nuclear irregularities are variable, and
do not correlate with lineage. The epider-mis is uninvolved, with a distinct Grenz
zone. The cells are interspersed among
dermal collagen fibres, without a stromal
or inflammatory response.
Immunoprofile
T-cell lymphoblastic leukaemia/ lym-phoma.  The tumour cells are positive for
terminal transferase (TdT), CD43, CD99
{1489,1949,2043}. They variably express
CD1a, CD2, CD3, CD4, CD5, and CD8.
CD10 may be positive in some cases.
Cytoplasmic CD3 appears before sur-face CD3. CD7 is nearly always positive
{1843}. The phenotype reflects stages in
the maturation of a thymic T-cell.
B-cell lymphoblastic leukaemia/ lym-phoma.  The tumour cells are positive for
TdT, CD43, and CD99 {1489,2043}. The
cells are usually positive for CD19 and
CD79a {326}. CD10 is expressed in most
cases. CD20, CD22, and CD24 are vari-ably expressed. LCA may be negative.
The cells may contain cytoplasmic  µ
heavy chain, usually in the absence of
light chains.
Histogenesis
Precursor T- or B- lymphoblast.
Somatic genetics
Rearrangement of immunoglobulin heavy
chain genes, and T-cell receptor genes
usually correlates with B-cell or T-cell lin-eage, respectively {544,1311}. However,
lineage infidelity is common in precursor
lymphoid malignancies. Light chain gene
rearrangement is a relatively late event in
B-cell differentiation.
The classification of lymphoblastic malig-nancies is closely related to a complex
series of genetic abnormalities that cor-relate with pathogenesis and clinical out-come {1121}.
Prognosis and predictive factors
Precursor lymphoblastic leukaemia/ lym-phoma is an aggressive disease.
However, cutaneous involvement is not a
poor prognostic factor, and response to
systemic multiagent chemotherapy may
be excellent {2043}.
Precursor T-lymphoblastic leukaemia/
lymphoma and precursor
B-lymphoblastic leukaemia / lymphoma
C.A. Sander
E.S. Jaffe
G. Burg
BA
Fig. 4.70  Precursor B lymphoblastic leukaemia/lymphoma.  A Soft non-ulcerated tumour on an erythema-tous plaque without scaling.  B Tumour cells expressing CD79a.
211Cutaneous involvement of myeloid leukaemia
Definition
Myeloid leukaemia is a heterogenous
malignant disorder of myeloid precursor
cells characterized by an increase in
blast forms in the peripheral blood and
bone marrow. Specific skin involvement
results from direct infiltration of the skin
by neoplastic cells.
Synonyms
Extramedullary myeloid sarcoma, granu-locytic sarcoma, chloroma.
Epidemiology
Acute myeloid leukaemia (AML)
accounts for 10-15% of childhood
leukaemia but the incidence increases
steadily with age. More than 50% of
patients are older than 60 years {1838}.
Chronic myelogenous leukaemia (CML)
is generally a disease of older adults,
with a median age between 50 and 60
years at presentation {1183}.
Skin involvement is reported to occur in
2% to 30% of patients with AML {35,125,
649}. Specific skin lesions are equally
common among males and females. It is
found more frequently in patients with
acute myelomonocytic (AMML) and
monoblastic/monocytic leukaemias
(AMOL). Specific cutaneous lesions are
less common in chronic myelomonocytic
leukaemia (CMML) and CML.
Clinical features
Specific skin lesions present as solitary
or multiple violaceous to red-brown
papules, nodules and plaques. The most
common sites of involvement are the
scalp, face, trunk, and extremities
{2288}. Haemorrhagic lesions are com-mon. Leukaemic gingival hyperplasia is
a striking feature of AMML and AMOL
{649}. In the majority of cases, specific
skin lesions develop in the setting of
established leukaemia. In rare instances,
leukaemic skin infiltrates may precede
peripheral blood and bone marrow
involvement {445,589,2368}.
Histopathology
There is a moderate or dense, diffuse or
nodular infiltrate in the dermis that
extends into the subcutaneous fat {329,
1172}. The epidermis usually is spared.
The infiltrates typically show perivascular
and periadnexal accentuation. A charac-teristic feature is the presence of rows of
atypical cells between collagen bundles
{2137}. The infiltrate is composed of
medium-sized or large neoplastic cells
with round, oval or folded basophilic
nuclei. Mitotic figures are usually pres-ent. In CML, the infiltrate is more pleo-morphic and dominated by mature and
immature cells of the granulocytic series.
Cutaneous infiltrates of plasmacytoid
monocytes may occur in CMML {297}.
Immunoprofile
The majority of the tumour cells shows
reactivity for lysozyme, myeloperoxidase,
CD45, CD43, and CD74. Staining for
chloroacetate esterase and CD68 is vari-able {1172,1899 }. Staining for CD34 is
variable, and often negative in mono-blastic leukaemias. The neoplastic cells
are negative for CD3, CD20, CD30 and
S-100 protein. The presence of CD56
expression in specific skin infiltrates of
AML has been reported {1163,1258}.
Histogenesis
Haematopoietic stem cells.
Somatic genetics
Genetic studies of specific cutaneous
lesions in AML are scant and limited to
isolated cases. An increased incidence
of trisomy 8 in AML with skin infiltration
has been reported {35}. Rarely, cases of
congenital AML may be present with skin
lesions.
Genetic susceptibility
Patients with Down syndrome, Fanconi
anaemia, ataxia telangiectasia, Bloom
syndrome, and Kostmann syndrome are
predisposed to AML.
Prognosis and predictive factors
The prognosis of patients with specific
skin lesions of AML is generally poor
{125,805}. In one series, all patients died
within 24 months after onset of skin
lesions {1172}.
Cutaneous involvement by myeloid
leukaemia
S. Büchner
D.W.P. Su
J. Vardiman
Fig. 4.71 Acute myeloid leukaemia presenting as
generalized erythematous papules and plaques.
BA
Fig. 4.72 Myeloid and monocytic leukaemias.  A Acute monocytic leukaemia. Immunohistochemical expres-sion of CD68.  B Acute myeloid leukaemia. Positive lysozyme stain.
212 Haematolymphoid tumours
Definition
The term pseudolymphoma (PSL) is
defined as a reactive polyclonal benign
lymphoproliferative process predomi-nantly composed of either B-cells or T-cells, localized or disseminated. It heals
spontaneously after cessation of the
causative factor (e.g. drugs) or after non-aggressive treatment.
Synonyms and historical annotation
In 1923, Biberstein coined the term lym-phocytoma cutis. Since then, a variety of
designations have been proposed:  lym-phadenosis benigna cutis {124}, pseu-dolymphoma of Spiegler {2237} and
Fendt. {721}, cutaneous lymphoid hyper-plasia and lymphocytoma cutis {401}. In
retrospect, most of these terms were
describing cutaneous B-cell pseudolym-phomas (B-PSL). The concept of cuta-neous T-cell pseudolymphomas (T-PSL)
was not widely accepted until the early
1980’s.
Epidemiology
Cutaneous pseudolymphomas affect all
age groups with a predilection of
Borrelia-induced B-pseudolymphomas in
children and young adults, whereas drug
induced T-pseudolymphomas more fre-quently are seen in adults. Even though
Borrelia-induced pseudolymphomas
may be precursors for B-cell lymphomas
of the skin, in general cutaneous pseudo-lymphomas are selfregressing and do
not affect survival.
Etiology
Pseudolymphomatous proliferations in the
skin may be induced by microbial, physi-cal or chemical agents including Borrelia
burgdoferi infection, tattoos and drugs.
Localization
In most cases, skin lesions are confined
to the site of external irritation, i.e. tick
bite. Due to the preferential “docking” of
ticks to body areas where the skin is rel-atively soft, e.g., scrotum of young boys,
the mamilla, ear lobes, large skin folds
are preferentially involved.
Clinical features
Several variants of cutaneous PSL exist,
presenting with different clinical symp-toms.
Pseudolymphoma (PSL) with
predominant T-cell infiltrates (T-PSL)
Lymphocytic infiltration (idiopathic or
drug induced)
Palpable migratory arciform erythema
Lymphomatoid contact dermatitis
Actinic reticuloid
Persistent nodular arthropod-bite
reactions
Inflammatory molluscum contagiosum
The original description of lymphocytic
infiltration (idiopathic or drug induced
cutaneous T-cell pseudolymphoma)
given by Jessner and Kanof in 1953
{1141} is still valid today.
The lesions are flat, discoid, more or less
elevated, pinkish to reddish brown, start-ing as small papules, expanding periph-erally, sometimes clearing in the centre,
sometimes showing a circinate arrange-ment. The surface is smooth, occasional-ly uneven. There is no follicular hyperker-atosis as seen in discoid lupus erythe-matosus, which may be simulated. There
may be only one, a few, or numerous
lesions
Histopathology
Characteristic is a sleeve-like, predomi-nantly lymphocytic infiltrate around the
vessels of the upper and mid dermis. In
addition, some macrophages and
eosinophils may be found.
Phenotyping has shown the infiltrate to
consist of both B and T cells {423} even
though T cells seem to predominate in
most cases {2521}.
Palpable migratory arciform erythema
clinically shows a circinate or annular
slightly elevated erythematous lesion.
Lymphoid infiltrates of the skin
mimicking lymphoma (cutaneous
pseudolymphoma)
G. Burg
W Kempf
C.A. Sander
Table 4.02  Differentiation between B-pseudolymphoma (B-PSL) and cutaneous B-cell lymphoma (CBCL)
Taken from Burg et al. {340}.
CBCL PSL
Clinical features
Number of lesions solitary or multiple  usually solitary
Extracutaneous involvement possible  absent
Recurrences likely usually no recurrences
Survival time affected  not affected
Histological features
Pattern of infiltrate diffuse or nodular, nodular (> 90%)
Structure of infiltrate “bottom-heavy” “top-heavy”
Border of the infiltrate convexe, sharply demarcated concave, poorly demarcated
“infiltrating” between
collagen bundles
Additional cells usually absent  eosinophils,plasma cells
Transformation may occur  never occurs
Immunophenotype
Immunoglobulin light chains monotypic (kappa or lambda) polytypic expression
B-cell marker expressing cells >50% cells  ≤50% cells
T-cell marker expressing cells usually few  >50% cells
CD21-positive dendritic cells  mostly absent mostly present
irregular pattern  regular pattern
Genotype
Ig heavy chain gene rearrangementpresent in most cases  absent in most cases
G Wood
U Schmid
S Cogliatti
213Lymphoid infiltrates of the skin mimicking lymphoma
Histologically there is a scant sleeve- like
perivascular lymphocytic infiltrate in the
mid or deep dermis.
Lymphomatoid contact dermatitis has
been reported as a reaction to various
allergens (i.e. nickel, Peru balsam) or
drugs (diphenylhydantoin) inducing
mycosis fungoides-like features {1975}.
Genotyping has shown clonal rearrange-ment in some cases. Such cases may be
closely related to “clonal dermatitis”
some of which develop into overt CTCL
{2545,2546}. Histologically, eczematous
features with epidermotropism of lym-phocytes and accumulations of CD1a-positive Langerhans cells may be found.
Actinic reticuloid is a chronic photoaller-gic infiltrative dermatitis of light exposed
areas associated bearing a clinical and
histological resemblance to malignant
lymphoma, especially to Sézary syn-drome. Histologically there is a dense
infiltrate of lymphocytes mixed with many
polyclonal plasma cells, eosinophils and
macrophages.
There is a considerable overlap between
T- and B-PSL in persistent nodular arthro-pod-bite reaction, nodular scabies and
inflammatory molluscum contagiosum
which show a dense polymorphous infil-trate consisting of a mixture of T-cells, B-cells, macrophages and predominantly
eosinophilic granulocytes.
Lymphomatoid papulosis even though
showing biologic features of pseudolym-phoma is considered to belong to the
group of lymphomas since despite spon-taneous regression of single lesions, the
disease is not curable and may show
transitions to other lymphomas.
PSL with predominant B-cell
infiltrates
Lymphadenosis benigna cutis (LABC)
{124} -the prototype of this group of B-PSL- is synonymous with lymphocytoma
cutis. In Europe it is most commonly
caused by infection with Borrelia
burgdorferi after a tick bite (Ixodes rici-nus). However other microbiological (
medicinal leeches, Hirudo medicinalis)
{2211}, physical or chemical agents as
well may induce lymphocytoma-like
reactions.
Two thirds of all lesions are situated on
the head, tending to occur on the ear
lobes. Other predilections are the nose
as well as the nipples, the inguinal area
and scrotum. Usually the lesion is a soli-tary papule or nodule, but several dis-seminated lesions may occur as well
{1068}.
Microscopic examination shows a nodu-lar dermal infiltrate with reactive follicles.
In addition, there is a rather diffuse infil-trate containing T cells, histiocytes,
eosinophils and polyclonal plasma cells.
The presence of macrophages contain-ing ingested nuclear material (tingible
body macrophages) within the follicles
producing a “starry sky” pattern is a
common feature in B-PSL and a hallmark
of all reactive germinal centres. The infil-trate is predominantly located in the
upper and mid dermis, but may extend
into the deep dermis. Small groups of
lymphoid cells between collagen bun-dles may be observed at the periphery of
the lesions. This is a helpful histological
criterion in the differentiation from cuta-neous B-cell lymphoma, in which the
nodular infiltrate shows convex rather
than concave sharply demarcated bor-ders.
Phenotypically {428} a polyclonal B-lym-phocytic infiltrate without light chain
restriction of the infiltrate is found in most
cases. The cells express the phenotype
of mature B-cells (CD 20, CD 79a). In B-PSL, regular and sharply demarcated
networks of CD21+ follicular dendritic
cells are present, whereas in CBCL these
networks are irregularly shaped {342}.
Acral pseudolymphomatous angioker-atoma of children (APACHE)  is a rare
benign pseudolymphomatous disorder
occurring mainly in children {1888}.
The typical clinical presentation is multi-ple (up to 40), asymptomatic, small
papules located unilaterally on the fin-gers, toes and hands. Their colour is
usually red-violet, accounting for their
angiomatous appearance {1887}.
Histologically the dermis contains a mod-erately to very dense, non-epidermotrop-ic infiltrate composed of small well-differ-entiated lymphocytes admixed with a few
plasma cells, histiocytes, and giant cells.
Blood vessels show prominent plump
endothelial cells {1165,1887}.
Immunohistochemically the cellular infil-trate represents a mixture of polyclonal
mature T- and B-lymphocytes {936}.
Inflammatory pseudotumour (IPT)  (plas-ma cell granuloma, inflammatory myofi-broblastic pseudotumour) refers to a
spectrum of idiopathic benign conditions
with unknown etiology that can develop
in various organs and deep tissues, par-ticularly in the lung. Cutaneous IPT
occurs as a solitary, slowly growing, ten-der nodule measuring 1-3 cm in diame-ter. Irrespective the anatomic location,
the lesions share common histological
features, showing well circumscribed
proliferation of myofibroblasts/fibroblasts
expressing smooth muscle actin (SMA)
and vimentin, a mixed cell infiltrate con-taining high numbers of plasma cells with
prominent germinal centres dispersed
throughout the lesion. The plasma cells
are polyclonal and are seen in the inter-follicular areas (plasma cell granuloma)
21, {508,509}. Later stages show marked
fibrosis/sclerosis with thick collagen bun-dles arranged in concentric whorls.
BA
Fig. 4.73 A Head of Ixodes ricinus fixed to the skin.  B 1384. Borrelia burgdorferi in the dermis, silver stain.
214 Haematolymphoid tumours
Histological variations include presence
of high endothelial venules, admixture of
eosinophils, calcification, psammoma
bodies, and presence of large polygonal
myofibroblasts (vimentin+, CD15-,
CD30-) {1476} with single, double or mul-tiple nuclei and prominent eosinophilic
nucleoli resembling Reed-Sternberg
cells {388,1084,1476,1881,2561}.
Differential diagnosis of cutaneous IPT
includes lymphoma, angiolymphoid
hyperplasia with eosinophilia and Kimura
and infectious dermatoses (mycobacte-ria, deep fungal infections). The later
stages of cutaneous IPT should be dis-tinguished from erythema elevatum
diutinum, granuloma faciale and der-matofibroma with lymphoid infiltrate.
PSL with mixed and
unclassified infiltrates
There are reactive lymphocytic infiltrates
in the context of other skin disorders that
can be referred to as pseudolymphoma-tous reactions in an even broader sense.
Neoplasms, especially squamous cell
carcinoma, basal cell carcinoma, and
malignant melanoma, or naevi (halo
[Sutton] naevi) may show a dense
mononuclear infiltrate, composed of T
cells or of B cells, sometimes with follicle
formation, with polyclonal plasma cells
being numerous especially in head and
neck localizations.
Histogenesis
Polyclonality is the hallmark of cutaneous
pseudolymphomas. Besides T-cells and
B-cells, mononuclear phagocytes repre-sent a considerable proportion of the
infiltrate. Eosinophils and polytypic plas-ma cells as well are present in most
cases of either B-cell or T-cell
pseudolymphomas of the skin {342}.
Somatic genetics
No clonal rearrangement of T-cell recep-tor genes or of immunoglobulin heavy
chain genes or light chain restriction of
plasma cells is found.
Prognosis and predictive factors
The prognosis of cutaneous pseudolym-phomas by definition is excellent, show-ing spontaneous regression of the
lesions after cessation of the causative
factor or due to treatment with non-aggressive treatment modalities. How-ever there is a potential for some cuta-neous pseudolymphomas to progress to
cutaneous B-cell lymphoma (CBCL)
{433,807,1339}, or to cutaneous T-cell
lymphoma (CTCL) {2545,2546}.
Fig. 4.74 Lymphadenosis benigna cutis (LABC, B-pseudolymphoma) following tick bite in the earlobe.
Fig. 4.75 B-PSL.  Reactive follicles in lymphadeno-sis benigna cutis (B-pseudolymphoma).
Fig. 4.76 Close up view showing follicular centre
with tingible-body macrophages featuring a starry
sky pattern.
BA
Fig. 4.77 A Tingible body macrophages containing ingested nuclear fragments.  B Regular network of CD21+
dendritic cells.
215Parapsoriasis
Definition
The term “parapsoriasis” is confusing. It
encompasses a number of different
pathologic states clinically manifested by
chronic recalcitrant erythematous scal-ing skin lesions .
Those diseases which have distinct clini-cal and histological changes do not fulfill
criteria of malignancy, deserve to be
labeled with a term which reflects this
intermediate situation and labels them as
distinct nosologic entities. This term
since the days of Brocq has been “para-psoriasis” and there is no reason for
changing it {311,312}. Otherwise there
will be a bias in epidemiologic data on
frequencies, mortality rates and other
parameters.
Two groups of parapsoriasis can be dif-ferentiated. The benign form (“parapsori-asis en plaques” [Brocq’s disease]),
which never evolves into malignant lym-phoma and large plaque forms with or
without poikiloderma which after several
decades may evolve into mycosis fun-goides or CTCL in up to 50% of the
cases. Table 4.3 summarizes criteria for
differentiation of benign and premalig-nant forms of parapsoriasis en plaques.
Small plaque parapsoriasis
Synonyms
Parapsoriasis, small patch (digitiform)
type (Brocq’s disease); Parapsoriasis en
plaques, benign type; digitate dermato-sis, xanthoerythrodermia perstans;
chronic superficial dermatitis
Epidemiology
This form preferentially occurs in young
adults and affects males more frequently
than females. There are no statistically
reliable data on the incidence, which is
estimated less than 0.1 per 100.000 per
year. There is little tendency to progress.
Survival is not affected since SPP never
evolves into malignant lymphoma
Clinical Features
Trunk and upper extremities are prefer-entially involved. Small (2-5cm in diame-ter), mostly oval or finger-like patches,
slightly erythematous, following skin
lines. The color is brown red, and fine
and powdery (pityriasiform) scaling may
be present. The surface is slightly wrin-kled resulting in a pseudoatrophic
appearance.
Histopathology
The epidermis is normal or slightly spon-giotic with patchy parakeratosis. Patchy
loose perivascular and disseminated
lymphocytic infiltrate, but no edema, are
present in the dermis. Significant epider-motropism of lymphoid cells is lacking.
Immunohistochemistry
Lymphoid cells exhibit mostly CD4+ and
some CD8+ {935}.
Somatic genetics
Clonal rearrangement for the T-cell
receptor genes is not detectable.
However clonal rearrangement of lym-phoid cells in the peripheral blood of
patients has been reported {1661}.
Prognosis and predictive factors
The skin lesions are extraordinarily stable
in shape and size over years and
decades without spreading to extracuta-neous localizations. Lymph nodes,
peripheral blood, bone marrow or inter-nal organs are not affected. Life-expectancy is normal. Progression into
mycosis fungoides or other CTCL does
not occur.
Parapsoriasis G. Burg
M. Santucci
B. Smoller
J. Guitart
M Everett
W. Kempf
Fig. 4.78 Parapsoriasis.  A Large plaque parapsoriasis with poikiloderma, showing large teleangiectatic  patches and a netlike pigmentation.  B Flattening of the epi-dermal rete ridges. Band like lichenoid infiltrate. Dilated small blood vesels in the upper dermis.
BA
216 Haematolymphoid tumours
Parapsoriasis – Large patch
type, with or without
poikiloderma
Definition
Pre-malignant inflammatory disorder with
tendency to evolve into mycosis fun-goides. Some authors consider this
lesion a manifestation of early cutaneous
T-cell lymphoma (CTCL).
Synonyms
Non-poikilodermatous variant. Parapso-riasis en plaques, premalignant type,
parapsoriasis en grandes plaques sim-ples.
Poikilodermatous variant : Prereticulotic
poikiloderma, parapsoriasis en grandes
plaques poikilodermiques; poikiloderma
vasculare atrophicans; parapsoriasis
lichenoides; parakeratosis variegata
Epidemiology
All age groups may be affected with a
slight male preponderance.
Localization
Breast and buttocks are most commonly
involved.
Clinical Features
Few large (more than 5 cm in diameter)
patches showing pityriasiform scaling
with (poikilodermatous variant), telang-iectasia and netlike pigmentation are
present. There is no palpable infiltration.
Tumour spread and staging
Lesions may stay unchanged over years
and decades, or slowly show enlarge-ment in a few cases. No plaques or
tumours occur, except when the disease
evolves into CTCL in some of the cases.
Histopathology
Under patchy parakeratosis there is
slight atrophy of the epidermis, due to
loss of rete ridges, in the poikiloderma-tous form. The subepidermal zone is free
of lymphocytes, which accumulate in a
band-like arrangement in the upper der-mis, sparing the papillary region. There is
no significant epidermotropism as usual-ly seen in early stages of mycosis fun-goides. The poikilodermatous variant of
the disease in addition shows dilated
blood vessels in the upper dermis.
Somatic genetics
T-cell receptor gamma gene rearrange-ment,which is clonal in about half of the
patients with LPP, is probably without any
prognostic significance {2186}.
Increased telomerase activity and short-ened telomere length was also detected
in CD4+ T cells from patients with parap-soriasis {2552}.
Prognosis and predictive factors
There is no significant difference
between the observed and expected
survivals in patients with less than 10%
skin involved. {2575}. However when skin
involvement exceeds10%, as seen in
LPP, sporadic cases have an increased
risk of transforming into mycosis fun-goides after years or decades {2031}.
Table 4.03
Criteria for distinguishing benign and premalignant forms of parapsoriasis en plaques.
Benign form (small patch type)  Premalignant form (large patch type)
with or without poikiloderma
Age distribution Adults All ages
Sex incidence (m:f) 5:1 2:1
Clinical features Small (2-5cm in diameter), mostly  Few large patches (>5cm in
oval, or finger-like patches,  diameter)  pityriasiform scaling
slightly erythematous and wrinkled  with or without telangiectases
surface (pseudoatrophy)  uniformly  and netlike pigmentation,
pinkish or yellowish with  sometimes slightly hyperkeratotic
pityriasiform scaling (parakeratosis variegata)
Preferential localizations Trunk and upper extremities Breast and buttocks
Histological features Patchy parakeratosis, slight  Slight epidermal atrophy with loss
perivascular patchy infiltrate,  of rete ridges, significant band-like
no oedema, no significant  dermal lymphocytic infiltrate sparing
epidermotropism the subepidermal zone, no significant
epidermotropism, no oedema;
telangiectases may be prominent
in the poikilodermatous variant
Prognosis  Life expectancy normal;  Life expectancy normal in most
no progression to mycosis fungoides  cases; progression to mycosis
fungoides occurs
217Langerhans cell histocytosis
Definition
Langerhans cell histiocytosis (LCH) is a
clonal disorder with systemic spread,
characterized by proliferation of dendrit-ic cells which bear morphologic and
phenotypic markers of Langerhans cells,
characterized by Birbeck granules and
expression of CD1a and  S-100.
ICD-O code   9751/1
Synonyms
Histiocytosis-X, Langerhans cell granulo-matosis, Langerhans cell disease
Epidemiology
LCH predominantly occurs in infants.
Median age at diagnosis is 3-5 years
{2,299}. It has also been reported in
patients up to the ninth decade of life
{1551,1578,1941}, and occurs equally in
men and women. The incidence has
been estimated as 0.1–0.5 per 100.000
population per year. There have been
reports on familiar cases with autosomal
recessive inheritance.
Etiology
The etiology is unknown. Different groups
have studied female patients with cuta-neous LCH using a variety of x-linked
polymorphisms to demonstrate clonality
{2530,2574}. In some cases, association
with lymphomas, leukaemias and lung
tumours {666} has been observed; in oth-ers, infections and environmental factors,
including El Nino, have been related to
childhood LCH {455}. Many view LCH as
reactive process {716,2583} because of
its tendency toward spontaneous remis-sion and response to mild, non-toxic
therapy.
Localization
Two thirds of the sites of involvement
diagnosed throughout the course of the
disease are present at diagnosis {2}.
Initial bone involvement is found in
almost all patients. Other organs
involved skin (25-100%, depending on
subtype), ear, liver, lung, and lymph
nodes {299}.
Clinical Features
The clinical presentation of LCH is very
diverse and depends on the subtype.
Skin lesions may be seen either as single
organ involvement or as part of a multior-gan systemic disease in 25-100% of
cases. Any anatomic site can be
involved including scalp, nails, palms
and soles as well as mucous mem-branes.
Letterer-Siwe Disease
This is the most severe, disseminated
form of Langerhans cell histiocytosis. It
affects children in their first year of life
but occurrence in adults has been
reported {1731}. Tiny (0.5 mm in diame-ter) rose-yellow or brownish-red, translu-cent papules and patches are found on
the scalp, diaper and seborrhoeic sites
like nasolabial folds, perioral region, and
on the upper trunk . In time, the papules
become scaly and crusted and may coa-lesce into plaques. Petechial and pur-puric lesions, pustules and vesicles as
Langerhans cell histiocytosis  B. Zelger
R.P. Rapini
W Burgdorf
G. Burg
Table 4.04
Langerhans cell histiocytoses and their characteristics. This classification has limitations because of the
highly variable manifestations of the disease with many overlapping features {340}.
Fig. 4.79 Multiple nodules in a patient with
Congenital self-healing reticulohistiocytosis
(CSHRH).
Disease Age Skin Clinical Course Prognosis
involvement Features
Letterer Siwe First years  ~90-100% Fever, weight loss, Acute Mortality
of life lymphadenopathy,  rate:
hepatosplenomegaly, 50-66%
pancytopenia, bone
lesions
Hand-Schüller Children ~30% Osteolytic bone Subacute Mortality
Christian adults lesions, to rate:
diabetes insipidus chronic < 50%
exophthalmos,
otitis
Eosinophilic Mainly  <10% Solitary bone or skin Chronic Favorable
granuloma adults lesions
Congenital Congenital 100% Skin lesions only Self Excellent*
self-healing healing
reticulohistio-cytosis (CSHR)
*Both relapses and conversion to systemic disease can occur, so long-term follow-up is needed {1369}.
218 Haematolymphoid tumours
well as small erosions can also be seen.
Nodules are uncommon, but may be
found on the trunk and tend to ulcerate.
Additional symptoms include fever,
weight loss, rash, lymphadenopathy,
hepatosplenomegaly, pancytopenia and
purpura.
Hand – Schüller – Christian
disease
The typical triad includes osteolytic skull
lesions (100%), hypopituitarism induced
diabetes insipidus (50%), and exophthal-mos (10%). Otitis media, generalized
lymphoadenopathy, hepatosplenome-galy, and pulmonary disease may be
additional findings.
Skin lesions occur in about 30% of
cases, usually in the intertriginous areas,
most often as papules and nodules
which may be ulcerated, erosive and
superinfected.
Eosinophilic granuloma
The most common site of involvement is
bone. The uncommon cutaneous lesions
are deep dermal or subcutaneous nod-ules which are not clinically distinct
{818,1956}. Lesions have to be differenti-ated from granuloma eosinophilicum
faciei, a chronic variant of leukocytoclas-tic vasculitis with variable presence of
eosinophils, but usually no extracuta-neous manifestation {452}.
Congenital self-healing reticulo-histiocytosis (CSHRH)
CSHRH (synonyms: Hashimoto-Pritzker
disease; congenital reticulohistiocytosis;
congenital self-healing Langerhans cell
histiocytosis) {981,2082} is a rare condi-tion (5% of all LCH), initially seen at birth
or in the neonatal period, with solitary,
localized to generalized papules, vesi-cles, or nodules on the trunk, head,
palms and soles, sometimes showing
central ulceration {217}. The skin lesions
tend to involute spontaneously within
weeks to months leaving behind hypo- or
hyperpigmented macules or patches
{979,1372}. Affected infants are other-wise well {1369}. Patients should be
carefully followed since relapses may
occur, including bone involvement, and
the occasional case may progress to
Letterer-Siwe disease {1445}. Some
cases of CSHRH may be clinically con-fused with the blueberry muffin syn-drome, congenital leukaemic infiltrates,
xanthogranulomas or mast cell disease,
but the microscopic picture brings clarity
{360}.
Histopathology
The hallmark and unifying feature of all
variants of LCH is a cell with large, pale,
folded or lobulated, often reniform, vesic-Fig. 4.80 Congenital self-healing reticulohistiocytosis (CSHRH).  A Papule of CSHRH with  B Characteristic kidney-shaped nuclei.
BA
Fig. 4.81 Langerhans cell histiocytosis.  A Typical ground glass (“reticulocytic”} appearance of Langerhans cells. B Langerhans cells with membranous staining
for CD1a .
BA
219Langerhans cell histocytosis
ular nucleus and abundant, slightly
eosinophilic or amphophilic cytoplasm.
Nucleoli are not prominent. Histological
variations correlate with the clinical
appearance of the lesions. Features may
be predominantly proliferative in Letterer-Siwe disease, xanthomatous in Hand-Schüller-Christian-disease, granuloma-tous as in eosinophilic granuloma, or
“reticulocytic” with abundant eosinophilic
cytoplasm (ground glass appearance of
giant cells) in Hashimoto-Pritzker dis-ease. Fully developed papules and
plaques show a dense band-like infiltrate
obscuring the dermo-epidermal junction.
Epidermotropism of LCs with intraepider-mal microabscess formation can be
found. In addition to LCs and eosino-phils, the infiltrate may contain variable
numbers of lymphocytes, epithelioid
macrophages including foam cells and
giant cells, neutrophils, plasma cells,
and extravasated erythrocytes.
Immunohistochemistry
The phenotypic hallmarks in LCH are
expression of CD1a, CD4 and S-100 pro-tein, while macrophage markers, includ-ing CD68 and lysozyme, are usually ne-gative.
Electron microscopy
Rod- or rocket-shaped granules measur-ing 200-400 nm  (Birbeck granules,
Langerhans cell granules) are the ultra-structural hallmark of LCs. The number of
Birbeck granules varies, with usually
greater prominence in early lesions. Co-existence of myelinoid laminated inclu-sions or “vermiform” bodies {1372} and
Birbeck granules is common in CSHRH.
Genetics
A variety of inconsistent cytogenetic
abnormalities have been found in sever-al patients with LCH studied so far using
comparitive genomic hybridization, loss
of heterozygosity (LOH) and other tech-niques {107,227,848,1666}. Heteroge-neous overexpression of TGFbeta recep-tor I and II, MDM2, p53, p21, p16, Rb,
and BCL2 has been detected in lesional
LCH cells {2097}. Familial clustering of
two different manifestations of LCH sup-port a role for genetic factor(s) in LCH
and raise the possibility of inherited
mutations that promote emergence of
clonal Langerhans cells {93,134,1200}.
LCH may follow percursor T-cell acute
lymphoblastic leukaemia, and in such
cases a clonal relationship has been
shown for T-cell receptor gene rear-rangements {720}.
Prognosis and predictive factors
The biologic behaviour of LCH ranges
from spontaneous remission to lethal dis-semination, and such behaviour cannot
be predicted on the basis of histologic
features {1941}. The presence and
degree of organ dysfunction, age less
than 1 year at diagnosis (except the
Hashimoto-Pritzker type), male sex, pro-gressive episodes, and the absence of
response to therapy are the most reliable
indicators of prognosis  {2,1019}. In gen-eral, about 10% of patients with multifo-cal disease die, 30% undergo complete
remission, and the remaining 60%
embark upon a chronic course {1065,
1425}.
Fig. 4.82 Electron microscopy with numerous
Birbeck or Langerhans cell granules. Courtesy Dr.
N. Romani, University of Innsbruck, Austria
220 Haematolymphoid tumours
Definition
Indeterminate cell histiocytosis (ICH) is a
proliferative cutaneous disorder of the so-called “indeterminate cells” (IC), i.e. dis-tinct dendritic cells of the skin that display
histological, ultrastructural and antigenic
features similar to those of Langerhans
cells, but do not contain Birbeck granules.
Epidemiology
The disease is very rare (about 15 cases
described up to 2003), usually occurs
during adulthood, although two cases
were in teenagers {1621,2019} and two
cases in children {1413,1524}. Both
sexes have been affected.
Etiology
The origin of indeterminate cells is still
debated. Indeterminate cells may
derivate from an arrest of Langerhans
cell migration and maturation {1302},
may represent precursors of Langerhans
cells which acquire Birbeck granules as
they transit from dermal to epidermal
sites {1499}. Furthermore it has been
suggested {222} that indeterminate cells
represent members of the epidermal/der-mal dendritic cell system which migrate
from skin to regional lymph nodes.
According to this concept, indeterminate
cell histiocytosis can be considered a
disorder due to locally arrested dermal
indeterminate cells proliferating prior to
their departure for lymph nodes.
Localization
Lesions are usually restricted to the skin.
Solitary lesions have been described on
the trunk and arms, while multiple lesions
are widespread.
Clinical features
The eruption consists of a solitary nodu-lar lesion {222,279,1413,1621} or of mul-tiple papulonodules {279,531,1499,2019,
2179}.
Solitary nodules are soft, red in colour
and about 1 cm in diameter, and may be
ulcerated. Multiple lesions are firm,
asymptomatic papulonodules ranging in
size from a few millimetres to 1 cm, vary-ing in colour from dark-red to brownish,
and covered by intact skin. These lesions
appear in successive crops. Mucous
membranes are always spared. Visceral
involvement has been observed only in a
child. Patients are in good general
health.
Histopathology
Light-microscopic evaluation reveals an
infiltration of histiocytic cells in the whole
dermis and sometimes within the epider-mis. The proliferating cells show an
abundant pale eosinophilic cytoplasm
and large irregular folded or twisted
nuclei.
A few mitotic figures and multinucleated
giant cells may be observed. Clusters of
lymphocytes are admixed.
Immunohistochemistry
Proliferating cells are weakly positive for
CD1a, CD68 (KP1), CD11c (Leu M5),
CD14 (OKM1), factor XIIIa, lysozyme,
α1-antitrypsin, HLA-DR, but negative for
CD207 (langerin) {1302,1499,1524,1621,
2179}.
Electron microscopy
The proliferating cells reveal an indented
nucleus and an abundant cytoplasm with
lysosomes, phagosomes and a well-developed endoplasmic reticulum.
Birbeck granules are absent {222,531,
1413}.
Prognosis and predictive factors
Most cases have exhibited complete or
partial spontaneous regression of lesions
without recurrences. Two cases dis-played malignant behaviour {279,1524}.
The prognosis is reasonably good, but
leukaemia may be associated with this
disease {279,1302}.
Indeterminate cell histiocytosis R. Caputo
E. Berti
Fig. 4.83 Indeterminate cell histiocytosis. Multiple
firm, asymptomatic papulonodules on the trunk,
ranging in size from few millimetres to 1 cm, vary-ing in colour from dark red to brownish.
Fig. 4.84 Indeterminate cell histiocytosis.  The pro-liferating cells show an irregular, often reniform,
vesicular nucleus, surrounded by abundant pale
cytoplasm. From: R. Caputo {378}.
Fig. 4.85 The proliferating cells reveal an indented
nucleus and an abundant cytoplasm with lyso-somes, phagosomes and a well developed endo-plasmic reticulum. Birbeck granules are absent.
221Sinus histiocytosis with massive lymphadenopathy
Definition
Sinus histiocytosis with massive lym-phadenopathy is a reactive condition of
unknown etiology, charactericed by a
poliferation of histiocytes which usually
exhibit emperipolesis of lymphocytes.
The disease can mimic lymphoma.
Extranodal involvement is frequent.
Synonyms
Sinus histiocytosis with massive lym-phadenopathy, Rosai-Dorfman disease
Epidemiology
Sinus histiocytosis is a rare non-neoplas-tic disease. Lymph nodes are predomi-nantly affected in children and young
male adults; the cutaneous form is par-ticularly seen during the third and fourth
decades in female patients {74,307,483}.
Etiology
The etiology is unknown. Lesions are
polyclonal, probably the consequence of
a cytokine dysregulation {1603}.
Localization
Cervical lymph node involvement is most
characteristic. Cutaneous lesions fre-quently occur on the head and neck,
mucous lesions {1105,2498} in the nose
and paranasal sinus. Extranodal disease
may also affect any other organ {2455}.
Clinical features
Children with massive cervical lymph
node swellings frequently suffer from
fever and malaise. Laboratory tests show
leukocytosis, anemia, polyclonal hyper-gammaglobulinaemia and an accelerat-ed erythrocyte sedimentation rate.
Extranodal involvement is common, up to
40%. Pure cutaneous forms are rare; soli-tary, clustered or wide-spread, red to
brownish papules, rarely plaques and
nodules are seen. Regression leaves
atrophic, brown macules.
Histopathology
Lymph node architecture is replaced by
sheets of faintly stained (“clear”) to
slightly eosinophilic macrophages. In
extranodal location infiltrates frequently
simulate lymph node sinuses (“sinu-soidal pattern”).
Emperipolesis of lymphocytes, erythro-cytes or other nuclear debris is promi-nent, but not specific; it can also be seen
in, e.g., subcutaneous T-cell lymphomas.
Lymphocytes, plasma cells, neutrophils
and fibrosclerosis are found to a variable
degree.
Immunohistochemistry
Macrophages are positive for CD68
(PGM1, KP1) and S100 protein; CD1a,
factor XIIIa and CD34 are negative
{1796}.
Electron microscopy
Macrophages ingest intact lymphocytes.
Phagolysosomal structures, but no
Birbeck granules are found.
Prognosis and predictive factors
Manifestation in children and lymph node
involvement are more readily and rapidly
associated with regression than in adults
and spread to extranodal sites. The vast
majority of lesions is self-limited and
benign. Rare fatalities have been associ-ated with immunologic disorders, lym-phomas of Hodgkin and non-Hodgkin
type, leukaemias {62}, and exceptional
cases with solid tumours {1900}.
Sinus histiocytosis with
massive lymphadenopathy
(Rosai-Dorfman disease)
B. Zelger
S. Kohler
W. Burgdorf
Fig. 4.86 Sinus histiocytosis with massive lymphadenopathy.  A Left: Brownish nodule of sinus histiocytosis on the nose. 1595  Right: Clustered brownish papules of
sinus histiocytosis on the trunk.  B Left: Sheets of macrophages in sinus histiocytosis positive for S100 protein. Right: Lymphocytes within cytoplasm of histiocytes,
i.e,. emperipolesis.
BA
222 Haematolymphoid tumours
Definition
Juvenile xanthogranuloma (JXG) is a
benign, self-healing, non-Langerhans-cell (LC) histiocytosis most frequently
seen in infants and children, character-ized by yellowish asymptomatic papules
and/or nodules located in the skin and
other organs and consisting of an infil-trate of macrophages with a variable
degree of lipidization in the absence of a
metabolic disorder.
Synonyms
Xanthoma multiplex {33}; Nevoxantho-endothelioma {1551}.
Epidemiology
JXG is the most common form of non LC
histiocytosis {378,824}. JXG appears
within the first year of life in about 75% of
cases; in 15-30% it is present at birth.
Etiology
The etiology is unknown. Foamy cells
constitute the main part of the mature
lesions of JXG and accumulate lipids,
despite normal levels of plasma lipids.
It has been suggested {208} that the
uptake of low-density lipoprotein choles-terol and the biosynthesis of intracellular
cholesterol are both enhanced; such
enhancement might play a role in the
process of accumulation of cholesterol
esters in the macrophage.
Localization
Cutaneous lesions are irregularly scat-tered throughout the skin without a ten-dency to cluster, and are mainly located
on the upper part of the body {378,824}.
Mucous membranes may rarely be
involved.
The most common extracutaneous mani-festation of JXG (occurring mainly in the
papular and subcutaneous {256} forms)
is ocular involvement {256,614,2045,
2603}. Ocular lesions may occur in about
1-10% of affected children and are
almost always unilateral and may lead to
haemorrhage and glaucoma. Such
lesions may precede or follow the cuta-neous lesions. The nodular variant of
JXG may occasionally be related to sys-temic lesions of lungs, bones, kidneys,
pericardium, colon, ovaries, testes and
central nervous system {378,824,2536}.
Clinical features
Two main clinical variants can be distin-guished: a papular form and a nodular
form {824}
The  papular form  is the most frequent
and is characterized by numerous (up to
100), firm hemispheric lesions, 2-5 mm in
diameter, that are red-brown at first and
then quickly turn yellowish. These lesions
are associated in perhaps 20% of
patients with café-au-lait spots of neurofi-bromatosis {1140} and may be related to
juvenile chronic myeloid leukaemia
{538,1650}.
The nodular form is less frequent, and is
marked by one or a few lesions. The nod-ules are round to oval, 1-2 cm in diame-ter, high-domed, shiny, translucent, yel-lowish or red brown and sometimes show
telangectasias on their surface. The term
giant JXG has been used to indicate
lesions larger than 2 cm. Unusual clinical
variants {378,383} are the mixed form
(simultaneous presence of both papules
and nodules) and the form en plaque, a
group of JXG lesions with a tendency to
coalesce into a plaque as the only
expression of the disease.
Histopathology
Early lesions are characterized by a
dense infiltrate of monomorphous, non-lipid containing, macrophages with
abundant, slightly eosinophilic, cyto-plasm {378,824}. With time the cyto-plasm of macrophages becomes laden
with lipid and appears foamy.
Mature lesions contain foamy cells, for-Juvenile xanthogranuloma  R. Caputo
B. Zelger
B
C
Fig. 4.87 Juvenile xanthogranuloma.  A Mixed form: this form is characterized by the simultaneous presence
of both red brown papules and nodules, irregularly scattered throughout the skin. Previously published by
R. Caputo in “Text Atlas of Histiocytic Syndromes. A Dermatological Perspective” , Martin Dunitz, London
1998 {378}.  B Plaqueform: this cluster of yellow nodules on the back of the neck is the only expression of
the disease.  C Nodular form: a round, high-domed, yellow brown nodule on the right shoulder.
A
223Juvenile xanthogranuloma
eign body giant cells and Touton giant
cells, mainly distributed in the superficial
dermis and on the border of the infiltrate.
In addition to macrophages and foamy
cells, there may be lymphocytes, eosino-phils, neutrophils and plasma cells scat-tered throughout the lesion. In older
lesions fibrosis replaces the cellular infil-trate, and lipids are not present extracel-lularly.
Immunohistochemistry
Immunohistochemically {824,2049} ma-crophages and Touton cells show a uni-form positive staining with CD14, CD68,
HAM56 (markers with specificity for
macrophages) and vimentin, frequent
positive staining for factor XIII (markers
of dermal dendrocytes) and for cathep-isin B and occasional staining for
MAC387 (a marker for monocytes and
macrophages).
S100 protein, CD1a (OKT6), CD15 (Leu
M1) and peanut agglutinin (PNA) are not
usually expressed on the macrophages
of JXG.
Electron microscopy
Under the electron microscope {378,
824}, the macrophages that characterize
the early stage of the disease exhibit
pleomorphic nuclei, are rich in pseud-opods, and contain many elongated and
irregular dense bodies.
Clusters of comma-shaped bodies, but
no Langerhans granules (LG) can occa-sionally be observed. In older lesions
there is a predominance of foamy cells,
the cytoplasm of which is completely
filled with lipid vacuoles, cholesterol
clefts, and myeloid bodies. The cells cor-responding to Touton giant cells are
large (150-250 µm) and sometimes con-tain more than 10 nuclei. At their periph-ery, such cells are rich in lipid material,
whereas in their centre, mitochondria
and lysosomes predominate.
Genetics
JXG is not linked to any genetic locus,
but the association with café-au-lait
spots of neurofibromatosis (NF1) {2536}
and the occasional association with
neurilemmomatosis (NF2) {1115} sug-gests that a JXG locus could reside on
chromosome 17q11.2 or 22q12. Clinical
{1115} and genetic analyses {1056} indi-cate that neurilemmomatosis and neu-rofibromatosis type 2 (NF2) genes are
identical.
Prognosis and predictive factors
The papules and nodules of the skin tend
to flatten with time and both the skin and
most of the visceral lesions disappear
spontaneously within 3-6 years. A few
cases of JXG with fatal evolution, proba-bly due to central nervous system
involvement {378} or fatal liver disease
{614}, have been reported. In JXG peri-odic complete blood count and peripher-al smears would be judicious during a
patient’s first two years of life, which is
the time of the peak incidence for juve-nile chronic myeloid leukaemia.
Fig.  4.88 Juvenile xanthogranuloma. Conventional microscopy. In mature lesions, giant cells are mainly dis-tributed in the superficial dermis and on the border of the infiltrate. From: R. Caputo {378}.
Fig. 4.89 Juvenile xanthogranuloma. Frozen section
showing large macrophages stained by CD14 .
Fig. 4.90 Juvenile xanthogranuloma. Electron
microscopy. This large macrophage exhibits lipid
droplets, myeloid bodies and cholesterol clefts.
224 Haematolymphoid tumours
Definition
Reticulohistiocytosis of the skin repre-sents a spectrum of rare clinical entities,
ranging from the solitary cutaneous form
(SCR) through the generalized cuta-neous form without systemic involvement
(GCR), to multicentric reticulohistiocyto-sis with systemic involvement (MR). The
skin lesions in all these conditions
demonstrate an identical histological
pattern, characterized by numerous
mononucleated or multinucleated macro-phages with abundant, eosinophilic,
homogeneous to finely granular cyto-plasm with a characteristic ground-glass
appearance.
Synonyms
Giant cell reticulohistiocytosis, giant cell
histiocytosis; cutaneous reticulohistiocy-toma, reticulomatosis with giant cell histi-ocytes; normocholesterolemic xan-thomatosis; lipoid dermatoarthritis; lipoid
rheumatism; multicentric reticulohistiocy-tosis; non-diabetic cutaneous xan-thomatosis; reticulohistiocytic granulo-ma; reticulohistiocytosis of the skin and
synovia.
Epidemiology
Reticulohistiocytosis mostly occurs in
adults over 40 years of age, but the dis-ease may appear during adolescence:
SCR and GCR have been also observed
in children. In adults, the most frequent
variant is MR, with about 50 and GCR
with 10 patients reported in the literature.
There is no preference for either sex
{167,465,1405,1462}.
Etiology
The etiopathogenesis is unknown.
Reticulohistiocytosis may represent an
abnormal macrophage response to dif-ferent stimuli. In solitary forms, local trau-ma such as insect bites, folliculitis or rup-tured infundibular cysts may play a role
{379}, while in systemic forms the associ-ation with autoimmune disorders and
internal malignancies suggests an
immunological basis for the initiation of
this reaction {1752}.
Localization
SCR involves mainly the head and the
neck, but may be found in any cutaneous
site {382,1082}. In GCR the lesions are
widely scattered on the skin {381,547,
847,2363}. In MR {167,413,465,1405,
1752} skin lesions preferentially affect the
fingers, the palms and the back of the
hands, the juxta-articular regions of the
limbs and the face. Oral, nasal and pha-ryngeal mucosa are involved in 50% of
cases. Osteoarticular lesions involve
mainly the hands (80%), knee (70%) and
wrists (65%).
Clinical features
The solitary cutaneous reticulohistiocyto-sis (SCR) or reticulohistiocytoma cutis
{382,1082} is characterized by a single,
firm, rapidly growing nodule varying in
colour from yellow-brown to dark-red.
The lesion is often clinically misdiag-nosed, it occurs without evidence of sys-temic involvement, and its onset may be
preceded by trauma.
Generalized cutaneous histiocytosis
(GCR) {381,547,847,2363} is a purely
cutaneous form characterized by the
eruption of firm, smooth, asymptomatic
papulonodular lesions, 3-10 mm in diam-eter. The colour of the recent lesions is
pink-yellow, while the older lesions show
a red-brown colour. Joint and visceral
lesions are absent. Possibly, this purely
cutaneous form could represent an early
stage of multicentric reticulohistiocytosis,
before the appearance of joint or viscer-al lesions.
The term multicentric reticulohistiocytosis
{167,413,465,1405,1752} is used to indi-cate a form of reticulohistiocytosis char-acterized by the association of a cuta-neous and mucous membrane papulon-odular eruption with severe arthropathy
and other visceral symptoms. The papu-lonodular lesions range in diameter from
a few mm to 2 cm, and are round,
translucent and yellow-rose or yellow-brown in colour. Grouping of lesions into
plaques can give a cobblestone appear-ance, but lesions are mostly scattered
and isolated. They do not tend to ulcer-ate, and are pruritic in about one-third of
cases. Osteoarticular manifestations
cause severe chronic polyarthritis with
arthralgias, and are the initial sign of the
disease in about 5-65% of cases {167,
465,1405}. The osteoarticular lesions
Reticulohistiocytosis  E. Berti
B. Zelger
R. Caputo
B CA
Fig.  4.91  Multicentric reticulohistiocytosis.   A Purplish-brown, firm nodules characteristically affect the fingers. Periungual papules are arranged about the nail
folds.  B Papulonodular lesions are spread on the face, lips and oral mucosa. Mucous membranes are involved in about 50% of cases.  C Symmetrical involvement
of the knees. In this patient, osteoarticular manifestations were the initial sign of the disease. From: R. Caputo {378}
225Reticulohistocytosis
show a progressive destructive course of
6-8 years, and then become stable.
Other systemic localizations, histopatho-logically documented are very rare.
Muscular {667} (myositis, myotonia and
myoatrophy), cardiopulmonary {532}
(pericarditis, cardiac insufficiency, pleuri-tis, pulmonary infiltration), ocular {667}
(exophthalmos, conjunctival infiltration),
gastric (gastric ulcer), thyroid (thyroid
nodules) and submandibular salivary
gland involvements have occasionally
been reported. Fever, weight loss and
weakness can be present. In MR there is
an association with a variety of autoim-mune disorders such as dermatomyosi-tis, lupus erythematosus, or Hashimoto
thyroiditis as well as internal malignan-cies in 15-27% of cases {167,413,1405,
1752}. Solid tumours such as bronchial,
breast, stomach and cervical carcino-mas are most common. Lymphomas and
myelodysplastic syndromes have been
found less frequently.
Histopathology
The histological findings in the three
types of reticulohistiocytosis and in the
different tissues are identical {167,465,
1405,1462}. Early lesions are composed
of macrophages and lymphocytes, and
therefore may be confused with other
histiocytoses of the skin. Older lesions
show the characteristic histological pat-tern: the presence of numerous large,
mononuclear or multinucleated macro-phages with an abundance of
eosinophilic, homogeneous to finely
granular cytoplasm having a ground
glass appearance. At times, phagocyto-sis of connective tissue and/or cellular
components may be seen {379,532}.
Histochemically, the granular material in
macrophages and giant cells stains with
periodic acid-Schiff, Sudan black and
scarlet red, indicating the presence of
glycolipids and/or glycoproteins and
neutral fat {167}.
Immunohistochemistry
Macrophages stain with macrophage
markers KP1/PGM1 (CD68), Ki-M1p, and
for the mesenchymal epitope of vimentin,
and show variable reactivity with HAM56
and for factor XIIIa, lysozyme and  α1-antitrypsin {381,382,424,2027,2585}. In
contrast, these cells are usually negative
for CD1α, S100 protein, Leu-M1 (CD15)
and MAC387. Rare exceptions have
been reported. According to Zelger et al.
{2585}, SCR differs histopathologically
and immunohistochemically from MR as
lesions are better circumscribed, multin-ucleated giant cells more prominent,
gigantic and bizarre, and macrophages
regularly negative for factor XIIIa in the
former entity.
Electron microscopy
The infiltrate is formed by large mononu-clear to multinucleated cells exhibiting
numerous peripheral villi {532,667}.
Nuclei are irregular and often polylobat-ed, with nucleoplasm of medium electron
density and one or two nucleoli. The
cytoplasm contains one or more Golgi
apparatus, and is rich in mitochondria,
lysosomes, dense bodies, phagosomes
and myelin figures. The cytoplasm of
about 5-40% of the cells of the infiltrate in
many cases contains the so-called pleo-morphic cytoplasmic inclusions {380-382,532}, varying in number from cell to
cell. The pleomorphic cytoplasmic inclu-sions are unique and highly complex
structures consisting mainly of unit mem-branes, occasionally surrounding elec-tron-dense areas containing vesicles.
Birbeck granules are absent. About 20%
of all macrophages show collageno-phagic activity {379,766}, but not pleo-morphic cytoplasmic inclusions.
Prognosis and predictive factors
The purely cutaneous forms of reticulo-histiocytosis (solitary and generalized)
may involute spontaneously {382,847}. It
is possible that the generalized purely
cutaneous form is an early stage of MR,
before the appearance of joint and vis-ceral lesions {381,847}, In MR, there is no
parallelism between the mucocutaneous
and articular manifestations. The muco-cutaneous lesions have an unpredictable
course, and may remit spontaneously. In
half of the patients, the osteoarticular
manifestations become stable, while in
the other half, they show a progressive
destructive course {1405}. The prognosis
is favourable for the cutaneous forms.
The prognosis of MR is related to the
importance of the osteoarticular manifes-tations and of the underlying immunolog-ic disorders and neoplasms.
B CA
Fig. 4.92 Reticulohistiocytosis. A Conventional microscopy: the histological pattern of the lesions is characterized by the presence of numerous, large, mononucle-ated histiocytes with an abundant eosinophilic, finely granular cytoplasm.  B Conventional microscopy: in these giant cells showing leukocyte phagocytosis, the
typical ground-glass appearance of the cytoplasm is evident.  C Conventional microscopy: Weigert-Van Gieson staining. Collagen phagocytosis is an occasional
finding.
Fig. 4.93 Reticulohistiocytosis. Electron micro-scopy: the polymorphism of the granules is evident
at higher magnification.
226 Haematolymphoid tumours
Definition
Mastocytosis is a heterogeneous group
of disorders characterized by the abnor-mal growth and accumulation of a clone
of mast cells in one or more organ sys-tem {1448}. Most patients have cuta-neous mastocytosis (CM) with indolent
disease that is confined to the skin and
that may regress spontaneously.
A minority of patients, usually adults,
have systemic mastocytosis (SM) that
may rarely be highly aggressive and
associated with multi-system involve-ment and short survival time, or that may
be associated with non-mast-cell
haematopoietic malignancies {1450,
2372,2405}.
ICD-O Codes
Cutaneous mastocytosis (CM); macu-lopapular or plaque type mastocytosis,
formerly urticaria pigmentosa (UP);
telangiectatic mastocytosis, formerly
telangiectasia macularis eruptiva per-stans (TMEP); diffuse cutaneous masto-cytosis (DCL); solitary mastocytoma
{965,2405} 9740/1
Indolent systemic mastocytosis
9741/1
Aggressive systemic mastocytosis
9741/3
Mastocytosis with associated
haematopoietic disorder 9741/3
Mast cell leukaemia 9742/3
Synonyms
Mast cell disease; mast cell proliferative
disease
Epidemiology
Cutaneous mastocytosis may be present
at birth and usually first appears before
six months of age.  A second peak inci-dence is found in young adults in their
3rd and  4th decades. Paediatric masto-cytosis usually regresses by adoles-cence.  Adult mastocytosis is more likely
to be persistent and may be associated
with SM, rarely also with aggressive sys-temic mastocytosis. There is no clear
gender or ethnic predominance of cases
{964,1450}.
Etiology
The KIT protein is a receptor tyrosine
kinase that is also known as the mast cell
growth factor receptor.  Adult mastocyto-sis and rare pediatric cases are associ-ated with somatic mutations in the c-KIT
proto-oncogene that alter the enzymatic
site of the KIT protein {361,1449}.  Rare
kindreds with familial mastocytosis have
germ line c-KIT mutations that affect reg-ulatory portions of the KIT protein, also
causing constitutive kinase activation.
These patients may also have gastroin-testinal stromal tumours (GISTs) which
are known to be caused by regulatory
type c-KIT activating mutations {189,
Mastocytosis  B.J. Longley
B.M. Henz
Fig. 4.94 Cutaneous mastocytosis.  A Wheal and flare of Darier sign. The skin lesions of all forms of cutaneous mastocytosis may urticate when stroked.  A palpa-ble wheal appears a few moments after physical stimulation, due to histamine from the mast cells.  B Tense blister containing clear fluid on skin of infant with dif-fuse cutaneous mastocytosis. The skin may appear thickened and reddish brown with diffuse involvement. Note the blister caused by mast cell degranulation  and
histamine release.  Blisters may form in infants because the dermal-epidermal junction is not yet well developed.  C Large pigmented papules of paediatric urticaria
pigmentosa.  D Reddish brown macules, patches and plaques on abdomen and arm of an adult with cutaneous and systemic mastocytosis.  E Telangiectasia mac-ularis eruptiva perstans form of cutaneous mastocytosis in an adult. F Pigmented macules of adult type urticaria pigmentosa. The number of lesions may range from
a few to thousands.
FED
CBA
227Mastocytosis
1447}. In skin and bone marrow mast
cells, there is also an increased expres-sion of anti-apoptotic molecules in both
paediatric and adult mastocytosis {963,
966}.
Localization
Eighty percent of patients with mastocy-tosis have disease confined to the skin.
Conversely, of the 20% of patients with
systemic mastocytosis, about half have
cutaneous involvement.  Essentially all
patients with SM are adults and have
involvement of the bone marrow, but any
other organ may also be involved, most
commonly the spleen, lymph nodes, or
gastrointestinal tract {116,580,2224,
2372}.
Clinical features
Cutaneous mastocytosis includes sever-al distinct clinico-pathologic entities
whose morphologies include solitary
tumours (Mastocytoma), maculo-papular
or plaque-type lesions that are mostly
symmetrically distributed (UP/TMEP),
and diffuse cutaneous involvement
(DCM).
Stroking of any lesion of CM may cause
mast cell degranulation with localized
swelling or urtication (Darier sign).
Clinically normal skin may also urticate
when stroked, (so-called dermo-graphism). Moderate itching is present in
about half of the patients {579}. Most
cutaneous lesions show an increase in
epidermal melanin pigment which, com-bined with the tendency of these lesions
to urticate, has led to the term “urticaria
pigmentosa”, a historic designation that
has recently been proposed to be aban-doned {2405}. Blistering or bullous mas-tocytosis is not a distinct entity but repre-sents an exaggeration of Darier sign
seen in infants whose dermo-epidermal
junction is not well developed so that
accumulation of edema fluid results in
the formation of localized blisters {964}.
Other symptoms of mastocytosis may be
due to mast cell infiltration of specific
organs or due to release of mast cell
mediators into the circulation. Organs
affected include: the gastrointestinal
tract (peptic ulcer disease, diarrhoea
and cramping) or the cardio-pulmonary
and cardio-vascular systems (flushing,
syncope, headache, seizures, hyperten-sion, hypotension including anaphylaxis,
tachycardia, and respiratory symptoms).
Patients with extensive involvement may
have relatively vague constitutional
symptoms including fatigue, weight loss,
fever, sweats, and non-specific psychi-atric symptoms {964,1450}.
Patients with SM may have also bone-related complaints such as pain, frac-tures, or arthralgias, secondary to direct
mass effects or generalized osteoporo-sis.
The diagnosis of cutaneous mastocyto-sis is established by skin biopsy that
demonstrates increased numbers of
mast cells in the dermis. Imaging studies
or biopsy of bone marrow or other inter-nal organs are usually not indicated in
the absence of abnormality of the
peripheral blood counts or specific signs
or symptoms pointing to internal organ
involvement.
The clinical presentation of CM may
range from subtle diffuse erythema to
grossly evident, widespread doughy der-mal thickening with accentuation of cuta-neous surface markings, giving a so-called “grain leather”, (peau chagrine) or
orange skin (peau d’orange) appear-ance {964,1449,1450,2430,2525}.  Tense
blisters filled with clear fluid, occasional-ly slightly-tinged with blood, may be seen
overlying lesions of any form of cuta-neous mastocytosis in infants.
Individual lesions in young children tend
to be lightly pigmented and occur as soli-tary nodules or multiple papules, or
rarely as large heavily pigmented mac-ules, large plaques, or diffuse infiltration
of the skin {964}. Large lesions or diffuse
involvement in children may point to the
presence of c-KIT activating mutations
{2405}.  In adolescents and adults, the
individual lesions tend to be more heavi-ly pigmented and macular, rather than
papular, like those of young children. The
term TMEP has been used for these
macular lesions and for larger, lightly pig-mented patches with telangiectasias that
may rarely occur in adults {964}. Cuta-neous involvement in SM usually
appears morphologically identical to CM
in adults, but may also show larger
plaque like lesions.
Histopathology
In haematoxylin and eosin (H&E) stained
sections, normal mast cells have moder-ately abundant, oval or polygonal
shaped cytoplasms with round to oval
nuclei, sometimes giving the appear-ance of a “fried egg”. The nuclei have
clumped chromatin and indistinct or
inapparent nucleoli. The cytoplasms are
filled with small, faintly visible, eosino-philic or amphiphilic granules which stain
metachromatically with the Giemsa or
toluidine blue stains.   Occasionally, mast
cells may be spindle shaped or show bi-or multi-lobated nuclei {1401,1450,1607,
2405}.
In normal skin, individual mast cells are
found perivascularly and scattered
throughout the dermis, without formation
of clusters. Mast cells in mastocytosis
also tend to accumulate perivascularly,
and are most often evident in the super-Fig. 4.95 Mastocytoma of the skin. Stains containing toluidine blue stain the mast cell cytoplasmic granules
metachromatically purple.
228 Haematolymphoid tumours
ficial dermis, within the dermal papillae
{1401,1607}. In solitary mastocytomas
and papular, nodular, or diffuse CM, the
papillary and/or reticular dermis may
show either scanty increases in mast cell
numbers or heavy mast cell infiltrates,
and there may be extension into the sub-cutaneous fat.  In CM, individual mast
cells may rarely be found in the lower
epidermis.  Unequivocal diagnosis of
cutaneous mastocytosis requires the
demonstration of aggregates of mast
cells within the dermis, and this may be
difficult and require multiple biopsies in
the TMEP form of adult mastocytosis.
Lesions of mastocytosis are usually com-posed of an infiltrate of monomorphous
mast cells, and rarely observed infiltrat-ing eosinophils should raise the possibil-ity of dermal hypersensitivity reaction,
parasitosis or an arthropod bite.
Immunohistochemistry
Mast cells are bone-marrow derived cells
and therefore express CD45 (CLA).  They
also express CD117 (the KIT protein)
and HLA-DR.  Relatively specific mast
cell markers include highly sulfated gly-cosaminoglycans like heparin (toluidine
blue stain), tryptase and chymase. CD-2
and/or CD25 may be  aberrantly ex-pressed in mast cells of SM {934, 2404,
2405}.
Histogenesis
Mast cells are derived from CD34+
haematopoetic precursor cells {1982}.
Somatic genetics
Mastocytosis is a clonal disease in both
adults and children {1448,1449}. The
tumour cells of almost all cases of adult
onset sporadic disease carry somatic
point mutations of c-KIT that change the
enzymatic site of the KIT protein, causing
constitutive activation {361,1449}.
Paediatric sporadic mastocytosis has
also been shown to be clonal, but c-KIT
activating mutations are rare {361,1449}.
Very rare cases of familial mastocytosis,
usually associated with GISTs tumours,
are associated with germ line c-KIT
mutations that activate KIT by affecting
regulatory portions of the molecule,
rather than the enzymatic site {189,
1447}.
Prognosis and predictive factors
Patients with mastocytosis confined to
the skin generally have a good progno-sis, and cutaneous involvement is usual-ly an indicator of a relatively better prog-nosis in SM. CM in paediatric patients
with solitary mastocytomas or typical
papular and macular rashes usually
regresses by adolescence. The pres-ence of enzymatic site type KIT activat-ing mutations may indicate persistent
disease in this population, and classifica-tion of mastocytosis based on both clini-cal and molecular genetic features may
eventually prove to be  both prognosti-cally and therapeutically useful {1446,
1465}.  In adults, although CM may be
symptomatic and persist, overall survival
is usually not adversely affected, even in
the face of concomitant systemic involve-ment. Patients having aggressive vari-ants of SM, however, may have a rapidly
progressive downhill course with survival
measured in months.  In patients with
associated haematologic malignancies,
the prognosis is determined by the
course of the related haematologic dis-ease {964}.
CHAPTER 5
Soft Tissue Tumours
Most soft tissue tumours are benign, outnumbering malignant
ones by about 100 to 1. Soft tissue sarcomas comprise over 50
histological types, many of which have more than one subtype.
Their behaviour varies from indolent to very aggressive, with
consequent variation in survival, according to histological type,
grade, and sometimes genetic constitution, but the overall 5
year survival is about 65-75%. In general, sarcomas in skin or
subcutis have a more favourable outcome than those located
beneath deep fascia. Only those tumours with a predilection for
the skin, and not already covered in the WHO Classification of
Tumours of Soft Tissue and Bone are described in this chapter.
230 Soft tissue tumours
WHO histological classification of soft tissue tumours
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of  Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.
Vascular tumour
Haemangioma of infancy 9131/0
Cherry haemangioma 9120/0
Sinusoidal haemangioma 9120/0
Hobnail haemangioma 9120/0
Glomeruloid haemangioma 9120/0
Microvenular haemangioma 9120/0
Angiolymphoid hyperplasia with eosinophilia
Spindle cell haemangioma 9136/0
Tufted angioma 9161/0
Arteriovenous haemangioma 9123/0
Cutaneous angiosarcoma 9120/3
Lymphatic tumours
Lymphangioma circumscriptum 9170/0
Progressive lymphangioma 9170/0
Smooth and skeletal muscle tumours
Pilar leiomyoma  8890/0
Cutaneous leiomyosarcoma  8890/3
Fibrous, fibrohistiocytic and histiocytic tumours
Dermatomyofibroma 8824/0
Infantile myofibromatosis 8824/1
Sclerotic fibroma 8823/0
Pleomorphic fibroma 8832/0
Giant cell fibroblastoma 8834/1
Dermatofibrosarcoma protuberans 8832/3
Dermatofibroma (fibrous histiocytoma) 8832/0
__________
From references {892,2219}.
Superficial tumour is located exclusively above the superficial fascia without invasion of the fascia; deep tumour is located either exclusively beneath the supeficial fascia, or super-ficial to the fascia with invasion of or through the fascia. Retroperitoneal, mediastinal and pelvic sarcomas are classified as deep tumours.
Primary Tumour (T)
TX: Primary tumour cannot be assessed
T0: No evidence of primary tumour
T1: Tumour ≤ 5cm in greatest dimension
T1a: superficial tumour*
T1b: deep tumour
T2: Tumour > 5cm in greatest dimension
T2a: superficial tumour
T2b: deep tumour
Regional lymph nodes (N)
NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastasis
N1: regional lymph node metastasis
Notes: Regional node involvement is rare and cases in which nodal status is not
assessed either clinically or pathologically could be considered NO instead of
NX or pNX.
Distant metastasis (M)
M0: no distant metastasis
M1: distant metastasis
G Histopathological Grading
Translation table for three and four grade to two grade (low vs. high grade)
system
TNM two grade system Three grade systems Four grade systems
Low Grade Grade 1 Grade 1
Grade 2
High Grade Grade 2 Grade 3
Grade 3 Grade 4
Stage grouping
Stage IA T1a NO,NX MO Low grade
T1b NO,NX MO Low grade
Stage IB T2a NO,NX MO Low grade
T2b NO,NX MO Low grade
Stage IIA T1a NO,NX MO High grade
T1b NO,NX MO High grade
Stage IIB T2a NO,NX MO High grade
Stage III T2b NO,NX MO High grade
Stage IV Any T N1 MO Any grade
Any T Any T M1 Any grade
TNM classification of soft tissue sarcomas
Epidemiology
Age-standardized incidence rates of soft
tissue sarcomas, which are fairly con-stant in most areas covered by cancer
registration, range from 1-3 per hundred
thousand population {1781}. Sarcomas
of cutaneous origin are relatively rare,
and are far outnumbered by carcinomas,
melanoma and benign mesenchymal
neoplasms of skin and subcutis (superfi-cial soft tissue). The most common
benign tumours are lipomas, fibrous his-tiocytomas, vascular or smooth muscle
lesions including angioleiomyomas, and
nerve sheath tumours (schwannoma,
neurofibroma). Some of these tumours
are covered elsewhere {756}. The vast
majority are located superficially and do
not exceed 5 cm in diameter.
Sarcomas are mostly found in older
adults. They arise mainly in the extremi-ties, especially the thigh, followed by
trunk, head and neck and retroperi-toneum.
Etiology
Most soft tissue sarcomas arise sponta-neously and are of unknown etiology. A
small number arise in rare familial cancer
syndromes with germline mutations. A
number of other congenital and inherited
syndromes are associated with benign
and malignant soft tissue tumours; type
examples include Mafucci syndrome
(chondroid and vascular tumours) and
Cowden disease (lipomas, haeman-giomas). Further details can be found in
the WHO Classification of Tumours of
Soft Tissue and Bone {756}.
Non-hereditary genetic factors are also
presumed to be pathogenetic in various
tumour types which have consistent
chromosomal translocations, although it
is not known how or in what cell these
rearrangements arise. Viruses associat-ed with sarcomas include human herpes
virus 8 (HHV8) in Kaposi sarcoma
{434,2487}, and EBV in some smooth
muscle tumours in children and adults
with immunosuppression, including
transplant recipients and patients with
HIV infection {1390,1547}. Angiosarcoma
complicating longstanding lymphoede-ma, especially after radical mastectomy
(Stewart-Treves) might also be due to
local immunosuppression {1995}.
An association between exposure to her-bicides, including dioxin, and sarcoma-genesis is controversial and remains
unproven. Sarcomas can arise in the
field of prior therapeutic irradiation. This
is a dose- and time-related phenomenon,
resulting mostly in subfascial, high-grade
pleomorphic sarcomas after an interval
of 5 or more years. Following irradiation
for carcinoma of breast, low-grade cuta-neous angiosarcomas have been
described after an interval as short as 18
months {1772}.
Clinical features
Benign and malignant tumours present
as usually painless masses, with varying
growth rate. Cutaneous lesions form a
plaque or elevated nodule that can ulcer-ate when malignant. Large (>5 cm)
superficial lesions, and all subfascial or
deep-seated tumours, should be referred
to a specialist multidisciplinary centre
before surgery and preferably before
biopsy {180}.
Pathology
In general, malignant soft tissue neo-plasms are characterized by nuclear
pleomorphism, mitotic activity including
abnormal forms, necrosis and vascular
invasion. Some benign tumours, howev-er, can show one or more of these fea-tures. Examples include nuclear atypia in
cutaneous pleomorphic fibroma and
atypical benign fibrous histiocytoma
(which can also display necrosis), and
frequent mitoses in nodular fasciitis.
Detailed diagnostic criteria are provided
for each subtype.
Diagnostic procedures
Investigation includes clinical assess-ment of size and depth of tumour, the use
of imaging modalities, and biopsy.
Imaging
Imaging is of value for assessing the
extent of a primary tumour and its rela-tionship to normal structures, and for
revealing metastases. Both computer-ized tomography (CT) and magnetic res-onance imaging (MRI) are used. CT is
particularly useful for tumours in body
cavities, and for detecting pulmonary
metastases. MRI can demonstrate intra-tumoural heterogeneity, including pres-ence of solid, fatty, fibrous, haemorrhag-ic or necrotic tissue, and the interface
between neoplastic and normal tissue
including involvement of neurovascular
bundles.
Biopsy
Superficial lesions smaller than 2-5 cm in
diameter can be excised in their entirety.
Larger ones, and all subfascial and
deep-seated tumours need diagnostic
sampling. For this, some practitioners
prefer open incisional biopsy with an
appropriately placed incision that is sub-sequently excised in continuity with the
formal resection. Needle core biopsy,
preferably using a Trucut or larger needle
can provide diagnostic information for
malignancy, subtype and grade, with
high sensitivity and specificity in experi-enced hands {1021,1040}. Fine-needle
aspiration cytology is used in a few cen-tres where a large volume of cases
allows accrual of sufficient experience
{46}; it is not particularly sensitive for
diagnosing malignancy in differentiated
adipose or in sub-typing low-grade myx-oid lesions, partly because the sample
might not be representative.
Tumour spread and staging
The recent WHO classification of
Tumours of Soft Tissue and Bone {756}
recognizes three behavioural categories:
1. Benign tumours. These rarely recur
locally, and those that recur do so in a
non-destructive fashion and are usually
cured by local excision. Exceptionally
rarely, an otherwise (and histologically
typical) benign tumour, such as cuta-neous fibrous histiocytoma, can metasta-size.
2. Intermediate tumours are those that
C. Fisher Soft tissue tumours: Introduction
231Introduction
are locally aggressive and/or very occa-sionally metastasizing. Locally aggres-sive tumours, such as fibromatosis, recur
locally and infiltrate surrounding tissues.
Rarely-metastasizing tumours are gener-ally dermal or subcutaneous tumours
which have a low (1-2%) but definite risk
of metastasis, most often to regional
lymph nodes but occasionally to lung.
Examples are recorded for plexiform
fibrohistiocytic tumour {2028} and
angiomatoid fibrous histiocytoma {693}.
3. Malignant tumours infiltrate and recur
locally and have an appreciable risk of
metastasis (exceeding 20%).
Grading
This is an attempt to predict clinical
behaviour based on histological vari-ables. Grading of a tumour should be
done on material from a primary untreat-ed neoplasm, though change (increase)
of grade can be noted in recurrent or
metastatic tumour. It is not applicable to
all sarcomas; for example, angiosarco-ma, clear cell sarcoma and epithelioid
sarcoma are always considered to be of
high-grade malignancy. Several grading
systems have been proposed, but that of
the French Cancer Centres is gaining
wide usage {917}. Briefly, tumours are
given a score of 1,2 or 3 depending on
degree of differentiation; 1, 2 or 3 for
number of mitoses per 10 hpf (<10, 11-20, or >20); and 0-2 for amount of necro-sis (0, <50%, >50%). A total score count
of 2 or 3 is classified as grade 1, a score
count of 4 or 5 as 2, and a score of 6, 7
or 8 as grade 3.
Staging
A widely used staging system for soft tis-sue sarcomas is that of the International
Union against Cancer (UICC) (TNM sys-tem) and American Joint Commission on
Cancer (AJCC) {892,2219}. Unlike for
many other tumours, staging of sarco-mas includes histological grading as well
as tumour size and depth from surface,
regional lymph node involvement and
distant metastasis.
Prognosis and predictive factors
Completeness of excision (assessed by
clear surgical margins in the excision
specimen) is the most important factor in
prevention of local recurrence {2376}.
Some sarcomas, notably epithelioid sar-coma, are relentlessly recurrent, even
though they might not metastasize until
late in the course of the disease {2238}.
For metastasis, general adverse factors
are large tumour size and increasing
depth from surface. Thus, cutaneous sar-comas have a lower risk of metastasis
than those located more deeply {2001};
indeed, histologically malignant leio-myosarcomas confined to skin are
essentially non-metastasizing tumours
{1164}. In some instances, histological
subtype is predictive, but one of the prin-cipal factors in assessing prognosis and
determining management is the histolog-ical grade. Low-grade sarcomas, howev-er, when located in sites where complete
surgical excision is difficult, such as
retroperitoneum or head and neck, have
a worse outcome than similar tumours in
the extremities. Molecular genetic find-ings, especially fusion gene types, might
relate to prognosis.
232 Soft tissue tumours
Haemangioma of infancy
Definition
Haemangioma of infancy (HOI) is a pro-liferation of benign capillaries character-ized by perinatal or congenital onset,
rapid proliferation in the first year, fol-lowed by spontaneous regression.
Strong expression of GLUT1 is distinctive.
ICD-O code 9131/0
Synonyms
Infantile haemangioma, juvenile haeman-gioma.
Epidemiology
HOI is the most common tumour of infan-cy, affecting up to 10-12% of children
{1051,1119}. There is a predilection for
females (at least 3:1) {1663}, Caucasians
and premature infants {1051,1853}.
Presentation is exclusively in infants,
although involuting lesions persist into
childhood.
Etiology
The unique immunophenotypic resem-blance of HOI and placental vessels
suggests shared regulatory mecha-nisms, or possibly a common cellular ori-gin {1723}. Two recent studies have
demonstrated endothelial cell clonality in
HOI {295,2452}, suggesting a possible
role for somatic mutation {2452}.
Localization
It most commonly affects the skin and
subcutis of the head and neck, followed
by the trunk and extremities. Visceral
involvement, although rare, is most com-mon in the liver, followed by the lung,
brain, and intestine {746}.
Clinical features
Nascent lesions appear as blanched
macules or erythematous patches, often
with central telangiectasias, typically
around 2 weeks of age. Approximately
30% are congenital. Following a rapid
growth phase of 3-18 months, involution
occurs over several years, often leaving
a fibrofatty residuum. Most develop as
focal masses, although some show a dif-fuse, segmentally distributed pattern
{2453}. Although usually solitary, many
affected infants have several lesions.
Rare cases of “diffuse neonatal haeman-giomatosis” have multiple small skin
lesions accompanied by visceral lesions
{1454}. Large facial haemangiomas may
be associated with posterior fossa mal-formations, aortic coarctation, cardiac
defects, arterial abnormalities, eye
abnormalities, and sternal clefting
(PHACES syndrome) {1591}. Lumbo-sacral haemangiomas may be associat-ed with spinal dysraphism, tethered cord
syndrome, and other caudal abnormali-ties {850}. MRI in the proliferative phase
shows a tumoural mass with flow voids.
Macroscopy
Proliferative phase lesions show solid tan
lobules, are well-defined but not encap-sulated.
Histopathology
Proliferative phase lesions are cellular
masses of plump endothelial cells and
pericytes with abundant cytoplasm and
enlarged nuclei that together form capil-laries with tiny rounded lumina. Investing
basement membranes are multilaminat-ed; mast cells are numerous. The capil-laries are arranged in delicately defined
lobules, separated by thin fibrous septi
or normal intervening tissue. Mitotic fig-ures may be numerous; supportive arter-ies and veins are prominent.
During involution, endothelial cells and
pericytes flatten, lumina enlarge, and
mitotic figures diminish. Capillaries pro-gressively drop out and are replaced by
loose connective tissue. End-stage
lesions often show isolated groups of
“ghost” vessels composed of thick, acel-lular basement membrane rings contain-ing apoptotic debris.
Immunohistochemistry
All stages are distinguished from other
vascular tumours by their strong
endothelial positivity for several antigens,
including GLUT1, Lewis Y antigen,
FcgRII, and IGF-II {1722,1723,1942}.
Basement membranes strongly express
merosin {1723}.
Differential diagnosis
Proliferative phase HOI must be distin-guished from other cellular vascular pro-liferations including congenital non-pro-gressive haemangioma, kaposiform hae-mangioendothelioma, tufted angioma,
pyogenic granuloma, and intramuscular
haemangioma. Involuting HOI may
mimic vascular malformations. The cha-racteristic GLUT1 immunoreactivity of
HOI is helpful in routinely fixed speci-mens {1722}.
Somatic genetics
HOI are generally sporadic, although
autosomal dominant inheritance has
been suggested in several kindreds
{259}. Monozygotic and dizygotic twins
show no significant difference in concor-dance for haemangioma development
{464}. No cytogenetic abnormalities have
been reported.
Cherry haemangioma
Definition
Cherry haemangioma (CH) is a benign,
acquired, well-circumscribed aggregate
of dilated capillaries and venules in the
superficial dermis.
ICD-O code 9120/0
Synonyms
Campbell de Morgan spots, de Morgan
spots, senile haemangioma.
Epidemiology
CH is rare before puberty, with a few
lesions developing in early adulthood.
Number and incidence increase through
adulthood, becoming almost universally
present with large numbers in some
patients. Sex predilection is not a feature,
with the exception of lesions that can
occur in pregnancy {169}.
233Vascular tumours
Vascular tumours M.C. Mihm, Jr.
K.J. Smith
H.G. Skelton
E.J. Glusac
G.F. Kao
P.E. North
D. Weedon
O. P. Sangueza
R.C. Kasper
P. LeBoit
E. Calonje
K.C. Lee
J. K.C. Chan
I. Sanchez-Carpintero
Etiology
Age is the most common factor in the
development of the majority of lesions.
Eruptive cases have been reported after
exposure to sulphur, mustard gas, bro-mide compounds and 2-butoxyethanol
solvent {510,747,1901}. There are two
reports of outbreaks in populations, with-out definite causes {1058,2145}. CH
lesions that develop in pregnancy can
involute in the puerperium and eruptive
lesions have been reported in two
patients with elevated prolactin levels
suggesting a hormonal factor in some
lesions {169,1924}.
Localization
The majority of lesions are located on the
trunk and upper limbs with relative spar-ing of the head and neck. There is no
predilection for exposed skin.
Clinical features
CH begins as a barely discernible red
macule that enlarges to become a slight-ly elevated erythematous papule 1-5 mm
in diameter. It may resist blanching with
pressure.
Histopathology
CH is a tightly grouped, well-circum-scribed collection of capillary vessels
and venules in the superficial dermis with
minimal dilatation of some lumena.
Elevated lesions show epidermal atrophy
with loss of rete ridges and sometimes an
epithelial collarette.
Endothelial cell nuclei may be protuber-ant. Sheaths of hyaline multilayered
basement membrane material com-posed of laminin, collagen IV and colla-gen VI surround most vessels {2317}.
Stromal mast cells may be increased
compared to normal skin {938}. The
endothelial cells are fenestrated and
show high levels of carbonic anhydrase
{668}. Ki-67 proliferating cell marker is
not positive in endothelial cells of CH
{2388}.
Histogenesis
Ultrastructural three-dimensional studies
show that CH is composed of intercon-nected spherical and tubular dilatations
of venous capillaries and postcapillary
venules in the dermal papillae {303}.
Somatic genetics
A genetic or angiogenic factor has not
yet been implicated in the development
of CH.
Sinusoidal haemangioma
Definition
Sinusoidal haemangioma is a benign
vascular neoplasm in which cavernous
appearing vascular spaces occur in a
well circumscribed, generally small
papule or nodule. Most clinicians use the
term cavernous haemangioma to refer to
much larger and more poorly circum-scribed lesions in infants.
ICD-O code 9120/0
Synonym
Cavernous haemangioma (erroneous, in
part).
Epidemiology
Most reported cases are in adult women.
Localization
The arms and torso are the most com-mon sites {366}.
Clinical features
Most sinusoidal haemangiomas are
freely movable deep dermal or subcuta-neous papules or small nodules. When
deep, they may be colourless or bluish,
but when superficial, they may be red.
Histopathology
Sinusoidal haemangiomas are round or
oval and very well circumscribed dermal
or subcutaneous neoplasms {366,1680}.
They are composed of thin walled ves-sels with capacious round lumena. The
vessels are very closely apposed to one
another (“back to back appearance”).
Occasional lesions have smooth muscle
in their walls. Thrombosis of vascular
channels occurs in a proportion of cases.
This can lead to intravascular papillary
endothelial hyperplasia (a potential stim-ulant of angiosarcoma in a partial biopsy)
and calcification may result {1680}.
Hobnail haemangioma
Definition
Hobnail haemangioma (HH) {389,916,
1584,1896,2052} is a benign vascular
proliferation characterized by a wedge-shaped dermal proliferation of irregular
vascular channels lined in its superficial
portion by endothelial cells with hobnail
morphology.
ICD-O code 9120/0
Synonym
Targetoid haemosiderotic haemangioma
Epidemiology
HH is relatively rare and presents mainly
in young to middle-aged adults with
predilection for males.
Etiology
Trauma may play a role in the formation
234 Soft tissue tumours
Fig. 5.1  Cherry haemangioma. Thickened basement membrane material around some vessels and protu-berant endothelial cells.
of these lesions {2052}. One possible ori-gin is via trauma to lymphangiomas or
angiokeratomas, resulting in dispersion
of endothelial cells and erythrocytes into
the surrounding dermis.
Localization
Most cases occur on the lower limbs with
predilection for the thigh followed by the
upper extremities and the trunk. Rare
lesions have been reported in the oral
cavity including the tongue and gingivae.
Clinical features
Some lesions show a characteristic
targetoid clinical appearance with vari-ably pigmented ecchymotic haloes sec-ondary to bleeding and haemosiderin
deposition within the tumour {2052}. Most
often however, the clinical presentation is
non-distinctive and the clinical differen-tial diagnosis includes haemangioma,
naevus or fibrous histiocytoma. HH is
asymptomatic, usually less than 2 cm in
diameter and increases in size very slow-ly. Patients usually describe cyclic
changes {389}. Multiple lesions are
exceptional. Similar histological changes
may occur after trauma {481}.
Histopathology
The most striking low-power feature is
the presence of a wedge-shaped vascu-lar proliferation consisting of superficial,
dilated and thin-walled vascular chan-nels lined by bland endothelial cells that
appear flat or have hobnail morphology.
Some of the vascular channels resemble
lymphatics. Focally, intraluminal small
papillary projections with collagenous
cores are occasionally seen. As the vas-cular channels descend further into the
reticular dermis they gradually become
smaller and disappear. Inflammation is
not usually a feature. Haemorrhage and
haemosiderin deposition are prominent
but vary according to the stage of evolu-tion. A Perls stain may be useful in high-lighting the haemosiderin.
Immunohistochemistry
The endothelial cells in HH stain diffuse-ly for vascular markers including CD31
and VWF (von Willebrand factor). CD34
is usually negative or very focal. A layer
of alpha-smooth muscle actin pericytes
surrounds some of the vascular chan-nels. The positive staining for vascular
endothelial growth factor receptor-3
(VEGFR-3) in some cases has led to the
suggestion that HH displays lymphatic
differentiation {1584}. VEGFR-3 is howev-er, not entirely specific for lymphatic
endothelium. Staining for human herpes
virus 8 is consistently negative {932}.
Differential diagnosis
Kaposi sarcoma differs by the absence
of dilated blood vessels lined by hobnail
cells.
Prognosis
The lesion is entirely benign and there is
no tendency for local recurrence.
Glomeruloid haemangioma
Definition
Glomeruloid haemangioma is a benign
vascular proliferation that occurs inside
ectatic blood vessels, producing a pat-tern reminiscent of renal glomeruli.
ICD-O code 9120/0
Epidemiology
This is a very rare vascular proliferation
that occurs exclusively in patients with
POEMS syndrome (Polyneuropathy,
Organomegaly, Endocrinopathy, Mono-clonal paraproteinaemia and Skin
lesions), which is associated with multi-centric Castleman disease {440,2562}.
Multiple haemangiomas occur in 24-44%
of all patients with POEMS syndrome,
with most being cherry-type haeman-giomas, and only some being glomeru-loid haemangiomas {1301,2312,2580}.
The reported cases of glomeruloid hae-mangiomas show female predominance,
with patients ranging in age from 40-68
years {440,1278,1285,1965,2083,2380,
2562}.
235Vascular tumours
Fig. 5.2 Hobnail haemangioma.  A Typical targetoid clinical appearance, only seen in a minority of cases.  B Intravascular papillae lined by hobnail endothelial cells
are sometimes seen.  C Dilated irregular superficial vascular spaces and prominent haemosiderin deposition.
A
B C
Etiology
Glomeruloid haemangioma has so far
only been found in patients with POEMS
syndrome. Its development may be
mediated by circulating vascular endo-thelial factor, which is present at high
titres in the blood of most patients with
POEMS syndrome {2225,2464}.
Localization
The lesions are mainly found on the
trunk, face and proximal limb, and
exceptionally also in the fingers and
deep soft tissues {440,1278,1285,
1965,2380,2562}.
Clinical features
The lesions manifest as multiple purplish-red papules or nodules, ranging in size
from a few to 15 mm {1278,1285,1965,
2380,2562}. They occur in patients
already known to have POEMS syn-drome, or as an early phenomenon
before the full-blown syndrome develops
{1278,1285,1965,2083,2380,2562}.
Histopathology
Glomeruloid haemangioma is mainly
centred in the upper and mid dermis. It is
characterized by tufts of proliferated,
coiled capillaries projecting inside thin-walled ectatic blood vessels, mimicking
renal glomeruli. The “sinusoidal” endo-thelial cells that line the ectatic vascular
spaces and the surface the vascular tufts
possess dark round nuclei. These cells
also show cleft-like extensions into the
cores of the vascular tufts. The capillary
loops within the tufts are lined by plump
endothelium with slightly larger and paler
nuclei, and supported by pericytes.
Scattered “interstitial” cells that contain
PAS-positive eosinophilic globules are
found between the capillary loops, but
similar cytoplasmic globules can also be
seen in some endothelial cells.
Immunohistochemistry
On immunohistochemical staining, the
endothelial cells of the capillary loops
stain for CD31 and CD34, and they are
well supported by actin-positive peri-cytes. The sinusoidal endothelial cells
covering the tufts are positive for CD31
but not CD34, while those lining the
ectatic vascular spaces are strongly
CD31 positive but weakly CD34 positive.
The eosinophilic globules probably rep-resent immunoglobulin. The cells that
contain these globules represent a mix-ture of histiocytes (CD68+) and endothe-lial cells (CD31+).
Precursor lesions
Progression from cellular immature, non-specific, vascular proliferation with slit-like canals reminiscent of tufted angioma
to classical glomeruloid haemangioma
has been reported {2562}. In addition,
cherry-type haemangiomas with minia-ture glomeruloid structures formation can
coexist with glomeruloid haemangiomas
in patients with POEMS syndrome {440}.
Thus these might represent precursor
lesions of glomeruloid haemangioma.
Histogenesis
The currently favoured view is that glo-meruloid haemangioma is a reactive vas-cular proliferation, perhaps representing
a distinctive form of reactive angioen-dotheliomatosis.
Prognosis and predictive factors
Glomeruloid haemangioma per se is a
totally innocuous lesion. The outcome of
the patients depends on the underlying
POEMS syndrome.
Microvenular haemangioma
Definition
Microvenular haemangioma is an
acquired, slowly growing asymptomatic
lesion with an angiomatous appearance
{1080}.
ICD-O code 9120/0
Etiology
A histogenetic relationship between
microvenular haemangioma and hor-monal factors such as pregnancy and
hormonal contraceptives has been pos-tulated {144,2065}, but this feature has
not been corroborated by other authors.
An example of microvenular haeman-gioma has developed in a patient with
Wiskott-Aldrich syndrome {1939}. Haem-angiomas identical to microvenular hae-mangioma can be seen in patients with
POEMS syndrome {25}.
Localization
It most commonly affects the upper
limbs, particularly the forearms.
236 Soft tissue tumours
Fig. 5.3  Glomeruloid haemangioma.   A The dermis shows a vascular proliferation occurring exclusively within thin-walled ectatic vascular spaces, producing a
glomerulus-like appearance.  B The vascular proliferation consists of aggregates of capillaries projecting as a broad tuft into a vascular space. The endothelial cells
that line the vascular space and surface of the tuft have dark-staining nuclei (“sinusoidal endothelium”), while those that line the capillaries have plumper and paler
nuclei. “Interstitial” cells containing eosinophilic hyaline globules are also seen.
BA
However, lesions on the trunk, face and
lower limbs have also been recorded
{65,1061}.
Clinical features
Microvenular haemangiomas appear as
sharply circumscribed, bright red, soli-tary lesions varying in size from 0.5-2 cm.
Histopathology
Microvenular haemangioma appears as
a poorly circumscribed proliferation of
irregularly branched, round to oval, thin-walled blood vessels lined by a single
layer of endothelial cells. They involve
the entire reticular dermis and a variable
degree of dermal sclerosis is present in
the stroma. The lumina of the neoplastic
blood vessels are inconspicuous and
often collapsed with only a few erythro-cytes within them.
The main differential diagnosis is with
Kaposi sarcoma in the patch stage.
Kaposi sarcoma shows irregular anasto-mosing vascular spaces, newly formed
ectatic vascular channels surrounding
pre-existing normal blood vessels and
adnexa (promontory sign), plasma cells,
hyaline (eosinophilic) globules, and
small interstitial fascicles of spindle cells.
All of these features are absent in
microvenular haemangioma.
Immunohistochemistry
Immunohistochemically, the cells lining
the lumina show positivity for factor VIII-related antigen and Ulex europaeus I
lectin {144,1080,2065} which qualifies
them as endothelial cells. Some smooth
muscle actin positive perithelial cells
have been also described surrounding
this vascular space {65,1061}.
Prognosis
Microvenular haemangioma is a benign
neoplasm and it is cured by simple exci-sion.
Angiolymphoid hyperplasia
with eosinophilia
Definition
Angiolymphoid hyperplasia with
eosinophilia (ALHE) is a benign skin or
subcutaneous tumour that is a circum-scribed combined proliferation of imma-ture blood vessels and chronic inflamma-tory infiltrate usually containing eosino-phils. Endothelial cells have a distinctive
epithelioid or histiocytoid appearance
with ample eosinophilic cytoplasm.
Synonyms
Epithelioid haemangioma, cutaneous
histiocytoid angioma, pseudo- or atypi-cal pyogenic granuloma, inflammatory
angiomatous nodule, intravenous atypi-cal vascular proliferation, nodular
angioblastic hyperplasia with eosinophil-ia and lymphofolliculosis {201,1154,
1967,1968,2381}.
Epidemiology
ALHE was originally described as a
lesion commonly found in young women
on the head and neck {1011}. Recent
reviews show a wide age range peaking
at 20-50 years without female predomi-nance {738,1753}. There is no predilec-tion for Asian populations.
Etiology
Reactive vascular proliferation and
inflammation {2441} in a traumatized vas-cular structure is a postulated cause of
some ALHE lesions. History of ante-cedent trauma, histologic evidence of
237Vascular tumours
Fig. 5.4 Angiolymphoid hyperplasia with eosinophilia. Lobulated proliferation of small to medium size blood
vessels with admixed inflammation and a central prominent vessel.
B CA
Fig. 5.5 Angiolymphoid hyperplasia with eosinophilia.  A Epithelioid endothelial cells with abundant cytoplasms, some of which are vacuolated.  B Proliferating imma-ture vessels with protuberant endothelial nuclei associated with lymphoid and eosinophilic inflammation.  C Epithelioid endothelial cells with abundant cytoplasms,
some of which are vacuolated.
adjacent vascular damage {738,2400}
and pre-existing arteriovenous malfor-mation {1754} are found in some cases.
Although earlier reported, HHV-8 has not
been consistently found in ALHE
{1130,1241}.
Localization
ALHE most commonly occurs on the
head and neck with a predilection for the
forehead, scalp and skin around the ear
{738,1011,1753}. Occurrence on distal
extremities and digits is not uncommon
{97}. Multiple other reported sites include
trunk, breast {1676}, oral mucosa {1512,
1530,1776}, orbital tissues {145,1513},
vulva {37,2125} and penis {2240}.
Clinical features
ALHE lesions are small red or violaceous
papules or plaques with an average size
of 1 cm, measuring up to 10 cm. When
symptomatic they can be pulsatile,
painful and pruritic with scale crust
{1011,1753}. When multiple they are usu-ally grouped or zosteriform {647} and
may coalesce. In contrast to Kimura dis-ease, lymphadenopathy, eosinophilia,
asthma and proteinuria are uncommon
and serum IgE is usually normal {97,
441}.
Histopathology
The lobulated, circumscribed dermal or
subcutaneous proliferation has a com-bined vascular and inflammatory compo-nent. Sometimes an origin from a medi-um-sized vessel, usually a vein, is seen.
There are arborizing small blood vessels
that may surround a larger vascular
structure. The vessel walls have smooth
muscle cells or pericytes and contain
mucin. The endothelial cells have distinct
abundant eosinophilic (epithelioid) cyto-plasms that can be vacuolated. They
protrude into and can occlude vascular
lumina or form solid sheets that may
mimic angiosarcoma {2582}. Their nuclei
have open chromatin, often with a central
nucleolus and may protrude into lumina
with occasional mitoses.
Multinucleate cells that are endothelial
sprouts or histiocyte-like cells can be
present {2020}. The density of the inflam-matory component between vessels is
variable with a prominence of lympho-cytes and eosinophils.
Plasma cells, mast cells and lymphoid
follicles with reactive germinal centres
can be present. Older lesions typically
become more fibrotic, less inflammatory
and their vascular nature becomes less
conspicuous.
Immunoprofile
The endothelial cells are positive for
CD31, CD34, VWF (VIIIrAg) and are ker-atin negative. The proliferative index of
the endothelial cells has been reported
as 5% using Ki-67 with negative staining
for Cyclin D1 and bcl-2. This may sup-port a reactive rather than neoplastic
endothelial proliferation {97}. Lympho-cytes are a mixture of T- and B-cells.
There is no light chain restriction {97,
1753}. One series has shown T-cell clon-ality in ALHE that may define a subgroup
of lesions with a higher incidence of
recurrences {1241}.
Differential diagnosis
Kimura disease is a distinct clinicopatho-logical entity, characterized by a more
prominent lymphoid proliferation and
less prominent vascular component with
almost complete absence of epithelioid
endothelial cells.
Prognosis and predictive factors
The lesions tend to persist if not com-pletely excised and only rarely will they
spontaneously regress. Local recurrence
can occur and may be related to persist-ence of an underlying arteriovenous fis-tula that is not completely excised {97,
1753,1754}.
Spindle cell haemangioma
Definition
Spindle cell haemangioma is a benign
238 Soft tissue tumours
Fig. 5.6 Spindle cell haemangioma. This tumour involving the dermis shows pushing borders, and compris-es cavernous vessels intimately intermingled with spindle cells.
Fig. 5.7 Spindle cell haemangioma.  A There is intri-cate mixing of cavernous vessels and spindly cells,
with irregular branching narrow vascular spaces
coursing through the latter component.   B Short
fascicles of uniform spindly cells are evident.
There are interspersed small groups of epithelioid
cells with lightly eosinophilic cytoplasm, some-times with vacuolation.
A
B
vascular tumour composed of an inti-mate admixture of cavernous blood ves-sels and Kaposi sarcoma-like spindle
cell vascular zones.
ICD-O code 9136/0
Synonym
Spindle cell haemangioendothelioma
{1807,2488}
Epidemiology
The tumour is uncommon, and mainly
affects children and young adults. Those
who present late in adulthood usually
have long-standing tumours {270,1807}.
There is no sex predilection.
Etiology
In a small proportion of cases, spindle
cell haemangioma develops in the set-ting of multiple enchondromas (Maffucci
syndrome), Klippel-Trenaunay syn-drome, venous malformation, early onset
varicose veins, or congenital lymphoede-ma {709,754,1807}. The onset in young
patients and frequent finding of abnor-mal vessels around the lesion suggest
that an underlying vascular malformation
may predispose to the development of
spindle cell haemangioma {754}.
Localization
They occur on the distal extremities and
less commonly on the proximal limb,
trunk, head and neck {1807}. Exceptio-nally, it has been reported in the spleen
{709}.
Clinical features
The tumour usually presents as a super-ficial, slow-growing, painless, solitary
purplish mass, or multiple nodules within
an anatomical region {1807}. Rare exam-ples may be painful {1784}. The lesion is
a discrete red-brown nodule that ranges
in size from a few mm to over 10 cm, but
most are smaller than 2 cm.
Histopathology
Spindle cell haemangiomas are mostly
found in the dermis and subcutis, and
occasionally in the deep soft tissues. The
tumour is often well-circumscribed but
non-encapsulated. It is characterized by
intricate blending of cavernous and solid
spindle cell zones. The cavernous blood
vessels are empty or filled with blood,
and may contain organizing thrombi or
phleboliths. In the spindle cell regions,
short fascicles of spindle cells are inter-spersed with ramifying narrow vascular
spaces. The spindle cells possess uni-form, elongated, dark nuclei and eosino-philic cytoplasm. There are scattered sin-gle or groups of vacuolated cells or
epithelioid cells with lightly eosinophilic
cytoplasm.
In about half of the cases, residual vessel
walls can be found in the periphery of the
lesion, indicating that the lesion is partly
or entirely intravascular {754,1807}.
Intravascular extension of the lesion can
sometimes be seen around the main
lesion.
Immunohistochemistry
The cells that line the vascular spaces
stain for VWF (VIIIrAg), CD31 and vari-ably for CD34. The spindle cells are neg-ative for the various endothelial markers
including CD34, and may show patchy
and variable staining for actin {754,796,
1667}.
Differential diagnosis
Spindle cell haemangioma can be distin-guished from Kaposi sarcoma by the fol-lowing features: irregular-shaped, dilated
and ramifying vascular spaces rather
than short narrow vascular slits among
the spindle cells, presence of vacuolated
endothelial cells, frequent partial or com-plete localization within muscular blood
vessels, absence of eosinophilic hyaline
globules, lack of CD34 immunoreactivity
in the spindle cells, and lack of associa-tion with HHV-8 {1034}.
Histogenesis
There are controversies on the nature of
spindle cell haemangioma, with theories
ranging from neoplastic, malformative to
hamartomatous {754,1100,1807}. The
lesion itself comprises heterogeneous
cellular populations, including endothe-lial cells, pericyte-like cells, fibroblasts,
smooth muscle cells and primitive mes-enchymal cells.
Somatic genetics
There are no molecular data on spindle
cell haemangioma; one studied case
shows a normal karyotype {754}. The
lesions are diploid on flow cytometric
analysis {796,1035}.
Prognosis and predictive factors
Recurrence after local excision occurs in
50-60% of cases, and often results from
new lesions developing within the same
anatomical region due to intravascular
extension. However, there is no metasta-tic potential.
Tufted angioma
Definition
Tufted angioma is an unusual, acquired,
benign vascular neoplasm characterized
by slow, indolent growth {1153,1475}.
ICD-O code 9161/0
Synonyms
Tufted haemangioma, progressive capil-lary haemangioma, angioblastoma of
Nakagawa.
Epidemiology
Tufted angioma most commonly affects
children and young adults, but both con-genital and very late onset cases have
been described {995,1264}.
239Vascular tumours
Fig. 5.8 Tufted haemangioma. Another example of
a tufted angioma present in the dermis and subcu-taneous tissue.
Localization
Tufted angioma favours the shoulders,
upper chest, back, and neck {1747},
although examples of these lesions have
also been reported on the oral mucosa,
extremities and head {1289,2458}.
Clinical features
The most common forms of presentation
are enlarging erythematous, brown mac-ules or plaques with an angiomatous
appearance. In other instances the
lesions resemble granulomas or a con-nective tissue naevus. Pain and hyper-hidrosis have been described {216,
2291}. Raised papules or nodules
resembling pyogenic granulomas are
sometimes seen within the lesion and
occasionally they adopt a linear arrange-ment {1765}. In some cases the patients
present with sclerosing plaques {412}.
Tufted angiomas have been associated
with vascular malformations including
naevus flammeus {1267,1601}, pregnan-cy {1272}, non-regressing lipodystrophy
centrifugalis abdominalis {1032}, and
liver transplant {482}. In some cases of
Kasabach-Merritt syndrome the underly-ing lesion is a tufted angioma {691,692,
2136}. In most cases the growth is halted
after some years, and in some cases
there is a slight tendency towards spon-taneous regression {1131}. Tufted
angioma grows slowly and insidiously,
and may eventually come to cover large
areas of the body.
Histopathology
There are multiple individual vascular
lobules within the dermis and subcuta-neous fat. These aggregations are more
prominent in the middle and lower part of
the dermis. Each lobule is composed of
aggregates of endothelial cells that whorl
concentrically around a pre-existing vas-cular plexus.
Some lobules bulge into the walls of dilat-ed thin-walled vascular structures,
crreating a slit-like or semi-lunar appear-ance of vessels. This peculiar shape in
addition to the angiocentricity of the vas-cular structures prompted the name “tuft-ed angioma.” Small capillary lumina are
identified within the aggregations of
endothelial cells. Unusual histopatholog-ic findings in tufted angioma include a
mucinous stroma, abundant sweat
glands {137}, an intravenous location
{795} of the lesion and a proliferation of
lymphatic-like channels.
Immunohistochemistry
Cells in the capillary tufts are weakly pos-itive or negative for VWF (VIIIrAg). They
exhibit strong positivity for CD31, CD34
and alpha-smooth muscle actin {1156,
1709}. The cells that show reactivity for
smooth muscle actin, most likely repre-sent pericytes.
Electron microscopy
Ultrastructural studies have shown char-acteristic crystalloid inclusions within
endothelial cells in addition to Weibel-Palade bodies {1709}.
Genetics
Most cases are sporadic, although a
family with several members affected by
tufted angioma has been reported {993}.
In this particular family the mode of trans-mission was autosomal dominant.
Prognosis
Tufted angioma showing spontaneous
regression is a rare event. Although
benign, symptomatic lesions need to be
treated {1131,1709,1948}.
Bacillary angiomatosis
Definition
Bacillary angiomatosis is a reactive vas-cular proliferation caused by infection
with bacteria of the genus Bartonella,
most commonly B. henselae and B. quin-tana {507,855,1383,1845,2492}.
Synonyms
Disseminated pyogenic granulomas (not
generally accepted), epithelioid
angiomatosis.
Epidemiology
Bacillary angiomatosis most commonly
occurs in immunosuppressed patients
although there have been a few reports
in apparently immunocompetent pa-tients, both adults and children {504,507,
1233,1383,1613,1793,1845,2111,2206,
2325}. Bacillary angiomatosis has most
frequently been seen in HIV/AIDS
patients.
Localization
Cutaneous involvement may occur at any
site and less commonly lesions may
involve mucosal surfaces and deeper
soft tissue such as muscle, bone, lymph
node and liver (peliosis hepatis)
{442,507,1383,1845,2085}.
Clinical features
The lesions present as multiple reddish
to red-brown cutaneous nodules and
occasionally as subcutaneous nodules.
In immunocompetent patients there may
be fewer nodules {507,1383,1845}.
Histopathology
Sections show a lobular proliferation of
well-formed vessels with plump occa-sionally epitheloid endothelial cells.
There is an oedematous to fibrous stroma
with a variable infiltrate of neutrophils
with nuclear dust, macrophages and ill-defined pale basophilic granular material
(representing the bacteria). Diagnosis is
made by identifying the characteristic
cocco-bacillary organisms with a Warthin
-Starry or Giemsa stain {507, 1383,1845}.
Differential diagnosis
Pyogenic granuloma lacks the character-istic basophilic granular material and the
dispersed pattern of neutrophils seen in
bacillary angiomatosis. Histologically
identical lesions can be seen in verruca
peruana (verruga peruana).
240 Soft tissue tumours
Fig. 5.9 Tufted haemangioma.  A The vascular lob-ules in the subcutaneous tissue are composed of
irregular vascular spaces, some of them lined with
prominent endothelial cells.  B The neoplastic cells
are uniform, in some areas with a slit-like or semi-lunar appearance.
A
B
Prognosis and predictive factors
The infection may be cleared by antibi-otics with resolution of the lesions. The
overall prognosis depends upon the
immune status of the patient and sites of
involvement {507,1383,1845}.
Reactive
angioendotheliomatosis
Definition
Reactive angioendotheliomatosis (RA) is
a relatively rare condition associated with
diverse systemic diseases, usually con-fined to the skin and characterized by a
multifocal dermal proliferation of capillar-ies {1559,2513}.
Synonym
Diffuse dermal angiomatosis. The so-called malignant angioendotheliomatosis
represents a form of intravascular lym-phoma not related to reactive angioen-dotheliomatosis {2512}.
Epidemiology
Presentation is mainly in adults with no
sex predilection. Occurrence in children
is exceptional {304}.
Localization
There is a predilection for the trunk and
limbs.
Clinical features
Clinical presentation is variable and con-sists of fairly widespread erythematous
macules, papules, nodules and plaques
{1559,2513}. Purpura is a frequent find-ing. Ulceration is very rare. Many sys-temic illnesses are related to the devel-opment of RA and it can be said that this
condition often represents a marker of
systemic disease.
Patients affected with RA not uncommon-ly are immunosuppressed as a result of
transplantation. Many conditions have
been associated with reactive angioen-dotheliomatosis including valvular car-diac disease, alcoholic cirrhosis,
rheumatoid arthritis, polymyalgia
rheumatica, cryoglobulinaemia, the
antiphospholipid syndrome, and sar-coidosis {551,1385,1559,2178,
2341,2361}. A more localized variant
may be seen in some patients and it is
usually associated with peripheral vas-cular atherosclerosis or iatrogenic arteri-ovenous fistulas {1266,1276,1918}.
Histopathology
Histologically, the dermis and rarely the
superficial subcutaneous tissue show
numerous clusters of closely packed
capillaries. Many of these capillaries pro-liferate within pre-existing blood vessels.
Cytological atypia is mild or absent but
endothelial cells are often prominent and
may show focal epithelioid cell change.
A layer of pericytes surrounds the newly
formed small vascular channels.
Extravasation of red blood cells tends to
be prominent. PAS positive microthrombi
are numerous in cases associated with
cryglobulinaemia. Dermal changes
resembling fasciitis have also been
described.
Differential diagnosis
Distinction from Kaposi sarcoma is easy
as in RA there is no proliferation of indi-vidual irregular lymphatic-like channels
around pre-existing normal blood ves-sels, proliferating vascular channels are
surrounded by a layer of pericytes and
inflammatory cells are very rare or
absent. Tufted angioma may be distin-guished from RA by the typical cannon-ball appearance at scanning magnifica-tion and the presence of slit-like crescent
shaped lymphatics around individual
tufts in the former. An unusual entity char-acterized by the presence of aggregates
of histiocytes within vascular lumina and
described as intravascular histiocytosis
has been recently described and may
closely mimic reactive angioendothe-liomatosis {1935}. Distinction from the
later may be difficult and in difficult cases
immunohistochemistry is useful in
demonstrating the histiocytic nature of
the intravascular cells.
Prognosis and predictive factors
RA tends to be self-limiting in the majori-ty of cases with complete spontaneous
resolution over weeks or months.
241Vascular tumours
CB
A
Fig. 5.10 Bacillary angiomatosis.  A Low power view of a skin lesion of bacillary angiomatosis shows dome
shaped expansion of the upper dermis due to a proliferation of small well formed vessels.  B High power
view showing the plump endothelial cells lining the vessels.   C A Warthin-Starry stain shows the small
cocco-bacillary organisms.
Verrucous haemangioma
Definition
Verrucous haemangioma (VH) is an
uncommon variant of haemangioma with
capillary or cavernous features {444,
2489}. It is evident at birth or in early
childhood and enlarges and becomes
hyperkeratotic in later life.
Synonyms
Haemangioma unilateralis naeviforme,
unilateral verrucous haemangioma,
angiokeratoma circumscriptum naevi-forme, naevus vascularis unius lateralis,
keratotic haemangioma, naevus angiok-eratoticus, naevus keratoangiomatosus
{363}.
Epidemiology
VH is usually apparent at birth or in the
first few years of life {1102}. The condi-tion is rare, and there is no known gender
predilection.
Localization
VH is almost always a unilateral isolated
condition, with most cases affecting the
leg. Less commonly, it presents on the
arm. It is not common on the trunk, but
when present on the back in association
with underlying spinal malformation, it is
a component of Cobb syndrome.
Clinical features
The condition usually presents with
lesions that are clustered, discrete to
nearly confluent, bluish-red, well demar-cated, soft and compressible {363,444,
1102}. The lesions that comprise these
clusters may coalesce to form large
lesions that cover broad areas over time.
Satellite lesions are typical. The condition
may show linear or serpiginous distribu-tion. Lesions become hyperkeratotic
over time and show a brown to bluish-black appearance. Hyperkeratosis may
be so pronounced as to appear verru-cous; consequently, the lesion may be
mistaken clinically for a wart or keratosis
{2560}. Size usually allows distinction
from the later two, as verrucous haeman-gioma tends to be large.
Histopathology
Within the superficial and deep dermis
and sometimes the subcutis there are
dilated capillaries and venules. Vessels
tend to be cavernous in the upper der-mis, few in numbers in the deep dermis,
and capillary-like in the subcutis. A pseu-do-infiltrating pattern may be seen in the
subcutis, but close inspection reveals an
overall lobulated pattern {444}. There
may be thrombosis with secondary pap-illary endothelial hyperplasia. The ves-sels are lined by a single layer of
endothelial cells without evidence of
endothelial proliferation. Inflammatory
cells, haemosiderin and fibrosis may be
associated. Older lesions show promi-nent acanthosis, hyperkeratosis with
crust and papillomatosis. Ulceration is
sometimes present.
Differential diagnosis
Angiokeratoma may also show verrucous
epidermal hyperplasia. Verrucous hae-mangioma differs from angiokeratoma by
its large size, involvement of deep vas-culature and the presence of vessels that
usually vary significantly in size.
Angiokeratomas also show a hereditary
basis in some cases, are often multiple
and show a predilection for the lower
trunk, thigh and external genitalia {444}.
Prognosis and predictive factors
VH has a propensity to recur locally
{2489}. The condition progresses over
time, and superficial therapy has been
reported to exacerbate spread {2560}.
This may be due, in large part, to the fact
that size of the lesion is usually underes-timated clinically {444}. Recurrence may
also be seen in skin grafts.
242 Soft tissue tumours
Fig. 5.11 Verrucous haemangioma.  A A large, irregularly outlined, hyperkeratotic lesion is typical of verrucous haemangioma.  B This low magnification view of ver-rucous haemangioma exhibits a superficial and deep proliferation of variously sized blood vessels.
BA
Pyogenic granuloma
Definition
Pyogenic granuloma (PG) are rapidly
growing, mostly exophytic lesions which
may ulcerate.
Synonym
Lobular capillary haemangioma
Epidemiology
An epidemiologic study of 325 cases,
{959} showed that 86% of the lesions
were cutaneous, while only 12% of the
cases affected mucosa. Overall, male
patients outnumbered female patients.
Pyogenic granuloma is especially com-mon in children and young adults and
the peak incidence is around the second
decade of life.
Etiology
Most authors consider PG to be a hyper-plastic rather than a neoplastic process
{598,1615}. Most lesions develop at sites
of superficial trauma; in some cases
lesions of PG are associated with endo-crine alterations or medication and usu-ally regress upon cessation of the stimuli.
Localization
PG preferentially affects the gingiva, lips,
mucosa of the nose, fingers, and face
{1247,1619}, but examples of pyogenic
granuloma have been described in all
parts of the skin and mucous mem-branes including vulva, scrotum, penis,
and glans penis {10,929,1477,2360}.
Clinical features
PG presents typically as a papule or
polyp with a glistening surface, which
bleeds easily. Pyogenic granuloma usu-ally develops at the site of a pre-existing
injury. The lesions evolve rapidly over a
period of weeks to a maximum size, then
shrink and become replaced by fibrous
tissue, which disappears within a few
months. Epulis gravidarum a gingival
lesion that develops during pregnancy, is
identical to pyogenic granuloma {1669}.
Occasionally, pyogenic granuloma
develop within a pre-existing lesion such
as a naevus flammeus {1394} or in a spi-der angioma {1748}. Multiple lesions
tend to be localized {1787,2309} but they
can also extend in an eruptive and dis-seminated fashion {2533}. With few
exceptions, multiple recurrent lesions are
more common in adolescents and young
adults, and they usually occur after
attempts of electrodesiccation or surgi-cal removal of the primary single lesion.
Multiple lesions may also occur after
removal of other lesions such as
melanocytic neoplasms {621} or in burns
{435}. Multiple lesions most commonly
affect the trunk, especially the inter-scapular region. In some cases, eruptive
widespread lesions of pyogenic granulo-ma are a paraneoplastic manifestation
{1800}. Rare variants of pyogenic granu-loma include the subcutaneous {1777}
and intravenous {540} forms.
Histopathology
Early lesions of pyogenic granuloma are
identical to granulation tissue, contain-ing, numerous capillaries and venules
disposed radially to the skin surface,
which is often eroded and covered with
scabs. The stroma is oedematous and
contains mixed inflammatory infiltrates
with lymphocytes, histiocytes, plasma
cells, neutrophils and an increased num-ber of mast cells. Fully developed lesions
of pyogenic granuloma are polypoid and
show a lobular pattern with fibrous septa
intersecting the lesion; hence the name
lobular capillary haemangioma used by
some authors for lesions at this stage.
Each lobule is composed of aggrega-tions of capillaries and venules lined by
plump endothelial cells. At this stage
most lesions have entirely re-epithelial-ized, and the epidermis forms collarettes
of hyperplastic adnexal epithelium at the
periphery, partially embracing the lesion;
inflammatory infiltrates are sparse and
the oedema of the stroma has disap-peared. In the late stages of pyogenic
granuloma there is a steady increase in
the amount of fibrous tissue, so as the
fibrotic struts widen, the lobules of capil-laries become smaller and, with time,
pyogenic granuloma evolves into a fibro-ma. When the specimen is deep enough,
a small feeding artery and one or more
veins may be seen ascending from the
subcutaneous fat throughout the reticular
dermis to directly enter the base of a
pyogenic granuloma. The histopatholog-ical findings are the same in all variants
of pyogenic granuloma.
Uncommon histopathological features in
lesions of pyogenic granuloma include
intravascular papillary endothelial hyper-plasia {1103} and extramedullary
haematopoiesis {1986}. When the lesions
of PG recur they may show some atypical
features which in some cases resemble
an angiosarcoma especially in the deep-er areas of the lesion. When lesions of PG
develop within a vein, they are usually
attached to the wall of the vein by a stalk
and the lobular pattern is less prominent
than in their extravascular counterparts.
Immunohistochemistry
PG lesions express factor VIII related
antigen positivity in the endothelial cells
lining large vessels, but are negative in
the cellular areas {346}, whereas Ulex
europaeus I lectin binds to the endothe-lial cells in both large vessels and cellu-lar aggregates {1606}. There is also
expression of inducible nitric oxide syn-thase {2169}, increased expression of
vascular endothelial growth factor {298},
low apoptotic rate expression of Bax/Bcl-2 proteins {1682}, and strong expression
of phosphorylated mitogen activated
protein kinase {79} in lesions of pyogenic
granuloma.
PCR investigations for human papillo-mavirus {1615} and human herpes virus
type 8 (HHV8) {598} have yielded nega-tive results.
Prognosis and predictive factors.
Lesions of PG are benign and easily
removed by electrodesiccation and
curettage; however lesions may recur,
especially in those cases in which the
proliferating vessels extend deep within
the reticular dermis.
Cavernous haemangioma
Until a few years ago, the term “cav-ernous haemangiomas” was used to
designate venous malformations. These
lesions were also erroneously consid-ered to be neoplasms, when in reality
they are vascular malformations. They
consist of slow-flowing, haemodynami-cally inactive vascular malformations,
which are present at birth and slowly but
progressively worsen throughout the life-time of the patient. In some cases the
lesions form a continuum of localized
venous malformations, which include
blue capillary spongy blebs, “cavernous”
lesions (in which the venous lacunae are
connected to the venous circulation by
capillaries), localized saccular anomalies
(connected by veins to the venous circu-lation) and diffuse venous ectasias.
Many of the apparently localized and
243Vascular tumours
superficial venous lesions tend to coexist
with venous ectasias and deep vein
anomalies.
Angiokeratomas
Definition
Angiokeratomas are acquired vascular
lesions that result from the ectatic dilata-tion of pre-existing vessels in the papil-lary dermis, accompanied by hyperkera-totic epidermis {1101}. Four clinical vari-ants of angiokeratomas have been rec-ognized, these are: solitary, angioker-atoma corporis diffusum, Mibelli and
Fordyce.
Epidemiology
Solitary angiokeratomas affect mainly
young adults. Angiokeratoma of Fordyce
affects elderly people {34}, however,
there are examples of congenital cases
{768}. Mibelli angiokeratomas usually
appear in childhood or adolescence and
they are more common in females {986}.
Angiokeratomas of Fabry disease usual-ly appear shortly before puberty and as
an X-linked disease, they exclusively
affect males; females may be asympto-matic carriers. Fabry disease is a rare
error of the metabolism that results in a
deficiency of the lysosomal enzyme
hydrolase alpha-galactosidase A. It is
transmitted as an X-linked recessive trait,
the gene responsible for the coding of
alpha-galactosidase A has been local-ized to the middle of the long arm of the
X chromosome {250,770}.
Etiology
Solitary angiokeratomas are thought to
be the result of injury, trauma, or chronic
irritation to the wall of a venule in the pap-illary dermis.
Fordyce angiokeratomas are usually
associated with varicocoele, inguinal
hernia and thrombophlebitis {1788}. The
lesions may develop after surgical
injuries to the genital veins {857}, and
there have been cases of angioker-atomas involving the glans penis mucosa
of young patients developing after cir-cumcisional surgery {249}. Similar
lesions have been described in the vulva
of young females {403,857}. These
lesions are thought to be the result of
increased venous pressure that occurs
during pregnancy or develops secondar-ily to the use of contraceptive pills.
Mibelli angiokeratoma is a condition that
is inherited in an autosomal dominant
fashion. Angiokeratoma corporis dif-fusum is the most unusual variant of all
the angiokeratomas. It represents a cuta-neous manifestation of a group of hered-itary enzymatic disorders, but there is
also an idiopathic form that presents with
no other associated anomalies. Fabry
disease is the disease most commonly
associated with angiokeratoma corporis
diffusum.
Localization
Solitary angiokeratomas may affect any
anatomic site, including the oral cavity,
although the lower limbs are the most fre-quent location {1101}. Fordyce angioker-atomas are most common in the scrotum
and vulva. Mibelli angiokeratomas usual-ly affect the dorsum of the fingers, toes
and interdigital spaces. Lesions of
angiokeratoma corporis diffusum in
Fabry disease affect the lower part of
abdomen, genitalia, buttocks, and thighs
in a bathing-trunk distribution.
Clinical features
Although their biologic significance
varies greatly, angiokeratomas range
from lesions that have very little clinical
repercussion to widespread eruptions
that are a manifestation of potentially
fatal, systemic, metabolic diseases.
Solitary angiokeratomas consist of small,
warty, black, well-circumscribed papu-les. Sometimes solitary angiokeratomas
develop thrombosis and recanalization
with the development of secondary
intravascular papillary clinically endothe-lial hyperplasia. Due to their colour, these
lesions may be clinically confused with
malignant melanoma {857}. Fordyce
angiokeratoma is characterized by the
presence of multiple purple to dark
papules, measuring 2-4 mm in diameter.
In Mibelli angiokeratoma, the lesions
consist of several dark papules with a
slightly hyperkeratotic surface, and may
be associated with acrocyanosis and
chilblains. In rare instances, ulceration of
the fingertips may appear as a complica-tion of Mibelli angiokeratoma {592}.
Lesions of angiokeratoma corporis dif-fusum are small punctate dark red
papules, some of them less than 1 mm in
diameter. A frequent and asymptomatic
finding is the so-called cornea verticilla-ta, which is a superficial corneal dystro-phy. This finding is of diagnostic impor-tance for the detection of mild cases and
female carriers. Other cutaneous mani-festations include dry skin, anhidrosis,
hyperthermic crises {1198}, and acro-paraesthesiae secondary to capillary
changes in the nail matrix {1132}. In rare
instances patients with Fabry disease
may also present with concurrent Klippel
-Trenaunay-Weber syndrome {821}.
Patients with Fabry disease who are
devoid of cutaneous lesions have been
reported {497}. Angiokeratoma corporis
diffusum is not exclusive to Fabry dis-ease and has also been described in
association with other rare inherited lyso-somal storage diseases. By the same
token, rare cases of angiokeratoma cor-poris diffusum have been described in
patients without metabolic anomalies
{565,1518}. In some of these patients the
angiokeratomas were multiple and pre-sented in a zosteriform distribution.
Histopathology
All variants of angiokeratomas are identi-cal under a conventional microscope.
Common features of all angiokeratomas
include the presence of dilated thin-walled blood vessels, lined by a layer of
endothelial cells, in the papillary dermis
and a variable degree of hyperkeratosis
{1101}. Occasionally, angiokeratomas
may be seen overlying deep vascular
malformations {1323}. Hyperkeratosis is
usually absent in Fordyce angioker-atomas and in angiokeratoma corporis
diffusum (Fabry disease). In patients with
Fabry disease there is vacuolization of
the cytoplasm of the endothelial cells of
the arterioles and smooth muscle cells of
the arrector pili. The presence of these
vacuoles may be a clue to the specific
diagnosis in sections stained with
haematoxylin and eosin. However, in
most cases the amount of glycolipid in
the skin is small making it extremely diffi-cult, if not impossible to identify them, in
routinely prepared sections. Special
stains such as Sudan black B and PAS
highlight the presence of glycolipid
deposits within the vacuoles in patients
with Fabry disease and related disor-ders. The lipid material is double refrac-tile, which can be demonstrated by
means of polaroscopic examination of
unfixed, or formalin fixed frozen sections.
Deposits of glycolipids in Fabry disease
are not restricted to the lesions of
angiokeratoma, but may also be seen in
skin that appears to be normal.
244 Soft tissue tumours
Electron microscopy
Ultrastructural studies in angiokeratomas
have demonstrated quantitative alter-ations of cytoplasmic organelles within
the endothelial cells {833}. Electron
microscopy examination of the skin in
Fabry disease show large electron dense
lipid deposits in endothelial cells, peri-cytes, fibroblasts, arrector pili muscles
and in secretory, ductal, and myoepithe-lial cells of the eccrine glands {1683}.
These deposits show a characteristic
lamellar structure {1366,2438}, not seen
in other types of angiokeratomas or in
lesions of angiokeratoma corporis dif-fusum with no enzymatic anomalies.
Other ultrastructural findings in patients
with Fabry disease consist of intersecting
short crescent shaped, tightly packed
membranes in the endothelial cells of the
small cutaneous blood vessels {679} and
cytoplasmic vacuoles in the epithelial
cells of the eccrine glands {1094}.
Arteriovenous haemangioma
Definition
Arteriovenous haemangiomas are
benign, asymptomatic vascular prolifera-tions. They are not associated with signif-icant arterio-venous shunting.
ICD-O code 9123/0
Synonyms
Cirsoid aneurysm, acral arteriovenous
tumour {384,385,528,1811}.
Epidemiology
It occurs mainly in middle-aged adults,
with no sex predilection.
Localization
Arteriovenous haemangioma is a neo-plasm mainly affecting facial skin.
Intraoral and vulvar examples have been
also described {1318,1376,1698,1972}.
Clinical features
Arteriovenous haemangioma presents as
a red, purple, or skin coloured asympto-matic papule measuring 0.5-1.0 cm.
Usually the lesions are solitary, although
multiple examples have been cited.
When the lesions are multiple they tend
to cluster. Occasionally, they are associ-ated with other abnormalities including
epidermal naevus syndrome, vascular
hamartomas and malformations {372}.
Several examples of multiple arteriove-nous haemangiomas have been
described in patients with chronic liver
disease {47}.
Macroscopy
Grossly, lesions of arteriovenous hae-mangioma present as raised papules
and on sectioning there is an admixture
of white and red to brown areas, which
represent the walls of the thick blood
vessels containing blood.
Histopathology
Arteriovenous haemangioma is a well-circumscribed vascular proliferation that
involves the upper and mid reticular der-mis. The neoplasm is composed mainly
of thick-walled muscle-containing blood
vessels, lined by a single layer of
endothelial cells. Intermingled with the
thick-walled blood vessels are thin-walled dilated blood vessels and vari-able amounts of mucin. Although the
thick-walled blood vessels resemble
arteries, they lack a well-formed elastic
internal membrane, and most likely rep-resent ectatic veins {1318}. In about one-fourth of the studied cases it is possible
to identify both the arteriovenous shunts
and the spiralled ascending small mus-cular artery (“feeder” vessel) with serial
sections {834}. The lesions recently
described as symplastic haemangioma
probably represent ancient arteriove-nous haemangiomas with atypical cells
due to degenerative changes that occur
in long-standing lesions {1351}.
Histogenesis
The precise nature of arteriovenous hae-mangioma is uncertain. Initially it was
considered to be a multicentric hamar-toma of the sub-papillary vascular plexus
with one or more arteriovenous anasto-moses {834}. Other authors have sug-gested that a hamartoma of the Sucquet-Hoyer canal of the glomus body is the
cause of this lesion. The latter interpreta-tion, however, is unlikely because glomus
cells are usually absent in arteriovenous
haemangioma, and to date, they have
been identified in only one example of all
the reported cases {1318}.
Prognosis
Arteriovenous haemangioma is a benign
lesion and local excision suffices.
Cutaneous angiosarcoma
Definition
Angiosarcoma is a malignant neoplasm
of endothelial cells. Differentiation
between lymphangiosarcoma and sarco-mas with blood vascular differentiation
appears problematic at the current time.
245Vascular tumours
Fig. 5.12  Superficial arteriovenous haemangioma (cirsoid aneurysm).   A Low power magnification that
shows a neoplasm characterized by vessels with thick walls at the base of the lesion and a proliferation of
small vessels on the surface.  B Irregular vessels with thick walls and lined by a single layer of epithelium.
BA
ICD-O code 9120/3
Synonyms
Lymphangiosarcoma, haemangiosarco-ma.
Epidemiology
There are low-grade forms of angiosar-coma that can occur outside the circum-scribed clinical settings detailed herein.
Almost all high-grade angiosarcomas are
in one of the following settings: the head
and neck of predominantly male elderly
patients (the most common setting)
{1046}, the chest of patients who have
undergone mastectomy for breast can-cer (Stewart-Treves syndrome) {2269},
lymphoedema (congenital or acquired),
or post-irradiation {2271}.
Localization
Most of the epidemiologic settings also
define the sites of disease.
Clinical features
Angiosarcoma, regardless of its genesis
usually begins as a very poorly defined
red plaque resembling a bruise {1046}.
Lesions can become quite large before
metastasis occurs. When it does, the
spread is usually haematogenous. Its
borders may extend for several centime-tres beyond what is visible {1969}. Areas
of nodularity arise after a time, but not in
all patients. Unless a lesion is detected
very early, multiple relapses and death
are frequent occurrences.
Histopathology
Angiosarcoma begins as a plaque, with
small, jagged thin walled vessels that
insinuate themselves between collagen
bundles of the reticular dermis. Unlike in
Kaposi sarcoma, there is no tendency of
spindled cells to first appear in increased
number around pre-existent vessels
and/or adnexa. The endothelial cells
become progressively more protuberant,
with enlarged, hyperchromatic nuclei.
Lymphoid nodules are sometimes seen.
The edges of plaques of angiosarcomas
can be very poorly demarcated, making
it practically impossible to provide accu-rate information about the resection mar-gins. Plaques of spindled endothelial
cells in the post-mastectomy setting are
not necessarily those of angiosarcoma,
as Kaposi sarcoma can also occur {59}.
The plaque stage of angiosarcoma can
give rise to nodules, composed of com-pact masses of spindled or epithelioid
cells, or both. Vascular lumina may be
hard to detect in such nodules, and care-ful inspection may be needed to differen-tiate these from melanoma and spindle
cell squamous carcinoma if only a partial
biopsy is submitted. Cytoplasmic vac-uoles may be a clue to endothelial differ-entiation in poorly differentiated cases.
Immunohistochemistry
The cells of angiosarcoma are usually
positive for CD31, CD34 or VWF(VIIIrAg).
Poorly differentiated tumours can lose
one or more of these antigens, necessi-tating a panel in difficult cases {1755}.
Recently FLI-1 has been described as a
useful marker with the additional advan-tage of nuclear staining {761}. Angio-sarcoma in the post-mastectomy setting
may show blood vascular differentiation,
despite a pathogenesis related to lym-phoedema {1277}. Angiosarcomas are
consistently negative for HHV-8 {1371}.
Differential diagnosis
It includes the atypical vascular prolifera-tion after radiation therapy, Kaposi sarco-ma and pseudovascular squamous cell
carcinoma.
Genetics
Cytogenetic changes include gains of
5pter-p11, 8p12-qter, and 20pter-q12,
losses of 7pter-p15 and 22q13-qter, and
–Y {2101}. Insufficient numbers of cases
have been analyzed to determine if there
are reproducible differences between
different types of angiosarcoma.
Prognosis and predictive factors
Metastases to regional lymph nodes and
to the lungs occur, often after repeated
local recurrences and surgical excisions.
The prognosis is poor, and in one series,
only 15% of patients survived for 5 years
or more after diagnosis {1046}. This, in
part, reflects the delayed diagnosis of
these lesions. This limited survival is
despite the use of various treatment
modalities, sometimes involving surgery,
radiotherapy, and chemotherapy.
246 Soft tissue tumours
Fig. 5.13 Angiosaroma of the upper arm in a patient
with a previous carcinoma of the breast (Stewart-Treves syndrome).
Fig. 5.14 Cutaneous angiosarcoma. The blood vessels have swollen endothelial cells with hyperchromatic
nuclei.
Lymphangioma
circumscriptum
Definition
Lymphangioma circumscriptum refers to
a vascular malformation involving the
lymphatic vessels of the superficial der-mis. A denomination as superficial lym-phatic malformation would be more
appropriate to describe this lesion.
ICD-O code 9170/0
Epidemiology
Usually, lymphangioma circumscriptum
is present at birth or appears early in life.
Localization
Lymphangioma circumscriptum may be
located in any anatomic site, but has
predilection for the axillary folds, shoul-ders, neck, proximal parts of the extrem-ities and tongue {750,1798,2502}.
Lesions involving eyelids and conjuncti-va {841} and genital skin of males and
females {149,419,2006,2436} have also
been described.
Clinical features
Clinically, the lesion consists of numer-ous small vesicle-like lesions, often with a
verrucous surface, grouped in a plaque.
Sometimes purplish areas within the
lesion are seen due to haemorrhage and
thrombus formation within the blood ves-sel component. Probably, the superficial
vesicles are the result of saccular dilata-tions of superficial lymphatics secondary
to raised pressure transmitted from the
underlying pulsating cisterns {2502}.
Magnetic resonance imaging accurately
demonstrates the true extent of involve-ment {1541}. In rare instances, superfi-cial lymphatic malformations are associ-ated with visceral lymphatic malforma-tions involving the mediastinum {1643} or
the bladder wall {1107}. Additional asso-ciations include Becker naevus {1762},
and superficial lymphatic malformations
have been described in patients with
Maffucci syndrome {2292} and Cobb
syndrome {2168}.
Macroscopy
The excised specimens of lymphan-gioma circumscriptum show dilated vas-cular spaces involving both the superfi-cial dermis and deeper subcutaneous
tissue, which correspond to the mal-formed lymphatic vessels.
Histopathology
The stereotypical superficial lymphatic
malformation is accompanied by deep
lymphatic dilated cisterns with muscular
walls situated in the subcutaneous fat,
resulting in swelling of the tissue beneath
the superficial vesicles {1768}. The
superficial component consists of dilated
lymph vessels, lined by flat endothelial
cells in a discontinuous layer, and situat-ed in the papillary dermis, and the super-ficial reticular dermis {179,750}.
Sometimes, the lymphatic vessels are
arranged in clusters in the papillary der-mis, resulting in a papillated or verrucous
skin surface. The vessels may contain
homogeneous eosinophilic proteina-ceous lymph or blood, and occasionally
foamy macrophages. Scattered lympho-cytes may be seen in the connective tis-sue stroma between dilated lymphatic
vessels. In extensive lesions, large irreg-ular lymphatic channels are usually seen
beneath the superficial vessels in deep
reticular dermis and subcutaneous fat.
Immunohistochemistry
The usual immunohistochemical markers
for endothelial cells, such as factor VIII-related antigen, Ulex europaeus, and
CD31 do not differentiate between blood
and lymphatic vessels {1799}. In these
cases, new endothelial cell markers such
as vascular endothelial growth factor
receptor-3 (VEGFR-3) {763,1463}, D2-40
247Lymphatic tumours
Fig. 5.15 Lymphangioma circumscriptum.  A Close-up view of the lesions showed that it consisted of numerous vesicle-like lesions, some of them with a verrucous
surface, grouped in a plaque. Purplish areas are seen due to haemorrhage and thrombus formation within a blood vessel component.  B Histopathologically, the
lesion consisted of dilated lymph vessels involving the superficial dermis and covered by hyperplastic epidermis with compact hyperkeratosis.
BA
L. Requena
W. Weyers
C. Díaz-Cascajo
Lymphatic tumours
.
{1179} and Prox1 {2535) may be helpful,
since these markers are expressed by
lymphatic endothelium {763,1463}.
Histogenesis
Lymphangioma circumscriptum results
from abnormalities in the embryologic
development of lymphatic vessels of the
skin. Lymphangioma circumscriptum
probably represents sequestrated der-mal lymphatic vessels that failed to link
up with the rest of the lymphatic system
{2502}. However, an ultrastructural study
suggested that lymphangioma circum-scriptum was induced by long-standing
lymphatic stasis {103}. In some patients,
lymphangioma circumscriptum has
developed after surgery or radiotherapy
on the involved area {1406,1859}.
Prognosis and predictive factors
Usually, lymphangioma circumscriptum
is a localized and superficial lymphatic
malformation that only causes cosmetic
problems and does not require treat-ment. The presence of a deep compo-nent may explain the tendency of the
lesions to persist after superficial exci-sion.
Progressive lymphangioma
Definition
Progressive lymphangioma is a benign,
localized, slow-growing neoplasm com-posed of thin-walled, interconnecting
vascular channels in the dermis and sub-cutis.
ICD-O code 9170/0
Synonyms
Acquired progressive lymphangioma,
benign lymphangioendothelioma.
Epidemiology
Progressive lymphangioma is rare. It
occurs chiefly in middle-aged or older
adults and does not show a sex predilec-tion {918}.
Etiology
Progressive lymphangioma has been
reported after trauma, such as surgical
procedures and tick bites. Inflammation
secondary to trauma has been claimed
to play a role {2463,2532}.
Localization
Lesions have been reported most com-monly on the lower extremities, but any
region of the skin may be affected {918}.
Clinical features
Lesions usually present themselves as
solitary, well-circumscribed, red or viola-ceous patches or plaques. Although usu-ally asymptomatic, patients may com-plain of tenderness, pain, or itching.
Because of slow growth over years,
lesions may measure several centimetres
in diameter {918,1157}.
Histopathology
Progressive lymphangioma is character-ized by delicate, often widely dilated vas-cular spaces lined by a monolayer of
monomorphous endothelial cells. In
some foci, endothelium-lined papillary
stromal projections extend into those
spaces. With progressive extension into
the deep dermis, vascular spaces
become narrower. They tend to dissect
between collagen bundles and to sur-round pre-existing vessels and adnexal
structures. Endothelial cells are more
numerous than in normal lymphatic ves-sels and may be closely crowded togeth-er. Nuclei may be hyperchromatic, but
there is no prominent nuclear atypia.
Immunohistochemistry
Endothelial cells are usually stained by
antibodies against CD31 and CD34,
whereas other endothelial markers give
more inconsistent results. Actin-positive
pericytes around vascular lumina are
present focally {918,1157}.
Differential diagnosis
Lymphangioma-like Kaposi sarcoma dif-248 Soft tissue tumours
Fig. 5.16 Lymphangioma circumscriptum.  A The lymphatic channels were lined by a discontinuous layer of flat endothelial cells.  B The stroma between the lym-phatic vessels was scant.
BA
Fig. 5.17 Progressive lymphangioma. Solitary,
rather well-circumscribed red patch on the thigh.
fers from progressive lymphangioma by
the presence of plasma cells, the invari-able presence of HHV-8 and more clas-sic areas of Kaposi sarcoma elsewhere
in the lesion. The so-called atypical vas-cular proliferation following radiotherapy
(benign lymphangiomatous papules) dif-fers from progressive lymphangioma
clinically and histopathologically by pre-senting as tiny vesicles and histopatho-logically by being associated with much
wider spaces in the upper dermis.
Moreover, these lesions are thought to
represent lymphangiectasias, rather than
a neoplastic process {628,1921}.
Histogenesis
Progressive lymphangioma is consid-ered to be a neoplastic proliferation of
lymphatic vessels. A neoplastic nature is
suggested by its slowly progressive
course. Derivation from lymphatic
endothelia has been suggested on the
basis of rare erythrocytes within and
around vascular lumina and absence of
a peripheral ring of actin-positive peri-cytes in most vessels.
Prognosis and predictive factors
Following surgical excision, local recur-rences are exceptional. Metastases do
not occur. Regression of lesions after
systemic therapy with corticosteroids
and in the absence of any treatment has
been reported {918,1577,2463}.
Lymphangiomatosis
Definition
Lymphangiomatosis is characterized by
a diffuse proliferation of lymphatic ves-sels that may involve bones, parenchy-mal organs, soft tissue, and skin.
Synonyms
Generalized lymphangioma, systemic
cystic angiomatosis, multiple lymphang-iectasias.
Epidemiology
Lymphangiomatosis is a rare disease
occurring mainly in the first two decades
of life. There seems to be no sex
predilection {862,1882}.
Localization
Lesions occur in the skin and the super-ficial soft tissues of the neck, trunk, and
extremities. Most cases of lymphan-giomatosis affect bones and parenchy-mal organs, especially the lung, pleura,
spleen, and liver. Soft tissue involvement
occurs in the mediastinum and retroperi-toneum.
Clinical features
Cutaneous and subcutaneous lesions
present themselves as soft, fluctuant
swellings that can be squeezed from one
area to another and that may be associ-ated with tiny vesicles. In patients with
involvement of bones and visceral
organs, the presenting signs range from
pathologic fractures to chylothorax, chy-lous ascites, and other symptoms related
to particular organs affected by the
process. The interconnected lymphatic
channels can be visualised by lymphan-giography or direct injection of contrast
media into cystic vascular spaces. Plain
x-rays often reveal osteolytic areas as a
consequence of involvement of bones
{862,1882}.
Histopathology
Cutaneous lesions of lymphangiomatosis
are characterized by markedly dilated
lymphatic channels throughout the skin
and subcutis that are lined by a single
attenuated layer of flattened endothelial
cells and usually appear empty. Those
channels tend to dissect between colla-gen bundles and to surround pre-exist-ing structures in a manner reminiscent of
well-differentiated angiosarcoma. Unlike
angiosarcoma, cytologic atypia, endo-thelial multilayering, and mitotic figures
are absent. The stroma often contains
numerous siderophages and focal
aggregates of lymphocytes. Exceptio-nally extramedullary haematopoiesis
may be seen.
Histogenesis
Lymphangiomatosis probably represents
a vascular malformation, rather than a
neoplastic process.
Prognosis and predictive factors
When present on the neck and trunk,
lymphangiomatosis of soft tissues is usu-ally associated with extensive osseous or
visceral involvement and carries a grave
prognosis with a high rate of mortality
{1882}. In lymphangiomatosis of the
limbs, involvement of bones and visceral
organs is usually insignificant and prog-nosis, therefore, favourable {1021}.
249Lymphatic tumours
Fig. 5.18 Progressive lymphangioma.  A Widely dilated, bizarre-shaped vascular spaces dissecting between collagen bundles and surrounding preexisting vessels.
Papillary stromal projections extend into vascular lumina.  B Vascular spaces are lined by a monolayer of monomorphous endothelial cells.
BA
Smooth muscle is found in the skin in the
arrector pili muscles, the walls of blood
vessels and in ‘genital’ skin, which
includes the scrotum (dartos muscle),
vulva and nipple (areolar smooth mus-cle). Each of these sites of smooth mus-cle can give rise to a tumour.
Tumours of striated muscle are exceed-ingly rare in the skin. Only the rhabdomy-omatous mesenchymal hamartoma (stri-ated muscle hamartoma) will be consid-ered below.
Smooth muscle hamartoma
Definition
Smooth muscle hamartoma is a prolifera-tion of dermal smooth muscle bundles
that is usually congenital.
Synonyms
Arrector pili hamartoma, congenital pilar
and smooth muscle naevus, congenital
smooth muscle naevus
Epidemiology
Smooth muscle hamartoma is usually
congenital with only occasional reports
of lesions with onset in adolescence or
adulthood {590,1069}. There is a slight
male predominance. The lesion is
uncommon {1028}.
Localization
The lesions are most often located on the
trunk and extremities, particularly proxi-mally {1145}. Cases have been reported
involving the head and neck region
{1290}, scrotum {1870} and conjunctiva
{1966}.
Clinical features
The typical presentation is as a solitary
patch or plaque of varying size, usually
between 1 and 10 cm, which may show
hyperpigmentation and/or hypertrichosis
{1145} and which may increase in size
with the growth of the patient {2610}. A
positive pseudo-Darier sign is seen in
most cases {2610}. Occasional cases
have an atrophic appearance {886}. Less
common presentations may include papu-lar follicular lesions {659}, multiple lesions
{915,2200} and the so-called “Michelin tyre
baby”, the latter typically in boys. Patients
with Michelin tyre syndrome may have var-ious other associated abnormalities
{2093}. A clinical classification has been
proposed in which type 1 refers to the
usual localized form, type 2 the follicular
variant, type 3 to multiple lesions and type
4 to the diffuse variant {819}.
Histopathology
There are increased numbers of variably
orientated discrete smooth muscle bun-dles within the dermis and sometimes
the subcutis and these may connect to
hair follicles {1145,2093}. The overlying
epidermis may show acanthosis and
basal hyperpigmentation and there may
be prominent folliculosebaceous units
present, although these do not appear to
be increased in number {206,1145}.
Immunohistochemistry
Lesions have been positive for smooth
muscle actin and desmin as expected
{886,1299,2093}. CD34 positive dendro-cytes have been reported to be an inte-gral part of the proliferation {1299}.
Differential diagnosis
Becker naevus may show dermal
changes identical to smooth muscle
hamartoma. It has been suggested that
these lesions may form a spectrum
{1145}.
Pilar leiomyoma differs from smooth mus-cle hamartoma in being acquired, fre-quently multiple, often painful and com-prising less discrete smooth muscle bun-dles with intervening collagen.
Genetic susceptibility
Rare cases of smooth muscle hamar-toma have been described in siblings
and in a mother and her children {915}.
Xp microdeletion syndrome is character-ized by an unbalanced translocation
between the X and Y chromosomes lead-ing to deletion of the distal short arm of
the X chromosome. Affected infants
show microphthalmia, linear skin defects
and sclerocornea. The linear skin defects
have been reported to show histological
features similar to smooth muscle hamar-toma {1794} although this was not
described in another case {686}.
A child with a familial paracentric inver-sion of chromosome 7q and Michelin tyre
syndrome with smooth muscle hamar-250 Soft tissue tumours
Smooth and skeletal muscle tumours D. Weedon
R.M. Williamson
J.W. Patterson
Fig. 5.19 Pilar leomyoma. Multiple pilar leiomyomas
of the upper back. The lesions were painful in
response to cold.
Fig. 5.20 Pilar leiomyoma. There are interlacing
bundles of smooth muscle fibres forming a nodule.
toma has been described. The rele-vance, if any, of the genetic abnormality
is unknown {2093}.
Pilar leiomyoma
Definition
Pilar leiomyoma is a benign tumour
derived from the arrector pili muscle
{1054,1878}.
ICD-O code 8890/0
Synonym
Piloleiomyoma
Epidemiology
Solitary lesions have a female prepon-derance. They usually develop in adult
life. Rarely, they are present at birth.
Multiple lesions usually have their onset
in the late second or third decades of life.
Localization
Solitary lesions may develop anywhere
on hair-bearing skin, particularly the
trunk and limbs. Multiple lesions have a
predilection for the face, back and exten-sor surfaces of the extremities.
Clinical features
Pilar leiomyomas may be solitary or mul-tiple, with up to several hundred lesions.
Multiple lesions may be grouped, linear,
or zosteriform. Solitary lesions may
measure up to 2 cm or more in diameter,
but multiple lesions are much smaller.
Leiomyomas are firm reddish-brown
papulonodules. Multiple lesions are usu-ally painful; solitary lesions are infre-quently so.
Histopathology
Pilar leiomyomas are circumscribed (but
not sharply so), non-encapsulated
tumours of the dermis, composed of
bundles of smooth muscle arranged in
an interlacing or haphazard pattern. The
cells have abundant cytoplasm and elon-gated nuclei with blunt ends. Mitoses are
infrequent or absent {1878}. Atypical
cells, similar to those seen in the sym-plastic leiomyoma of the uterus, are
uncommon {1486}. Granular cell variants
are extremely rare {1586}.
Small amounts of fibrous stroma are
present between the muscle bundles in
older lesions, but there is usually less
stromal collagen than in the smooth mus-cle hamartoma. Overlying epidermal
hyperplasia is sometimes present {1878}.
The tumour cells stain for desmin and
smooth muscle actin.
Genetics
Some of the multiple cases are familial,
with an autosomal dominant inheritance
{728}. The syndrome of multiple cuta-neous and uterine leiomyomas is also
autosomal dominant with the locus on
chromosome 1q42.3-q43 {51,1526}.
Cutaneous leiomyosarcoma
Definition
Cutaneous (dermal) leiomyosarcoma is a
malignant neoplasm of smooth muscle
cells arising in the dermis. Subcutaneous
and soft tissue leiomyosarcomas are dis-cussed in the soft tissue monograph.
ICD-O code 8890/3
Epidemiology
Over 100 cases of dermal leiomyosarco-ma have now been reported {1164}. Most
cases develop in adults, with a peak inci-dence in the sixth decade. Childhood
cases are extremely rare {2563}. There is
a male predominance.
Localization
These tumours have a predilection for
the extensor surfaces of the extremities
and to a lesser extent the scalp and trunk
{593}.
Clinical features
Dermal leiomyosarcomas are solitary,
firm nodules measuring 0.5-3 cm in
diameter. They are usually asympto-matic, but pain and tenderness have
been recorded.
Histopathology
By definition, the major portion of the
tumour is in the dermis, although subcu-taneous extension is present in some
cases. They have an irregular outline with
tumour cells infiltrating into, or blending
with the collagen fibres at the periphery.
The tumour is composed of interlacing
bundles of elongated spindle-shaped
cells with eosinophilic cytoplasm and
blunt-ended nuclei. Sometimes there is a
suggestion of nuclear palisading. There
is at least one mitosis per 10 high-power
fields in cellular areas. Pockets of greater
mitotic activity (mitotic ‘hot spots’) are
found, usually in areas showing nuclear
pleomorphism. Granular cell, epithelioid,
inflammatory and desmoplastic variants
have all been described {2476}.
Two different growth patterns have been
described: A nodular pattern which is
quite cellular with nuclear atypia and
many mitoses; and a diffuse pattern
which is less cellular with well-differenti-ated smooth muscle cells and inconspic-uous mitoses {1164}.
251Smooth and skeletal muscle tumours
Fig. 5.21  Leiomyosarcoma. confined to the dermis. There are bundles of spindle shaped cells and scattered
mitotic figures. Not the nuclear pleomorphism.
Immunohistochemistry
The cells express smooth muscle actin.
Desmin is present in the majority of
cases. Pan-muscle actin (HHF-35) is
sometimes present focally.
Histogenesis
The majority of tumours are derived from
the arrector pili muscles. Rare cases
derived from areolar smooth muscle in
the nipple {1452} and dartos muscle in
the scrotum {758} have been reported.
Genetics
An unequivocal genetic fingerprint for
these tumours is currently lacking {2175}.
Various genes have been identified that
are expressed differentially in tumour
and normal tissue. Soft tissue leio-myosarcomas most often show genomic
alterations in the 13q4-q21 region {622}.
Prognosis and predictive factors
Dermal leiomyosarcomas may recur
locally, but the reported incidence (5-30%) varies widely {2476}, but metas-tases of confirmed cases are unknown
{1139}.
Rhabdomyomatous
mesenchymal hamartoma
Definition
Rhabdomyomatous mesenchymal ha-martoma (RMH) refers to single or multi-ple, congenital, frequently polypoid
lesions that typically arise near the mid-line of the head and neck. They contain
skeletal muscle fibres within the dermis
{1618}.
Synonyms
Striated muscle hamartoma {1008}, con-genital midline hamartoma.
Epidemiology
About 25 examples of this lesion have
been reported {1973,2320}. Typically, the
lesions have been present since birth or
early childhood, and most patients are
children. Rare cases have been reported
in adults {2037}. Thus far, the male:
female ratio is 2:1.
Etiology
These lesions may be derived from striat-ed muscle of the branchial arch {105,
899,1008,1973}.
Localization
RMH typically arises in the midline of the
head and neck, with a particular
predilection for the nose and chin. There
have also been cases involving the
preauricular region {1902,2010,2122},
lateral forehead {1973}, and cheek
{2320}.
Clinical features
The majority of lesions are described as
papules or polyps, but a few have pre-sented as nodules {105,1973,2320} or
“sessile masses” {1685}. RMH lesions
are generally asymptomatic, but they
can demonstrate the interesting property
of contractile motion, spontaneously or
during crying or feeding {1973,2010}.
Most patients lack other congenital
anomalies, but there have been associa-tions with cleft lip and palate, ocular
abnormalities (coloboma, microph-thalmia, limbal dermoid), low-set ears,
craniofacial clefts, thyroglossal duct
sinus, lipoma of the brain, and upper
extremity and syndactyly {1008,1902,
1973,2010,2037}. Histologic features of
RMH have been found in the cutaneous
polyps {2037} of a case of Delleman syn-drome, which consists of orbital cysts,
cerebral malformations, and focal dermal
hypoplasia as well as cutaneous
appendages {723}. In addition, a patient
{1902} with RMH in association with ipsi-lateral limbal dermoid and coloboma
(Goldenhar syndrome), has been report-ed.
Initially, it was believed that RMH might
be an X-linked disorder, as the first few
cases were reported in males, but this
252 Soft tissue tumours
BA
Fig. 5.24 Rhabdomyomatous mesenchymal hamartoma.  A In the superficial dermis, small skeletal muscle
fibers surround eccrine sweat ducts.  B This high power view shows mature intradermal skeletal muscle
fibers with cross-striations.
Fig. 5.22 Rhabdomyomatous mesenchymal hamartoma. Low power view of rhabdomyomatous mesenchy-mal hamartoma, showing polypoid configuration, intact epidermis, numerous small vellus follicles, and a
central core containing skeletal muscle.
was not substantiated when a number of
examples were described in girls. Thus
far, familial occurrence of this lesion has
not been documented.
Histopathology
The most striking feature is the presence
of intersecting bundles of mature skeletal
muscle fibres, with demonstrable cross
striations, and with a general orientation
perpendicular to the surface epidermis.
Varying amounts of collagen and mature
fat surround these muscle fibres {2037}.
They extend through the reticular dermis
and become attenuated in the papillary
dermis {1618}, where they appear to sur-round adnexal structures, particularly
vellus follicles and sebaceous glands
{678,713,1618}. Sebaceous and eccrine
sweat glands are usually observed, and
in one case there were ectopic apocrine
glands {2320}. Nerve elements in these
lesions vary considerably; in some cases
they are not prominent {2010}, but in oth-ers there may be numerous small nerve
twigs {987} or a large nerve bundle in the
central core of the lesion {2037}. One
example contained elastic cartilage
{2037}, and calcification or ossification
have also been reported {2010}. In some
cases, elastic fibre distribution has been
reported to be normal {1618}, while in
others these fibres are markedly
decreased {2037}.
Immunoprofile
Skeletal muscle fibres in RMH stain posi-tively for actin, desmin and myoglobin
{678,899}.
Differential diagnosis
Although RMH bears a resemblance to
fibroepithelial polyp, naevus lipomato-sus, and accessory tragus, the combina-tion of midline location and a microscop-ic skeletal muscle component should
permit distinction from those lesions
(though small amounts of skeletal muscle
have been reported in accessory tragic)
{324}). Deeper or more primitive tumours
such as fetal rhabdomyoma, fibrous
hamartoma of infancy, or neuromuscular
hamartoma (benign Triton tumour)
should not be difficult to distinguish from
RMH {678,2010}.
Somatic genetics
There has been speculation about a
human homolog of the mouse disorgani-zation gene (Ds), which is responsible,
directly or indirectly, for the development
of hamartomas and other defects
{1973,2242}.
253Smooth and skeletal muscle tumours
Fig. 5.23 Rhabdomyomatous mesenchymal hamar-toma. In the lower part, skeletal muscle fibers
among thick collagen bundles of the reticular der-mis. In the upper part there are eccrine sweat coils
and aggregates of smooth muscle.
254 Soft tissue tumours
Keloid scar
Definition
Keloid scars are raised scars that extend
beyond the confines of the original
wound.
Epidemiology
Keloid scars occur with equal frequency
in men and women. They affect all races,
but are more common in dark-skinned
individuals. In Black, Hispanic, and
Asian populations, the incidence ranges
between 4.5 and 16%. Keloids occur
chiefly in persons under 30 years of age
{1711,2149}.
Etiology
There is a genetic predisposition to the
formation of keloid scars. Moreover, hor-monal and immunological factors may
play a role. Keloids often appear in
puberty and tend to enlarge during preg-nancy; they have been claimed to be
more common in patients with signs of
allergy and increased serum levels of
IgE. Wounds subjected to great tension
or become infected are more likely to
heal with a keloid scar {1711,2149}.
Localization
Keloids are most common on the ear-lobes, cheeks, upper arms, upper part of
the back, and deltoid and presternal
areas. They are seen only rarely on the
genitalia, eyelids, and on palms and
soles {1711,2149}.
Clinical features
Keloids are well-circumscribed, firm,
smooth-surfaced erythematous papules
or plaques that occur at the site of an
injury. The preceding injury may be only
minor and, therefore, not always appar-ent (e.g., rupture of an inflamed hair folli-cle). Older lesions may be pale or hyper-pigmented. Especially in early stages,
keloids are often itchy, tender, or painful
{1711,2149}.
Histopathology
After a prolonged period of wound heal-ing thick, homogeneous, strongly eosino-philic bundles of collagen, in haphazard
array, develop {1498}. Those “keloidal“
collagen bundles are the histopathologic
hallmark of keloid scars, but are not seen
in many cases fulfilling the clinical defini-tion of keloids. The border of keloids is
often irregular, with tongue-like exten-sions of bands of thickened collagen
underneath normal appearing epidermis
and superficial dermis.
Histogenesis
Keloid scars are characterized by an
enhanced proliferation and metabolic
activity of fibrocytes that seems to result,
in part, from the excess of various
cytokines produced by inflammatory
cells, including transforming growth fac-tor-b1 and platelet-derived growth factor.
Moreover, a deficiency of cytokines that
down-regulate collagen synthesis and
inhibit proliferation of fibrocytes, such as
interferon-a, has been noted. There is
also evidence of reduced degradation of
collagen caused, in part, by inhibition of
collagenase activity through acid muco-polysaccharides, proteoglycans, and
specific protease inhibitors {1686,1711,
2149,2551}.
Genetic susceptibility
Keloidal scar formation may run in fami-lies. It is also more common in Black indi-viduals. A relationship with various
human leukocyte antigens has been
reported {1711}.
Prognosis and predictive factors
The clinical and histopathologic features
of keloid scars indicate a high probabili-ty of recurrence following surgical exci-sion alone. Recurrence rates of 45-100%
have been described {1711}.
Hypertrophic scar
Definition
Hypertrophic scars are raised scars that
do not extend beyond the confines of the
original wound. As such, they are closely
related to keloids, both being examples
of a disturbance of wound healing lead-ing to the formation of exuberant fibrous
tissue. Whether hypertrophic scars are
simply a less severe variant of keloid
scars or represent a different pathologic
process is controversial.
Epidemiology
Hypertrophic scars are common. The
incidence of hypertrophic scarring (in-cluding keloid scars) ranges between 39
and 68% after surgery and between 33
and 91% after burns, depending on the
depth of the wound {1711}.
Localization
Hypertrophic scars are most common
above the flexor aspects of joints and on
the abdomen {2149}.
Clinical features
By definition, hypertrophic scars differ
from keloid scars by remaining confined
to the original wound. Other distinguish-ing features are earlier manifestation of
Fibrous, fibrohistiocytic and
histiocytic tumours
W. Weyers
T. Mentzel
R.C. Kasper
A. Tosti
M. Iorizzo
B. Zelger
R. Caputo
H. Kamino
J. D. Harvell
P. Galinier
G.F. Kao
E.J. Glusac
E. Berti
D. Weedon
C. Rose
Fig. 5.25 Keloid. Raised erythematous plaques are
present.
255Fibrous, fibrohistiocytic and histiocytic tumours
hypertrophic scars (usually within 4
weeks after injury, whereas keloids may
manifest themselves several months
later), a tendency to regression and to
contractures not seen in keloid scars, a
lower tendency to recur after surgery,
and different sites of predilection. In
other respects, the clinical features of
hypertrophic and keloid scars are essen-tially the same {2149}.
Histopathology
Hypertrophic scars differ from normal
scars chiefly by presence of nodular
aggregates of collagen with many fibro-cytes. The main distinguishing feature
from keloid scars is the absence of
keloidal (i.e., thick, strongly eosinophilic)
bundles of collagen. Moreover, unlike
keloid scars, hypertrophic scars show
prominent blood vessels arranged per-pendicularly to the skin surface. Borders
of hypertrophic scars tend to be more
regular, and nodules of collagen tend to
be distributed more evenly.
Differential diagnosis
Keloids show thick hyaline collagen bun-dles. Cases with overlap features
between keloids and hypertrophic scars
are seen.
Histogenesis
No principal differences have been
noted in the histogenesis of hypertrophic
scars and keloid scars {1711}.
Prognosis and predictive factors
Although hypertrophic and keloid scars
are closely related, the distinguishing
features, clinically and histopathological-ly, allow a judgment to be made about
the probability of recurrence following
surgical excision. In one series, the
recurrence rate of hypertrophic scars
was 10%, as opposed to 63% in keloid
scars {257}.
Dermatomyofibroma
Definition
Dermatomyofibroma is a distinct biologi-cally benign fibroblastic/myofibroblastic
cutaneous proliferation occurring fre-quently, but not exclusively in young
female patients.
ICO-O code 8824/0
Synonym
Plaque-like dermal fibromatosis
Epidemiology
Dermatomyofibroma represents a rela-tively rare cutaneous mesenchymal neo-plasm and usually occurs in young
women. Infrequently, dermatomyofibro-ma is seen in male patients {1073,1189,
1581} and children {1654,1970}.
Localization
Most cases of dermatomyofibroma arise
in the shoulder and axilla regions, fol-B CA
Fig. 5.27 Dermatomyofibroma.  A Neoplastic cells in dermatomyofibroma have typical cytological features of myofibroblasts with an ill-defined, pale eosinophilic
cytoplasm and elongated, tapering nuclei.  B Characteristically, elastic fibres are slightly increased and fragmented in dermatomyofibroma in comparison to non-neoplastic tissue (bottom).  C Neoplastic cells in dermatomyofibroma stain variably positive for alpha-smooth muscle actin.
Fig. 5.26 Keloid.  A Nodular masses of collagen and fibrocytes separated from one another by elongated bands of collagen and containing foci of thick homoge-neous, strongly eosinophilic collagen bundles.  B Thickened homogeneous, strongly eosinophilic bundles of collagen (“keloidal collagen”) are the histopathologic
hallmark of keloid scars.
BA
256 Soft tissue tumours
lowed by the trunk, the neck, and the
upper arm {523,1073,1189,1581,2322,
2375}; more rarely these lesions are seen
on the thigh {1073,1189}.
Clinical features
The patients usually present with a slow-ly increasing, plaque-like, indurated,
often red-brown lesion; rarely these neo-plasms may reach a considerable size
{1073,2375} or may occur as multiple
lesions. Grossly, most neoplasms are cir-cumscribed, oval or annular and present
as firm plaques or flat nodules measur-ing usually 1-2 cm, however, larger
lesions have been reported {2375}.
Histopathology
Dermatomyofibroma is characterized by
an ill-defined proliferation of cytologically
bland spindle-shaped tumour cells
arranged mainly in bundles and fascicles
oriented parallel to the overlying epider-mis.
Adnexal structures are typically spared.
In most cases the lesions are confined to
the dermis, however, a focal extension
into superficial subcutaneous tissue is
sometimes noted {1581}. The tumour
cells contain an ill-defined pale
eosinophilic cytoplasm and uniform
fusiform nuclei that are either elongated
with tapering edges containing an even-ly distributed chromatin or vesicular with
small nucleoli.
Tumour cells are set in a collagenous
matrix with slightly increased and frag-mented elastic fibres, a helpful clue in
the distinction of dermatofibroma and
scarring processes. The overlying epi-dermis may show mild acanthosis and
focal hyperpigmentation.
Immunoprofile
Tumour cells in dermatomyofibroma stain
variably for actin and alpha-smooth mus-cle actin {1189,1581}. As in other myofi-broblastic conditions, the expression of
actin seems to be dependent on the age
and activity of neoplastic cells, and only
approximately 50% of cases are positive
for this marker {1582}. Lesional cells are
negative for S-100 protein, CD34,
desmin, and h-caldesmon {581,1074,
1189,1581}.
Prognosis and predictive factors
Complete excision is advised since
these neoplasms may reach a consider-able size.
Infantile myofibromatosis
Definition
Infantile myofibromatosis (IM) is a tumour
of the skin and soft tissues of disputed
histogenesis, which is solitary in two
thirds of cases. Multicentric lesions
(myofibromatosis) occur {634A}.
ICD-O code 8824/1
Synonyms
Solitary cutaneous myofibroma.
Historical annotation
IM was described by Chung and
Enzinger in 1981 as a proliferative disor-der of myofibroblasts {486}. Cases had
been described earlier as congenital
fibrosarcoma {2529}, congenital general-ized fibromatosis {1229} and congenital
mesenchymal hamartoma {203}.
Epidemiology
Most lesions are present at birth, or
appear in the first 2 years of life; onset in
adults also occurs {2541}. There is a
male predominance.
Clinical features
About a third of lesions are situated in the
deep soft tissues and the remainder are
located in the skin and/or the subcu-tananous tissues {1778}. The head, neck
and trunk are the usual sites.
They measure 0.5 to 7 cm or more in
diameter; they are greyish-white in
colour, and fibrous in consistency.
Histopathology
The nodules are reasonably well circum-scribed, although there be an infiltrative
border in the subcutis. There are plump
to elongated spindle cells, grouped in
short fascicles. Delicate bundles of colla-gen separate or enclose the cellular
aggregates. Mitoses are variable in num-ber, but not atypical {486,753}.
Vascular spaces resembling those seen
in haemangiopericytoma are often found
in the centre of the tumour, giving a
biphasic appearance. Necrosis, hyalin-ization, calcification, and focal haemor-rhage may be present centrally {753}.
For details, see WHO Classification of
Tumours of Soft Tissue and Bone {756}.
Immunoprofile
The tumour cells are positive for vimentin
and alpha-smooth muscle actin, but neg-ative for S-100, myoglobin, and cytoker-atins {2425}. Reports on immunorreactiv-ity for desmin vary {923}.
Histogenesis
Fletcher and colleagues have suggested
that the spindle cell component shows
smooth muscle differentiation {753}.
Requena et al have suggested an origin
from myopericytes. {1920}. Recently, the
lesion has been included in a spectrum
of tumours showing perivascular myoid
differentiation {882}.
Genetics
Familial occurrence is too rare to allow
any conclusions regarding genetic sus-ceptibility {2427}
Prognosis
The prognosis is excellen, with recur-rence unlikely after excision; aggressive
variants are rare {849}. There are no fea-tures predictive of recurrrence.
Sclerotic fibroma
Definition
Sclerotic fibroma is a benign soft tissue
tumour composed of eosinophilic colla-gen bundles arranged in a storiform pat-tern {1895}.
ICD-O code 8823/0
Synonym
Storiform collagenoma
Epidemiology
Solitary sclerotic fibroma is rare and
occurs in both sexes at any age, from
infancy to adulthood. Multiple tumours
are typical of Cowden disease, a rare
genodermatosis.
Localization
Most frequent sites of involvement are
the face, upper and lower extremities
and trunk.
Clinical features
Sclerotic fibroma presents as a translu-cent, white, flesh-coloured or waxy nod-ule. It is usually unique and measures
less than 1 cm. It has a slowly progres-sive growth, over months or years. The
lesion is asymptomatic {1590,1895,
2369}.
257Fibrous, fibrohistiocytic and histiocytic tumours
Histopathology
The tumour is usually situated in the retic-ular dermis. It is sharply demarcated and
it is composed of hyalinized bands of
collagen with a decreased number of
fibroblasts. The collagen fibres are thick,
glassy and aligned in parallel bundles
with a storiform pattern. Elastic fibres are
absent. The proliferation tends to
expand, pushing aside the normal der-mal collagen without engulfing the
adnexae {1590,1895,2369}. Alcian Blue
staining reveals an increased amount of
mucopolysaccharide.
Immunoprofile
Staining for S100 protein, myelin basic
protein and neuron specific enolase and
desmin are negative {1590,1895}.
Prognosis and predictive factors
Although the lesion is benign, it should
be removed due to its tendency to
expand.
Digital mucous cyst
Definition
Two types of lesions both with a pseudo-cystic circumscribed dermal mucin dep-osition exist. In the more common type a
connection with the underlying joint cavi-ty can be demonstrated (ganglion type).
The second type represents a focal
mucinosis produced by fibroblasts (myx-omatous type).
Synonyms
Myxoid pseudocysts of the digits, gan-glion of the distal interphalangeal joint,
digital focal mucinosis.
Epidemiology
Women are more often affected and
patients are middle aged or elderly.
Localization
They typically occur on the dorsum of the
fingers near the distal interphalangeal
joint or near the proximal nail fold. The
index fingers and thumb are primarily
affected. The toes are rarely involved
{1148,2221}.
Clinical features
The lesions are solitary, soft, smooth sur-faced and usually not greater than 1.5
cm. A connection of the pseudocyst to
the underlying joint can be demonstrated
in the majority of cases by magnetic res-onance imaging or injection studies with
dye {599,1034}. Osteoarthrosis is some-times evident.
Histopathology
Myxomatous type: this variant has a
large pseudocystic area with a myxoma-tous stroma with scattered spindle-shaped or stellate fibroblasts analogous
to focal mucinosis in other areas of the
body. The overlying epidermis is often
attenuated. The mucin contains muco-polysaccharides which stain positively
with alcian blue and colloidal iron.
Ganglion type: cystic spaces containing
mucin with a collagenous fibrous wall
characterize these lesions. Occasionally
in some areas of the wall a synovial lining
can be demonstrated.
Digital fibrokeratoma
Definition
Digital fibrokeratoma is a benign fibrous
tumour often accompanied by a hyper-plastic epidermis that arises mostly in the
periungual area.
Synonyms
Acquired ungual fibrokeratoma, periun-gual fibromas of tuberous sclerosis
(Koenen tumours), subungal and periun-gual fibromas, acral fibrokeratoma.
Epidemiology
Most patients are adults. Males are
affected more frequently than females
{2429}. More than half the patients with
tuberous sclerosis develop about puber-ty multiple fibrokeratomas {2470}.
Localization
The majority of lesions occur on a finger
or a toe. Occasionally, lesions present on
the palms or soles.
Clinical features
The patients usually present with a soli-tary lesion. Normally, tumours are small
and measure 3-5 mm in diameter. A case
of a huge lesion measuring up to 5 cm
has been described {1181}.
Histopathology
Digital fibrokerat