Williams Hematology



Inflammatory Disorders of Histiocytes

Familial and Sporadic Hemophagocytic Histiocytosis

Infection, Disease, or Drug-Induced Hemophagocytic Histiocytosis

Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Syndrome)
Clonal Histiocytosis

Langerhans’ Cell Histiocytosis

Malignant Histiocytosis
Malignant Fibrous Histiocytoma and Giant-Cell Tumor of the Bone
Chapter References

Clinical disorders that are the consequence of a primary proliferation of histiocytes (macrophages) may result from a metabolic, inflammatory, or neoplastic pathogenetic mechanism. This chapter deals with the latter two and Chap. 79 with the former.
Three principal inflammatory disorders of macrophages affect the marrow or lymph nodes and are relevant to hematologists. The first is familial hemophagocytic histiocytosis, usually a disease of infancy; about two-thirds of cases occur in siblings. Fever, anorexia, hepatosplenomegaly, and lymphadenopathy are common. Jaundice and ascites may develop. Anemia and thrombocytopenia are frequent, and a marrow or splenic aspirate will show macrophages phagocytizing blood cells or precursors. Stem cell transplantation is the most successful form of treatment. The second disorder is infectious hemophagocytic histiocytosis, an infrequent but severe and dramatic reaction to a viral, bacterial, fungal, or protozoal infection. Fever, myalgias, lethargy, and hepatosplenomegaly are often present. Bi- or pancytopenia is common. Activated macrophages ingesting blood cells or precursors are abundant in the marrow specimen. The disorder produces a severe systemic illness but may resolve in weeks if the underlying infection is treated successfully or resolves. The third relevant disorder is sinus histiocytosis with massive lymphadenopathy, which usually manifests itself by massive, painless cervical lymph node enlargement. Other nodes or extranodal sites are involved in many patients. Biopsy of an involved area will show engorgement of sinuses or tissue by activated, phagocytic macrophages. The disease is usually self-limited and regresses spontaneously in several months. Progressive disease can be treated with glucocorticoids or chemotherapy.
Clonal histiocytic disorders include Langerhans’ cell histiocytosis and malignant histiocytosis. Langerhans’ cell histiocytosis can be localized to skin, bone, or other sites or be widespread, involving almost any organ. In the latter form, diabetes insipidus is common. The diagnosis requires localization of S-100 protein and CD 1a on the histiocytic cells in the infiltrate and identification of Langerhans’ cell (Birbeck) granules by electron microscopy. In the localized form, excisional biopsy, observation, or local treatment may suffice. In the progressive or disseminated form, multidrug chemotherapy or stem cell transplantation may be required. Malignant histiocytosis is an uncommon tumor that had been over-diagnosed before stringent criteria, including absence of evidence for immunoglobulin or T-lymphocyte receptor–chain gene rearrangement, were required to eliminate masquerading lymphoma. The disease is usually disseminated, involving marrow, lymph nodes, liver, and spleen, and requires multidrug chemotherapy.

Acronyms and abbreviations that appear in this chapter include: CD, cluster of differentiation; GM-CSF, granulocyte-monocyte colony-stimulating factor; HLA, human leukocyte antigens; IL, interleukin; M-CSF, monocyte colony-stimulating factor; TGF-b, transforming growth factor b; TNF-a, tumor necrosis factor a.

Diseases associated with the proliferation of histiocytes can be grouped into three categories: inflammatory disorders, neoplastic (clonal) disorders, and storage diseases (Table 78-1). The storage diseases are described in Chap. 79. This chapter describes disorders that may be evaluated by hematologists. The large number of histiocytoses that affect principally the skin are not discussed.1


The terms macrophage and histiocyte have been synonyms. The former designation is favored for discussions of the cell biology and pathophysiology of the mature cell found in tissues in the monocyte-macrophage system. In the medical literature, the terms histiocyte and histiocytosis are used to describe histopathological lesions of macrophage disorders. Macrophages can subsume varied and highly distinctive phenotypes, and these specialized cells localize to specific tissues (e.g., Langerhans’ cells of the skin, dendritic cells of the lymph node, etc.: see Chap. 73, Chap. 74 and Chap. 75). Histiocytic diseases may reflect these distinctions, making specific diagnosis complex, requiring careful assessment of cell phenotype and genotype. More recently, it has been suggested that the term histiocyte be used as a designation to encompass macrophages that process antigen and dendritic cells that present antigen, focusing solely on the role of these cells in the immune system.2 Such a proposal may be difficult to implement, given the extensive and long-standing more general use of the term.
Considerable confusion existed in the classification of disorders of histiocytes when morphologic characterization of pathological specimens using light microscopy was the principal basis for diagnosis. The use of electron microscopy to identify the specific granules in Langerhans’ cells (Birbeck bodies) (Fig. 78-1) and the development of a series of antibodies and immunocytochemical techniques that recognize cluster of differentiation (CD) sites present on monocytes or macrophages or their intracellular features has helped substantially in the classification and diagnosis of these diseases. These tools, coupled with molecular genetic studies of T and B lymphocyte gene rearrangements to exclude diseases of lymphocytes that are phenocopies of histiocytic disorders, have lead to improvement in diagnostic accuracy. In addition, refined phenotyping has permitted discernment of disorders of dendritic histiocytes, for example, Langerhans’ cell histiocytosis, and macrophages involved in the secondary hemophagocytic syndromes.

FIGURE 78-1 Transmission electron micrograph of a pathologic Langerhans’ cell from a bone lesion. The cell contains typical cytoplasmic Langerhans’ granules (Birbeck bodies; arrow). The latter have a characteristic racquet shape. (From BE Favara and ER Jaffe, Hematol Oncol Clin North Am 1:75, 1987, with permission.)

Familial hemophagocytic histiocytosis was first described in 1952 and also has been referred to as familial reticulosis and familial erythrophagocytic lymphohistiocytosis. The disease affects neonates and infants, and 90 percent of patients are symptomatic by 2 years of age. The annual incidence in Sweden is about 1 per million children, or 1 per 50,000 births.3 Males and females are equally affected. Over two-thirds of cases occur in siblings.4,5 and 6 Parents of patients are consanguineous in about one-quarter of cases, suggesting autosomal recessive inheritance. The disease, if untreated, is usually lethal.
The most prevalent signs in infants are fever, anorexia, vomiting, and irritability. Hepatic or splenic enlargement is present in virtually every case. As the condition progresses, lymphadenopathy, jaundice, ascites, and edema can occur. The spleen can become greatly enlarged.3,4,5,6 and 7
Anemia, reticulocytopenia, and thrombocytopenia are present in most patients. Leukopenia and neutropenia are less common. With progression of the disease, pancytopenia is the rule.
Marrow examination may be normal and erythrophagocytic histiocytes inconspicuous, but later in the course it often shows decreased numbers of normal precursors and increased numbers of macrophages ingesting blood cells (hemophagocytic histiocytes).7 Fine-needle aspiration of the spleen shows swollen histiocytes engorged with erythrocytes and other blood cells, often when hemophagocytosis is less prominent in the marrow. Liver and lymph node sinuses and alveolar spaces are often congested with macrophages engorged with erythroid cells and other blood cells (e.g., neutrophils, lymphocytes, or platelets).
Central nervous system signs of meningitis, seizures, hemiplegia, and coma may ensue. The cerebrospinal fluid frequently has an increased concentration of mononuclear cells, sometimes including macrophages. The spinal fluid total protein level is elevated in most children.8
Serum glutamic-oxaloacetic transaminase, glutamate pyruvate transaminase, and bilirubin levels may be elevated. The serum ferritin and triglyceride concentrations frequently are elevated. The serum albumin and fibrinogen levels are often low, and overt disseminated intravascular coagulation can be present.5,6 and 7
Increased serum concentrations of interferon-g, tumor necrosis factor a(TNFa), soluble interleukin-2 (IL-2) receptor, soluble FAS ligand, and soluble CD8 are evident in most affected children, and increased IL-6 occurs in one-third of children. These alterations indicate that there is a close correlation of the disease manifestations with cytotoxic T-cell and natural killer cell activation and their exaggerated elaboration of inflammatory cytokines.9,10,11 and 12
The diagnosis of the clinical syndrome in infants is supported by biopsies showing a lymphohistiocytic infiltrate in the liver, spleen, lymph nodes, or marrow. The macrophages do not have the cytologic features of malignant cells but are engorged with phagocytosed erythrocytes and occasionally neutrophils, lymphocytes, platelets, or erythroblasts. Early in the disease, histiocytes are prominent in the T-cell zones and sinuses of lymph nodes. Later, lymphoid depletion in the paracortex of lymph nodes and the white pulp of the spleen is characteristic.6,7,13
Treatment has not been studied systematically.
Etoposide, tenoposide, vinca alkaloids, glucocorticoids, and methotrexate have been used as single or multiple agents with or without intrathecal methotrexate followed by cranial irradiation to treat central nervous system disease. Remissions have occurred in a very small proportion of patients.6 Stem cell transplantation from an appropriate donor can result in sustained remissions.6,14,15 Splenectomy, plasmapheresis, plasma exchange transfusion, cyclosporine A, and antithymocyte globulin have been used in individual patients with occasional reports of improvement or remission.16 The efficacy of high-dose dexamethasone, etoposide, cyclosporine A, and intrathecal methotrexate, if the latter is indicated, is currently being assessed.16
The disease, if untreated, is rapidly fatal, although temporary improvement can occur with the varying interventions noted above. Unless successful treatment, usually with stem cell transplantation, is instituted, infection, hemorrhage, or central nervous system abnormalities eventually result in death. Results from stem cell transplantations have been encouraging, and the estimated 5-year survival rate for patients treated with chemotherapy (»10%) compared to that for stem cell transplantation (»65%) in uncontrolled studies, highlights the value of the latter modality.6
Since the mid-1970s, a syndrome of exaggerated histiocytic proliferation and activation has been defined that is usually associated with systemic viral infection,17,18 especially with Epstein-Barr virus,19,20,21,22 and 23 and occasionally occurs with bacterial, fungal, or protozoal infections.24,25,26 and 27 The disease affects children and adults, and Epstein-Barr virus, herpes simplex virus, cytomegalovirus, varicella zoster virus, adenovirus, human immunodeficiency virus, dengue virus, parvovirus, enteric bacteria, streptococcus, staphylococcus, rickettsia, mycobacteria, Candida, Histoplasma, Cryptococcus, leishmania, and Babesia have been implicated.17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41 and 42
Hemophagocytic histiocytosis also can occur during the accelerated phase of Chédiak-Higashi syndrome.43 A similar syndrome can occur in patients with a variety of malignancies, perhaps as a result of the enhanced susceptibility to infection of the immunosuppressed state associated with cancer, chemotherapy, radiotherapy, and inanition.29,33,44,45,46,47,48,49,50,51,52,53,54,55 and 56 The syndrome can occur with lymphomas as a result of cytokines released by lymphoma cells that stimulate histiocyte proliferation and phagocytosis.39,49,51,57 The syndrome has developed in patients with lupus erythematosus;58 other autoimmune diseases,59 including Still’s disease;60 after phenytoin administration;61 and in association with other, miscellaneous disorders.62
The manifestations of the disorder are thought to be mediated by inflammatory cytokines, including interferon-g, TNF-a, soluble IL-2 receptor, FAS ligand, granulocyte-monocyte colony-stimulating factor (GM-CSF) and monocyte colony-stimulating factor (MCSF), and perhaps others.10,11 and 12,49,51,63 Agents like Epstein-Barr virus activate T lymphocytes, resulting in cytokine release.63,64 Elevated levels of TNF-a, soluble IL-2 receptor, IL-1, and FAS ligand are associated with the severity of the manifestations.10,11 and 12 Soluble IL-2 receptor is thought to contribute to immune impairment by negating the effect of IL-2. Endothelial cell activation and capillary leakage coupled with hepatic injury from histiocyte infiltration, bile acids, and the FAS/FAS ligand pathway may combine to account for hypoalbuminemia and hypofibrinogenemia. Endothelial cell injury may induce microvascular thrombosis and consumption of labile coagulation factors, which contributes to the fibrinogenopenia and coagulopathy. Cytopenias may result from the effects of elevated concentrations of interferon-g, TNF-a, or transforming growth factor b (TGF-b)–mediated suppression of the marrow and M-CSF–mediated accelerated clearance of platelets by histiocytes.65,66
The signs and symptoms of this disease include fever, severe malaise, myalgias, lethargy, and often hepatic and splenic enlargement.17,18,32,33,64 The last two findings are less prevalent in adults. Children may also have prominent lymphadenopathy. Pulmonary infiltrates can develop occasionally.
Severe anemia (<9.0 g/dl), leukopenia [(<2500/µl) <2.5 × 109/liter], and thrombocytopenia [(<50,000/µl) <50 × 109/liter], or a combination of two cytopenias can be seen in nearly all cases.17,18,27,33,67 A careful search may uncover macrophages in the blood film. The marrow is often hypocellular, and granulopoiesis and erythropoiesis, in particular, are markedly decreased. The number of megakaryocytes in the marrow and platelet counts are normal or reduced slightly.
An increase in marrow macrophages is a constant finding. The macrophages may range from being slightly more prominent to replacing hematopoietic tissue.17,18,27,33,67 They are often vacuolated, with ingested cellular material in varying stages of digestion. Ingestion of erythrocytes and erythroblasts is usual, but phagocytosis of platelets and, rarely, neutrophils also can occur (Fig. 78-2). A lymph node biopsy contains increased hemophagocytic histiocytes, but lymph node architecture is not effaced. Occasionally, histiocytic proliferation may involve the meninges, gastrointestinal tract, lung, or other sites.

FIGURE 78-2 A composite showing macrophages from a patient with histiocytosis. These macrophages show (a) erythrophagocytosis, (b) platelet phagocytosis, and (c) band neutrophil (and erythro) phagocytosis.

During the acute phase of the illness, the plasma concentrations of inflammatory cytokines and acute-phase reactants are elevated. Interferon-g, TNF-a, and IL-6 levels are often markedly elevated, as is soluble IL-2 receptor. Soluble IL-2 receptor and CD3+, HLA-DR+ cells in the blood are elevated notably in Epstein-Barr virus–induced hemophagocytic syndrome. Hypertriglyceridemia, hyperferritinemia, and elevated serum phenylalanine levels are frequent. Plasma fibrinogen and plasminogen activator inhibitor-1 levels are often very low, and these changes may reflect consumptive coagulopathy.40
Patients with this unusual, exaggerated histiocytic inflammatory reaction to infection, although severely ill, often recover in weeks as a result of antimicrobial therapy or natural resolution. Complete disappearance of the histopathologic evidence of histiocytosis follows in months.17,33,42,49 In patients in whom disease- or drug-induced immunodeficiency is present, such as renal transplant patients, immunosuppressive therapy should be decreased or stopped until the viral infection subsides.18 Treatment with cyclosporine A,21,60 antithymocyte globulin,68 gamma globulin,69,70 and 71 or etoposide72 has resulted in striking improvement of Epstein-Barr virus–associated hemophagocytic syndrome.
The disease severity has been correlated with older age, lower hemoglobin and platelet concentrations, and elevated plasma ferritin, b2 microglobulin, or serum bilirubin concentration.67
The disease can be distinguished from malignant histiocytosis by clinical and serologic evidence of an antecedent viral infection, the clinical setting in which the disease occurs, the absence of cytologic evidence of malignant histiocytes (see “Malignant Histiocytosis”), and the absence of effacement of lymph node architecture.
Sinus histiocytosis with massive lymphadenopathy is usually a self-limited disorder of unknown etiology described in 1969 by Rosai and Dorfman73 that principally occurs in the first two decades of life but can occur at any age. The disease can be recurrent or progressive and can lead to death in some patients.73,74
Signs and Symptoms The typical presentation is characterized by massive bilateral, painless cervical lymphadenopathy, which may be isolated or associated with generalized adenopathy. Early, the nodes may be discrete, but they often progress to adherent, multinodular masses. Axillary and inguinal adenopathy may develop in about half the patients. Fever is frequent, and weight loss may occur. Extranodal involvement is present in nearly one-half of patients, especially in the head and neck region, involving the skin, soft tissue, orbit, eye lids, uvea, lacrimal glands, paranasal sinuses, salivary glands, thyroid, or oral cavity. The respiratory tract, breast, mediastinum, thymus, heart, liver, kidneys, testes, synovia, bone, meninges, and spinal cord may also be involved.74
Patients frequently have signs of chronic inflammation: anemia, neutrophilia, elevated erythrocyte sedimentation rate, hypoalbuminemia, and polyclonal hypergammaglobulinemia. Marrow examination is usually uninformative, and histiocytic proliferation is usually not present.74 Efforts to find an etiologic infectious agent have been unsuccessful. Epstein-Barr virus and human herpes virus-6 have been detected in some cases but not others.75,76
Excisional biopsy or needle aspiration of a lymph node or an extranodal site can provide specimens for diagnostic study.74,77 The histopathologic features in the lymph node biopsy are usually diagnostic: marked fibrosis in the capsular and pericapsular areas and distention and engorgement of medullary and subcapsular sinusoids by phagocytic histiocytes. Lymphophagocytosis and erythrophagocytosis by histiocytes in the lymph node sinus are characteristic.74 The active phagocyte is a histiocyte that is positive for S-100 protein, CD11c, CD14, CD33, CD68, acid phosphatase, and nonspecific esterase.74,77,78 and 79 Lymphocytes and plasma cells are prominent in the intersinal spaces. Eosinophils are absent or rare. Later in the disease, continued proliferation can lead to effacement of the node. The histiocytic proliferation is polyclonal.80 The histopathological appearance of extranodal biopsies is strikingly similar to that of lymph nodes.
The course of the disease is influenced by the degree of immune impairment or dysfunction that coexists. A significant number of cases appear in children with underlying immunologic disorders, including Wiskott-Aldrich syndrome, autoimmune hemolytic disease, polyarthritis, glomerulonephritis, or severe pneumonia.74,81,82 In other cases, no specific immune abnormality characterizes the disease.
The lymph node enlargement usually progresses for weeks to months, reaches a maximum, and then gradually recedes, so that most patients have little or no residual evidence of disease 9 to 18 months after onset.74 Some patients have persistent lymphadenopathy but stable disease, and others have progressive disease and may have a fatal outcome. The latter patients usually have an accompanying immunologic disease and/or widespread nodal involvement that may encroach on vital organs.74,82
Other than excisional biopsy for diagnosis, many patients require no therapy, since the disease will run its course and abate. Glucocorticoids, cytoxic agents, radiotherapy, and antibiotics have had no consistent effect on the duration of the disease.74,83 In patients with severe or progressive disease, there have been reports of successful treatment with acyclovir,84 glucocorticoids,85,86 interferon-a,87,88 thalidomide,89 or combination chemotherapy.83,90,91
Langerhans’ cells are macrophages with an irregularly shaped nucleus. They are normally present in the epidermis, oral and vaginal mucosa, and the lungs.92,93 They are derived from the hematopoietic stem cells in marrow, as are all other types of macrophages.94,95 Langerhans’ cells differ from other tissue cells in their racquet-shaped ultrastructural inclusions (Birbeck bodies;96 their content of the b chain of the neuroprotein S-100,93,97 neuronal-specific enolase,99 and cell surface CD 1a immunoreactivity (Table 78-2).100,101


The Langerhans’ cell is a macrophage that is specialized to be a component of the immune accessory cell system. It processes antigens, migrates from the skin to the lymph nodes, transforms to a dendritic phenotype, and presents antigen to paracortical T cells. The antigen-presenting cells partially degrade antigen and express peptides on the cell surface in association with HLA molecules, making them recognizable to T-lymphocytes.92,93,101,102 The veiled cell of afferent lymphatics may represent a Langerhans’ cell in transit. After antigen presentation, the Langerhans’ cell may alter its phenotype to an interdigitating dendritic cell.92,93,101
The cell was described in the epidermis by Paul Langerhans in 1868.103 In 1973 it was recognized that the macrophages of “histiocytosis X” have the characteristics of epidermal Langerhans’ cells.104 The preferred term Langerhans’ cell histiocytosis should be used for all the eponymic diseases Lichtenstein embraced with the term histiocytosis X,105 including eosinophilic granuloma, Abt-Letterer-Siwe disease, and Hand-Schüller-Christian disease, as well as several added since the time of his writing, including self-healing histiocytosis, eosinophilic xanthomatous granuloma, pure cutaneous histiocytosis, Langerhans’ cell granulomatosis, type II histiocytosis, Hashimoto-Pritzker syndrome, eosinophilic xanthomatosis of the normocholesterolemic type, and nonlipid reticuloendotheliosis.106
The etiology and nature of Langerhans’ cell histiocytosis have been enigmatic. The syndrome was thought to be inflammatory, with granulomatous, xanthomatous, or fibrotic elements being observed during the evolution of the histopathologic lesions. These cellular changes were thought to be the manifestation of an autoimmune process. The cells do not appear malignant, although a high mitotic index is not uncommon. An infectious etiology has not been identified.
A neoplastic etiology was suggested in 1940 based on the x-ray appearance of bone lesions107 and in 1986, when aneuploidy was demonstrated by flow cytometric study of the DNA content of cutaneous Langerhans’ cells from a patient.108 These speculations were proved when molecular studies indicated that the proliferating histiocytes represent a monoclonal population, and this is the case whether the lesions examined are localized or widespread.109 Thus, the disorder appears to be a neoplasm, which can be localized and non-progressive or disseminated and progressive and which often behaves like a chronic inflammatory disease, perhaps because the cells involved can secrete a variety of inflammatory cytokines inappropriately,109 leading to autocrine stimulation, especially by GM-CSF and TNF-a.110 The loss of E-cadherin expression in Langerhans’ cells has been associated with dissemination from the skin.111
Initially the lesions contain abundant numbers of pathologic Langerhans’ cells. Macrophages, eosinophils, and lymphocytes frequently participate in the formation of granulomatous lesions. The masses proliferate and can be destructive. Later in the course of the disease, the lesions may become less cellular, xanthomatous, and fibrotic.101,112,113
The lesions usually involve bone, especially the flat bones of the skull, face, ribs, and pelvis, and the skin, lungs, liver, marrow, lymph nodes, spleen, thymus, central nervous system, and pituitary gland. Occasionally, the gastrointestinal tract is involved.112,113
Mode of Inheritance and Epidemiology The disease has been reported in siblings and identical twins, but most cases are sporadic, and a strong genetic influence is not apparent, consistent with the presumptive neoplastic pathogenesis.250
The incidence of Langerhans’ cell histiocytosis is estimated to be 1 per 200,000 children. Seventy-five percent of patients are diagnosed before age 10 years, and 90 percent before age 30. Males are more frequently (3:1) affected by limited or non-progressive disease. Females and males are affected equally by chronic progressive or fatal disease. About 90 percent of cases with multisystem involvement occur before the age of 20 years.113,114,115 and 116
Symptoms and Signs Lesions fulfill common histopathologic criteria, but the extent of disease and the clinical features vary.112,113,117 The disease may be localized to a bone or to a soft-tissue site, multifocal involving only bone, or multifocal involving bone and other sites.118,119 and 120
The expression of the disease is correlated frequently with the age of the patient at onset. Infants may present with fever, otitis media, or mastoiditis.121 Enlargement of the liver, spleen, and lymph nodes is frequent, as is dermatitis. A self-limited syndrome, benign cephalic histiocytosis, can occur during the first year of life. Papules and macules, which when biopsied reveal a histiocytic infiltrate, occur on forehead, ears, and cheeks and later elsewhere, and resolve spontaneously in weeks to months.122
Skin lesions can resemble seborrheic, eczematoid, pustular, or nodular dermatitis and often involve the scalp in infants. Tumors limited to the skin can be the sole manifestation of the disease.123,124 Lesions of the bones or soft tissues of the head and neck are present in over 75 percent of children.125,126 In children and adolescents, pain, tenderness, and swelling in the head, face, leg, back, chest, or groin may be the only evidence of an osteolytic lesion involving the skull, orbit, jaw, femur, vertebra, rib, or pelvis.118,119 and 120 Protrusion of the eye may occur. Gastrointestinal tract involvement in children can result in vomiting, diarrhea, and ulceration and bleeding.127,128 Hepatic involvement is very uncommon.129,130 Polyuria and polydipsia can signal hypothalamic involvement and the onset of diabetes insipidus (Fig. 78-3).131,132,133 and 134 Diabetes insipidus occurs in about one-quarter of cases, usually in patients with multisystem disease and usually during the course of the disease, but not as an initial manifestation.113,117

FIGURE 78-3 Magnetic resonance imaging study demonstrating hypothalamic involvement by Langerhans’ cell histiocytosis. The arrow indicates the anterior pole of the greatly enlarged hypothalamic region, expanded by the tumor mass.

Primary pulmonary involvement, which is rare in children, is seen predominately in male adults.135,136 Chronic nonproductive cough, chest pain, shortness of breath, and wheezing are the most common symptoms. The presence of more than 5 percent CD1a-positive cells in bronchoalveolar lavage fluid is evidence that favors pulmonary involvement by Langerhans’ cell histiocytosis.137 The radiographic picture initially shows a reticular pattern but can progress to cystic changes.138,139,140,141 and 142 Pneumothoraces tend to occur and recur, especially when honeycomb changes are present on the chest x-ray. A high prevalence of other pulmonary cancers has been associated with pulmonary histiocytosis.143 Isolated generalized lymphadenopathy is more common in adults than in children.144,145 Langerhans’ cells may occur incidentally in lymphomatous lesions and thus create a diagnostic problem.146,147
A late neurologic syndrome that includes cerebellar ataxia occurs in patients years after they appeared to be disease-free.148 Autopsy studies indicate that active disease of neurologic tissue rather than damage from therapy is the usual mechanism. Dentate nuclear involvement is often prominent. Rare cases of diffuse cerebral involvement occur, although intracranial involvement is usually limited to the hypothalamus.149
Involvement of the female genital tract usually occurs in young women, but may occur in childhood. The ovary, endometrium, cervix, vagina, or vulva may be involved.150,151 The disease may be localized or represent one site of multicentric involvement. Pregnancy presents special problems in women with Langerhans’ cell histiocytosis.152 The most common complication is the onset or exacerbation of diabetes insipidus. Involvement of the vagina, vulva, or pelvic bones may interfere with a normal vaginal delivery. Reactivation of the disease after years of remission has been reported during pregnancy. Reduced fecundity can occur, possibly from hypothalamic-pituitary axis involvement, resulting in decreased gonadotropins and elevated prolactin levels.
The disease, when it affects adults, involves principally the skin, lungs, bone, pituitary, and lymph nodes, and diabetes insipidus is common.153,154
Neutrophilia, increased sedimentation rate, and increased serum alkaline phosphatase levels may occur. The diagnosis is based on a biopsy of involved organs, especially skin, bone, liver, or lymph node, whichever is most involved and most accessible.101,113 Imaging studies of bone lesions can be strongly suggestive of the disease. The key diagnostic feature is the presence of pathologic Langerhans’ cells, which may be abundant in proliferative lesions or scarce in fibrotic, hypocellular lesions. Giant cells with multiple nuclei resembling osteoclasts are features of the lesion, but they are not derived from Langerhans’ cells. Marker studies for the presence of S-100, CD1a, peanut lectin binding, and adenosinetriphosphatase, and ultrastructural studies for Birbeck bodies are used to identify the Langerhans’ cells conclusively.93,98,100,101,105,112,113,117
The differential diagnosis in adult patients depends on the site of involvement and can include a chronic infectious (granulomatous) disease, lymphoma, collagen- vascular disease, pneumoconiosis, and amyloidosis.113,117,154 Several diseases associated with proliferative histiocytes need to be differentiated from Langerhans’ cell histiocytosis, including xanthogranuloma,155 histiocytic necrotizing lymphadenitis (Kikuchi’s disease),156 and Erdheim-Chester disease.157,158 Biopsy specimens from these entities are usually distinguishable by an experienced pathologist.
Langerhans’ cells may be present in the biopsies of patients with solid tumors, Hodgkin disease, lymphoma, or chronic lymphocytic leukemia.159,160,161,162,163,164,165 and 166 The focal nature of Langerhans’ cell lesions and their absence from most other cancers suggest that they are a reaction to the lymphoma.160
Langerhans’ cells also have been found in a thymus removed for the treatment of myasthenia gravis167 and in a variety of dermatologic disorders.168
Spontaneous fluctuations and remissions are features of the disease.101,113,117,169 Treatment should be considered in patients with symptomatic localized or progressive multifocal disease.
Localized disease may be managed by local means. Isolated lymph node disease may be treated by excisional biopsy. Patients with bone lesions should be assessed for the possibility of pathologic fractures. Curettage, excision,170 or intralesional glucocorticoids171 or non-steroidal anti-inflammatory agents can be used, depending on circumstances. Physical exertion may have to be restricted in individuals with vertebral or other lesions who are at risk for pathologic fractures. Radiation therapy needs to be individualized according to the size, number, severity, and location of bone lesions.172,173 and 174 Radiotherapy can be used for bone lesions that are painful, are inaccessible, or compromise vital organs or for large lesions in weight-bearing bones.118,119,169 The dose employed is usually between 400 and 800 cGy. Grafts may be required also for large lesions in weight-bearing bones. Extension from a vertebra to the spinal cord requires the urgent use of radiation therapy.
Skin disease, if localized, may be treated by excisional biopsy, often required for diagnosis. If mild, skin lesions may respond to topical or interlesional therapy. Use of an aqueous solution of mustine hydrochloride (nitrogen mustard) can be very effective and is especially useful in outpatients.175,176 Psoralen coupled with ultraviolet A light treatment may be the most consistently effective treatment.177 Intradermal interferon-b has been associated with resolution of skin lesions.178,179 Glucocorticoids, although frequently used in the past, are of modest, short-term benefit usually. High-potency preparations are required for the best results. Radiation therapy should be restricted to local, obstinate lesions, especially if they result in a sinus tract from an underlying visceral lesion. Etoposide, isotretinoin, trimethoprim-sulfamethoxazole, and thalidomide may be very useful for skin lesions but require further study. The former may be particularly useful for progressive, multiple sites of skin involvement.180
Chemotherapy may be useful for patients with progressive, multisystem disease.169,181,182 and 183 Many agents have been used alone, but few systematic studies of single agents are available. Vinca alkaloids, alkylating agents, purine or pyrimidine antagonists, anthracycline antibiotics, epipodophyllotoxins, adenosine deaminase inhibitors, cyclosporine, and others may be useful as single agents. The distribution of the disease, threat to organ function, rate of progression, and age of the patient should be considered in deciding on the best approach to therapy. Etoposide can suppress multisystem disease and may have a special role in the treatment of disease in the skin or central nervous system.169 For progressive multisystem disease, various combinations of three- or four-drug therapy, given at regular intervals for about 6 to 9 months, have been used in a manner akin to treatment of higher-risk lymphomas.169,182,183 Table 78-3 lists drugs and drug combinations that have been used to ameliorate this disorder.184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201 and 202


In older children and adults, multisystem Langerhans’ cell histiocytosis often has a relapsing and remitting course and may regress. The decision to use systemic multidrug cytotoxic therapy requires integration of the extent and progression of disease with the potential adverse effects.
There is controversy as to whether fully established diabetes insipidus requiring desmopressin therapy can be reversed by means of radiotherapy.203,204 Early partial diabetes insipidus associated with a mass lesion seen by computed tomography or magnetic resonance imaging may be kept from advancing by treatment with radiotherapy, but reversal of fully developed diabetes insipidus, although reported, is felt to be improbable, and symptomatic therapy with desmopressin is required in virtually all cases.251
Blood-component therapy may be required in patients with marrow involvement and cytopenia. If the spleen is grossly enlarged, splenectomy may be useful in patients who require frequent red cell transfusions. Since this complication usually occurs in younger patients, the risk of post-splenectomy infection should be weighed against the risks of long-term, frequent red cell transfusions.
Marrow transplantation has resulted in benefit in some patients with severe multisystem disease.205,206 Progressive hepatic failure has been treated by liver transplantation.207,208 Pulmonary failure has been treated with lung transplantation.
The following factors are associated with a poor prognosis: disease onset during the first 2 years of life, fever not explained by infection, failure to thrive in infants, blood cytopenias, abnormalities of liver function test results, and splenic enlargement. A salutory response of multisystem disease to combination chemotherapy within 6 weeks identifies patients who are likely to have a good long-term response to therapy. Isolated skin or bone lesions point to a good prognosis. The mortality rate in patients with multisystem disease, especially in those under 2 years, remains in the 25 percent range despite therapy. Some patients achieve resolution of disease, and some show marked regression (»50%). Others have an intermediate response, with some improvement of existing sites but with new sites developing. Long-term results await the follow-up of ongoing clinical trials.169
There may be an association between Langerhans’ cell histiocytosis and acute lymphocytic leukemia and retinoblastoma.166 The high frequency of other cancers in patients may be the consequences of chemotherapy.
In 1939, Scott and Robb-Smith209,210 reported cases of a rapidly fatal disease associated with jaundice, lymphadenopathy, refractory anemia, leukopenia, and often hepatic and splenic enlargement that they called histiocytic medullary reticulosis. However, the suspected histiocytic cell proliferation could not be established beyond visual impression. Israels211 expanded on the clinical description and histopathology and referred to the disease as giant-cell reticulosis, based on the use of the term reticulum cells for large malignant cells that are found to be either lymphocytes or histiocytes when assessed by more specific immunocytochemical techniques. In 1966, Rappaport212 introduced the term malignant histiocytosis and focused on the nature of the malignant process, which he believed to be an invasive, progressive proliferation of neoplastic histiocytes, again based principally on the proliferating cells resembling histiocytes by light microscopy.
The introduction of techniques to characterize specific markers of macrophages and the requirement for the absence of immunoglobulin gene and T-lymphocyte receptor–chain gene rearrangements have resulted in the reclassification of most cases of malignant histiocytosis as anaplastic large T-cell (CD 30+) lymphoma or, less frequently, B-cell lymphoma or a tumor without definitive markers.213,214,215,216,217,218,219 and 220 It is estimated that about 1 case in 200 to 300 lymphomas is a histiocytic malignancy, based on appropriate criteria.216,217 Malignant histiocytosis is referred to in some reports as histiocytic sarcoma or true histiocytic lymphoma. Although there are precedents for the use of sarcoma with hematopoietic tumors (i.e., granulocytic sarcoma), the term usually refers to tumors derived from cells in connective tissue or muscle. The term histiocytic lymphoma reflects a chimeric term of two distinct tissues (macrophages and lymphocytes) and should be discarded.
Only recent case studies have verified meticulously the phenotype of the cellular infiltrate in this disease using specific and sensitive markers for lymphoid and macrophagic cells. Thus, uncommon clinical correlates await the accumulation of additional cases. Moreover, in some otherwise well-studied cases, which report the absence of lymphocytic markers and the presence of macrophage markers on tumor cells, immunoglobulin and T-cell receptor–chain gene rearrangement studies have not been done, making conclusions about the diagnosis uncertain.
The disease affects all age groups, and, in three studies totaling 18 patients, the age range was 2 to 74 years. The disease occurs more often in men than in women.216,219,221
Fever, headache, weakness, weight loss, dyspnea, and sweating occur commonly in most patients who have generalized disease.219,221,222 Splenomegaly, hepatomegaly, and lymphadenopathy are very frequent.219,221,222 Skin, central nervous system, and lung involvement may accompany the aforementioned findings. Localized presentation in the skin, a lymph node group, or especially the intestines may occur.219,220,223,224,225,226,227,228 and 229 The appearance of malignant histiocytosis on a background of prior lymphoma may represent a biological predisposition to progress to other hematolymphoid tumors or reflect a therapy-induced event.226,227
Anemia and thrombocytopenia are very common (>90% of cases), and neutropenia occurs in the majority of cases, although the white cell count can be elevated. Marrow examination may show infiltration with histiocytic cells, and cytophagocytosis by histiocytes may be evident. Cytophagocytosis was thought to be an infrequent feature of malignant histiocytosis, but this may have been a reflection of the lack of specific diagnostic criteria; most cases were actually lymphomas. The serum lactic dehydrogenase and serum bilirubin levels are often elevated, but liver-derived serum enzyme levels are not. It is significant that renal function is not disturbed.221 Elevated serum levels of TNF, IL-6, IL-1a receptor, lysozyme, a1-antitrypsin, and angiotensin-converting enzyme may be found.221
The diagnosis of malignant histiocytosis requires biopsy of a tumor mass in lymph node, skin, liver, intestine, marrow, or other involved site and immunohistochemical verification of a macrophagic phenotype including expression of some or most of the following: CD11b, CD11c, CD14, CD15, CD33, CD36, CD68, and MAC-387. The presence of cellular enzymes, including lysozyme, a1-antitrypsin, and a1-antichymotrypsin, are supporting markers but not sufficient in and of themselves for diagnosis. The cells in air-dried specimens of blood, marrow, or touch preparations of tissue react for non-specific esterase but not peroxidase. The cells should not express multiple T- or B-lymphocyte markers and should not show rearrangement of lymphoid lineage genes (immunoglobulin or T-receptor chains).230,231
The principal diseases that can mimic malignant histiocytosis include anaplastic and other large-cell lymphomas,216,217 and 218,220,232 Hodgkin disease,229 malignant fibrous histiocytoma (a myofibroblastic tumor),229 hemangiopericytoma,229 and inflammatory pseudotumor of lymph nodes.229
It seems probable that malignant histiocytosis is related closely to other clonal stem-cell or progenitor-cell disorders that express a monocytic or macrophagic phenotype, analogous to the spectrum of lymphoma to lymphocytic leukemia. Indeed, variants such as Langerhans’ cell sarcoma, follicular dendritic cell tumors,225,226 tumors derived from fixed as compared to free histiocytes,233 and leukemic presentation234,235,236 and 237 or progression238 of malignant histiocytosis have been described, as have localized malignant histiocytomas.239
No systematic multicenter clinical trials have been yet reported using stringent diagnostic criteria. The infrequency of this tumor makes single-center studies of limited value. Four-drug combinations, such as cyclophosphamide, doxorubicin, vincristine, and prednisone; lomustine, vincristine, bleomycin, and prednisone; or mechlorethamine hydrochloride, procarbazine, prednisone, and either vincristine or teniposide given at monthly intervals have been used for patients with generalized disease.221 The disease is often very rapidly progressive, and most patients have not had a sustained remission of long duration. Remissions are not infrequent, however, and a remission duration of beyond 7 years has been reported in two patients.221 Stem cell transplantation in younger patients with appropriate donors may be useful.240 Most patients who have received transplantation prior to the development of specific diagnostic criteria probably had lymphomas.
Localized follicular dendritic cell tumors may be excised with or without the use of either local irradiation or chemotherapy.228,229 Whether such additional therapy is beneficial is unclear.
The precise cell of origin of malignant fibrous histiocytoma and giant-cell tumor of the bone has been the subject of dispute. A monocyte-macrophage and a fibroblast are the two principal cell types that have been thought to undergo malignant transformation in both tumors.241 Current evidence points to the fibroblast or, occasionally, the myoblast, and both types of malignancy are usually fibrosarcomas or myosarcomas, not a type of malignant histiocytosis.242,243,244,245,246 and 247 The histiocytic cells present in the tumor are considered reactive and may appear as a result of the release by the tumor cells of cytokines that recruit monocyte.248,249

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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