CHAPTER 101 PATHOLOGY OF MALIGNANT LYMPHOMAS
CHAPTER 101 PATHOLOGY OF MALIGNANT LYMPHOMAS
PETER M. BANKS
Definition and History
Contribution of Immunology to Lymphoma Classification
The Revised European-American Lymphoma (REAL) Classification
Major Predictive Groupings of Non-Hodgkin Lymphoma Low-Grade
Nodular Lymphocyte-Predominance Hodgkin Lymphoma
Classical Hodgkin Lymphoma
Mixed Cellularity Type
Lymphocyte Depletion Type
Nodular Sclerosis Type
Practical Considerations for Diagnosis
Clonal diseases of larger granular lymphocytes (LGL) can arise from either T cells or natural killer (NK) cells. Although T-LGL and NK-LGL cells have a similar morphology, they have distinctive surface antigen phenotypes and represent two discrete diseases with different clinical features and clinical outcomes. Current treatment for either disease is not considered curative. This chapter describes these two disease entities and outlines current therapeutic approaches.
DEFINITION AND HISTORY
In 1832 Thomas Hodgkin published the first treatise on primary lymphatic malignancy: “On Some Morbid Appearances of the Absorbent Glands and Spleen.” His work derived from clinical and gross autopsy findings in seven cases.5 Subsequently, Virchow distinguished lymphoma from leukemia in 18466 and coined the terms lymphoma7 and lymphosarcoma.8 Billroth, in 1871, was the first to use the term malignant lymphoma.9
The category of follicular lymphomas initially was recognized in 1916 by Ghon and Roman, who related such neoplasms to normal lymphoid follicles.13 Brill and others, in 1925,14 and Symmers, in 1927,15 failed to appreciate the neoplastic nature among many of their cases of “giant follicular hyperplasia”; however, this oversight was corrected in 1938 with information gained through long-term follow-up.16 Thus, the neoplastic, albeit indolent, nature of this category of lymphomas became recognized.
In addition to perceiving the aggressive nature of lymphomas composed of large cells, Roulet, in 1930, proposed that the origin of such neoplasms was the sinus lining, and he compared their morphology with that of the normal reticulum, or syncytial network of nodal sinuses.17 His term Retothelsarkom was subsequently popularized but mistranslated as reticulum cell sarcoma, and the term reticulum cell was applied in varying ways in diverse disorders.18
By the middle of the twentieth century, clinically useful systems of classification were formulated. For Hodgkin lymphoma, the Jackson and Parker system (1947) separated the unfavorable sarcoma and favorable, but rare, paragranuloma from the large intermediate grouping of granuloma.20 In 1966, Lukes, Butler, and Hicks, incorporating others’ observations, proposed a six-part pathologic subclassification of Hodgkin lymphoma that correlated closely with clinical survival.21
For the lymphomas two fundamental features were correlated with differences in survival, namely the identification of certain cell types and growth patterns. Neoplasms composed of small, nonreplicating lymphocytes (lymphocytic, well-differentiated lymphocytic) were recognized as a favorable group. Those featuring atypical, mitotically active lymphocytes (lymphoblastic, poorly differentiated lymphocytic) were less favorable. Those made up of large cells were erroneously, in retrospect, considered as nonlymphoid (stem cells, clasmatocytic, undifferentiated, or histiocytic) in derivation. The presence of a follicular or nodular growth pattern was an important, favorable predictive feature.22 Based upon these simple principles, with ever-increasing detail and precision, sequential classification systems were developed: those of Gall and Mallory (1942), Gall and Rappaport (1958), and Rappaport (1966).23,24 and 25 During the 1970s, great strides were achieved in the therapy of lymphomas, as the predictive accuracy of the Rappaport system was demonstrated in selecting those aggressive histologic types for which intensive intervention was required (see Chap. 103).26 The Working Formulation for Clinical Usage represented a simple, morphologically based system for stratification of lymphomas into major predictive groups27 (see Table 101-1). Even as this system gained widespread popularity, its scientific validity came into question in the face of data from newly applied methods.
TABLE 101-1 ALPHABETIC DESIGNATIONS FOR CATEGORIES OF NON-HODGKIN LYMPHOMAS OF WORKING FORMULATION* ALLOW COMPARISON WITH REVISED EUROPEAN-AMERICAN LYMPHOMA (“REAL”) CLASSIFICATION OF 1994† (MODIFIED 1999)‡
CONTRIBUTION OF IMMUNOLOGY TO LYMPHOMA CLASSIFICATION
Advances in immunology and immunogenetics have provided new insights into the cytogenesis of lymphomas, allowing for a newer classification system.4 For example, immunophenotyping of large cell lymphomas dispelled the previously popular “reticulum cell” or histiocytic theories of this lymphoma’s cytogenesis.28 Analyzing immunoglobulins from whole-tumor homogenates, a monoclonal B-cell composition in most lymphomas was demonstrated, including the large cell types—reticulum cell or histiocytic.29 Subsequent studies using immunophenotyping and molecular techniques have characterized these large cell lymphomas as being either B-cell or, less commonly, T-cell proliferations.30 Only rarely are cases found to be of true histiocytic origin.31
Lymphomas with a nodular or follicular growth pattern are neoplastic counterparts of germinal centers. Desmosomal dendritic reticulum cells are present in both benign and neoplastic follicles.32 Immunologic analyses show that they have common functional properties.33
Burkitt and “Burkitt-like” lymphoma variants, designated as undifferentiated in the Rappaport system, are B-cell neoplasms.30
Lymphoblastic lymphoma is an important clinicopathologic entity. It is distinct from other lymphomas with which it had been included as “poorly differentiated lymphocytic” in the original Rappaport system. Immunologic, enzymatic, and cytochemical evidence revealed this neoplasm to be of embryonic precursor cell type, more often having a pre-T cell rather than a pre-B cell phenotype.34 Such neoplasms uniformly possess nuclear terminal deoxynucleotidyl transferase activity and often progress to an unfavorable form of acute lymphoblastic leukemia (see Chap. 101). This entity corresponds to Sternberg’s mediastinal “leukosarcoma,”35 thus explaining Cooke’s clinical observations made four decades previously (see “History”).
Within the Working Formulation type of diffuse, small cleaved cell lymphoma is an entity newly recognized in relation to both clinical and molecular genetic characteristics—mantle cell lymphoma.36 These neoplasms are composed of small cleaved B lymphocytes with a diffuse or faintly follicular growth pattern. Unlike neoplasms of germinal center differentiation, i.e., follicular lymphomas, these B-cell tumors coexpress the T cell-related antigen CD5. In addition, these tumors frequently have genetic translocations that involve BCL-1, a proto-oncogene that encodes a protein cyclin D1 involved in regulation of cell proliferation.37 Clinically this is an unfavorable disease of older males, usually with disseminated lymph node involvement or, less commonly, leukemia.38 A spectacular clinical variant presentation of this process is so-called lymphomatous polyposis of the gastrointestinal tract.39
Another distinctive entity deriving largely from the Working Formulation diffuse, small cleaved cell grouping is B-marginal zone lymphoma. Although there is little specific to the B-cell immunophenotype of these tumors, microscopically they are characterized by a subtle mixture of small round lymphocytes, small cleaved cells with clear cytoplasm (monocytoid B-cells), and plasmacytic or plasmacytoid forms. Interestingly, clinical behavior depends largely on distribution. Tumors localized to extranodal parenchymal tissues (stomach, salivary gland, lung, skin, etc.) tend to remain restricted to these sites with potential for cure, in striking contrast to most low-grade lymphomas. This phenomenon corresponds to the mucosa associated lymphoid tissue (MALT) lymphoma concept pioneered by Isaacson.40 Early gastric MALT type lymphomas often regress with antimicrobial therapy for Helicobacter pylori.41 Trisomy 3 is the cytogenetic abnormality most closely associated with MALT type lymphomas.42 B-marginal zone lymphomas of lymph nodes behave clinically in a manner similar to other low-grade lymphoma, i.e. with systemic distribution and a protracted course.36 Those presenting with splenic enlargement, so-called “splenic lymphoma with villous lymphocytes” show cellular, immunophenotypic and clinical overlap with hairy cell disease43 (see Chapter 99).
Although relatively uncommon, anaplastic large cell lymphoma affords conceptual insights into the relationship between Hodgkin and non-Hodgkin lymphoma.44,45 The process was first described in 1982 as “regressing atypical histiocytosis” of the skin.46 Histologically, tumor cells show extreme nuclear anaplasia and abundant cytoplasm with a cohesive growth pattern suggestive of metastatic carcinoma or histiocytic malignancy. The surprisingly favorable clinical behavior seen in some cases seems to correlate with its propensity to afflict young patients and to be limited to the skin.47 Another independent favorable prognostic factor is the expression of the p80 or ALK-1 protein, based on a t(2;5) translocation.48 The immunophenotype is that of activated lymphocytes. Most notably these tumors express the activation antigen CD30 (Ki-1) and an incomplete constellation of lymphoid markers, usually those associated with the cytotoxic T-cell subset. Unlike the tumor cells of Hodgkin lymphoma, those of anaplastic large cell lymphoma usually do express both CD45 (leukocyte common antigen) and epithelial membrane antigen (see Fig. 101-2).
FIGURE 101-1 Newly recognized distinct variants of certain lymphomas (right column) are related to types in the Working Formulation (left column). The following abbreviations are used: AIL, angioimmunoblastic lymphoma; ATLL, adult T-cell leukemia/lymphoma; H.D.-like, Hodgkin disease-like; and MH, malignant histiocytosis. (From Banks,45 with permission.)
FIGURE 101-2 Simplified conceptual schema representing the interrelationship of Hodgkin lymphoma with other lymphomas. In general, lymphomas are composed of neoplastic cells that have immunophenotypes very similar to that of their normal cell counterparts, whereas Hodgkin lymphoma tumor cells are activated, very abnormal cells that express very few lymphocyte-associated antigens. The Hodgkin-like grouping is intermediate with respect to these two extremes. Note that there is a partial overlap of these groupings, representing cases that are difficult to assign to one or the other group.
A predominance of T-cell lymphoma was observed in the southern islands of Japan.49 This observation led to the discovery of the association between the human T-lymphotropic virus, (HTLV-1) and adult T-cell leukemia-lymphoma. Sporadic HTLV-1-positive cases were subsequently observed among native Caribbean and American southern blacks.50
THE REVISED EUROPEAN-AMERICAN LYMPHOMA (REAL) CLASSIFICATION
Although the Working Formulation for Clinical Usage served as a practical system for classifying lymphomas into major predictive groupings, by the late 1980s it was becoming clear that it was imprecise in not specifically recognizing these newly identifiable types of lymphoma.51 Furthermore, there was divergence in the practice of lymphoma classification, as most Europeans used the Kiel classification with its inclusion of immunologic criteria,1 and some in North America preferred the Lukes-Collins system2 for similar reasons. In 1993 the International Lymphoma Study Group began a year-long effort to establish a new classification which would acknowledge recent advances in discernment of distinct types of lymphoma, based on combined clinical, microscopic, immunologic, and, in some cases, genetic data. This system was entitled the “REAL” classification, an acronym for Revised European-American Lymphoma; the term also signified the basis for distinguishing the respective lymphoma types as real, i.e., actual, bioglogically distinct entities.4 Emphasized in this classification are the immune cell types to which the various neoplasms correspond. Thus, the major division of lymphomas is between B-cell and T-cell (see Table 101-1). Explicit in the REAL Classification’s exposition is the mutability of any such system in deference to clinical and scientific advances. Members of the original International Lymphoma Study Group collaborated with an assembly of other specialists, both clinicians and pathologists, to develop a modified, updated REAL Classification52 (see Table 101-1). In the summary presentation which follows, emphasis is placed on major groupings of lymphomas according to aggressiveness on natural, untreated tumor behavior.
MAJOR PREDICTIVE GROUPINGS OF NON-HODGKIN LYMPHOMA LOW-GRADE
Almost all favorable lymphomas are of B-cell immunophenotype, the prototype being follicle center lymphomas (types “B” and “C,” follicular small cleaved and follicular mixed types of the Working Formulation (see Table 101-1). These neoplasms correspond to germinal centers, and can be confidently recognized as B-cell tumors by virtue of their follicular growth pattern which, as in benign follicles, is imparted by associated dendritic cells (see Plate XXII-7). There is always some mixture of small cleaved lymphocytes and larger, proliferative “centroblasts.” There is a predominance of small cells in the small cleaved cell type (grade I of the REAL classification) (see Plate XXII-8). The distinction from follicular mixed type (grade II of the REAL classification) is often somewhat subjective, and so has been described as an exercise in grading rather than classification in the REAL system.4 These lymphomas are usually disseminated and, with conventional therapy, effectively incurable, however, patients survive with this disease for prolonged periods (see Chapter 103).53 These neoplasms appear to represent neoplastic immortalization of germinal center cell lines by bcl-2 (or bcl-6) translocation.54
Another major type of low-grade lymphoma is small lymphocytic type, which shows a strong tendency to circulate as chronic lymphocytic leukemia. Microscopically, this is a diffuse lymphoma, but faint nodules are usually discernible, so-called proliferation centers, representing concentrations of prolymphocytes (see Plate XXII-5). This pattern is useful in recognition of this process, both in relation to accurate classification and in distinguishing this process from benign lymphocytic infiltrates.55 The neoplastic cells are indistinguishable from benign inactive lymphocytes, featuring clumped heterochromatin and inapparent cytoplasm (see Plate XXII-6). Mitotic figures are infrequent. Immunologically, this is a homogeneous entity, with tumor cells positive for B-cell CD markers such as CD19 and CD20 and with coexpression of CD5. Surface immunoglobulin is expressed faintly. Cases with plasmacytoid or plasmacytic features correspond clinically and serologically to immunosecretory disorders such as Waldenström macroglobulinemia (see Chapter 108). Rare cases with similar microscropic features are of T-cell phenotype. These most often exhibit subtle pleomorphism with a dispersion of prolymphocytes and abundant mitotic figures, and are of helper subset T-cell phenotype. Prolymphocytic variants, whether B-cell or T-cell, pursue an aggressive clinical course.56 The only T-cell neoplasms that behave as low-grade disease are the large granular (CD8) lymphocytosis (see Chapter 100)57 and early (patch stage) cutaneous T-cell lymphomas.58
Newly recognized by the REAL classification is the low-grade grouping of B-marginal zone lymphomas, characterized microscopically by a heterogenous mixture of small round and cleaved lymphocytes, often with some plasmacytic differentiation and a component of monocytoid B-cells. Immunologically, these are B-cell neoplasms expressing heavy chain other than IgD, usually without CD5 coexpression. They can be usefully subdivided into three types clinically. Nodal marginal zone lymphomas behave as classic low-grade lymphoma,36 splenic marginal zone lymphomas show some overlap with hairy cell disease43 (see Chapter 99) and extranodal marginal zone (MALT) lymphomas behave unlike typical low-grade disease, remaining long localized to primary parenchymal sites for a long period of time.40,41
This grouping is extremely diverse, including lymphomas of different immunophenotype and pathobiology. Two of the Working Formulation types, diffuse small cleaved and diffuse mixed, have disappeared entirely in the REAL classification, having been distributed into various more precisely defined entities. Most lymphomas originally classified as diffuse small cleaved cell type are recognizable today as either low-grade B-marginal zone lymphomas or as intermediate grade mantle cell lymphomas. The latter is composed of relatively uniform small cleaved cells, coexpresses CD5 and is positive for cyclin D1 by virtue of the bcl-1 t(11;4) translocation.36,37 Blastic variants of mantle cell lymphoma are extremely aggressive, truly high-grade neoplasms.38
Diffuse mixed lymphoma is only a starting point, a simple microscopic description of lymphomas, which tells the managing physician little about predicted clinical behavior.59 Neoplasms now separately recognizable within this crude grouping include low-grade pleomorphic variants of small lymphocytic lymphoma and B-marginal zone lymphoma, intermediate grade diffuse counterparts of follicle center neoplasms, and high-grade T-cell lymphomas and so-called T-cell-rich B-cell lymphomas.60
Although most T-cell lymphomas are heterogenous in cellular composition, often including a rich interspersion of benign inflammatory elements recruited by T-cell lymphokines, several clinically distinctive entities have been identified in the updated REAL system.52 These include nasal NK/T-cell (“angiocentric”) type, associated with Epstein-Barr virus (“destructive midline granuloma”); angioimmunoblastic T-cell lymphoma, usually presenting as a systemic syndrome; subcutaneous panniculitic T-cell lymphoma, with a stuttering progression of widespread skin lesions and often eventuating in a hemophagocytic syndrome; and enteropathy-type intestinal T-cell lymphoma, an extremely aggressive neoplasm often derived from preexistent gluten enteropathy.61
There is a continuum of clinical aggressiveness among both B-cell and T-cell lymphomas with “diffuse mixed” microscopic appearance, ranging from intermediate- to high-grade.53,59 In general, a high proliferative rate, as gauged by the pathologist on the basis of frequency of mitotic figures, is a useful predictor for more aggressive behavior.62 Large B-cell lymphomas likely to follow an intermediate grade course are those with preserved (even focally) follicular growth pattern, the more delicate cellular microscopic features of large follicle center cells (see Plate XXII-10) rather than immunoblastic features, and a relatively low mitotic rate.
Lymphomas with a high mitotic rate have an aggressive natural course, representing a therapeutic emergency (see Chapter 103). Since these tumors may present at early stage, prognosis is highly influenced by such evaluation.
Large B-cell lymphomas with immunoblastic features or with a high mitotic rate should be considered high-grade. Some such tumors show microscopic, immunophenotypic, genetic, and clinical features overlapping those of Burkitt lymphoma, and have been described as “Burkitt-like.” Large-cell lymphomas of T-cell immunophenotype usually display pleomorphic immunoblastic features. It is important to distinguish the subgrouping of anaplastic large-cell lymphomas, since these often behave in a more favorable way, particularly if the translocation protein product p80 or ALK-1 is expressed.47,48 Immunostaining for CD30 reveals uniformly strong reactivity among the neoplastic cells of anaplastic large-cell lymphoma.
Burkitt lymphomas show an extremely high mitotic rate and are composed of medium sized cells with one to four prominent nucleoli and deeply basophilic cytoplasm (see Plate XXII-17). The characteristic “starry sky” low magnification appearance is imparted by interspersed macrophages, reflecting the high cellular turnover of such a proliferative neoplasm (see Plate XXII-16). The Burkitt lymphoma was one of the first human neoplasms associated with a specific cytogenetic event: t(8;14), t(2;8) or t(8;22). This was subsequently shown to represent translocation of the c-myc oncogene on chromosome 8 to one of the immunoglobulin encoding regions on chromosome 2, 14 or 22.63 In recent times this type of lymphoma has been associated with human immunodeficiency virus infection.64
Lymphoblastic lymphomas have been renamed precursor B-cell or precursor T-cell neoplasms in the REAL classification in recognition of their normal cell counterparts within the immune system. They may present as, or progress to acute lymphoblastic leukemia. Tumor cells have delicate nuclear chromatin and inapparent cytoplasm. The mitotic rate is moderate or high. The disease-specific marker is terminal deoxynucleotidyl transferase, an enzyme in the nucleus that plays a role in the somatic gene rearrangement that takes place in normal lymphoblasts, the basis for the diverse library of immunologically responsive lymphoid cells (see Chapter 10). This enzyme can be demonstrated by immunostains in conventional paraffin sections, allowing definitive recognition of this lymphoid neoplasm.34,65 Accurate diagnosis of this disease entity, as distinct from other high-grade lymphomas, is critical because therapeutic regimens that are highly effective for this disease grouping differ from those designed for other aggressive lymphoma types.66
The histologic hallmark of Hodgkin lymphoma that sets it apart from other lymphomas is the mixture of benign, reactive cells with neoplastic cells. Efforts to isolate and characterize the tumor cells have been impeded by the intimate association of these cells with reactive host inflammatory cells. The diagnosis of Hodgkin lymphoma should not be made unless bizarre, giant (Reed-Sternberg) tumor cells are present (see Plate XXII-13). To qualify, a cell must be large and have two or more nuclei (or nuclear lobes), each containing a large amphophilic or eosinophilic inclusion-like nucleolus. The presence of Reed-Sternberg cells, however, is not diagnostic of Hodgkin lymphoma, since cells with similar morphology may be present in other processes, both benign and malignant.67
In most cases careful evaluation of combined clinical and histopathologic findings permits their assignation to either Hodgkin or non-Hodgkin lymphoma. However, with the application of high-resolution ancillary study methods throughout the 1980s it has become clear that there is some true continuity linking these two major groupings of lymphoma. In rare cases, the features are overlapping and the diagnostic distinction cannot be made (see Fig. 101-2).68
The mysterious Reed-Sternberg tumor cell currently is considered to be a highly abnormal, activated lymphoid cell that expresses only a few T or B cell–associated antigens. An exception is the nodular variant of lymphocyte predominance type, which expresses a B-cell immunophenotype and, in this and other respects, should be considered an entity separate from the rest of Hodgkin lymphoma (see below)69. Typically, however, the Reed-Sternberg cells, and the mononuclear variant forms (“Hodgkin cells”), express CD30 (Ki-1) and CD15 (Leu-M1) antigens but not CD45 (leukocyte common) antigen.44 These Hodgkin cells express other “activation” markers, including interleukin-2 receptors, transferrin receptors, and DR antigens. Recent highly sensitive molecular probe studies of single, isolated Reed-Sternberg cells indicate them to be abnormal “crippled” immunoblasts which are incapable of successfully producing immunoglobulin.70,71
The original six-part classification of Lukes, Butler, and Hicks21 has been modified in the REAL classification into a five-part system (see Table 101-2).
TABLE 101-2 PATHOLOGIC CLASSIFICATION OF HODGKIN LYMPHOMA BASED ON THE “REAL” CLASSIFICATION OF 1994† (MODIFIED 1999)‡
NODULAR LYMPHOCYTE-PREDOMINANCE HODGKIN LYMPHOMA
Lymphocyte predominance Hodgkin lymphoma, clinically the most favorable type, exhibits a very low ratio of neoplastic cells to reactive cells, and very few Reed-Sternberg cells. Variant forms of atypical cells, so-called “L and H” cells, predominate (see Plate XXII-12). These have sparse cytoplasm and delicate, mutilobated nuclei with small nucleoli. Reactive cells consist of any combination of small lymphocytes, benign epithelioid histiocytes, and occasional plasma cells. Neutrophils and eosinophils usually are not present, and necrosis is not associated with this type of disease (see Plate XXII-11). Two forms of this type are recognized in the original six-part system: the nodular and the diffuse.21 In the diffuse type, although neoplastic cells may show some clustering, the background cellularity has a diffuse pattern, resembling a diffuse lymphoma at low magnification. Using immunostain for B-cells, some nodularity can be perceived even in these cases which initially appear diffuse in conventional stains. In the nodular type, the reactive cells of the background are massed into nodules, and the neoplastic cells are centrally located within these nodules. At low magnification, this process resembles follicular lymphoma. Indeed, large peculiar follicles, so-called progressively transformed germinal centers, often are associated with this process, and the large L and H variant cells express B-cell phenotype. These have been demonstrated to be clonal post-follicular B-cells.70,71 The nodular variant is the most indolent of all the Hodgkin lymphoma types but has a predilection for late relapse and also for eventual development into high-grade lymphoma.72,73
CLASSICAL HODGKIN LYMPHOMA
In the REAL classification most types of Hodgkin lymphoma are considered “classical”, in that these show many overlapping clinical, microscopic, and immunophenotypic features. Tumor cells (Reed-Sternberg and Hodgkin cells) are largely negative by immunostaining for B-cell and T-cell lymphoid markers, positive for CD30 (Ki-1) and often but not invariably positive for CD15(Leu-M1).
A newly apearing term, lymphocyte-rich type connotes classical Hodgkin lymphoma in which tumor giant cells are relatively sparse in an inflammatory background which is predominately lymphocytic.74 The distinction from nodular lymphocyte predominance Hodgkin lymphoma on the basis of conventional microscopy can be difficult or impossible.75 Immunostains are necessary to ascertain the nature of the tumor cells, i.e., whether B-cell or as in classical Hodgkin lymphoma.
MIXED CELLULARITY TYPE
Mixed cellularity type Hodgkin lymphoma contains an intermediate ratio of neoplastic cells to reactive cells. Usually, though not always, Reed-Sternberg cells are identified readily, and mononuclear variant forms of Reed-Sternberg cells are abundant (see Plate XXII-13). Reactive cells consist of any combination of lymphocytes, histiocytes, plasma cells, neutrophils, or eosinophils. A mixed background of reactive cells need not be present. There may be suppuration and necrosis. Recent studies suggest a strong association between mixed cellularity type and Epstein-Barr virus.76
LYMPHOCYTE DEPLETION TYPE
Lymphocytic depletion Hodgkin lymphoma is the least favorable type clinically. The more common reticular form has a high ratio of neoplastic cells to reactive cells, and extremely large, bizarre, malignant giant cells are often present. With the advent of specific cell lineage markers, many cases previously considered reticular lymphocytic depletion Hodgkin lymphoma actually have proved to be anaplastic large-cell lymphomas. The diagnosis is very uncommon and is effectively one of exclusion. The distinction of reticular variant lymphocyte depletion Hodgkin lymphoma from anaplastic large cell lymphoma is, at most, a very subtle one.78 The diffuse fibrosis variant is rare but diagnostically less controversial than the reticular variant. A hypocellular process replaces involved tissues with nonbirefrigent precollagen matrix, scant inflammatory cells, and rare diagnostic Reed-Sternberg cells.
NODULAR SCLEROSIS TYPE
Nodular sclerosis Hodgkin lymphoma is distinctive clinically and pathologically. Young adult females are most commonly affected and there is strong predilection for disease involving the anterior mediastinum (see Chap. 102). Part of the reactive background includes fibrosis emanating from the capsule and connective tissue trabecula. This response begins with the formation of granulation tissue and progresses to the formation of dense bands of hyaline fibrosis that encircle nodules of cells (see Plate XXII-14). Within these nodules is a mixture of reactive and neoplastic cells, and the proportion may range from “lymphocyte predominance” to “lymphocyte depletion,” a finding that apparently does have slight predictive value.79 Reed-Sternberg cells may be present, but more often only lacunar cell variants are evident on which to base the diagnosis. Lacunar cells contain abundant clear cytoplasm that retracts from the surrounding lymphocytes upon fixation with formalin, producing a space, or lacuna. These bizarre cells contain many nuclear lobes, sometimes in a circular or semicircular array at the cell margin and sometimes clustered centrally, each containing a small nucleolus (see Plate XXII-15). Lymph nodes with very early involvement by nodular sclerosing disease do not exhibit capsular or trabecular fibrosis but rather show only nodules with central clusters of lacunar cells. Such a pattern has been described as a “cellular” or “presclerotic” phase of the disease.
PRACTICAL CONSIDERATIONS FOR DIAGNOSIS
Pathologists should interpret a lymph node biopsy in a way that provides answers to the following questions: Is the process an orderly immune response? Are there features that suggest a specific cause, for example, an infection? Is there evidence of neoplasia, and, if so, is it lymphoid in origin?80 And what are the implications for the therapist?
Effective study of lymph node biopsy specimens requires careful tissue sampling and processing. In consultation with the hematologist and pathologist, the surgeon should biopsy the largest and most pathologically involved lymph nodes. The pathologist should monitor the laboratory’s methods to assure that good-quality conventional slides are made and that adequate tissue samples are allocated for special studies (Table 101-3).65,81
TABLE 101-3 ANCILLARY SPECIAL STUDIES FOR LYMPH NODE INTERPRETATION
Reactive hyperplastic lymph nodes may contain clues to the pathogenesis of the lymphadenopathy.87 Certain infectious agents, such as Toxoplasma gondii and the cat-scratch bacillus, elicit specific cellular responses. Other clinicopathologic entities, such as angiofollicular lymph node hyperplasia (Castleman disease) and sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease), can be identified but are of unknown etiology.88,89
The most important task for the pathologist is to distinguish benign from malignant proliferations.80 Hyperplasia can exhibit features that suggest neoplasia, e.g., extreme cellular pleomorphism, abundant mitotic activity, and cellular atypia. On the other hand, lymphoid neoplasia can be difficult to recognize when there is only early, partial involvement of a lymph node or when the neoplasm is composed of small, mitotically inactive cells. The diagnosis of malignancy can be made confidently if the normal functional components of a lymph node are totally replaced by a process of uniform cellular composition (see Plate XXII-5) or if cytomorphologic study reveals features of atypia beyond the limits of reactive lymphoid or histiocytic response.
In some instances ancillary studies must be applied to achieve a definitive diagnosis. Frozen section immunostaining for immunoglobulin light chains is a practical and decisive means of distinguishing low-grade B-cell lymphoma (follicular or small lymphocytic) from hyperplasia.82 In cases of T-cell proliferation, even detailed immunophenotyping often fails to provide direct evidence of malignancy, and cytogenetics or gene probe studies may be necessary to prove the presence of a monoclonal (neoplastic) process (see Table 101-3).83 Even with sophisticated methodology, the pathologist should be circumspect, since in exceptional situations monoclonality is not equivalent to clinical malignancy, for example, the salivary gland lesions in Sjogren syndrome90 or the bizarre cellular infiltrate in lymphomatoid papulosis.91
Exceptionally strong immune stimuli, especially in patients with primary or induced immunodeficiency, can elicit cellular responses in nodal or tonsillar tissues so atypical in appearance as to simulate neoplasm.80,92 In some cases, such processes may progress eventually to actual lymphoma.93
Even when a lymph node obviously is effaced by malignancy, there is potential for diagnostic error. Anaplastic malignancies converge in histomorphologic appearance, so that high-grade lymphomas, in particular, are closely simulated by other neoplasms, such as granulocytic sarcoma (myeloblastoma) and anaplastic carcinoma. Special methods, including immunophenotyping, histochemistry (chloroacetate esterase for granulocytic differentiation), electron microscopy (for subtle features of epithelial differentiation), and immunostaining, may be required to determine cellular origin.65,80 Since these distinctions are crucial for clinical management, sometimes rebiopsy specifically for ancillary studies is necessary.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn