An Overview of the Classification of Non-Hodgkin's Lymphomas: an Integration of Morphological and Phenotypical Concepts1

[CANCER RESEARCH (SUPPL.) 52, 5447s-5452s. October I. 1992| An Overview of the Classification of Non-Hodgkin's Lymphomas: An Integration of Morphological and Phenotypical Concepts1

Elaine S. Jaffe,2 Mark Raffeid, L. Jeffrey Medeiros, and Maryalice Stetler-Stevenson

Hematopathology Section, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20982

Abstract As a result of this dissatisfaction, a variety of classification An analysis of trends in the incidence of non-Hodgkin's lymphoma schemes were proposed. Two of them, the Lukes and Collins Classification (3) and the Kiel Scheme (4), as proposed by Len- requires an understanding of individual disease entities within this broad group. The non-Hodgkin's lymphomas represent a diverse group nert and colleagues, are shown in Table 1. The complexity of of malignancies that have in common an origin from lymphoid cells. this terminology is obvious. All of these terms have been in Nevertheless, these disorders are heterogeneous in their clinical behav International Classification of Diseases for Oncology, and ior, morphological appearance, cellular origin, etiology, and pathogen- probably all are reflected in the SEER data at one point or esis. A modern classification of non-Hodgkin's lymphomas must include another. Moreover, if one tries to discern individual disease an integration of morphological, immunophenotypical, and molecular entities from these data, it is virtually impossible. concepts in order to delineate individual diseases within this broad The National Cancer Institute responded to this problem by group. Existing classification schemes such as the working formulation, funding a study to test the six major classification schemes while they may be useful in providing a guide to clinical management, cannot provide this information in the absence of other data. proposed at this time. They examined 1175 cases of lymphoma This point is most readily made with the low-grade B-cell lymphomas that had been prospectively staged and treated in a uniform which include follicular lymphomas, mantle cell lymphomas, small lym- manner at one of four major treatment centers (5). Not surpris phocytic lymphomas, immunosecretory disorders, and lymphomas of ingly, all six classification schemes could identify tumors of mucosa-associated lymphoid tissues. Each of these malignancies has a low- or high-grade clinical behavior, and no one scheme seemed distinct phenotype and genotype, and indubitably each has a different to work significantly better than any other. etiology. The postthymic T-cell tumors are equally diverse. Analysis of Consequently, the investigators involved in that study pro epidemiolÃ³gica! data from cancer registries must include a recognition posed a working formulation for non-Hodgkin's lymphoma di that our ability to recognize individual diseases from historical data is limited. Studies of trends in the non-Hodgkin's lymphomas should at agnosis, and they divided the tumors into morphological groups tempt to delineate biological markers that may be of relevance to patho- ranked according to their clinical behavior in these 1175 cases genesis in both historical and prospectively accrued cases. (Table 2). At the time that the working formulation was pub lished, the authors (5) of it stated that it was "not proposed as a new classification, but as a means of translation among the Introduction various systems." Unfortunately, this subtle distinction has not The non-Hodgkin's lymphomas are not a single disease always been appreciated. but represent a diverse group of clinicopathological and biolog The working formulation categories do not identify individ ical entities. The modern approach to lymphoma diagnosis ual disease entities. The terms that it uses are microscopic should include both morphological and phenotypic techniques. descriptors. They describe the cellular population that the pa The Rappaport classification is not in current use; however, thologist sees in the histolÃ³gica! section, but one cannot infer when this classification scheme was proposed in the 1960s, it that each category is an individual disease. In fact, we have very immediately became popular among clinicians and is the ter good evidence today that most of these categories do not rep minology that has been most widely utilized in the Surveillance resent individual diseases. If one wishes to understand the ep Epidemiology and End Results program (SEER) data base (Ta idemiology of lymphomas and to understand time trends, one ble 1)(1). The classification of non-Hodgkin's lymphomas, as proposed must step away from this approach and look at individual dis by Rappaport (1), first divided lymphomas according to their eases rather than morphological categories. architectural pattern, nodular or diffuse, and then according to Essential to this process is the use of immunological ap the cytological cell type. If the cells were small, they were proaches. The malignant lymphomas are tumors of the immune termed "lymphocytic," or if large, "histiocytic." However, dur system, and the malignant cells retain both the phenotypic and ing the 1970s when the field of immunology was undergoing a functional properties of their precursors. Using the tools of rapid expansion, the scientific basis for this scheme came into immunology, we can begin to dissect out individual diseases question. It became apparent that the large cell tumors that among the malignant lymphomas. Rappaport termed histiocytic were, in fact, composed of trans The development of monoclonal antibodies has been invalu formed lymphoid cells. Furthermore, the Rappaport scheme able in providing us with a battery of reagents that can be did not take into consideration the phenotypic heterogeneity of consistently used among different laboratories. Most of these the immune system as it related to the classification of lympho reagents have to be applied to freshly isolated cells, either in cell mas (2). suspension or in frozen sections, but increasingly, monoclonal antibodies are available that can be used on routinely processed paraffin-embedded sections (6). These reagents provide an im 1 Presented at the National Cancer Institute Workshop, "The Emerging Epi portant step in permitting the use of these techniques on a demic of Non-Hodgkin's Lymphoma: Current Knowledge Regarding Etiological routine basis for most lymphomas. Factors," October 22-23, 1991, Bethesda. MD. The vast majority of non-Hodgkin's lymphomas diagnosed in 2 To whom requests for reprints should be addressed, at Hematopathology Sec tion, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20982. the United States and in Europe are of B-cell origin and fall into 5447s

Table 1 Comparison of commonly used classifications for non-Hodgkin's lymphomas

Modified Rappaport Working Lukes and Collins Working Working classification formulation" classification formulation Kiel classification formulation Nodular Undefined cell type Low-grade malignancy Lymphocytic, well differentiated A T-cell type, small lymphocytic A Lymphocytic, chronic lymphocytic/ Lymphocytic, poorly B T-cell type, SÃ©zary-mycosisfungoides leukemia A differentiated C (cerebriform) Lymphocytic, other A Mixed, lymphocytic and histiocytic D T-cell type, convoluted lymphocytic I Lymphoplasmacytoid A Histiocytic T-cell type, immunoblastic sarcoma Centrocytic E Diffuse (T-cell) H Centroblastic-centrocytic, follicular Lymphocytic, well differentiated A B-cell type, small lymphocytic A without sclerosis B, C without plasmacytoid features B-cell type, plasmacytoid lymphocytic A Centroblastic-centrocytic, follicular D Lymphocytic, well differentiated A Follicular center cell, small cleaved B-E with sclerosis with plasmacytoid features E Follicular center cell, large cleaved D-G Centroblastic-centrocytic, follicular Lymphocytic, poorly I Follicular center cell, small J and diffuse, without sclerosis differentiated I noncleaved D-G Centroblastic-centrocytic, follicular Lymphoblastic, convoluted F Follicular center cell, large and diffuse, with sclerosis Lymphoblastic, nonconvoluted G noncleaved Centroblastic-centrocytic, diffuse Mixed, lymphocytic and histioytic G Immunoblastic sarcoma (B-cell) H Low-grade malignant lymphoma, F Histiocytic without sclerosis J Subtypes of follicular center cell unclassified Histiocytic with sclerosis J lymphomas High-grade malignancy Burkitt's tumor 1. Follicular Centroblastic Undifferentiated 2. Follicular and diffuse Lymphoblastic, Burkitt's type G Malignant lymphoma, unclassified 3. Diffuse Lymphoblastic, convoluted cell type J Composite lymphoma 4. Sclerotic with follicles Lymphoblastic, other (classified) I 5. Sclerotic without follicles Immunoblastic Histiocytic High-grade malignant lymphoma, H Malignant lymphoma, unclassified unclassified Malignant lymphoma, unclassified (unable to specify "high grade" or "low grade") Composite lymphoma " Letters indicate equivalent or related category in the working formulation as shown in Table 2.

Table 2 National Cancer Institute working formulation of non-Hodgkin's Follicular lymphoma is the prototype of the low-grade B-cell lymphomas for clinical usage (Ref. 5) lymphomas and is the single largest group of non-Hodgkin's Low grade A. Small lymphocytic lymphomas, accounting for approximately 45% of all cases (5). B. Follicular, predominantly small cleaved cell It is a disease of adult life and occurs equally in males and C. Follicular, mixed small cleaved and large cell females. The neoplastic cells form follicular aggregates, which Intermediate grade D. Follicular, predominantly large cell tend to mimic normal lymphoid follicles. Cytologically, the cell E. Diffuse, small cleaved cell types that we see within follicular lymphomas resemble the cells F. Diffuse, mixed small cleaved and large cell G. Diffuse, large cell within the normal germinal center, as described by Lukes and High grade Collins (3) and Gerard-Marchant et al. (4). Follicular lympho H. Large cell, immunoblastic mas are subclassified according to the proportion of these var I. Lymphoblastic J. Small noncleaved cell ious cytological cell types (7). In the working formulation, the Miscellaneous small cleaved and mixed small cleaved and large cell categories Composite are in the low-grade group, whereas the follicular large cell type Mycosis fungoides Histiocytic is in the intermediate-grade group, based on its more aggressive Extramedullary plasmacytoma clinical behavior. However, all of these cells exist in all follic Unclassifiable, other ular lymphomas, and the Kiel classification takes the approach of considering all tumors centrocytic/centroblastic, without the the midstage of B-cell differentiation (6). At this stage of dif identification of cytological subgroups. ferentiation, cells express monoclonal surface immunoglobulin, The follicular lymphomas are monoclonal B-cell neoplasms; most often IgM, with or without IgD, and usually express the pan-B-cell antigens, CD 19, CD20, and CD22. the cells express monoclonal surface immunoglobulin and are frequently confined to the neoplastic nodules (8, 9). In fact, in early lymph node involvement, one can show that the neoplastic Low-Grade B-Cell Lymphomas cells selectively home to or colonize the germinal centers, Within the working formulation, virtually all low-grade lym focally involving these structures within the lymph node (10, phomas are of B-cell origin, but one can begin to recognize 11). different disease entities among the low-grade B-cell lympho The cells seem to be held together within these follicles by mas that are not readily apparent in the pure working formu dendritic reticulum cells, which are a normal structural and lation approach. First and foremost among these is follicular functional component of the germinal center. These cells are an lymphoma, which is well recognized in the working formulation invariant component of follicular lymphomas but are not con but spans three separate clinical groups, in both the low-grade sidered neoplastic. When the dendritic reticulum cells are lost, and intermediate-grade categories. Other disease entities are the process tends to become diffuse, although these events may less readily identified in the working formulation (Table 3). For not be causally related. Follicular lymphomas usually present example, mantle zone lymphoma, or mantle cell lymphoma, with generalized lymphadenopathy and frequent involvement falls within several different working formulation groups. Con of the bone marrow with paratrabecular lymphoid aggregates versely, the small lymphocytic lymphoma group (A) includes (5, 12, 13). In approximately 10% of patients, neoplastic cells several different disease entities. are identified morphologically in the peripheral blood. 5448s

Table 3 A disease-oriented approach to lymphoma classification positive (20, 21). Like normal mantle zone cells, the tumor cells Low-grade B-cell lymphomas Working formulation also often coexpress IgM and IgD. Follicular lymphoma B.C. D In the working formulation, mantle cell lymphomas fall into Mantle cell lymphoma A, B, E the diffuse small cleaved category, which is in the intermediate- IDL"/centrocytic/mantle zone grade group. However, unlike all other intermediate-grade lym Small lymphocytic lymphoma/CLL A Immunosecretory disorders A, F phomas, the survival curve does not show a plateau or evidence WaldenstrÃ¶m's macroglobulinemia of a cured population (20). In this regard, they resemble low- MALT A, E Monocytoid B-cell lymphoma grade lymphomas. However, the median survival is only 5 years, somewhat less than other low-grade lymphomas (20). ' IDL, lymphocytic lymphoma of intermediate grade of differentiation. Recent studies have shed light on the pathogenesis of mantle cell lymphomas. They are often associated with the t(ll;14) involving the bcl-l breakpoint region (22, 23). Recently, an When more sensitive molecular techniques are used, even a oncogene, PRAD\, located near this breakpoint has been shown higher proportion of patients can be shown to have peripheral blood involvement. Follicular lymphomas are characterized by to be overexpressed in centrocytic or mantle cell lymphomas (24). a consistent cytogenetic abnormality; the t(14;18) is found in A third category of low-grade B-cell lymphoma is the small 90% of cases of follicular lymphoma (14). This translocation lymphocytic malignancies, which include chronic lymphocytic involves the immunoglobulin heavy chain locus on chromo some 14 and the bcl-2 gene on chromosome 18. Probes to the leukemia (25, 26). These tumors are composed of cells that are bcl-2 gene can be used to detect this translocation at the mo relatively uniform in their appearance, resembling normal lym lecular level, using either Southern blot hybridization or the phocytes, and thus in the Rappaport classification they were called well-differentiated lymphocytic lymphomas. Small lym polymerase chain reaction technique (15). Mantle cell lymphoma is a distinct clinicopathological entity, phocytic malignancies can present either as chronic lympho equivalent morphologically to lymphocytic lymphoma, inter cytic leukemia or, less commonly, with primarily lymph node mediate grade of differentiation (IDL) of the modified Rappa- disease, as a lymphoma. In the latter case, there is usually port scheme (16); centrocytic lymphoma of the Kiel classifica generalized lymphadenopathy and only focal bone marrow in tion; and mantle zone lymphoma, a term popularized by volvement. However, whether the presentation is leukemic or Weisenburger et al. (17). This form of lymphoma was originally lymphomatous, the process is identical phenotypically and called intermediate because it was believed to be intermediate in morphologically and represents different clinical presentations its cytological characteristics between the well-differentiated of the same neoplastic population. Like mantle cell lympho and poorly differentiated lymphocytic lymphomas of the Rap- mas, this B-cell neoplasm also expresses CDS in most cases. paport scheme (18). The cells are slightly cleaved and angulated Small lymphocytic malignancies may represent a block in the terminal maturation of a B-cell toward a plasma cell. These with an atypical appearance. In contrast to follicular lymphoma, in which selective in patients often have hypogammaglobulinemia and humoral im munodeficiency (10). volvement of germinal centers is seen, in mantle cell lymphoma, WaldenstrÃ¶m's macroglobulinemia represents one step fur residual normal germinal centers are often uninvolved by the neoplastic process (16). This mantle zone growth pattern can be ther in the maturation of a B-lymphocyte (27). In this disease, seen in the small intestine, bone marrow, and other extranodal the cells express surface and cytoplasmic IgM and secrete im sites and provides evidence for a mantle zone derivation of the munoglobulin resulting in a monoclonal paraproteinemia. Morphologically, the cells also appear more plasmacytoid. malignant cells. WaldenstrÃ¶m's macroglobulinemia usually presents as lym In fact, this tumor can have a vaguely nodular growth pattern, which derives from its propensity to grow as an expanded man phoma with generalized lymphadenopathy, although in about tle around residual germinal centers. As such, (mis)diagnosis as 10% of patients it may present as chronic lymphocytic leukemia follicular small cleaved in the working formulation may occur. with a lymphocytosis (27). In tumors with plasmacytic differ Such an error may be avoided if careful cytological criteria are entiation, there is often a change in the antigenic phenotype utilized. For example, follicular lymphomas always have a mix (28). The cells may lose many of the pan-B-cell antigens at this ture of cell types, so-called "centrocytes" and "centroblasts," late stage of B-cell differentiation. In addition, there is eventu whereas mantle cell lymphomas are much more homogeneous ally a loss of surface immunoglobulin and a predominance of cytologically. In addition, in contrast to follicular lymphomas, cytoplasmic immunoglobulin in these secretory B-Iymphocytes. in which one finds a tight meshwork of dendritic reticulum The last category of low-grade B-cell lymphomas, which has cells, in mantle cell lymphomas, the dendritic reticulum cells been recently proposed by Isaacson and Spencer (29, 30), is are often disorganized, correlating with the vaguely follicular lymphomas of MALT3. MALT lymphomas usually occur in growth pattern (19). Another distinguishing feature of this lym extranodal sites, such as the stomach and the lung. Many of phoma and one that is useful from a diagnostic standpoint is these tumors were called pseudolymphomas prior to the devel that this tumor, like chronic lymphocytic leukemia, is almost opment of the MALT lymphoma concept because they fre always CDS positive (20, 21). CDS is an antigen expressed on quently contain hyperplastic germinal centers. However, inumi normal T-cells but also expressed on a subset of B-cells. True nophenotypic studies have revealed a monoclonal pattern of follicular lymphomas are always CDS negative. light chain expression in the small lymphocytic component. Mantle cell lymphomas are unique in that a greater propor The reclassification of these lesions because of a change in tion of these cases express monoclonal X-light chain than mon diagnostic criteria might provide a partial explanation for the oclonal K.For most of the non-Hodgkin's lymphomas, there is recently observed increase in the incidence of lymphoma. a predominance of Kbecause there is a predominance of normal K-bearing cells in the peripheral blood. But centrocytic lympho mas or mantle cell lymphomas are more often Xpositive than K ' The abbreviation used is: MALT, mucosa! associated lymphoid tissue. 5449s

Clinically, the MALT lymphomas have a unique and often Table 5 Classification ofpostthymic T-cell malignancies indolent behavior. They tend to recur in extranodal sites but T-cell "chronic" lymphocytic leukemia usually do not disseminate widely to bone marrow or to lymph CD4 positive (prolymphocytic) CDS positive/large granular lymphocytes nodes (31). In the working formulation, most would fall into the Mycosis fungoides-Sezary syndrome small lymphocytic group, but their often heterogeneous cellular Lymph node-based peripheral T-cell lymphomas IBL-like" T-cell lymphoma composition might place them in other categories as well (Table Large cell anaplastic lymphoma (KÃ•-1+) 3). In contrast to the other small lymphocytic lymphomas, they Adult T-cell leukemia/lymphoma are CDS negative rather than CDS positive (31). Monocytoid Subcutaneous panniculitic T-cell lymphoma B-cell lymphomas, originally described in lymph nodes, appear Angiocentric immunoproliferative disease to be the nodal counterpart of MALT lymphomas and show a IBL, immunoblastic lymphadenopathy. high frequency of extranodal disease (32-34). The small noncleaved cell lymphomas fall into two groups. Aggressive B-Cell Lymphomas Small noncleaved cell lymphoma of the Burkitt's type is a dis Recognition of distinct disease entities within the aggressive tinct clinicopathological entity, both in its endemic form in lymphomas is more difficult. The more high-grade lymphomas Africa and in its sporadic form in the United States and else can occur de novo, or they can occur as a consequence of his- where (42, 43). In the working formulation, Burkitt's lym tological transformation of a low-grade lymphoma (35-37). phoma is called small noncleaved because the nuclei of the The diffuse aggressive B-cell lymphomas fall into four catego tumor cells approximate in nuclear diameter the nuclei of the ries in the working formulation: diffuse mixed small and large admixed starry histiocytes. This tumor is very uniform in its cell, diffuse large cell, large cell immunoblastic, and small non- cytological composition and has a very high-growth fraction (44). cleaved cell. In the working formulation, diffuse large cell and Burkitt's lymphoma usually presents in extranodal sites. In small noncleaved cell lymphomas are almost always of B-cell origin. By contrast, diffuse mixed, or diffuse large cell immu the United States, the most common presentation is as an ab noblastic lymphomas are phenotypically heterogeneous and can dominal mass involving the ileocecal region. In women, it may be derived from either B- or T-lymphocytes (38). present with ovarian or even breast involvement. Burkitt's lym The diffuse aggressive lymphomas differ from the low-grade phoma is primarily a disease of young children with, of course, sporadic cases occurring in older age groups. Burkitt's lym lymphomas in their biological and clinical manifestations (Ta ble 4) (11). Rather than demonstrating homing to microscopic phoma is also commonly seen in association with human im compartments of the lymphoid system, these tumors more of munodeficiency virus infection (45). By contrast, small noncleaved (or undifferentiated) lympho ten spread as large masses. In addition, these tumors have a mas of the non-Burkitt's type are much more heterogeneous greater propensity to involve privileged sites, such as the testes and in particular the central nervous system. Virtually all cen and do not represent a disease entity. They exhibit a wide age tral nervous system lymphomas are of aggressive histolÃ³gica! distribution, ranging from children to adults (5, 44). Morpho logically, these tumors are heterogeneous. While some cells grade. closely resemble those of Burkitt's lymphoma, others are more Cytologically, many diffuse aggressive lymphomas resemble the large follicular center cells encountered in follicular pleomorphic in terms of nuclear size and shape. lymphomasâ€”large cleaved, large noncleaved, and immuno The non-Burkitt's cell lymphomas also differ from classic blastic. Moreover, if one looks for evidence of the bcl-2 trans- Burkitt's at the molecular level. Whereas Burkitt's lymphomas are frequently associated with c-myc translocations, this translocation characteristic of follicular lymphoma, one can find location is uncommonly seen in the non-Burkitt's lymphomas bcl-2 translocations in approximately 35% of patients with dif fuse aggressive B-cell lymphomas presenting de novo (39, 40). (46). In fact, some of these tumors contain bcl-2 translocations, Either these tumors arose as follicular lymphomas and trans suggesting that they may be more closely related to the diffuse formed prior to clinical presentation or they represent another follicular center cell neoplasms. manifestation of the bcl-2 translocation. The aggressive B-cell lymphomas also can represent trans Postthymic T-Cell Lymphomas formations of other low-grade disorders. For example, small lymphocytic lymphomas or chronic lymphocytic leukemias can The postthymic T-cell malignancies represent a heteroge transform into large cell lymphomas, so-called Richter's syn neous group of disease entities that can present as leukemia or drome. While such cases may not be recognizable on purely lymphoma (Table 5). They also range in their clinical behavior morphological grounds, the neoplastic cells may retain the CDS from low to high grade. Some clinicopathological entities, such as mycosis fungoides-SÃ©zarysyndrome, are considered sepa antigen characteristic of small lymphocytic malignancies (41). rately from the other non-Hodgkin's lymphomas and are listed Table 4 Clinical, pathological, and experimental characteristics oflow- in the "miscellaneous" group (Table 2). and high-grade malignant lymphomas Lymphomas with a mature T-cell phenotype are relatively Low grade High grade uncommon and account for only 10-15% of all non-Hodgkin's Indolent clinical course Aggressive clinical course lymphomas. The neoplastic cells express one or more of the Relatively long survival Short survival without therapy pan-T-cell antigens, as well as one of the major subset antigens, Not curable with chemotherapy Potential for long remission (cure) with modern chemotherapy CD4 or CDS, in most cases (47). Virtually all of the postthymic Nondestructive growth pattern Destructive growth pattern T-cell lymphomas are clinically aggressive and fall into inter Absence of cellular atypia Presence of cellular atypia/anaplasia mediate- and high-grade categories in the working formulation. Respect privileged sites Invade privileged sites Respond to regulatory influences Autonomous Peripheral T-cell lymphomas have a high incidence of involve Fail to grow in culture Immortalized in culture ment of skin and/or mucosal sites, in addition to frequent gen Nontransplantable Transplantable in immunodeficient host eralized adenopathy. Clinically, they have an aggressive natural 5450s

Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1992 American Association for Cancer Research. CLASSIFICATION OF NON-HODGKIN'S LYMPHOMAS history but will respond to multiagent chemotherapy, with References long-term remission in some cases. i. Rappaport, H. Tumors of the hematopoietic system. In: Atlas of Tumor Unfortunately, the working formulation is not helpful in de Pathology, Section 3, Fascicle 8. pp. 9-14. Washington, DC: Armed Forces Institute of Pathology, 1966. lineating the different categories of T-cell malignancy or in Jaffe, E. S. Non-Hodgkin's lymphomas as tumors of the immune system. In: identifying distinct clinicopathological entities. For example, C. W. Berard (moderator): A multidisciplinar} approach to non-Hodgkin's adult T-cell leukemia-lymphoma, a distinct disease associated lymphomas. Ann. Intern. Med.. 94: 218-235, 1981. with human T-cell leukemia virus, type 1, is not separately Lukes, R. J., and Collins. R. D. Immunological characterization of human malignant lymphomas. Cancer (Phila.), 34: 1488-1503. 1974. identified in the working formulation (48). Morphologically, it Gerard-Marchant. R.. Hamlin, I.. Lennert, K., Rilke, F., Stansfeld, A. G., might fall into the diffuse mixed small and large cell or large and Van Unnik, J. A. M. Classification of non-Hodgkin's lymphomas. Lan cell immunoblastic groups. In fact, most peripheral or postthy- cet, 2:406-408, 1974. Rosenberg, S. A., Berard, C. W., Brown, B. W.. Burke, J.. Dorfman, R. F., mic T-cell lymphomas are classified in these two categories in Glatstein. E.. Hoppe, R. T.. and Simon. R. National Cancer Institute spon the working formulation. However, even these working formu sored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer (Phila.), 49: lation groups are not phenotypically homogeneous and include 2112-2135. 1982. both B- and T-cell lymphomas. Jaffe, E. S. The role of immunophenotypic markers in the classification of Recent studies have shed light on the spectrum of diseases non-Hodgkin's lymphomas. Semin. Oncol., Â¡7:11-19, 1990. included in the broad group of T-cell lymphomas, and newly Mann, R. B., and Berard, C. W. Criteria for the cytologie subclassifÃ¯cationof lolliriil.il lymphomas: a proposed alternative method. Hematol. Oncol., /: emerging entities have been identified (Table 5). It is also ap 187-192, 1983. parent that these diseases vary in their pathogenesis, a fact that Jaffe, E. S.. Shevach, E. M., Frank. M. M.. Berard, C. W., and Green, I. Nodular lymphomaâ€”evidence for origin from follicular B lymphocytes. N. is of great importance in understanding lymphoma trends. For Engl. J. Med., 290: 813-819, 1974. example, the angiocentric lymphomas appear to be associated 9. Warnke, R., and Levy, R. Immunopathology of follicular lymphomas: a with Epstein-Barr virus, whereas the large cell anaplastic lym model of B-lymphocyte homing. N. Engl. J. Med., 298: 481-486, 1978. 10. Mann. R. B., Jaffe, E. S., and Berard. C. W. Malignant lymphomas: a phomas are frequently found to contain the t(2;5)(p23;q35) conceptual understanding of morphologic diversity. Am. J. Pathol., 94:105- translocation (49-53). The recognition of distinct disease enti 192, 1979. ties in the T-cell lymphoma group requires a multidisciplinar) 11. Jaffe, E. S. Follicular lymphomas: possibility that they are benign tumors of the lymphoid system. J. Nati. Cancer Inst., 70: 401-403, 1983. approach using clinical, pathological, immunophenotypic, mo 12. Horning. S. J., and Rosenberg, S. A. The natural history of initially untreated lecular, and virological data. low-grade non-Hodgkin's lymphomas. N. Engl. J. Med., 311: 1471-1475, 1984. 13. Anderson. T., Chabner, B. A., Young, R. C.. Berard, C. W., GarvÃn,A. J., Lymphoblastic Malignancies Simon. R. M., and DeVita, V. T. Malignant lymphoma. I. The histology and staging of 473 patients at the National Cancer Institute. Cancer (Phila.), 50: The last category to be considered in the non-Hodgkin's lym 2699-2707, 1982. 14. Tsujimoto. Y., Cossman, J., and Jaffe. E., and Croce. C. M. Involvement of phomas are the lymphoblastic malignancies; these include lym- the bcl-2 gene in human follicular lymphoma. Science (Washington DC), phoblastic lymphomas and acute lymphoblastic leukemias. The 288: 1440-1443, 1985. 15. Cossman, J., and Medeiros. L. J. Molecular genetics of human lymphopro- morphological criteria that distinguish lymphoblastic lym liferative disorders. In: J. Cossman (ed.). Molecular Genetics in Cancer Di phoma from other lymphomas have been clearly delineated, agnosis, pp. 189-202. New York: Elsevier Scientific Publishing. Inc.. 1990. and lymphoblastic lymphoma is a morphological entity (54, 16. Jaffe, E. S., Bookman, M. A., and Longo, D. L. Lymphocytic lymphoma of intermediate differentiationâ€”mantle zone lymphoma. A distinct subtype of 55). The nuclei of the neoplastic cells have finely distributed B-cell lymphoma. Hum. Pathol., 18: 877-880. 1987. chromatin and resemble the lymphoblasts of acute lymphoblas 17. Weisenburger, D. D., Kim, H.. and Rappaport, H. Mantle zone lymphoma: tic leukemia. a follicular variant of intermediate lymphocytic lymphoma. Cancer (Phila.). Most lymphoblastic lymphomas have an immature T-cell 49: 1429-1438, 1982. 18. Berard, C. W. Reticuloendothelial system: an overview of neoplasia. In: J. W. phenotype; they are usually terminal transferase positive and Rebuck, C. W. Berard, and M. R. Abell (eds.). The Reticuloendothelial CD7 positive and express one or more of the pan-T-cell anti System, pp. 301-317. Baltimore. MD: Williams & Wilkins, 1975. gens. Less commonly, these tumors have a precursor B-cell 19. Harris, N. L., Nadler, L., and Bhan. A. K. Immunohistologic characteriza tion of two malignant lymphomas of germinal center type (centroblastic/ phenotype comparable to what one would see in common acute centrocytic and centrocytic) with monoclonal antibodies: follicular and dif lymphocytic leukemia or precursor B-cell leukemia. The pre fuse lymphoma of small cleaved cell types are related but distinct entities. cursor B-cell type differs from the precursor T-cell type clini Am. J. Pathol.. 117: 262-272, 1984. 20. Lardelli, P., Bookman, M. A., Sundeen. J., Longo. D. L., and Jaffe, E. S. cally in that it often presents in skin and/or bone, with an Lymphocytic lymphoma of intermediate differentiation: morphologic and absence of a mediastinal mass (56-58). Morphological criteria immunophenotypic spectrum and clinical correlations. Am. J. Surg. Pathol., 14:152-16), 1990. are not helpful in identifying the immunophenotypic subtypes 21. Swerdlow, S. H.. Habeshaw, J. A.. Murray, L. J., Dhaliwal. H. 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Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1992 American Association for Cancer Research. An Overview of the Classification of Non-Hodgkin's Lymphomas: An Integration of Morphological and Phenotypical Concepts

Elaine S. Jaffe, Mark Raffeld, L. Jeffrey Medeiros, et al.

Cancer Res 1992;52:5447s-5452s.

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