Section 1 -

History of the Modern Classifications of Hodgkin's Lymphoma Nancy Lee Harris Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts, USA

Hodgkin's disease differs from most malignant tumors in its unique cellular composition: a minority of neoplastic cells (Reed-Sternberg [RS] cells) in an inflammatory background. This phenomenon suggests that a specific immunologic reaction is an important part of this disease. Indeed, the clinical features and responses to treatment of Hodgkin's disease differ dramatically from those of other, so-called "non-Hodgkin's" lymphomas. Thus, although we now know that the neoplastic cells in most cases of both lymphocyte predominance and classical types are B cells, the distinct pathological and clinical features still warrant a separate category for this disease. Nonetheless, since it is now clear that Hodgkin's disease is indeed a lymphoma, the new W.H.O. Classification of hematologic neoplasms proposes to recognize this by changing the name to Hodgkin's Lymphoma (HL). Differences in the morphology of the RS cells and the composition of the cellular background are associated with differences in patient demographics, clinical sites of disease, and natural history. These features form the basis for the pathologic subclassification of Hodgkin's lymphoma. The early classification of Jackson and Parker [1] was replaced by that of Lukes and Butler , modified at the Rye Conference in 1966 [2, 3]. In 1994, the International Lymphoma Study Group introduced an updated classification, incorporating new immunologic and molecular data, as part of the Revised European-American Lymphoma (R.E.A.L.) Classification (Table 1) [4]. These concepts were incorporated in the World Health Organization (W.H.O.) classification (Table 2) [5]. There are several differences between the R.E.A.L. and W.H.O. classifications of HL and older classifications. Most important is the recognition that there are two distinct diseases that have been called HL: "classical" HL, which consists predominantly of nodular sclerosis and mixed cellularity, and nodular lymphocyte predominance HL (NLHPL). Simply a predominance of lymphocytes in the background is not sufficient to classify a case as NLPHL; cases that have the RS-cell morphology and immunophenotype of classic HL, even if they contain predominantly lymphocytes, are classified as lymphocyte-rich classical HL. Finally, in the Lukes-Butler and Rye classifications, mixed cellularity was a heterogeneous category, including both typical cases and all other cases that did not fit into one of the other categories. It is now recommended that mixed cellularity be restricted to typical cases, and that unclassifiable cases be classified as "HL unclassifiable." An important corollary to the recognition that HL is a neoplasm of B cells is that borderline cases may exist between HL and B-cell lymphomas. Usually, immunophenotyping will resolve this problem, but some cases truly show overlapping features. These tumors have been called "grey-zone" lymphomas, and they remain one of the puzzles in this area that need to be solved. [6] Nodular Lymphocyte Predominance Hodgkin's Lymphoma (NLPHL) NLPHL differs both morphologically, immunophenotypically, and clinically from classic HL [7]. Some observers feel it should be classified among the non-Hodgkin's lymphomas; however, it resembles classical HD more that it resembles other B-cell lymphomas, in having scarce neoplastic cells in an inflammatory background, and in its tendency to present with localized disease and to respond to local treatment. NLPHL is defined as having at least a partially nodular growth pattern; diffuse areas are present in a minority of the cases, and it is controversial whether purely diffuse cases exist. The RS cell variants have vesicular, polylobated nuclei and distinct but small, usually peripheral nucleoli, without perinucleolar halos; these have been called L&H cells (lymphocytic and/or histiocytic of Lukes and Butler ) or "popcorn" cells [2]. A better term might be "LP" cells, for "lymphocyte predominant". In occasional cases the RS cells may resemble classical or lacunar types; in such cases, immunophenotyping is helpful in establishing the diagnosis. The background is predominantly lymphocytes and epithelioid histiocytes. Occasional sclerosis may resemble nodular sclerosis. LP cells are CD45+, express B-cell associated antigens (CD19, 20, 22, 79a), and EMA, lack CD15 and usually CD30. Immunoglobulin kappa light chain restriction is common. LP cells express nuclear bcl-6, associated with normal germinal center B-cells, but are CD10-. Small lymphocytes in nodules are a mixture of polyclonal B cells of mantle zone type (IgM and IgD+), and numerous T cells, many of which are CD57+, similar to the T-cell population in normal germinal centers. T cells may have nuclear enlargement and irregularity, resembling centrocytes. In contrast to the T cells in reactive or progressively transformed follices, which are scattered singly and often concentrated in the light zone or at the junction with the mantle zone, T cells in NLPHL form small aggregates, surrounding tumor cells. A concentric meshwork of FDC is present within the nodules. The interfollicular region contains predominantly T cells; when there are diffuse areas, the background lymphocytes are also predominantly T cells, and the FDC meshwork is lost. NLPHL comprises 4-5% of HL. The median age is in the 30's, but it occurs both in children and the elderly. The male:female ratio is >3:1. NLPHL usually involves peripheral lymph nodes, with sparing of the mediastinum. About 80% of the patients stage I or II, but rare patients have stage III or IV disease, with a worse prognosis. Over 90% have a complete response to therapy, and 90% are alive at 10 years. Relapses occur as frequently as in classical HL, and both late and multiple relapses are more common than in other types of HL; however, these are usually isolated nodal recurrences, and are not associated with poor survival. The cause of death is often NHL, other cancers, or complications of treatment, rather than HL. Classical Hodgkin's Lymphoma Classical HL is defined by the presence of classic, diagnostic RS cells in a background of either nodular sclerosis, mixed cellularity or lymphocyte depletion, with the immunophenotype of classic HL (CD15+ CD30+, T and B-cell-associated antigens usually negative). Classic HL includes nodular sclerosis, mixed cellularity and lymphocyte depletion, as well as the proposed new category of lymphocyte-rich classical HL [5]. Morphologic Features: NSHL has at least a partially nodular pattern, with fibrous bands separating the nodules; necrosis is common. The RS cells are lacunar type, with multilobated nuclei, small nucleoli, and abundant, pale cytoplasm, The background usually contains lymphocytes, histiocytes, plasma cells, eosinophils and neutrophils. In MCHL, the infiltrate is diffuse or vaguely nodular, without band-forming sclerosis, although fine fibrosis may be present. RS cells are of the classic, diagnostic type, with bilobed, double, or multiple nuclei, and a large, eosinophilic, inclusion-like nucleolus in at least two lobes or nuclei; mononuclear variants are usually also present. The infiltrate typically contains lymphocytes, epithelioid histiocytes, eosinophils, neutrophils and plasma cells. Some cases of HL with Reed-Sternberg cells of the classical type have a background infiltrate that consists predominantly of lymphocytes, with rare or no eosinophils. These cases are now called lymphocyte-rich classical HL [8]. Many have a nodular pattern, with remnants of regressed germinal centers in the nodules, and RS cells and variants located within the mantle zones and interfollicular regions, mimicking NLPHL. The infiltrate in LDHL is diffuse and often appears hypocellular, with diffuse fibrosis and necrosis; RS cells include bizarre "sarcomatous" variants, with few inflammatory cells. Confluent sheets of RS cells and variants may occur ("reticular" variant or "Hodgkin's sarcoma"). Before the availability of immunophenotyping studies, many cases diagnosed as LDHL were in reality cases of large B-cell lymphoma or anaplastic large cell lymphoma (ALCL). Clinical Features: NSHL is the most common subtype of HL in developed countries (60-80%), with a bimodal age distribution and a peak adolescents and young adults; females equal or exceed males. The mediastinum and other supradiaphragmatic sites are commonly involved. MCHL comprises 15-30% of HL cases; it may be seen at any age and in underdeveloped countries, without the early adult peak of NSHL . Involvement of the mediastinum is uncommon, and abdominal lymph node and splenic involvement are common. LRCHL comprises about 5% of HL. The clinical features are intermediate between those of LPHL and classic HL: predominantly males with an older median age than NLPHL or NSHL, with early stage disease, no B symptoms; sparing the mediastinum. The survival is intermediate between cHL and NLPHL [8]. These data are consistent with either an early phase of MCHL or a novel subtype. LDHL now comprises less than 1% of the cases of HL. It is seen in the elderly and in HIV+ individuals, often with abdominal, spleen, liver and bone marrow involvement; response to treatment is reported not to differ from other subtypes. The tumor cells are CD15+ (80%), CD30+, CD45-, CD20-/+ Bcl6-. In EBV+ cases, the tumor cells express EBV latent membrane protein (LMP) but not EBNA2. RS cells have clonal VDJ rearrangements in most cases, but do not make Ig mRNA or protein, possibly because of crippling mutations in the Ig gene or lack of the immunoglobulin promotors Bob.1 and OCT.2. Rare cases of HL are reported to have rearranged T-cell receptor genes. Epstein-Barr Virus in Hodgkin's Lymphoma In the U.S. and western Europe, the tumor cells of classical HL are EBV+ in about 50% of the cases (NSHL 15-30%, MCHL 60-70%). However, EBV is least common in the most common form (NSHL in young, affluent females) and present in the least common forms (immunosuppressed, third world) of HL. In positive cases, the EBV is in clonal episomal form, , indicating infection before neoplastic transformation. Since EBV can immortalize B cells, and since cells in infected cases have clonal EBV and express the most potent transforming protein (LMP-1), most observers conclude that EBV must be important in the pathogenesis of HL. However, the fact that EBV is not present in all the cases leaves open the question of the pathogenesis of EBV-negative cases, and, more importantly, the question of whether EBV is important even in positive cases. At least three hypotheses can be advanced to explain the EBV-negative cases. First, another virus could be involved in these cases; however, studies have not identified one. Second, EBV may be involved in all the cases, but is undetectable in some; this has been referred to the "hit and run" theory. Third, EBV is not important in the pathogenesis of HL, and that its presence in some cases simply reflects the presence of a larger reservoir of latently infected EBV+ cells in these individuals. Conclusions The past 15 years have seen dramatic advances in our understanding of the nature of the malignant cell in Hodgkin's lymphoma, and in our ability to distinguish this clinically distinctive disease from other lymphomas. Many questions remain. What is the nature of the event that results in malignant transformation of a B cell that cannot make an immunoglobulin molecule? Are there cases of T-cell Hodgkin's lymphoma? What is the role of EBV: is it important in pathogenesis? What is the relationship of PTGC to NLPHL? What is the relationship of THRLBCL to NLPHL? What is the relationship of CD30+ large B-cell lymphomas to classical HL? Finally, are pathologic or immunophenotypic features that will predict prognosis within categories of HL? Table 1. Classifications of Hodgkin's Lymphoma Jackson and Parker Lukes and Butler Rye Conference R.E.A.L. Classification Paragranuloma Lymphocytic and/or histiocytic, nodular Lymphocyte predominance Nodular lymphocyte predominance Classical HL Lymphocytic and/or histiocytic, diffuse Lymphocyte-rich lassical HL Granuloma Nodular sclerosis Nodular sclerosis Nodular sclerosis Mixed cellularity* Mixed cellularity* Mixed cellularity Sarcoma Diffuse fibrosis Lymphocytic depletion Lymphocyte depletion Reticular *includes unclassifiable cases Table 2. Comparison of W.H.O classification and Rye classification of HL W.H.O. Classification Rye Classification Lymphocyte predominance, nodular Lymphocyte predominance, nodular (most cases) Classical HL   Lymphocyte rich classical HL Lymphocyte predominance, diffuse Lymphocyte predominance, nodular   Nodular sclerosis classical HL Nodular sclerosis   Mixed cellularity classical HL Mixed cellularity (most cases)   Lymphocyte depletion classical HL Lymphocyte depletion   Unclassifiable classical HL Mixed cellularity (some cases) Table 3. Morphologic and Immunophenotypic Features of CHL and NLPHL Classical HL NLPHL Pattern Diffuse, interfollicular, nodular Nodular, at least in part Tumor cells Diagnostic RS cells; mononuclear or lacunar cells LP cells Background Lymphocytes, histiocytes, eosinophils, plasma cells Lymphocytes, histiocytes Fibrosis Common Rare CD15 + - CD30 + - CD20 -/+ + CD45 - + Oct.2 -/+ + Bob.1 -/+ + EMA - + EBV (in RS cells) + (~50%) - Background lymphocytes T cells > B cells B cells > T cells CD57+ T cells - + Ig genes Rearranged, clonal, mutated Rearranged, clonal, mutated, ongoing Table 4. Clinical Features of NLPHL and Classical HL Classical HL NLPHL Age distribution Bimodal (NS) Unimodal % male sex NS: 50%, MC: 70% 70% Sites involved Mediastinum, abdomen, spleen Peripheral lymph nodes Stage at diagnosis Often II or III Usually I B-symptoms 40% <20% Course Aggressive, curable Indolent, late relapses Risk of B-cell lymphoma <1% 2-3% References Jackson H, Jr., Parker F, Jr.: Hodgkin's disease and allied disorders. New York , Oxford University Press, 1947 Lukes R, Butler J, Hicks E: Natural history of Hodgkin's disease as related to its patholgical picture. Cancer 19:317, 1966 Lukes R, Craver L, Hall T, Rappaport H, Ruben P: Report of the nomenclature committee. Cancer Res 26:1311, 1966 Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary M, Delsol G, DeWolf-Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink HK, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA: A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84:1361, 1994 Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumors of hematopoietic and lymphoid tissues. Lyon: IARC Press; 2001. Rudiger T, Jaffe ES, Delsol G, et al. Workshop report on Hodgkin's disease and related diseases ('grey zone' lymphoma). Ann Oncol 1998;9 Suppl 5:S31-8. Mason D, Banks P, Chan J, Cleary M, Delsol G, de Wolf-Peeters C, Falini B, Gatter K, Grogan T, Harris N, Isaacson P, Jaffe E, Knowles D, Muller-Hermelink H, Pileri S, Piris M, Stein H, Ralfkiaer E, Warnke R: Nodular lymphocyte predominance Hodgkin's disease: a distinct clinico-pathological entity. Am J Surg Pathol 18:528, 1994 Anagnostopoulos I, Hansmann ML, Franssila K, et al. European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 2000;96(5):1889-99.