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New concepts on histopathology of Hodgkin's disease
Annals of Oncology 3 (Suppl. 4): S35-S38, 1992. O 1992 Kluwer Academic Publishers. Primed in the Netherlands.
Original article New concepts on histopathology of Hodgkin's disease A. Georgii Medizinische Hochschule Hannover, Hannover, Germany
Key words: histopathology, lymphocytic predominant Hodgkin's disease (NLP.HD), borderline lymphomas
to vary between 4% [10] to 7% [34, 50, 67]. However, it is still under discussion, whether all of these cases do represent real transgressions from one to another lymphoma or whether at least some of them result from a second independent clonal transformation, representing composite tumors [4, 5, 12, 24, 37, 38, 67, 69, 70]. It might be rather difficult to distinguish by histopathology between transformation of HD and composite neoplasia [79]. Therewith, LP.HD represents a peculiar group which is different from the other more frequent of types HD. The question of its treatment must be considered therefore, since life expectance was not enhanced by therapy [30, 61]. Moreover, common schemes of HD-therapy may enhance the chance of transformation into a higher malignant lymphoma. Finally the question is discussed, if monoclonality in LP.HD is obligate, or continuous transformation is preceeded by a non-monoclonal stage of lymphoproliferation with similar histologic features [2, 34]. Even in T-cell rich B-cell lymphoma only 1/6 cases revealed monoclonality [20, 21, 40]. There are certain cases which are difficult to distinguish between Hodgkin and Non-Hodgkin lymphomas when both present with mainly large cell patterns [14, 19, 35, 59]. Increasing attention is paid to this grey zone or borderline lymphomas [44], which causes dissent typing within panel classification of Hodgkin lymphomas in about 3.5% among a series of 1,000 biopsies [26]. These cases focus mainly on large cell T.NHL or anaplastic large cell lymphoma (ALCL) versus the pleomorphic NS grade 2 or syncytial variant of NS.HD. Immunophenotyping by CD 15 (LeuMl) versus CD 30 (BerH2) may resolve some of these cases, when histologic hallmarks such as sinus infiltration are not available to verify anaplastic large cell lymphoma [1]. Therefore characterizing such cases by molecular genetics has become a most interesting field. Distinguishing these lymphomas by genotypic analysis is useful diagnostically, e.g. analyses of the T-cell receptor (TCR) and immunoglobulin (Ig) gene rearrangements, because the absence of gene rearrange-
Downloaded from http://annonc.oxfordjournals.org/ at UQ Library on June 18, 2015
Histopathology from biopsies, extended by immunoand geno-typing provides the data for a better understanding of Hodgkin's Disease (HD). Increasing interest is paid not only to understand but also to calculate this disease in its manipulated course under protocol therapy as well as its outcome in cured cases. Primary attention is therefore emphasized on reliable histological classification which not only can be understood but also can be repeated by other observers. Conspicuous differences of survival times were reported when Nodular Sclerosis - NS.HD - had been subtyped to a grade 1 and grade 2 category, based upon the large number of 3,600 cases of the British National Lymphoma Investigation - BNLI - [6-9, 45, 46). These results were confirmed by the EORTCgroup in clinical trials [76]. However, present experiences [16, 23, 47], as well as first results of the German National Trial have not confirmed these results so far [27]. Differences that have to be considered are due to the variations of the therapy protocol as well as performance of histological classifications by individuals [9, 17,27,42,51,78]. No diagnostic monoclonal antibody is available presently to characterize the large, presumably neoplastic RS-cell unequivocally from other large or multinucleated cells. However, the staining with monoclonal antibodies of different CD clusters, i.e. CD15, CD20, CD22, CD30, CD45, helps to support the diagnosis of HD on its characteristic background [11, 15, 22, 3 1 33,39,41,57,64,65,72,75]. Progress was made in understanding lymphocytic predominant Hodgkin or Nodular Paragranuloma (NLP.HD). This entity behaves almost benign in its clinical course, although dissemination with bone marrow involvement may occur. Furthermore, distinctive differences were revealed by immunotyping its diagnostic L.a.H. cell versus RS-cells within the 3 other HD-groups [36, 38, 52-56, 58]. LP.HD is a B-cell rich disease associated with progressive transformation of its germinal centers and mantle zone transgressing to large B-cell lymphomas of increased T-cell content [55, 56]. The frequency of this transformation was reported
36
References 1. Agnarsson BA, Kadin ME. Ki-I positive large cell lymphoma. A morphologic study of 19 cases. Am J Surg Pathol 1988; 12: 264-74. 2. Algara P, Martinez P, Sanchez L et al. Lymphocyte predominance Hodgkin's disease (nodular paragranuloma) - a bcl-2 negative germinal centre lymphoma. Histopathology 1991; 19: 69-75. 3. Anagnostopoulos I, Herbst H, Niedobitek G, Stein H. Demonstration of monoclonal EBV genomes in Hodgkin's disease and Ki-1-positive anaplastic large cell lymphoma by combined Southern blot and in situ hybridization. Blood 1989; 74: 810816. 4. Banks PM, Lust JA, Thibodeau SN. Nodular lymphocyte predominance Hodgkin's disease (NLPHD) and its transition to large cell lymphoma (LCL): Immunophenotypic and genetic probe analysis. Lab Invest 1989; 60: 5A(28). 5. Banks PM. The Pathology of Hodgkin's Disease. Semin Oncol 1990; 17 (6): 683-95. 6. Bennett MH, MacLennan KA, Easterling MJ, Vaughan Hudon B, Jelliffe AM, Vaughan Hudson G. The prognostic signifi-
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ments is more consistent with a diagnosis of HD [19, 28, 43]. However, clonal rearrangements of Ig heavy or light chain and TCR genes have also been reported in patients with HD supporting the idea that results of genotypic analysis have to be interpreted in the context of histopathological and immunohistochemical finding |3, 28, 29, 60, 73]. Pitfalls have been repeatedly pointed out since [67, 71, 77]. The chromosomal 14; 18 translocation involving the bcl-2 oncogene has been detected in approximately one third of HD cases [66] whereas others failed to demonstrate a bcl-2 gene-rearrangement in HD [62, 63]. Recently, several studies suggested that a notable proportion of HD patients have clonal proliferations of cells infected with Epstein-Barr virus. By in situ hybridization, the EBV genome has been localized within RSC and HC [3, 13, 25, 74]. Whether an EBV infection is really a specific phenomenon in RSC, however, is still in discussion [48]. The significance or impact of EBV infection in cells of HD tissue cannot be explained at present, but must be cleared by future experiments. Although gene rearrangements studies have assisted in defining the nature and border of HD, considerable difficulties remain in distinguishing HD from other Band T-cell lymphomas. In addition to molecular genetics the application of immunophenotyping should be performed in patients evaluated from clinical trials to evaluate positive correlations [79]. Finally, borderline cases should be treated as NHL [79] since their clinical course is worse than typical HD, but stayed the same as the large cell NHL. Considering these very shortly-outlined facts, increasing interest must be paid to scrutinous immunoand geno-typing based upon reliable histologic classifications to answer the open questions concerning the influence of EBV-infections, borderline zones to NHL or other large cell tumors. Last, but really not least, correlation of morphology to clinical outcome of the disease are to be considered.
37 44. Leoncini L, Del Vecchio MT, Kraft R et al. Hodgkin's disease and CD-30-positive anaplastic large cell lymphomas - A continuous spectrum of malignant disorders. Am J Pathol 1990; 137: 1047-57. 45. MacLennan KA, Bennett MH, Tu A, Vaughan Hudson B, Easterling MJ, Vaughan Hudson C, Jelliffe AM. Prognostic significance in cytologic subdivision in nodular sclerosing Hodgkin's disease: An analysis of 1156 patients. Malignant Lymphomas and Hodgkin's Disease: Experimental and Therapeutic Advances, Cavalli F, Bonnadonna G, Rosenczweig M (eds), Nijhoff, Boston 1985; 187-200. 46. MacLennan MA, Bennett MH, Tu A, Vaughan Hudson B, Easterling J, Vaughan Hudson G, Jelliffe AM. Relationship of histopathologic features to survival and relapse in nodular sclerosing Hodgkin's disease. Cancer 1989; 64: 1686-93. 47. Masih AS, Weisenburger DD, Vose JM, Bast MA, Armitage JO. Histologic grade in nodular sclerosing Hodgkin's disease does not predict outcome. Lab Invest 1989; 60: 59 A (347). 48. Masih A, Weisenburger D, Duggan M, Armitage J, Bashir R, Mitchell D, Wickert R, Purtilo DT. Epstein-Barr virus genome in lymph nodes from patients with Hodgkin's disease may not be specific to Reed-Sternberg cells. Am J Pathol 1991; 139: 37-43. 49. Medeiros U , Weiss LM, Warnke RA, Dorfman RF. Utility of combining antigranulocyte with antileukocyte antibodies in differentiating Hodgkin's disease from Non-Hodgkin's lymphoma. Cancer 1988; 62: 2475-81. 50. Miettinen M, Franssila KO, Saxen E. Hodgkin's disease, lymphocytic predominance nodular. Cancer 1983; 51: 2293-300. 51. Miller TP, Byrne GE, Jones SE. Mistaken clinical and pathologic diagnoses of Hodgkin's disease: A Southwest Oncology Group Study. Cancer Treat Rep 1982; 66: 645-51. 52. Nicholas DS, Harris S, Wright DM. Lymphocyte predominance Hodgkin's disease - an immunohistochemical study. Histopathology 1990; 16: 157-65. 53. Pinkus GS, Said JW. Hodgkin's disease, lymphocyte predominant type nodular - a distinct entity? Unique staining profile of L and H variants of Reed-Sternberg cells to leukocyte common antigen, granulocyte specific antigen and B-cell specific antigen. Am J Pathol 1985; 118: 1-6. 54. Pinkus GS, Said JW. Hodgkin's disease, lymphocyte predominance type, nodular- further evidence for a B cell derivation. Am J Pathol 1988; 133:211-7. 55. Poppema S, Kaiserling E, Lennert K. Hodgkin's disease with lymphocytes predominance, nodular type (nodular paragranuloma) and progressively transformed germinal centers: A cytohistological study. Histopathology 1979; 3: 295-308. 56. Poppema S, Kaiserling E, Lennert K. Nodular paragranuloma and progressively transformed germinal centres: Ultrastructural and immunohistologic findings. Virchows Arch B Cell Path 1979; 31: 211-25. 57. Ree HJ, Teplitz C, Khan AA. The Lewis X antigen. A new paraffin section marker for Reed-Sternberg cells. Cancer 1991; 67: 1338-46. 58. Regula Jr DP, Hoppe RT, Weiss LM. Nodular and diffuse types of lymphocyte predominance Hodgkin's disease. N Engl J Med 1988; 318: 214-9. 59. Rosso R, Paulli M, Magrini U, Kindl S et al. Anaplastic large cell lymphoma, CD30/Ki-l positive, expressing the CD 15/ Leu-Ml antigen. Immunohistochemical and morphological relationship to Hodgkin's disease. Virchows Arch A (Pathol Anat) 1990; 416: 226-35. 60. Roth MS, Schnitzer B, Bingham E et al. Rearrangement of immunoglobulin and T-cell receptor genes of Hodgkin's disease. Am J Pathol 1988; 131:331-8. 61. Russell KJ, Hoppe RT, Colby TV, Burns BF, Cox RS, Kaplan HS. Lymphocyte predominant Hodgkin's disease: Clinical presentation and results of treatment. Radiother Oncol 1984; 1: 197-205. 62. Said JW, Sassoon AF, Shintaku IP, Kurtin PJ, Pinkus GS. Absence of bcl-2 major breakpoint region and J-H gene rear-
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25. Gaffey MJ, Weiss LM. Viral Oncogenesis: Epstein-Barr Virus. Am J Otolaryngol 1990; 11:361-75. 26. Georgii A, Bernhards J, Fischer R, Hiibner K, Schwarze E-W. Results of histological pajiel classification within the National German Hodgkin Trial. Ann Oncol 1992; in preparation. 27. Georgii A, Fischer R, Hiibner K, Schwarze E-W, Bernhards J. Histopathologische Klassifikation von Hodgkin-Lymphomen. Bericht der Referenzpathologie der Deutschen HodgkinStudie. Pathologe 1990; 11:322-6. 28. Gledhill S, Krajewski AS, Dewar AE, Onions DE, Jarrett RF. Analysis of T-cell receptor and immunoglobulin gene rearrangements in the diagnosis of Hodgkin's and non-Hodgkin's lymphoma.J Pathol 1990; 161:245-54. 29. Griesser H, Feller A, Lennert K et al. Rearrangement of the beta chain of the T-cell antigen receptor and immunoglobulin genes in lymphoprohferative disorders. J Clin Invest 1986; 78: 1179-84. 30. Guinee VF, Giacco GG, Durand M et al. The prognosis of Hodgkin's disease in older adults. J Clin Oncol 1991; 9: 947-53. 31. Hall PA, DArdenne AJ. Value of CD 15 immunostaining in diagnosing Hodgkin's disease: A review of published literature. J Clin Pathol 1987; 40: 1298-304. 32. Hall PA, D'Ardenne AJ, Stansfeld AG. Paraffin section imraunohistochemistry. II. Hodgkin's disease and large cell anaplastic (Ki l)lymphoma. Histopathology 1988; 13: 161-9. 33. Hansmann M-L, Radzun HJ, Nebendahl C, Parawaresch MR. Immunoelectromicroscopic investigation of Hodgkin's disease with monoclonal antibodies against histiocytes. Eur J Haematol 1988; 40: 25-30. 34. Hansmann M-L, Fellbaum C, Hui PK, Moubayed P. Progressive transformation of germinal centers with and without association to Hodgkin's disease. Am J Clin Pathol 1990; 93: 219-26. 35. Hansmann M-L, Fellbaum C, Bohm A. Large cell anaplastic lymphoma: Evaluation of immunophenotype on paraffin and frozen sections in comparison with ultrastructural features. Virchows Arch A Pathol Anat 1991; 418: 427-33. 36. Hansmann M-L, Stein H, Dallenbach F, Fellbaum C. Diffuse lymphocyte-predominant Hodgkin's disease (diffuse paragranuloma). A variant of the b-cell-derived nodular type. Am J Pathol 1991; 138:29-36. 37. Hansmann M-L, Fellbaum C, Hui PK, Lennert K. Morphological and immunohistochemical investigation of non-Hodgkin's lymphoma combined with Hodgkin's disease. Histopathology 1989; 15:35-48. 38. Hansmann M-L, Wacker H-H, Radzun HJ. Paragranuloma is a variant of Hodgkin's disease with a predominance of B-cells. Virchows Arch A Pathol Anat 1986; 409: 171-81. 39. Hsu S-M, Ho Y-S, Li P-J, Monheit J, Ree HJ, Sheibani K, Winberg CD. L & H variants of Reed-Sternberg cells express sialyated Leu Ml antigen. Am J Pathol 1986; 122: 199-203. 40. Hsu SM, Hsu PL. Lymphocyte functional antigens stabilize agglutination between Reed-Sternberg cells and T-cells, but are not responsible for homotypic binding of Hodgkin's ReedSternberg cells. Am J Pathol 1990; 137:563-74. 41. Jack AS, Cunningham D, Soukop M, Liddle CN, Lee FD. Use of Leu Ml and antiepithelial membrane antigen monoclonal antibodies for diagnosing Hodgkin's disease. J Clin Pathol 1986; 39: 267-70. 42. Kim H, Zeiman RJ, Fox MA, Bennett JM, Berard CW, Butler JJ, Byrne GE Jr, Dorfman RF, Hartsock RJ, Likes RJ, Mann RB, Neiman RS, Rebuck JW, Scheehan WW, Variakojis D, Wilson JF. Pathology panel for lymphoma clinical studies: A comprehensive analysis of cases accumulated since its inception. J Natl Cancer Inst 1982; 68:43-67. 43. Knowles DM, Neri A, Pelicci PG et al. Immunoglobulin and T-cell receptor B-chain rearrangement analysis of Hodgkin's disease: Implications for lineage determination and differential diagnosis. Proc Natl Acad Sci USA 1986; 83: 7942-6.
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Correspondence to: Dr. A. Georgii, Professor fur Pathologie Direktor des Pathologischen Institutes Medizinische Hochschule Hannover Konstanty-Gutschow-StraBe 8 W-3000 Hannover 61, Germany
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Original article New concepts on histopathology of Hodgkin's disease A. Georgii Medizinische Hochschule Hannover, Hannover, Germany
Key words: histopathology, lymphocytic predominant Hodgkin's disease (NLP.HD), borderline lymphomas
to vary between 4% [10] to 7% [34, 50, 67]. However, it is still under discussion, whether all of these cases do represent real transgressions from one to another lymphoma or whether at least some of them result from a second independent clonal transformation, representing composite tumors [4, 5, 12, 24, 37, 38, 67, 69, 70]. It might be rather difficult to distinguish by histopathology between transformation of HD and composite neoplasia [79]. Therewith, LP.HD represents a peculiar group which is different from the other more frequent of types HD. The question of its treatment must be considered therefore, since life expectance was not enhanced by therapy [30, 61]. Moreover, common schemes of HD-therapy may enhance the chance of transformation into a higher malignant lymphoma. Finally the question is discussed, if monoclonality in LP.HD is obligate, or continuous transformation is preceeded by a non-monoclonal stage of lymphoproliferation with similar histologic features [2, 34]. Even in T-cell rich B-cell lymphoma only 1/6 cases revealed monoclonality [20, 21, 40]. There are certain cases which are difficult to distinguish between Hodgkin and Non-Hodgkin lymphomas when both present with mainly large cell patterns [14, 19, 35, 59]. Increasing attention is paid to this grey zone or borderline lymphomas [44], which causes dissent typing within panel classification of Hodgkin lymphomas in about 3.5% among a series of 1,000 biopsies [26]. These cases focus mainly on large cell T.NHL or anaplastic large cell lymphoma (ALCL) versus the pleomorphic NS grade 2 or syncytial variant of NS.HD. Immunophenotyping by CD 15 (LeuMl) versus CD 30 (BerH2) may resolve some of these cases, when histologic hallmarks such as sinus infiltration are not available to verify anaplastic large cell lymphoma [1]. Therefore characterizing such cases by molecular genetics has become a most interesting field. Distinguishing these lymphomas by genotypic analysis is useful diagnostically, e.g. analyses of the T-cell receptor (TCR) and immunoglobulin (Ig) gene rearrangements, because the absence of gene rearrange-
Downloaded from http://annonc.oxfordjournals.org/ at UQ Library on June 18, 2015
Histopathology from biopsies, extended by immunoand geno-typing provides the data for a better understanding of Hodgkin's Disease (HD). Increasing interest is paid not only to understand but also to calculate this disease in its manipulated course under protocol therapy as well as its outcome in cured cases. Primary attention is therefore emphasized on reliable histological classification which not only can be understood but also can be repeated by other observers. Conspicuous differences of survival times were reported when Nodular Sclerosis - NS.HD - had been subtyped to a grade 1 and grade 2 category, based upon the large number of 3,600 cases of the British National Lymphoma Investigation - BNLI - [6-9, 45, 46). These results were confirmed by the EORTCgroup in clinical trials [76]. However, present experiences [16, 23, 47], as well as first results of the German National Trial have not confirmed these results so far [27]. Differences that have to be considered are due to the variations of the therapy protocol as well as performance of histological classifications by individuals [9, 17,27,42,51,78]. No diagnostic monoclonal antibody is available presently to characterize the large, presumably neoplastic RS-cell unequivocally from other large or multinucleated cells. However, the staining with monoclonal antibodies of different CD clusters, i.e. CD15, CD20, CD22, CD30, CD45, helps to support the diagnosis of HD on its characteristic background [11, 15, 22, 3 1 33,39,41,57,64,65,72,75]. Progress was made in understanding lymphocytic predominant Hodgkin or Nodular Paragranuloma (NLP.HD). This entity behaves almost benign in its clinical course, although dissemination with bone marrow involvement may occur. Furthermore, distinctive differences were revealed by immunotyping its diagnostic L.a.H. cell versus RS-cells within the 3 other HD-groups [36, 38, 52-56, 58]. LP.HD is a B-cell rich disease associated with progressive transformation of its germinal centers and mantle zone transgressing to large B-cell lymphomas of increased T-cell content [55, 56]. The frequency of this transformation was reported
36
References 1. Agnarsson BA, Kadin ME. Ki-I positive large cell lymphoma. A morphologic study of 19 cases. Am J Surg Pathol 1988; 12: 264-74. 2. Algara P, Martinez P, Sanchez L et al. Lymphocyte predominance Hodgkin's disease (nodular paragranuloma) - a bcl-2 negative germinal centre lymphoma. Histopathology 1991; 19: 69-75. 3. Anagnostopoulos I, Herbst H, Niedobitek G, Stein H. Demonstration of monoclonal EBV genomes in Hodgkin's disease and Ki-1-positive anaplastic large cell lymphoma by combined Southern blot and in situ hybridization. Blood 1989; 74: 810816. 4. Banks PM, Lust JA, Thibodeau SN. Nodular lymphocyte predominance Hodgkin's disease (NLPHD) and its transition to large cell lymphoma (LCL): Immunophenotypic and genetic probe analysis. Lab Invest 1989; 60: 5A(28). 5. Banks PM. The Pathology of Hodgkin's Disease. Semin Oncol 1990; 17 (6): 683-95. 6. Bennett MH, MacLennan KA, Easterling MJ, Vaughan Hudon B, Jelliffe AM, Vaughan Hudson G. The prognostic signifi-
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ments is more consistent with a diagnosis of HD [19, 28, 43]. However, clonal rearrangements of Ig heavy or light chain and TCR genes have also been reported in patients with HD supporting the idea that results of genotypic analysis have to be interpreted in the context of histopathological and immunohistochemical finding |3, 28, 29, 60, 73]. Pitfalls have been repeatedly pointed out since [67, 71, 77]. The chromosomal 14; 18 translocation involving the bcl-2 oncogene has been detected in approximately one third of HD cases [66] whereas others failed to demonstrate a bcl-2 gene-rearrangement in HD [62, 63]. Recently, several studies suggested that a notable proportion of HD patients have clonal proliferations of cells infected with Epstein-Barr virus. By in situ hybridization, the EBV genome has been localized within RSC and HC [3, 13, 25, 74]. Whether an EBV infection is really a specific phenomenon in RSC, however, is still in discussion [48]. The significance or impact of EBV infection in cells of HD tissue cannot be explained at present, but must be cleared by future experiments. Although gene rearrangements studies have assisted in defining the nature and border of HD, considerable difficulties remain in distinguishing HD from other Band T-cell lymphomas. In addition to molecular genetics the application of immunophenotyping should be performed in patients evaluated from clinical trials to evaluate positive correlations [79]. Finally, borderline cases should be treated as NHL [79] since their clinical course is worse than typical HD, but stayed the same as the large cell NHL. Considering these very shortly-outlined facts, increasing interest must be paid to scrutinous immunoand geno-typing based upon reliable histologic classifications to answer the open questions concerning the influence of EBV-infections, borderline zones to NHL or other large cell tumors. Last, but really not least, correlation of morphology to clinical outcome of the disease are to be considered.
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Correspondence to: Dr. A. Georgii, Professor fur Pathologie Direktor des Pathologischen Institutes Medizinische Hochschule Hannover Konstanty-Gutschow-StraBe 8 W-3000 Hannover 61, Germany
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