- Email: [email protected]
Immunosuppression, autoimmunity, and lymphoproliferative disorders
Human PATHOLOGY VOLUME
25
July 7994
NUMBER
7
Editorial Immunosuppression, Autoimmunity, and Lymphoptoliferative Disorders macytic hyperplasias, small lymphoid cell proliferations, and diffuse large cell lymphomas; other types of nonHodgkin’s lymphomas are more rare, except in the Xlinked lymphoproliferative syndrome in which almost half of the cases are of the small noncleaved cell type. This spectrum is different from that observed in AIDS in which atypical LPDs are rare and the lymphomas are mostly of the immunoblastic or small noncleaved cell type, and both are different from the even larger spectrum of the B-cell LPDs arising in transplant recipientsYe5 Among these, the lymphomas of either small or large noncleaved cells or immunoblasts, as seen in the nonimmunosuppressed population and referred to as “monomorphic,” represent a minority (14%) of the totaL3 The most common and typical of the posttransplant situation are the LPDs that our Minnesota group has described under the term “polymorphic”,6 a nomenclature now adopted widely.s5 These are identified by a characteristic mixture of cell types, including small and large cells, the former having round or irregular (most often angulated) nuclei and scant cytoplasm or showing plasmacytoid/plasmacellular features and the latter resembling either large noncleaved cells or immunoblasts or manifesting atypical, often multiple and bizarre nuclei. These lesions vary from minimally polymorphic (with predominance of the mature stages of plasma cell differentiation) s,’ to polymorphic B-cell hyperplasia (with a mixture of small and large plasmacytoid cells, fewer angulated small cells, rare or no atypical large cells, and sparse single cell necrosis) and polymorphic B-cell lymphoma (with a lesser plasmacytoid component, frequent and marked atypia of the large cells, and extensive areas of necrosis with geographic configuration) .6 These last two terms predate the use of molecular techniques to determine the monoclonality of a lymphoid proliferation and the entities they define do not seem to differ in the genomic characteristics studied so far.x However, they identify characteristic histological types of lymphoproliferation that we have not seen in other immunosuppression/immunodeficiencyrelated LPDs and that only by approximation can be
An association of immunosuppression with an increased risk of lymphoproliferative disorders (LPDs) has been shown in several clinical situations: prototypically in patients with genetically determined immunodeficienties, then in recipients of organ or bone marrow trans plants and in patients treated for malignant neoplasms, and most recently in sufferers of the acquired immunodeficiency syndrome (AIDS). The interesting report by Kamel et al in this issuer describes the development of LPDs in a group of 18 patients with rheumatoid arthritis (RA) or dermatomyositis; the authors suggest that a sub set of these lesions has features associated with immunosuppression, which in these cases was brought about by the treatment received, especially methotrexate (MTX). The conclusion-that “therapeutic immunosuppression may contribute, at least in part, to the development of these lymphoid neoplasms”-is appro priately cautiously worded and several “potentially confounding variables” are mentioned, such as the lack of information on the duration and severity of the rheumatic disease, the variety of therapies administered to the patients (MTX or mild immunosuppression), and the variety of LPDs, some of which (follicular lymphomas, Tcell lymphoma, and Hodgkin’s disease) are not typically associated with immunosuppression. To evaluate these findings it may be helpful to separate the larger group of RA patients from the three patients with dermatomyositis and to concentrate on the LPDs of B-cell type, which are those classically related to iatrogenic immunosuppression and immunodeficiencies. The interpretation of some of them as immunosuppression-related lymphomas is based on three features: large cell (61.5%) or polymorphous morphology, presence of Epstein-Barr virus (EBV), and extranodal location. These are indeed common features in LPDs that develop in diverse immunosuppressed/immunodeficient states, but they are neither manifested in all these states equally nor specific to them without precise qualifications. The histological spectrum of the LPDs in primary immunodeficiencies” includes immunoblastic and plas627
HUMAN
PATHOLOGY
Volume 25, No. 7 (July 1994)
qualified as having “large cell morphology.” Thus, the usual large cell histology (large noncleaved or immunoblastic), which represents one of the many types of LPDs observed in primary immunodeficiencies and only a minority of those arising posttransplantation but is instead quite common (-30%) in the nonimmunosup pressed population, is not strong supporting evidence for the relation of an LPD to immunosuppression. The presence of the EBV genome in two (15%) of the RA-associated B-cell LPDs (as well as one case of Hodgkin’s disease) would seem to be a stronger piece of evidence. In fact, EBV is almost a given in the B-cell posttransplant LPDs and is also present in a large proportion of cases arising in primary and acquired immunodeficiencies.’ On the other hand, it might not be necessary to make recourse to immunosuppression to explain the presence of EBV in these cases. Epstein-Barr virus also is detected in a small proportion of normal lymphoid tissues” and in a variable proportion of LPDs in patients without known immunosuppressive disorders (8% of diffuse large cell lymphomas”’ and five of five B-cell pulmonary LPDs with features of lymphomatoid granulomatosis) ” without counting the known association with peripheral T-cell lymphomas of various types and Hodgkin’s disease. There is also some evidence that EBV might play a causative role in RA itself.” Thus, Kamel et al’ pointedly call for “additional studies of larger groups of rheumatic patients who develop lymphoid neoplasms and control rheumatic patients without lymphoid neoplasms.” A thorough search for EBV is required in the two groups to determine the magnitude of the pathogenetic role of EBV in RA and RA-associated LPDs and whether there is an additional effect from immunosuppressive therapy in the development of these LPDs. Over half (61.5%) of the RA-associated B-cell LPDs in the Stanford study’ occurred at extranodal sites, approximately the same incidence of extranodal occurrences as was detected in posttransplant LPDs.” However, there are provocative differences in the sites of involvement: the former were distributed equally between mucosa-associated lymphoid tissue (MALT) (three in the salivary glands and one in the large intestine) and non-MALT sites (two each in skin and soft tissues), whereas the latter, in contrast, most frequently involve Waldeyer’s ring, small intestine, lung,“,’ and, in the days of conventional (noncyclosporine-based) immunosuppression, the central nervous system2.’ (salivary glands, skin, and soft tissues all represent very uncommon sites). The predominance of salivary gland involvement (23% of the total) is especially interesting because, irrespective of the clinical diagnosis of Sjoegren’s syndrome, salivary glands in RA may be the site of myoepithelial sialadenitis,‘” a fertile ground for the development of B-cell LPDs. This involvement brings to the forefront autoimmunity rather than immunosuppression as a predominant pathogenetic factor. The relative contribution of these two factors to the increased risk of LPDs in RA is unclear. Despite some opinions to the contrary, the weight of evidence indicates that RA by itself is associated with an increased risk of LPDs; this has been calculated at 24fold over 628
that of the general population in IWO different studand chronic immune stimulation, increased ies,“,” proto-oncogene expression, excessive production of interleukin-6,‘” ’ and EBV, as we mentioned, may all contribute to it. There is no large study reporting the organ distribution of F&associated I,PDs, but their distribution by histology is provided in a series of 19 such cases that antedate the use of MTX in the treatment of RA.” This distribution is different from that seen in the series of Kamel et al’ because diffuse large cell lymphomas represented only 31.5% (u 61.5%) of the total and chronic lymphocytic leukemia/small lymphocytic lymphoma predominated (37% u none), as would be expected from the primary role of the CD5+ B-cell subset in both RA and CLL. It might then be asked whether and how immunosuppression influences the incidence, the site of involvement, and the histology of RA-associated B-cell LPDs in the Stanford series.’ In this study the LPDs are equally distributed between the MTXtreated group (seven cases) and the mildly suppressed patients (six cases); mucosa-associated lymphoid tissue sites are somewhat more often involved in the former group than in the latter (three of seven, 43%, u one of six, 17%); in contrast, the two major histological categories (diffuse large cell and follicular lymphomas) are identically represented in the two groups. Thus, the data do not offer clear-cut answers to these questions. In conclusion, it is very difficult at this point to extricate from the recognized pathogenetic role of autoimmunity in the development of RA-associated LPDs any potential additional role for iatrogenic immunosuppression. Based on the lack of carcinogenic effect of MTX in patients with choriocarcinomalx and psoriasis’!’ and the rarity of previous reports of LPDs in RA patients treated with MTX, it might be concluded, as have Kingsmore et al,‘” that “any carcinogenic effect of MTX in RA must be modest.” Also mitigating against such a role in the series of Kamel et al’ are the equal distribution of LPDs between the MTX-treated group and the lessimmunosuppressed group and the fact that these LPDs differ in organ distribution and histology from those seen in transplant recipients. However, the histological differences between the LPDs that arose in the MTX-treated RA patients and those described in non-MTX-treated RA patients” as well as the regression of one lesion with the discontinuation of immunosuppression suggest that a role for MTX in lymphomagenesis may exist. If it does, this study also suggests that it might be more effective in the salivary glands, where it may add to the potential effects of autoimmunity and EBV infection. GLAUCO FRIZZERA, MD Department of Pathology New York University Medical New York, NY
School
REFERENCES 1. Kamel OW, van de Rijn M, LeBrun DP, et al: Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: Frcquency of Epstein-Barr virus and other features associated with immunosuppression. HUM PATHOI. 25:638-643, 1994
EDITORIAL
(Glauco
Frizzera)
11. Guinee D, Kingma D, Fishhack N, et al: Pulmonary lesions with features of lymphomatoid granulomatosis/angiocentric immunoproliferative lesion (LYG/AIL): Evidence for Epstein-Barr virus within B lymphocytes. Mod Pathol 7:151A, 1994 (ahstr) 12. Decker JL (moderator) : Rheumatoid arthritis. Evolving concepts of pathogenesis and treatment. Ann Intern Med 101:810-824, 1984 13. Schmid U, Helhron D, Lennert K: Development of malignant lymphoma in myoepithelial sialadenitis (Sjoegren’s syndrome). Virchows Arch A [Pathol Anat] 395: 1143, 1982 14. Prior P: Cancer and rheumatoid arthritis: Epidemiologic considerations. Am J Med 78:15-21, 1985 (suppl 1A) 15. Symmons DPM: Neoplasms of the immune system in rheumatoid arthritis. Am J Med 78:22-28, 1985 (suppl 1A) 16. &gal GH, Clough JD. Tuhhs RR: Autoimmune and iatrogenie causes of lymphadenopathy. Semin Oncol20:61 l-626, 1993 17. Banks PM, Witrak GA, Conn DL: Lyrnphoid neoplasia following connective tissue disease. Mayo Clin Proc 54:104108. 1979 18. Rustin GJS, Rustin F, Dent J. et al: No increase in second tumors after cytotoxic chemotherapy for gestational trophohlastic tumors, N Engl J Med 308:47.3-476, 1983 19. Bailin PL, Tindall JP, Roegnigk HH. et al: Is methotrexate therapy for psoriasis carcinogenic? A modified retrospective analysis. JAMA 232:359-362, 1975 20. Kingsmore SF, Hall BD, Allen NB, et al: Association of methotrexate. rheumatoid arthritis and lymphoma. Report of 2 cases and literature review. J Rheumatol 19:1462-1465, 1992
2. Frizzera G: Atypical lymphoproliferative disorders, in Knowles DM (ed): Neoplastic Hematopathology. Baltimore. MD, Williams & Wilkins, 1992, pp 459-495 3. Nalesnik MA, Jaffe R, StarLl TE, et al: The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporinc A-prednisone immunosuppression. Am J Pathol 133:173-192, 1988 4. Ferry JA, Jacohson.JO, Conti D, et al: Lymphoproliferative disorders and hematologic malignancies following organ transplantation. Mod Pathol 2583592, 1989 5. Swcrdlow SHS: Post-transplant lymphoproliferative disorders: A morphologic, phenotypic and genotypic spectrum of disease. Histopathology 20:37.3-385, 1992 6. Frizzera G, Hanto DW. Cajl-Peczalska KJ, et al: Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients. Cancer Res 41:42624279, 1981 7. Chadhum A, Frizzera G, Chen J, et al: Clinicopathologic analysis of 28 post-transplantation lymphoproliferative disorders (PTLPDs). Mod Pathol 7: 104A. 1994 (ahstr) 8. Cesarman E, Chadhurn A, Frizzera G, et al: Molecular genetic analysis of post-transplantation lymphoproliferative disorders (PTLPDs). Mod Pathol 7:104A, 1994 (ahstr) 9. Cheung WY, Chan ACL. Loke SL, et al: Latent sites of EpsteinBarr virus infection. Am J Clin Pathol 100:502-506, 1993 10. Staal SP, Amhinder R, Beschorner WE, et al: A survey of Epstein-Barr virus DNA in lymphoid tissue. Frequent detection in Hodgkin’s disease. Am J Clin Pathol 91:1-5, 1989
629
25
July 7994
NUMBER
7
Editorial Immunosuppression, Autoimmunity, and Lymphoptoliferative Disorders macytic hyperplasias, small lymphoid cell proliferations, and diffuse large cell lymphomas; other types of nonHodgkin’s lymphomas are more rare, except in the Xlinked lymphoproliferative syndrome in which almost half of the cases are of the small noncleaved cell type. This spectrum is different from that observed in AIDS in which atypical LPDs are rare and the lymphomas are mostly of the immunoblastic or small noncleaved cell type, and both are different from the even larger spectrum of the B-cell LPDs arising in transplant recipientsYe5 Among these, the lymphomas of either small or large noncleaved cells or immunoblasts, as seen in the nonimmunosuppressed population and referred to as “monomorphic,” represent a minority (14%) of the totaL3 The most common and typical of the posttransplant situation are the LPDs that our Minnesota group has described under the term “polymorphic”,6 a nomenclature now adopted widely.s5 These are identified by a characteristic mixture of cell types, including small and large cells, the former having round or irregular (most often angulated) nuclei and scant cytoplasm or showing plasmacytoid/plasmacellular features and the latter resembling either large noncleaved cells or immunoblasts or manifesting atypical, often multiple and bizarre nuclei. These lesions vary from minimally polymorphic (with predominance of the mature stages of plasma cell differentiation) s,’ to polymorphic B-cell hyperplasia (with a mixture of small and large plasmacytoid cells, fewer angulated small cells, rare or no atypical large cells, and sparse single cell necrosis) and polymorphic B-cell lymphoma (with a lesser plasmacytoid component, frequent and marked atypia of the large cells, and extensive areas of necrosis with geographic configuration) .6 These last two terms predate the use of molecular techniques to determine the monoclonality of a lymphoid proliferation and the entities they define do not seem to differ in the genomic characteristics studied so far.x However, they identify characteristic histological types of lymphoproliferation that we have not seen in other immunosuppression/immunodeficiencyrelated LPDs and that only by approximation can be
An association of immunosuppression with an increased risk of lymphoproliferative disorders (LPDs) has been shown in several clinical situations: prototypically in patients with genetically determined immunodeficienties, then in recipients of organ or bone marrow trans plants and in patients treated for malignant neoplasms, and most recently in sufferers of the acquired immunodeficiency syndrome (AIDS). The interesting report by Kamel et al in this issuer describes the development of LPDs in a group of 18 patients with rheumatoid arthritis (RA) or dermatomyositis; the authors suggest that a sub set of these lesions has features associated with immunosuppression, which in these cases was brought about by the treatment received, especially methotrexate (MTX). The conclusion-that “therapeutic immunosuppression may contribute, at least in part, to the development of these lymphoid neoplasms”-is appro priately cautiously worded and several “potentially confounding variables” are mentioned, such as the lack of information on the duration and severity of the rheumatic disease, the variety of therapies administered to the patients (MTX or mild immunosuppression), and the variety of LPDs, some of which (follicular lymphomas, Tcell lymphoma, and Hodgkin’s disease) are not typically associated with immunosuppression. To evaluate these findings it may be helpful to separate the larger group of RA patients from the three patients with dermatomyositis and to concentrate on the LPDs of B-cell type, which are those classically related to iatrogenic immunosuppression and immunodeficiencies. The interpretation of some of them as immunosuppression-related lymphomas is based on three features: large cell (61.5%) or polymorphous morphology, presence of Epstein-Barr virus (EBV), and extranodal location. These are indeed common features in LPDs that develop in diverse immunosuppressed/immunodeficient states, but they are neither manifested in all these states equally nor specific to them without precise qualifications. The histological spectrum of the LPDs in primary immunodeficiencies” includes immunoblastic and plas627
HUMAN
PATHOLOGY
Volume 25, No. 7 (July 1994)
qualified as having “large cell morphology.” Thus, the usual large cell histology (large noncleaved or immunoblastic), which represents one of the many types of LPDs observed in primary immunodeficiencies and only a minority of those arising posttransplantation but is instead quite common (-30%) in the nonimmunosup pressed population, is not strong supporting evidence for the relation of an LPD to immunosuppression. The presence of the EBV genome in two (15%) of the RA-associated B-cell LPDs (as well as one case of Hodgkin’s disease) would seem to be a stronger piece of evidence. In fact, EBV is almost a given in the B-cell posttransplant LPDs and is also present in a large proportion of cases arising in primary and acquired immunodeficiencies.’ On the other hand, it might not be necessary to make recourse to immunosuppression to explain the presence of EBV in these cases. Epstein-Barr virus also is detected in a small proportion of normal lymphoid tissues” and in a variable proportion of LPDs in patients without known immunosuppressive disorders (8% of diffuse large cell lymphomas”’ and five of five B-cell pulmonary LPDs with features of lymphomatoid granulomatosis) ” without counting the known association with peripheral T-cell lymphomas of various types and Hodgkin’s disease. There is also some evidence that EBV might play a causative role in RA itself.” Thus, Kamel et al’ pointedly call for “additional studies of larger groups of rheumatic patients who develop lymphoid neoplasms and control rheumatic patients without lymphoid neoplasms.” A thorough search for EBV is required in the two groups to determine the magnitude of the pathogenetic role of EBV in RA and RA-associated LPDs and whether there is an additional effect from immunosuppressive therapy in the development of these LPDs. Over half (61.5%) of the RA-associated B-cell LPDs in the Stanford study’ occurred at extranodal sites, approximately the same incidence of extranodal occurrences as was detected in posttransplant LPDs.” However, there are provocative differences in the sites of involvement: the former were distributed equally between mucosa-associated lymphoid tissue (MALT) (three in the salivary glands and one in the large intestine) and non-MALT sites (two each in skin and soft tissues), whereas the latter, in contrast, most frequently involve Waldeyer’s ring, small intestine, lung,“,’ and, in the days of conventional (noncyclosporine-based) immunosuppression, the central nervous system2.’ (salivary glands, skin, and soft tissues all represent very uncommon sites). The predominance of salivary gland involvement (23% of the total) is especially interesting because, irrespective of the clinical diagnosis of Sjoegren’s syndrome, salivary glands in RA may be the site of myoepithelial sialadenitis,‘” a fertile ground for the development of B-cell LPDs. This involvement brings to the forefront autoimmunity rather than immunosuppression as a predominant pathogenetic factor. The relative contribution of these two factors to the increased risk of LPDs in RA is unclear. Despite some opinions to the contrary, the weight of evidence indicates that RA by itself is associated with an increased risk of LPDs; this has been calculated at 24fold over 628
that of the general population in IWO different studand chronic immune stimulation, increased ies,“,” proto-oncogene expression, excessive production of interleukin-6,‘” ’ and EBV, as we mentioned, may all contribute to it. There is no large study reporting the organ distribution of F&associated I,PDs, but their distribution by histology is provided in a series of 19 such cases that antedate the use of MTX in the treatment of RA.” This distribution is different from that seen in the series of Kamel et al’ because diffuse large cell lymphomas represented only 31.5% (u 61.5%) of the total and chronic lymphocytic leukemia/small lymphocytic lymphoma predominated (37% u none), as would be expected from the primary role of the CD5+ B-cell subset in both RA and CLL. It might then be asked whether and how immunosuppression influences the incidence, the site of involvement, and the histology of RA-associated B-cell LPDs in the Stanford series.’ In this study the LPDs are equally distributed between the MTXtreated group (seven cases) and the mildly suppressed patients (six cases); mucosa-associated lymphoid tissue sites are somewhat more often involved in the former group than in the latter (three of seven, 43%, u one of six, 17%); in contrast, the two major histological categories (diffuse large cell and follicular lymphomas) are identically represented in the two groups. Thus, the data do not offer clear-cut answers to these questions. In conclusion, it is very difficult at this point to extricate from the recognized pathogenetic role of autoimmunity in the development of RA-associated LPDs any potential additional role for iatrogenic immunosuppression. Based on the lack of carcinogenic effect of MTX in patients with choriocarcinomalx and psoriasis’!’ and the rarity of previous reports of LPDs in RA patients treated with MTX, it might be concluded, as have Kingsmore et al,‘” that “any carcinogenic effect of MTX in RA must be modest.” Also mitigating against such a role in the series of Kamel et al’ are the equal distribution of LPDs between the MTX-treated group and the lessimmunosuppressed group and the fact that these LPDs differ in organ distribution and histology from those seen in transplant recipients. However, the histological differences between the LPDs that arose in the MTX-treated RA patients and those described in non-MTX-treated RA patients” as well as the regression of one lesion with the discontinuation of immunosuppression suggest that a role for MTX in lymphomagenesis may exist. If it does, this study also suggests that it might be more effective in the salivary glands, where it may add to the potential effects of autoimmunity and EBV infection. GLAUCO FRIZZERA, MD Department of Pathology New York University Medical New York, NY
School
REFERENCES 1. Kamel OW, van de Rijn M, LeBrun DP, et al: Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: Frcquency of Epstein-Barr virus and other features associated with immunosuppression. HUM PATHOI. 25:638-643, 1994
EDITORIAL
(Glauco
Frizzera)
11. Guinee D, Kingma D, Fishhack N, et al: Pulmonary lesions with features of lymphomatoid granulomatosis/angiocentric immunoproliferative lesion (LYG/AIL): Evidence for Epstein-Barr virus within B lymphocytes. Mod Pathol 7:151A, 1994 (ahstr) 12. Decker JL (moderator) : Rheumatoid arthritis. Evolving concepts of pathogenesis and treatment. Ann Intern Med 101:810-824, 1984 13. Schmid U, Helhron D, Lennert K: Development of malignant lymphoma in myoepithelial sialadenitis (Sjoegren’s syndrome). Virchows Arch A [Pathol Anat] 395: 1143, 1982 14. Prior P: Cancer and rheumatoid arthritis: Epidemiologic considerations. Am J Med 78:15-21, 1985 (suppl 1A) 15. Symmons DPM: Neoplasms of the immune system in rheumatoid arthritis. Am J Med 78:22-28, 1985 (suppl 1A) 16. &gal GH, Clough JD. Tuhhs RR: Autoimmune and iatrogenie causes of lymphadenopathy. Semin Oncol20:61 l-626, 1993 17. Banks PM, Witrak GA, Conn DL: Lyrnphoid neoplasia following connective tissue disease. Mayo Clin Proc 54:104108. 1979 18. Rustin GJS, Rustin F, Dent J. et al: No increase in second tumors after cytotoxic chemotherapy for gestational trophohlastic tumors, N Engl J Med 308:47.3-476, 1983 19. Bailin PL, Tindall JP, Roegnigk HH. et al: Is methotrexate therapy for psoriasis carcinogenic? A modified retrospective analysis. JAMA 232:359-362, 1975 20. Kingsmore SF, Hall BD, Allen NB, et al: Association of methotrexate. rheumatoid arthritis and lymphoma. Report of 2 cases and literature review. J Rheumatol 19:1462-1465, 1992
2. Frizzera G: Atypical lymphoproliferative disorders, in Knowles DM (ed): Neoplastic Hematopathology. Baltimore. MD, Williams & Wilkins, 1992, pp 459-495 3. Nalesnik MA, Jaffe R, StarLl TE, et al: The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporinc A-prednisone immunosuppression. Am J Pathol 133:173-192, 1988 4. Ferry JA, Jacohson.JO, Conti D, et al: Lymphoproliferative disorders and hematologic malignancies following organ transplantation. Mod Pathol 2583592, 1989 5. Swcrdlow SHS: Post-transplant lymphoproliferative disorders: A morphologic, phenotypic and genotypic spectrum of disease. Histopathology 20:37.3-385, 1992 6. Frizzera G, Hanto DW. Cajl-Peczalska KJ, et al: Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients. Cancer Res 41:42624279, 1981 7. Chadhum A, Frizzera G, Chen J, et al: Clinicopathologic analysis of 28 post-transplantation lymphoproliferative disorders (PTLPDs). Mod Pathol 7: 104A. 1994 (ahstr) 8. Cesarman E, Chadhurn A, Frizzera G, et al: Molecular genetic analysis of post-transplantation lymphoproliferative disorders (PTLPDs). Mod Pathol 7:104A, 1994 (ahstr) 9. Cheung WY, Chan ACL. Loke SL, et al: Latent sites of EpsteinBarr virus infection. Am J Clin Pathol 100:502-506, 1993 10. Staal SP, Amhinder R, Beschorner WE, et al: A survey of Epstein-Barr virus DNA in lymphoid tissue. Frequent detection in Hodgkin’s disease. Am J Clin Pathol 91:1-5, 1989
629