Age-related Epstein-Barr virus (EBV)–associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients

Abstract

Age-related Epstein-Barr virus-associated Bcell lymphoproliferative disorder (aEBVLPD)is a disease group characterized by EBVassociated large B-cell lymphoma in the elderly without predisposing immunodeficiency. In nearly one-third of cases, aEBV-LPD occurs as a polymorphous subtype with reactive cell-rich components, bearing a morphologic similarity to classic Hodgkin lymphoma (cHL). The aim of this study was to clarify clinicopathologic differences between the polymorphic subtype of aEBV-LPD (n ‫؍‬ 34) and EBV ؉ cHL (n ‫؍‬ 108) in patients aged 50 years or older. Results showed that aEBVLPD was more closely associated with aggressive clinical parameters than cHL, with a higher age at onset (71 vs 63 years); lower male predominance (male-female ratio, 1.4 vs 3.3); and a higher rate of involvement of the skin (18% vs 2%), gastrointestinal tract (15% vs 4%), and lung (12% vs 2%). aEBVLPD was histopathologically characterized by a higher ratio of geographic necrosis, greater increase (> 30%) in cytotoxic T cells among background lymphocytes, higher positivity for CD20 and EBNA2, and absence of CD15 expression. As predicted by the clinical profile, aEBV-LPD had a significantly poorer prognosis than EBV ؉ cHL (P < . IntroductionEpstein-Barr virus (EBV), a member of the herpes virus family, infects more than 90% of the worldwide adult population. 1,2 In vitro, EBV randomly infects resting B cells and transforms them into lymphoblastoid cell lines. This property makes it a candidate causative agent for many human cancers, including Burkitt lymphoma, 3,4 Hodgkin lymphoma, 1 immunodeficiency-associated lymphoproliferative disorders (LPDs), 5 and some diffuse large B-cell lymphomas. 6 Although the mechanism of this effect has not been precisely identified, 2 events that cause the lymphoblastoid cell to survive and evolve into a lymphoma are assumed: first, the EBV-infected cell must be unable to exit the cell cycle to become a resting memory B cell; and second, the cytotoxic T-cell response must be impeded so that the lymphoblast is not killed. It is thus widely accepted that T cells play a prominent role in controlling EBV-associated oncogenesis. 1 In support of this, administration of immunosuppressive agents such as tacrolimus or cyclosporin A to prevent the rejection of organ transplants sometimes causes EBV-positive B-cell LPDs. 7,8 On these bases, the tumor microenvironment is thought to play an important role in the pathogenesis and tumor progression of EBV-associated B-cell neoplasms.The World Health Organization (WHO) classification for hematopoietic neoplasm currently categorizes immunodeficiencyassociated LPDs into 4 main groups 9 : (1) LPDs associated with primary immunodeficiency syndromes and other primary immune disorders 10-12 ; (2) lymphomas associated with infection with human immunodeficiency virus (HIV) [13][14][15] ; (3) posttransplantation LPDs (PTLDs) in patients who have received a solid organ or bone marrow allograft [16][17][18][19] ; and (4) methotrexate-associated LPDs, most commonly seen in p...

Geographic variation in the prevalence of Epstein–Barr virus-positive diffuse large B-cell lymphoma of the elderly: a comparative analysis of a Mexican and a German population

“…The strong, homogeneous CD20 positivity combined with the lack of CD15 are useful features in the differential diagnosis with EBV þ classical Hodgkin lymphoma. 24 As already described, 13 all polymorphic cases revealed a nongerminal center B-cell phenotype. In contrast, two of the three EBV þ diffuse large B-cell lymphoma of the elderly with monomorphic type showed a germinal center B-cell phenotype with expression of CD10 and BCL-6 or BCL-2.…”

EBV-positive diffuse large B-cell lymphoma of the elderly is an aggressive post-germinal center B-cell neoplasm characterized by prominent nuclear factor-kB activation

“…The single monomorphic case showed clearcut immunoblastic features, in line with all other cases. This degree of immunoblastic differentiation and prominent geographic necrosis have previously been described as common features, 3,13,14 and can aid in the morphological recognition of the entity. More challenging is the differential diagnosis of Hodgkin lymphoma-like cases with EBV-positive classical Hodgkin lymphoma in elderly patients.…”

“…3,13,14 Morphologically, these tumors showed a variety of patterns of growth and differentiation that needs to be recognized to allow a diagnosis of suspicion before confirmation with phenotypic studies. All but one case have a polymorphic histology, with a noticeable variability in cell size and differentiation found within the tumor.…”

“…12 Patients with EBV-positive diffuse large B-cell lymphoma have a worse prognosis than those with EBV-negative diffuse large B-cell lymphoma or EBVpositive classical Hodgkin lymphoma. 8,13,14 Published studies of clinical series have identified a high risk of treatment failure in these patients. 5,8 Among the clinical factors that have an impact on patient outcome, only B symptoms and an age of 70 þ years are independently predictive of survival, while the International Prognostic Index score did not seem to separate different risk groups as in conventional EBVnegative diffuse large B-cell lymphomas.…”

The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications

“…In addition to lymphomatoid granulomatosis, the WHO now includes EBVpositive DLBCL of the elderly initially described in Asia [39][40][41][42] and DLBCL associated with chronic inflammation, most often chronic pyothorax. [43][44][45][46] In these lesions EBV-infected cells frequently express a latency type 3 with positivity for the viral proteins latent membrane protein 1 and EBV nuclear antigen 2, suggesting that the lymphoid proliferation may be related primarily to a decrease in the host immunosurveillance.…”