EBV+ Diffuse Large B cell Lymphomas in HIV+ Individuals Are Frequently Non-germinal B Cell Type, Usually Devoid of Common Translocations, and Predict Poor Survival
Kishor Bhatia*1, C Chang1, W Cozen2, L Weiss3, C Kim1, L Morton1, and E Engels1
1NCI, NIH, Rockville, MD, US; 2Univ of Southern California, Keck Sch of Med and Norris Comprehensive Cancer Ctr, Los Angeles, US; and 3City of Hope Natl Med Ctr, Duarte, CA, US
Background: Epstein-Barr Virus (EBV) is frequently associated with diffuse large B cell lymphomas (DLBCL) in HIV+ individuals. Recently, a distinct DLCBL subtype has been recognized in HIV individuals, related to immunosenescence and obligate EBV positivity. This raises the question whether EBV+ DLCBL in HIV+ and HIV individuals share common clinical and pathologic features. We therefore compared molecular and histogenic features of EBV+ DLCBL according to HIV status.
Methods: Formalin-fixed paraffin embedded tissue specimens obtained from DLCBL patients during 1977 through 2003 were obtained from the Los Angeles cancer registry tumor discard repository. Expression of CD10, GCET1, MUM-1, and FoxP1 was used to assign a germinal (GCB) or non-germinal center (non-GCB) phenotype. Fluorescence in situ hybridization was used to detect translocations involving c-Myc t(8;14)(q24;q32), bcl6 (t(3;14)(q27;q32), and bcl2 t(14;18)(q32;q21). EBV positivity was assessed by in situ hybridization for detection of EBV early RNA EBER-I. Frequencies of EBV positivity were compared using c2 tests. Survival analyses were done using Cox proportional hazards models, adjusting for age, cancer site, translocations, and phenotype.
Results: We retrieved 156 cases of DLCBL: 48 were HIV+ and 108 from HIV patients. DLCBL from HIV+ patients were 5-fold more likely to be EBV+ (HIV 12%, HIV+ 63%, p <0.0001). EBV presence was weakly associated with extranodal (vs nodal) disease in HIV+ patients (p = 0.08), but not in uninfected patients (p = 0.52). Among HIV+ patients, EBV positivity was higher in non-GCB (87%) subtype compared with the GCB subtype (13%) (p = 0.002), but did not differ in HIV patients. For EBV+ DLBCL, cases from HIV+ patients were less likely to carry translocations than those from HIV patients (13% vs 38%). Double and triple hit lymphomas (10 of 108) were identified only among HIV patients and 9 of these cases were in EBV tumors. Among HIV+, but not HIV, patients, EBV positivity was associated with adverse prognosis (HR = 4.1, 95%CI 1.7 to 9.8, p = 0.002)
Conclusions: In HIV+ patients, EBV positivity segregates with a non-GCB phenotype, absence of common translocations, presence of extranodal disease and poorer outcome. A detailed systematic study comparing EBV positive DLBCL in HIV+ and HIV is warranted.