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.