Immunohistochemical Expression Pattern of Germinal Center and Non-Germinal Center Markers in Age-Related Epstein Barr Virus-Associated B-Cell Lymphoproliferative Disorder

BACKGROUND: Age-related Epstein Barr virus (EBV)-associated B-cell lymphoproliferative disorder (LPD) is a newly described entity initially reported in Japanese patients with diffuse large B-cell lymphoma (DLBCL) and coinfection with EBV. It usually affects elderly patients and is characterized by poor survival. Immunohistochemical analysis of patients with DLBCL using bcl-6, CD10 and MUM1 can further subclassify DLBCL in germinal center (GC)-like or non-germinal center (non-GC) phenotypes. Non-GC phenotypes have been associated with resistance to conventional therapy and poorer prognosis when compared to GC-like phenotypes, even in the rituximab era.

AIM: The goal of this study was to evaluate the immunohistochemical pattern of GC and non-GC markers in patients with diagnosis of age-related EBV-associated B-cell LPD.

PATIENTS AND METHODS: Between January 2002 and June 2008, twelve patients with age-related EBV-associated B-cell LPD were identified and included in the analysis. Clinical data were reviewed retrospectively and patient’s biopsies were analyzed for the immunohistochemical expression of bcl-6, CD10, CD30 and MUM-1/IRF4 by tissue microarray technique. Cases were also investigated for EBV-encoded RNA (EBER) using an in-situ hybridization technique.

RESULTS: In this cohort, the mean age was 72 years old (range 34–85) at diagnosis; the male to female ratio was 1.4. B symptoms occurred in 5 out of 10 patients. ECOG performance status was higher than 1 in 9 of 10 patients. Advanced stages (III/IV) were observed in 8 of 10 patients. IPI score was higher than 2 in 8 of 10 patients. Extranodal involvement was identified in pleura (n=2), suprarenal gland (n=1), stomach (n=1), cecum (n=1) and bone marrow (n=1). Morphology in all cases was consistent with large cell lymphoma. All cases were positive for EBER and CD20 expression. Two cases had strong positivity to CD30. Ten cases (83%) had non-GC phenotype and 2 cases (17%) had GC-like phenotype. From the non-CG group, five patients (50%) received CHOP regimen. Two had complete response and three had progressive disease. Most of the cases died during the first year with the exception of two patients; one patient had a survival of 42 months and the other is currently receiving treatment with CHOP. From GC-like phenotype group, one patient received CHOP regimen with progressive disease and died 3 month after diagnosis. The other case was lost to follow-up.

CONCLUSION: The majority of patients in this report who were diagnosed with the newly described age-related EBV-associated B-cell LPD had a non-GC immunophenotype. This distinct subtype of DLBCL presents with advance stages, high IPI scores, extranodal involvement and short survival. Further research is necessary to elucidate the lymphomagenetic role and the prognostic value of EBV and to improve therapies, which are highly needed in this group of LPD.