Follicular Helper T-Cell Lymphomas With Epstein-Barr Virus-Positive Neoplastic Cells: A Rare Scenario With Diagnostic Implications

Abstract

Follicular helper T-cell lymphomas (TFHLs) of the angioimmunoblastic type (AITL) and other TFHL variants often contain Epstein-Barr virus (EBV)-positive B blasts, but EBV infection of the neoplastic T cells has rarely been documented. Here, we report 10 cases of TFHL (9 AITLs and 1 TFHL not otherwise specified) associated with EBV infection in neoplastic T cells. The patients (5 men and 5 women), aged 56 to 81 years, presented with polyadenopathy (8/8), B symptoms (7/7), and skin lesions (4/7). EBV was confirmed in neoplastic follicular helper T-cell (TFH) by double labeling for EBV, T-cell markers (CD5 or CD3), and PD1/ICOS. In 2 patients, EBV infection in TFH was demonstrated in biopsies at relapse of an AITL (n = 2). In 3 cases, the abundance of EBV in large atypical B cells had led to a mistaken diagnosis of either classic Hodgkin lymphoma or EBV-positive large B-cell lymphoma, with the diagnosis subsequently confirmed as AITL in 2 of the 3 patients. A high viral load was observed in the 3 tested patients. Lymph node biopsies showed the typical pathological, phenotypic, and genetic features of TFHL with a CD4+ (10/10), CD10+ (5/10), PD1+ (10/10), ICOS+ (8/8), CXCL13+ (8/8), BCL6+ (5/9) TFH phenotype of the neoplastic cells, follicular dendritic cell expansion (9/10), and mutations in TET2 (10/10), RHOA (p.G17V variant in 8 cases and a previously unreported RHOA p.D120N variant in 1 case), DNMT3A (5/10), and CD28 (2/9) genes. Using PCR, type-1 EBV was detected in all 9 patients tested. All 7 patients with follow-up data available showed rapid disease progression and died 2-8 months after the diagnosis. This study shows that EBV type 1 can infect TFH cells in TFHL. Further studies are needed to understand whether the crosstalk between TFH cells and EBV-infected B cells plays a role in this phenomenon and to determine the potential clinical relevance of EBV in TFHL.

Keywords: Epstein-Barr virus; diagnostic challenges; follicular helper T-cell lymphoma; outcome; peripheral T-cell lymphoma.