Follicular helper T-cell lymphomas with EBV-positive neoplastic cells: a rare scenario with diagnostic implications.

Follicular helper T-cell lymphomas (TFHL) of the angioimmunoblastic type (AITL) and other TFHL variants often contain 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 NOS) associated with EBV infection in neoplastic T cells. The patients (5 males, 5 females), 56-81 years old, presented with polyadenopathy (8/8), B symptoms (7/7), and skin lesions (4/7). EBV was confirmed in neoplastic TFH by double labelling for EBV, T-cell markers (CD5 or CD3) and PD1/ICOS. In two patients, EBV infection in TFH was demonstrated in biopsies at relapse of an AITL (n=2). In three 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 two of the 3 patients. A high viral load was observed in the three 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 one case), DNMT3A (5/10), and CD28 (2/9) genes. By PCR, all nine patients tested showed type-1 EBV. All seven patients with follow-up data available showed rapid disease progression and died 2 to 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.