Lymphomas of T-follicular helper origin (T-follicular helper-cell lymphoma [TFHL]) are often accompanied by an expansion of B-immunoblasts, occasionally with Hodgkin/Reed-Sternberg-like (HRS-like) cells, making the differential diagnosis with classic Hodgkin lymphoma (CHL) difficult. We compared the morphologic, immunophenotypic, and molecular features of 15 TFHL and 12 CHL samples and discussed 4 challenging cases of uncertain diagnosis. Compared with CHL, TFHL disclosed more frequent sparing of subcortical sinuses, high-endothelium venule proliferation, dendritic cell meshwork expansion, T-cell atypia, and aberrant T-cell immunophenotype. HRS-like and HRS cells were CD30+, often CD15+ and EBV infected. There was a variable loss of B-cell markers in both diseases, with an expression of CD20, CD79a, CD19, or OCT-2 more frequently preserved in HRS-like cells of TFHL. The T-cell infiltrate was predominantly CD4+/CD8-, with expression of at least 2 TFH-markers in all TFHL and 75% of CHL. The most useful TFH marker was CD10 (positive in 86% TFHL and no CHL). Twelve/15 TFHL contained CD30+ neoplastic TFH cells, whereas CD30 expression was mostly restricted to HRS cells in CHL. We detected monoclonal TR rearrangements in 75% of TFHL and no CHL
and monoclonal IG rearrangements in 23% of TFHL and 42% of CHL. All TFHL had TET2 mutations
13/14 presented RHOA mutations, 3 accompanied by DNMT3A and 1 DNMT3A + IDH2 mutations. Three CHL had TET2 mutations, likely attributable to clonal hematopoiesis. Our study further underlines that HRS(-like) cells are not pathognomonic of CHL. Since no single pathologic criterion distinguishes TFHL and CHL, an integrative approach ideally comprising molecular investigations is fundamental.