B-cell and plasma cell proliferations associated with T follicular helper cell lymphomas: clinical-pathological and genetic features

Nodal T-follicular helper cell lymphomas (nTFHL) are aggressive peripheral T-cell lymphomas with unique clinical-biological features. B-cell and/or plasma cell proliferations (B/PCP) are frequently reported in nTFHL, yet their histological spectrum remains incompletely defined. This study aims to delineate the clinical, pathological and molecular features of a retrospective series of nTFHL-associated B/PCP, with particular emphasis on recurrent disease patterns. To this aim, we retrospectively analyzed 39 nTFHL with 45 synchronous and/or metachronous B/PCP, collected from five Italian referral centers for hematological disorders. Multiple B/PCP were documented in 5/39 (12.8%) patients. All diagnoses were established according to the 2022 WHO/ICC criteria, using the nomenclature proposed by the 2023 SH/EA4HP Workshop on T-cell lymphomas. Clinical and pathological data were collected, and recurrent histological patterns were categorized. RHOAG17V, TET2, DNMT3A, and IDH2 mutations were tested in 16 cases. The cohort included 20 males and 19 females (median age: 73.3 years). B/PCP clustered into six diagnostic categories: (i) diffuse large B-cell lymphoma (DLBCL)-like proliferations associated with nTFHL (19/45 [42.2%]), (ii) nodular large B-cell proliferations associated with nTFHL (5/45 [11.1%]), (iii) secondary DLBCL without co-localization of nTFHL (3/45 [6.7%]); (iv) EBV-positive polymorphic B-cell proliferations (10/45 [22.2%]), (v) monotypic plasma cell proliferations (5/45 [11.1%]), and (vi) small B-cell lymphoma-like proliferations with plasma cell differentiation (3/45 [6.7%]). TET2 mutations were detected in 10/16 (62.5%) cases with high allelic burden, whereas DNMT3A and IDH2 mutations were rare. The RHOAG17V mutation was detected in 3 cases, most likely representing contamination by minor nTFHL clones. In conclusion, TFHL-associated B/PCP are a heterogeneous group of lymphoproliferative and plasma cell disorders, displaying recurrent histological patterns and frequent clonal hematopoiesis-associated mutations. Further studies on larger cohorts of patients are warranted to elucidate their biological and clinical implications.