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

Abstract 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. RHOA G17V , 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 RHOA G17V 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.