Marginal Zone Lymphoma With T-Follicular Helper Hyperplasia: Paving the Way for New Concepts in Cellular Plasticity and Unveiling Histopathologic Pitfalls.

Abstract

The expression of T-follicular helper (TFH) markers, initially described in nodal T-cell lymphomas arising from TFH-cells, has been reported in several non-TFH lymphomas, including B-cell lymphomas. It has also been observed in marginal zone lymphomas (MZL), whereas it is poorly characterized in nodal MZL (NMZL). The present study, therefore, aimed to characterize MZL with TFH cell expansions, by providing an extensive description of their histologic and molecular features. Thirty-two MZL with nodal involvement (25 primary nodal, 4 extranodal, and 3 primary splenic) showing TFH hyperplasia and 2 sequential cases [successive occurrences of angioimmunoblastic T-cell lymphoma (AITL) and MZL in the same patients] were retrospectively identified. Four histologic patterns were observed: AITL-like (44%), MZL-like (38%), biphasic (12%), and T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL)-like (6%). PD1 expression patterns differed significantly among subtypes ( P =0.037); found in the center of the B-cell nodules in MZL-like cases, expanded in interfollicular areas in AITL-like and biphasic cases, and displaying rosettes around B cells in THRLBCL-like cases. Targeted next-generation sequencing identified recurrent MZL-type associated variants ( KMT2D , KLF2 , and TNFAIP3 ) and the absence of TFH-lymphoma specific variants ( RHOA , IDH2 ). In 4 cases, clonal T-cell populations coexisted with B-cell populations, yet the integration of molecular and histologic data supported a MZL diagnosis. The present study highlights that TFH hyperplasia is challenging in the differential diagnosis of MZL and AITL, both morphologically and immunophenotypically. An integrated approach combining histology, immunohistochemistry, clonality studies, and molecular profiling is essential to establish the correct diagnosis, given that misinterpretation may lead to inappropriate treatment.