Background: Nodal T-follicular helper cell lymphoma (nTFHL) may contain Hodgkin/Reed–Sternberg (HRS)-like cells and mimic classic Hodgkin lymphoma (CHL), but it is usually distinguishable from CHL by other histopathological features. We recently encountered a treatment-refractory case with highly convincing CHL morphology and immunophenotype, in which detection of the RHOA G17V mutation and shared T-cell receptor rearrangements in the lymph node and bone marrow redirected the diagnosis to nTFHL (Figure). This prompted us to investigate whether a subset of cases diagnosed as CHL based on morphology may represent “nTFHL with CHL features”.
Methods: We retrospectively analyzed 153 cases initially diagnosed as CHL based on excisional lymph node specimens in our consultation files (86 mixed-cellularity type and 67 nodular sclerosis type). RHOA G17V mutation was assessed using the PNA-LNA PCR clamp method, a highly sensitive assay suitable for low–tumor content samples. Clinicopathological features, histological findings, immunophenotype, EBV status, T-cell receptor gene rearrangement, treatment response, and clinical outcomes were compared according to RHOA mutation status.
Results: RHOA mutations were identified in 20/153 cases (13.1%), and all RHOA-mutated cases were detected exclusively among advanced-stage cases (p<0.001). Compared with advanced-stage RHOA-wild-type cases, RHOA-mutated cases showed distinctive background features, including increased interfollicular vascularity and EBV-positive small- to medium-sized lymphoid cells (both p<0.001). In the matched cohort, RHOA-mutated cases showed a poorer response to CHL-directed therapy and significantly shorter progression-free survival (p<0.01), with a trend toward inferior overall survival(p=0.08).
Conclusions: RHOA G17V mutations were detected in a substantial proportion of advanced-stage cases with CHL morphology, and these cases showed clinicopathological features suggestive of nTFHL. They may be better conceptualized as “nTFHL with CHL features” rather than conventional CHL. Given that morphology and immunophenotype alone make differentiation extremely challenging, RHOA mutation analysis should be considered in advanced-stage or treatment-refractory cases with CHL morphology, as its detection may have important diagnostic and therapeutic implications.
Rio Yamada, Midori Filiz Nishimura, Asami Nishikori, Yoshito Nishimura, Ritsuro Suzuki, Yasuharu Sato