Insights into Nodal T-Follicular Helper Cell lymphomas and Peripheral T-Cell Lymphomas, Not Otherwise Specified, in Slovenian Patients: Mutational Landscape, Clinicopathological Characteristics, and Outcomes

Nodal T-follicular helper (TFH) cell lymphomas (nTFHLs) are the most common mature nodal T-cell lymphomas (nTCL) in Europe, characterized by an aggressive course, poor prognosis, and recurrent expression of TFH markers. Their mutational landscape and the impact of these mutations on survival outcomes remain underexplored. In this study, we characterized nTCL features in a Slovenian cohort, comprising 91 nTFHL, 9 peripheral TCL, not otherwise specified (PTCL-NOS), and 8 composite lymphomas [co-occurrence of nTFHL, angioimmunoblastic type (nTFHL-AI) with monoclonal B-cell proliferation], with a median follow up of 23 months. Using immunohistochemistry, clonality testing, and high-throughput sequencing with a lymphoma panel targeting 172 genes, we analyzed their mutational landscape and examined the mutational impact on survival outcomes. The mutational analysis uncovered TET2 (43%), RHOA (26%), IDH2 (9%), PLCG1 (8%), and DNMT3A (6%) as the most commonly mutated genes. RHOA mutations correlated with TET2, IDH2, and DNMT3A mutations, and CD10 expression was linked to TET2 mutations. Multiple mutations, high International Prognostic Index, progressive disease after first-line treatment, and the absence of autologous stem cell transplantation (ASCT) were independent predictors for shorter survival. To date, this study is one of the largest nTCL series, confirming that nTFHLs outnumber PTCL-NOS (92% vs. 8%). Our findings underscore the complex role of genetic factors in nTCL's clinical behaviour and emphasize the importance of ASCT. We also highlight the need for prospective clinical trials, which explore tailored therapeutic interventions, such as hypomethylating agents or IDH inhibitors, for improving survival in specific genetic contexts.