Nodal T-follicular helper cell lymphoma with hodgkin/reed-sternberg-like cells: Clinicopathologic and molecular characterization of 11 cases.

[BACKGROUND] Angioimmunoblastic T-cell lymphoma (AITL), a subtype of nodal T-follicullar helper (TFH) cell lymphoma, may pccasionally contain Hodgkin/Reed-Sternberg (HRS)-like cells, which poses significant diagnostic challenges. These large atypical cells ofthen express CD30 and weak PAX5, making classical Hodgkin lymphoma (CHL) and increasing the risk of misdiagnosis. Accurate recognition requires integration of histological, immunophenotypic, viral, and molecular features.

[METHOD] We retrospectively analyzed 11 patients diagnosed with AITL containing HRS-like cells between January 2020 and January 2025. All cases were consultation cases from a regional lymphoma diagnostic center, with available formalin-fixed, paraffin-embedded lymph node tissue. A comprehensive review included histomorphology, immunohistochemistry, Epstein-Barr virus-encoded RNA (EBER) in situ hybridization, T-cell receptor (TCR) and immunoglobulin (IG) gene rearrangement studies, and targeted next-generation sequencing (NGS) of lymphoma-associated genes.

[RESULTS] The cohort included 7 men and 4 women, with a median age of 63 years. Histologically, all cases showed partial to complete effacement of nodal architecture, proliferation of high endothelial venules, expansion of follicular dendritic cell (FDC) meshworks, and scattered HRS-like cells. Immunophenotypically, HRS-like cells were consistently CD30-positive, weak PAX5-positive (9/11), and variably CD15-positive. Background T cells expressed TFH markers including CD4, PD-1, CD10, BCL-6, CXCL13, and ICOS. EBER was positive in 10 cases. TCR gene clonality was detected in 9 patients, while 2 also showed B-cell clonality. NGS identified frequent mutations in TET2 (11/11) and RHOA (8/11), with additional alterations in DNMT3A, KMT2D, CREBBP, BRD4, and PLCG1.

[CONCLUSIONS] AITL with HRS-like cells is prone to misdiagnosis as CHL due to overlapping morphological and immunophenotypic features. Integration of EBER, TCR/IG clonality assessment, and molecular profiling, particularly the identification of TET2 and RHOA mutations is essential for accurate classification. Recognizing this entity is critical for avoiding diagnostic pitfalls and guiding appropriate therapeutic strategies.