BRAF V600E-mutated marginal zone lymphoma may exhibit features that partially overlap with hairy cell leukemia.

OBJECTIVES: To establish the occurrence of BRAF mutation in marginal zone lymphomas (MZLs) and study its impact on clinical presentation, pathologic features, and disease classification. METHODS: Conventional histology, immunohistochemistry, flow cytometry, and molecular methods were used. RESULTS: We identified 2 BRAF‑mutated MZL cases: a nodal MZL (NMZL) with BRAF V600E and partial morphologic/immunophenotypic overlap with hairy cell leukemia (HCL) and an extranodal MZL with a non-V600E BRAF mutation co‑occurring with TET2, KRAS, and TP53 variants. The NMZL case showed strong CD25 and CD123 expression and patchy cyclin D1 expression; together with the presence of a BRAF V600E mutation, these features overlapped with HCL. However, the absence of annexin A1 and CD103 expression, along with the remaining morphologic features in the lymph node, supported accurate classification as NMZL. CONCLUSIONS: These 2 cases expand the mutational spectrum of MZL and illustrate important diagnostic pitfalls. These observations underscore that BRAF V600E, while highly specific and clinically useful for HCL in the context of a B‑cell lymphoproliferative process involving blood and marrow, is not entirely pathognomonic and must be interpreted alongside morphology and a full immunophenotypic panel. Integrating BRAF testing into the workup of challenging small B‑cell lymphomas may refine diagnosis and reveal rare, potentially targetable MAPK pathway lesions.