Prominent expansion of EBV⁺ large B cells obscuring follicular helper T-cell lymphoma

An older adult patient presented with diffuse rash, lymphadenopathy, and hepatosplenomegaly. Hematoxylin and eosin staining of a skin biopsy revealed proliferation (panel A, 20× lens objective) of medium to large lymphocytes (panel B, 200× lens objective), expressing CD20 (panel C, 200× lens objective) and EBER (panel D, 200× lens objective), with interspersed CD3⁺ T cells (panel E, 200× lens objective), high Ki-67 (panel F, 200× lens objective) and clonal immunoglobulin H gene rearrangement. EBV⁺ diffuse large B-cell lymphoma (DLBCL) was diagnosed. The patient was treated with rituximab, cyclophosphamide, doxorubicin, Oncovin (vincristine), and prednisone. After an initial response, new lesions developed 1 month later. A subsequent biopsy revealed skin infiltration (panel G, 20× lens objective) by small to medium lymphocytes (panel H, 200× lens objective), negative for CD20 (panel I, 200× lens objective) and EBER (panel J, 200× lens objective), expressing PD1 and CD3 (inset) (panel K, 200× lens objective) and high Ki-67 (panel L, 200× lens objective). Flow cytometry showed CD4⁺ expansion, with CD7 and surface CD3 loss. Follicular helper T-cell lymphoma was diagnosed. The B-cell component was absent (treatment effect).

Molecular studies in both biopsies showed clonally related T-cell receptor γ gene rearrangements and identical DNMT3A p.R882H (VAF 45.1%), RHOA p.G17V (VAF 42.0%), TET2 p.L879fs (VAF 44.5%), and TET2 c.3804-1G>A (VAF 44.8%) mutations, with KRAS p.Q61H (VAF 54.3%) in the second biopsy (clonal evolution). EP300 p.N377fs (VAF 20.0%) and TET2 p.Q746∗ (VAF 25.4%) mutations were detected only in the first biopsy. JAK-STAT or NOTCH mutations found in EBV⁺ DLBCL were absent. Prominent EBV⁺ B-cell proliferations may obscure underlying follicular helper T-cell lymphoma, which was present in the initial biopsy, based on common mutations and retrospective PD-1 staining (not shown).

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