A 90-year-old man with no history of lymphoma presented with a right base of tongue mass and ipsilateral lymphadenopathy. Blood counts were normal except for mild anemia (hemoglobin 12.9 g/dL). A right submandibular lymph node biopsy revealed nodal architectural effacement by sheets of large centroblastic and immunoblastic cells (panel A; original magnification ×600). Neoplastic cells were diffusely positive for CD20 (panel B; original magnification ×400) and Epstein-Barr virus (EBV)-encoded RNA (77% of cells; panel C; original magnification ×400), with Ki-67 labeling index approaching 100% (panel D; original magnification ×200). They were diffusely positive for CD10 (panel E; original magnification ×200), MYC (panel F; original magnification ×400), BCL2 (panel G; original magnification ×200), and BCL6 (panel H; original magnification ×200), but negative for CD5, BCL1, LMP1, and EBNA2 (type 1 latency). Fluorescence in situ hybridization detected MYC rearrangement (32%; panel I), MYC gain (18%), and BCL6 rearrangement (76%; panel J). Next-generation sequencing revealed pathogenic point mutations in BCL2 (c.585 + 7G>A;p.P59A;p.H3Q;p.K17N suggestive of somatic hypermutation), CREBBP, FBXW7, and ID3. There was no evidence of structural variants in BCL2, although a cryptic BCL2 translocation could not be entirely excluded.

This case is an example of EBV-positive MYC/BCL6 double-hit, high-grade B-cell lymphoma, an extremely rare disease entity that is not included in the 2017 World Health Organization classification, which states that such EBV-positive cases should be reported as EBV-positive diffuse large B-cell lymphoma not otherwise specified and not as high-grade B-cell lymphoma with MYC and BCL2/BCL6 rearrangements. This case expands the spectrum of EBV-positive B-cell lymphomas and highlights the importance of gene rearrangement testing, even in EBV-positive cases.