Challenging cases of Epstein-Barr virus positive lymphomas

Epstein-Barr virus (EBV)-associated lymphomas can develop in both immuno- competent and immunocompromised patients, such as those with human immunodeficiency virus (HIV) infection, other primary or acquired immunodeficiencies, or post transplantation. The current World Health Organization classification consolidated immunodeficiency/dysregulation-related lymphoproliferative disorders into three major histopathological categories: hyperplasia, lymphoproliferative disorder of varied malignant potential, and lymphoma; and reporting the histopathological category, the presence or absence of causally associated viruses (EBV, KSHV/HHV-8), and the immune deficiency/dysregulation setting is recommended. In hematopathology practice, EBV is best confirmed by EBV-encoded RNA in situ hybridization, while immunohistochemistry is used as a complementary test for the presence of EBV-related proteins. Often, additional analyses such as fluorescence in situ hybridization and polymerase chain reaction for B- and T-cell clonality have to be applied for the final classification. This review, summarizing a lecture given at the 10th Course of the Academy of Immunohistochemistry in Cracow, Poland (June 2026), presents some challenging examples of EBV-related lymphomas. Cases include EBV+ mucocutaneous ulcer with subsequent EBV+ diffuse large B-cell lymphoma, EBV+ diffuse large B-cell lymphoma with plasma cell differentiation, post therapy EBV+ Burkitt lymphoma and cutaneous NK/T-cell lymphoma.