Lymphoproliferation in inborn errors of immunity: From challenging diagnosis to histologic revision

Inborn errors of immunity (IEI) are genetic disorders that not only heighten infection risk but also disrupt immune regulation, frequently leading to lymphoid tissue overgrowth known as lymphoid proliferations (LPD). We retrospectively reviewed 38 patients with genetically or clinically confirmed IEI and persistent LPD, comparing those with nonneoplastic/reactive hyperplasia to those who developed overt lymphoid neoplasm (lymphoma). Overall, 26% developed lymphoma-predominantly classical Hodgkin lymphoma or diffuse large B cell lymphoma-often after earlier IEI onset. Immunophenotyping and principal component analysis revealed that patients with common variable immunodeficiency developing Hodgkin lymphoma shared a distinctive T cell profile, differing from immunocompetent lymphoma cases. Centralized histologic re-evaluation reclassified several presumed lymphoma as nonneoplastic/reactive hyperplasia and identified Castleman-like and germinal center transformation patterns in nonneoplastic/reactive LPD. Notably, elevated blood IgM and circulating T follicular helper cells mirrored IgM deposits and PD-1⁺ T cells in lymph nodes. These findings highlight the importance of an integrated approach involving clinical, genetic, and pathological reviews to improve IEI diagnosis and avoid overtreatment.