Atypical lymphoproliferations associated with germline genetic variants: a report of the 2024 EA4HP/SH lymphoma workshop.

Session 2 of the 2024 European Association for Haematopathology/Society for Hematopathology lymphoma workshop was dedicated to atypical lymphoproliferations in association with germline genetic variants. The first group of cases were lymphoproliferations occurring in the context of primary immunodeficiencies (PID), a heterogeneous group of diseases with increasing incidence and number of different diseases due to better recognition. The workshop contained a spectrum of different PIDs and associated lymphoproliferations with autoimmune lymphoproliferative syndrome, activated phosphoinositide 3-kinase delta syndrome, ataxia-telangiectasia and common variable immune deficiency being the most common. Both children and adults were affected, and the diagnosis of an underlying PID often required a high index of suspicion and correlation with clinical presentation and immunological/ infectious workup. Recognition of a PID allows specific treatment and can influence the interpretation of lymphoproliferations occurring in this context. The spectrum of lymphoproliferations ranged from reactive to overt lymphoma, both EBV-positive and -negative. In a subset of cases, it was very difficult or impossible to establish the boundary between reactive and neoplastic in the context of a PID. The second group represented a heterogeneous group of lymphoproliferations in the context of mutations in germline haematopoietic malignancy risk genes, without associated immunodeficiency. It was often difficult to determine if the genetic defect and the lymphoproliferation were causally related or coincidental, especially if the patient was also treated for non-lymphoid conditions. This is a rapidly evolving field in which future studies are expected to shed more light on the relationship between germline mutations and lymphoid malignancy.