CAR-T cell therapy and its complications: Role of the pathologist in diagnosis

CAR-T cell therapy has transformed the treatment of patients with hematologic malignancies but has also introduced a spectrum of post-therapy complications that frequently require histopathologic evaluation. While clinical toxicities such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are well characterized, the pathologist's role in interpreting post–CAR-T biopsy specimens remains underdefined and challenging. In this review, we focus on the histopathologic, immunophenotypic, and molecular features of post–CAR-T complications, including cytopenias, immune effector cell–associated syndromes, therapy-related myeloid neoplasms, secondary malignancies, and CAR-derived lymphoproliferations. We emphasize diagnostic pitfalls, differential diagnoses, and practical approaches to distinguishing reactive, inflammatory and neoplastic processes. Our aim in this review is to provide a pathology-centered framework to guide accurate diagnosis, prevent misclassification and support clinical decision-making in the evolving landscape of CAR-T therapy.