The histopathological differential diagnosis of BPDCN and other plasmacytoid dendritic cell proliferations

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive precursor cell hematological malignancy with a dismal prognosis, necessitating prompt and accurate diagnosis. However, its blastoid morphology and immunophenotype may lead to diagnostic confusion with a broad spectrum of hematological neoplasms. This systematic review delineates the critical morphological, immunophenotypic, and molecular features required to distinguish BPDCN from its mimics across common sites of involvement (skin, bone marrow, and lymph nodes). We reinforce the diagnostic criteria for BPDCN and provide an in-depth analysis of its differential diagnosis, structuring it into two groups: (A) hematological neoplasms with blastoid morphology (e.g., ALL/LBL, blastoid MCL, AML, myeloid sarcoma), and (B) myeloid malignancies with pDC-associated markers (e.g., AML with pDC-like phenotype, AML with pDC expansion, mature pDC proliferation). We emphasize the integration of immature and lineage-specific markers, and molecular data (e.g., ZRSR2, MYB/MYBL1, NPM1, FLT3, RUNX1, DNMT3, CCND1 status) to resolve diagnostic dilemmas. The aim is to provide a comprehensive diagnostic review and guide to standardize the workup and facilitate the early initiation of appropriate treatment for this challenging disease.