Distinguishing Plasmablastic/Anaplastic Plasma Cell Neoplasms from Plasmablastic Lymphoma: A Narrative Review and Proposed Integrated Clinicopathologic Framework

Plasmablastic/anaplastic plasma cell neoplasms (P/APC-N) and plasmablastic lymphoma (PBL) represent two categories of highly aggressive hematolymphoid malignancies. Their distinction is clinically important because they are classified and treated within different disease frameworks, yet no single morphologic, immunophenotypic, viral, cytogenetic, or molecular finding reliably resolves all cases. The proposed approach begins with the clinical and systemic context, including a pre-existing plasma cell neoplasm, marrow and serum findings, myeloma-defining events, immune status, and disease distribution. Morphologic assessment is followed by a panel evaluating plasma-cell differentiation, conventional B-cell markers, light-chain restriction, proliferative activity, and tumor-cell Epstein–Barr virus-encoded RNA (EBER) by in situ hybridization. Evidence of an established plasma cell neoplasm and a coherent myeloma-associated genomic background favor the relevant plasma cell neoplasm subtype, whereas tumor-cell EBER positivity in a compatible context supports PBL but is not specific. MYC protein overexpression, MYC rearrangement, high proliferative activity, light-chain restriction, and loss of conventional B-cell markers can occur in both categories and should not be used as stand-alone discriminators. When evidence does not converge, reports should state the findings favoring each category, identify unresolved conflicts, and recommend the next diagnostic steps. This framework remains to be validated in independent cohorts.