Diagnostic challenges posed by the wide morphological and immunophenotypic spectrum of plasma cell neoplasms

Plasma cell neoplasms (PCNs) are a group of malignant neoplasms originating from the monoclonal expansion of immunoglobulin-secreting, terminally differentiated B cells, i.e., plasma cells (PCs). PCNs include monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma (solitary plasmacytoma of the bone and extramedullary plasmacytoma), multiple myeloma (MM)/plasma cell myeloma, and rare PCNs associated with paraneoplastic syndromes. MM is a multifocal, bone marrow-based clonal PCN associated with end-organ damage and a monoclonal paraprotein (M protein) in the serum and/or urine. Morphologically, MMs are typically composed of mature to atypical PCs with a typical immunophenotype (CD38 + bright, CD138 + , CD19-, and monotypic light-chain expression), which are usually diagnostically straightforward. However, rare cases with morphological variants or immunophenotypic aberrancies may pose diagnostic challenges. Small, mature-appearing PC variants of MM at times may be difficult to differentiate from mature B-cell lymphomas with plasmacytic differentiation, such as lymphoplasmacytic lymphoma and marginal zone lymphoma, particularly in core needle biopsies. CD20 + and cyclin D1 + MM may mimic mantle cell lymphoma. Plasmablastic and pleomorphic/anaplastic variants are prone to present as extramedullary lesions mimicking plasmablastic lymphoma (PBL) or various types of lymphomas with pleomorphic/anaplastic morphology. Moreover, neoplastic PCs may exhibit aberrant expression of CD3, CD4, CD117, and cyclin D1, leading to potential diagnostic pitfalls. Diffuse CD30 expression with anaplastic morphology may be mistaken for anaplastic large-cell lymphoma. In rare instances, the neoplastic cells of PCNs are positive for Epstein-Barr virus (EBV), more frequently in cases with plasmablastic morphology and extramedullary involvement, which may raise suspicion for PBL. In this review, we emphasize the rare morphological and immunophenotypic features and variants of PCNs and utilize a few examples to highlight the diagnostic challenges.