When Myeloma Masquerades: Rare Plasma Cell Variants That Fool Pathologists

Multiple myeloma is usually one of the more straightforward diagnoses in hematopathology. The malignant plasma cells that define the disease carry a recognizable look under the microscope and a characteristic fingerprint on the flow cytometer: bright CD38, strong CD138, loss of CD19, and a single restricted light chain. But a new open-access review published in Blood Research argues that this comfortable picture hides a treacherous minority of cases in which plasma cell neoplasms disguise themselves as entirely different lymphomas, carcinomas, or even T-cell malignancies, with potentially serious consequences for patients.

The review, authored by Shih-Sung Chuang and Chung-Che Chang, systematically catalogs the rare morphological and immunophenotypic variants of plasma cell neoplasms, a family that includes monoclonal gammopathy of undetermined significance, plasmacytoma, and multiple myeloma itself. Under the fifth edition of the WHO Classification of Haematolymphoid Neoplasms, myeloma is defined as a bone marrow-based, multifocal proliferation of plasma cells, together with either disease-related organ damage or laboratory and imaging findings indicating a high risk of such damage within two years. That damage is summarized in the familiar CRAB acronym: hypercalcemia, renal insufficiency, anemia, and lytic bone lesions.

The first diagnostic trap sits at the small end of the cellular spectrum. In a study of 351 myeloma cases cited in the review, Heerema-McKenney and colleagues identified twelve cases, or 3.4 percent, of a small-cell variant in which the neoplastic plasma cells look deceptively like mature lymphocytes. These cells typically express strong CD20 and cyclin D1, and they often carry the t(11;14) translocation involving the IGH and CCND1 genes, the very hallmark of mantle cell lymphoma. The review describes one such case: a 41-year-old man who presented with a compression fracture of a lumbar vertebra, whose bone biopsy showed sheets of small, plasmacytoid tumor cells expressing CD20, CD138, and cyclin D1 with CCND1 rearrangement confirmed by FISH.

Distinguishing this variant from lymphoplasmacytic lymphoma is the central challenge. That lymphoma is defined by small lymphocytes with plasmacytic differentiation, a frequent monoclonal IgM paraprotein, and the MYD88 L265P mutation, present in roughly 95 percent of cases. The review notes that lytic bone lesions, absence of the MYD88 mutation, and a high serum free light-chain ratio favor myeloma, while the small-cell variant lacks CD45 and expresses CD138. Marginal zone lymphoma, which can show extensive plasmacytic differentiation, complicates matters further, particularly in limited needle core biopsies. Plasma cells associated with B-cell lymphoma tend to be CD45-positive, CD19-positive, CD56-negative, and surface immunoglobulin positive, and IgM-type M proteins are rare in plasma cell neoplasms, all clues the authors urge pathologists to weigh alongside molecular testing.

At the opposite, large end of the spectrum lies an even sharper dilemma. Plasmablastic myeloma and plasmablastic lymphoma exhibit nearly identical cytomorphology and immunophenotypic profiles, making them impossible to separate on pathological grounds alone. Plasmablasts are large cells with vesicular nuclei, prominent nucleoli, and abundant basophilic or amphophilic cytoplasm. Epstein-Barr virus infection is far more commonly associated with the lymphoma than with the myeloma, but the authors report that in immunocompetent patients, the plasmablastic variant of both plasmacytoma and myeloma is more frequently EBV-positive than non-blastic variants, blurring that distinction too. In their own cohort of 25 cases of plasmablastic myeloma, defined as at least 30 percent plasmablasts in tissue sections, 15 patients, or 60 percent, had extramedullary disease, and in nine cases it was the initial presentation, most often in soft tissue and skin.

The resolution, according to the review, rests on myeloma-defining features: extensive marrow involvement of at least 60 percent plasmablasts, a serum free light-chain ratio of 100 or more, CRAB features, and serum M protein. Targeted FISH findings such as del(13q14), gain of chromosome 1q, loss of chromosome 1p, and IGH::FGFR3 may also help. One illustrative case involved a 41-year-old HIV-infected man whose marrow was overrun by sheets of plasmablasts expressing CD138 and MYC. The authors also flag a cautionary discrepancy: while one study reported CD117 expression in six of eight plasmablastic myelomas and none of eight plasmablastic lymphomas, their own 25-case series found no CD117 expression at all, meaning the marker’s usefulness requires further study.

Pleomorphic or anaplastic myeloma is rarer still, documented mainly in isolated case reports and small series, and the authors argue it should be treated as a variant distinct from the plasmablastic form. These anaplastic cells, with multinucleated and multilobated nuclei, represent an aggressive form of myeloma that may appear at initial diagnosis or emerge at relapse through transformation of better-differentiated cells. They usually present at extramedullary sites and show a poor response to both conventional and novel therapies. One case in the review began as inguinal lymphadenopathy in a 71-year-old man, with anaplastic cells expressing CD56 and CD138, and was initially misdiagnosed as nodal peripheral T-cell lymphoma because the cells strongly and diffusely expressed both CD3 and CD45.

That misdiagnosis illustrates a broader immunophenotypic theme. Although most plasma cell neoplasms are CD45-negative, expression has been reported in up to 14 percent of myelomas, and it is more common in early disease, so CD45 positivity should never be used to exclude the diagnosis. Neoplastic plasma cells may also aberrantly express CD3, CD4, CD117, and cyclin D1. Diffuse CD30 expression with anaplastic morphology can mimic anaplastic large-cell lymphoma. EMA, conventionally an epithelial marker, is expressed in around 60 percent of myelomas, and cytokeratin in one-quarter to one-third of plasmacytoma and myeloma cases, meaning extramedullary disease can be mistaken for metastatic carcinoma. The authors recommend comprehensive panels including additional T-cell markers, plasma cell markers such as CD38, CD138, MUM1, Blimp1, and XBP1, and clonality studies of both immunoglobulin and T-cell receptor genes.

Extramedullary disease, defined as clonal plasma cells outside the marrow, occurs in 7 to 18 percent of myeloma patients and is more frequent with plasmablastic and pleomorphic morphology, typically signaling advanced or relapsed disease. At diagnosis it favors skin and soft tissue; at relapse, the liver, kidney, lymph nodes, central nervous system, breast, pleura, and pericardium. The review also covers plasma cell leukemia, redefined by the International Myeloma Working Group in 2021 as five percent or more circulating plasma cells in patients with symptomatic myeloma. Primary plasma cell leukemia, which accounts for 60 to 70 percent of cases, carries a grim prognosis, with a median progression-free survival of only four months even in the era of proteasome inhibitors, according to a cohort of 53 Turkish patients. Secondary leukemia develops in roughly one percent of myeloma cases, a median of 31 months after initial diagnosis in a multicenter study of 101 patients. Notably, a flow cytometry study found that patients with as few as 2 percent circulating neoplastic plasma cells had outcomes comparable to primary plasma cell leukemia, suggesting the threshold should prompt flow cytometric assessment during diagnostic workup.

The review’s closing message is a sober one for laboratory medicine: an increased number of plasma cells in the marrow is not diagnostic of myeloma, since reactive plasmacytosis, seen in infections, autoimmune disease, angioimmunoblastic T-cell lymphoma, and other conditions, can exceed 20 percent and may even occur in the peripheral blood. Reactive plasma cells express CD19 and CD138 but not CD56, CD117, or cyclin D1, and show polytypic light chains. Morphology alone is usually not diagnostic, and even immunophenotyping carries pitfalls. Only the integration of detailed morphology, laboratory assays, careful marker interpretation, molecular studies including clonality testing and FISH, and clinical correlation, the authors conclude, allows pathologists to unmask these masterful mimics and ensure patients receive the correct diagnosis and appropriate management.

Subject of Research: Diagnostic challenges posed by rare morphological and immunophenotypic variants of plasma cell neoplasms

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

Article References: Chuang, S.-S., & Chang, C.-C. (2026). Diagnostic challenges posed by the wide morphological and immunophenotypic spectrum of plasma cell neoplasms. Blood Research, 61(1), Article 61. https://doi.org/10.1007/s44313-026-00179-6

Image Credits: AI Generated

DOI: 10.1007/s44313-026-00179-6

Keywords: multiple myeloma, plasma cell neoplasms, plasmablastic myeloma, lymphoplasmacytic lymphoma, mantle cell lymphoma, diagnostic pathology, immunophenotyping, extramedullary disease, plasma cell leukemia, cyclin D1, EBV, WHO classification