The diagnostic work-up of most plasma cell neoplasms with adequate sampling demonstrate clearcut morphology, classic clinical findings, and plasma cell aberrancy (i.e., expression of plasma cell markers, aberrant loss of CD19, aberrant expression of CD56, cytoplasmic light chain restriction). However, a subset of plasma cell neoplasms may initially present in extramedullary sites, demonstrate atypical morphology and immunophenotype, or present with limited sampling that can preclude ancillary studies for further characterization. In these instances, neoplastic plasma cells may show significant clinical and pathologic overlap with other mature B-cell neoplasms.

The focus of this review will be on the differential diagnosis of multiple myeloma with an emphasis on the most common low-grade B-cell lymphomas with plasmacytic differentiation and aggressive B-cell lymphomas with plasmablastic morphology that can mimic true plasma cell neoplasms. Incorporation of clinical history, laboratory data, morphology, immunophenotype, cytogenetic studies, and molecular sequencing analysis may be necessary in establishing an accurate diagnosis.

Plasma cell neoplasms (PCN) can involve bone and extramedullary tissue with clonal plasma cells, as a part of plasma cell (multiple) myeloma (MM) or a solitary lesion without evidence of MM in bone marrow (BM) or end-organ damage due to PCN. Solitary plasmacytoma of the bone (SBP) mainly arises in bones with active hematopoiesis, affecting the axial skeleton more often than the appendicular skeleton.1, 2, 3 Extramedullary plasmacytoma (EMP) most commonly arise in the upper respiratory tract (e.g., nasal cavity, paranasal sinuses, nasopharynx, larynx) and occasionally involves the lymph nodes, lungs, gastrointestinal tract, and skin. EMP and occasionally SBP may show plasmablastic or anaplastic morphology with large nuclei, open chromatin, prominent nucleoli, and high nuclear-cytoplasmic ratio, and a high proliferation index (Fig. 1A). This sub-entity is referred to as extramedullary plasmablastic/anaplastic plasmacytoma (P-EMP) and warrants a differential diagnosis with plasmablastic lymphoma (PBL).

Plasmablastic lymphoma (PBL) is a clinically aggressive large cell lymphoma commonly associated with immune deficiency/dysregulation (e.g., HIV infection, immunosuppressive therapy for BM stem cell and solid-organ transplantation, or autoimmune diseases).4,5 EBV reactivation, with type I occasionally type II latency, plays a role in lymphoma pathogenesis.6,7 PBL usually arises in extranodal sites, such as the nasal/oral cavity and digestive system. It is characterized by a diffuse proliferation of large cells with plasmablastic or immunoblastic morphology with variably pleomorphic cells and a high proliferation index, and phenotypically by a terminally differentiated B-cell immunophenotype (i.e., plasma cell-like immunophenotype). The PC-like immunophenotype includes diminished to absent expression of B-cell markers (CD19, CD20, and PAX5) with expression of plasmacytic markers CD138, CD38, MUM-1, and variably restricted kappa or lambda light chain expression (Fig. 1B). Patients with PBL usually have a poor prognosis despite aggressive chemotherapy.

The differential diagnosis between P-EMP and PBL is important as these two diseases have very different clinical and therapeutic implications.2, 3, 4,8 However, their distinction can cause a diagnostic dilemma due to their shared morphological and immunophenotypic features. Table 1 summarizes the key features to aid in distinguishing P-EMP from PBL. Despite their shared morphology and immunophenotype, their clinical features, EBV status, and genetic features are less overlapped, which could be helpful in their differential diagnosis. P-EMP typically occurs in immunocompetent patients and may arise from a concurrent plasma cell neoplasm, while PBL typically occurs in immunosuppressed patients with de novo presentation. EBV positivity, as defined by EBV-encoded small RNA (EBER), is more common in PBL (∼60 %) than in P-EMP (rarely detected, but a recent study reported ∼10 % positivity in EMP (60 % as P-EMP9); notably ∼10 % EBV positivity in SBP).3, 4, 5,9,10 Both P-EMP and PBL lack expression of KSHV/HHV8 and ALK, as these features help distinguish them from extracavitary/solid primary effusion lymphoma and ALK-positive large B-cell lymphoma, respectively. From a genetic perspective, primary chromosomal translocations frequently encountered in MM (MM-type translocations) other than MYC rearrangements have not been described in de novo PBL. MYC rearrangements are frequent in PBL, more commonly seen in EBV-positive cases; approximately 50 % of PBLs harbor MYC rearrangement accompanied by high MYC expression by immunohistochemistry and MYC::IGH fusion in almost all reported cases.11, 12, 13, 14 As expected, primary MM-type translocations are present in P-EMP but MYC rearrangements are much less common than in PBL, reported in ∼10 % in MM with MYC::IGH fusion in a recent study.15 In PBL, somatic mutations involving JAK/STAT, MAPK/ERK, and NOTCH pathways are frequently detected together with TP53 mutations.7,14,16,17 EBV-negative PBL cases show a higher mutation load and more frequent TP53, CARD11, and MYC mutations, whereas EBV-positive PBLs tend to have more mutations affecting the JAK/STAT pathway.16 In contrast, the gene mutation spectrum of P-EMP, other than TP53 mutations, remains largely unknown although mutations that activate the RAS or NF-kB pathways, and mutations in DIS3 or FAM46C that drive precursor stages of disease toward MM have been reported.18,19 Taken together, the different characteristics between P-EMP and PBL may aid in rendering a correct diagnosis in most patients through a comprehensive assessment including clinical features, EBV status, and genetics.

Though most plasma cell neoplasms can be differentiated from B-cell lymphomas based on clinical presentation (e.g., lytic bone lesions, hypercalcemia, monoclonal gammopathy, etc.) their distinct morphology and immunophenotype, there are uncommon plasma cell neoplasm variants that can mimic mature B-cell lymphomas. In addition to morphologic examination, flow cytometry is a helpful tool in differentiating B-cell lymphomas of small to medium cells size (BCL-SM) with plasmacytic differentiation from PCN. Identification of plasmacytic cells harboring an immunophenotype of CD19(+)/CD45(+)/CD56(-) in addition to a clonal B-cell population is more typical of BCL-SM in contrast to PCN plasma cells harboring an immunophenotype of CD19(-)/CD45(-)/CD56(+) (Fig. 2).

The small-cell subtype of multiple myeloma (MMsc) accounts for <5 % of multiple myeloma cases.20, 21, 22 This rare subtype is characterized by plasma cells with small lymphocyte-like morphology, resembling B-cell lymphoma (Fig. 3). The neoplastic plasma cells typically exhibit a diffuse interstitial pattern of bone marrow infiltration with the following immunophenotype: CD19(-/dim+), CD20(+), CD38(bright +), CD45(-), CD56(-), CD138(+). Frequent expression of CD20 and less frequent expression of CD56 can make cell classification by immunophenotype a challenge. Most are associated with cyclin D1 overexpression due to t(11;14) CCND1::IGH, which can mimic mantle cell lymphoma, and high expression of B-cell genes such as CD20, PAX5, and VPREB3 have been reported. MMsc can also harbor genetic alterations involving cyclin D3 (CCND3). Lack of CD56 (neural cell adhesion molecule, NCAM) is an adhesion molecule, and when it is absent on neoplastic plasma cells, may reduce cell-to-cell interactions and enhanced peripheral blood and extramedullary organ involvement, further mimicking B-cell lymphoma.22 Lack of CD45 expression, dim to negative CD19 expression, CD138 positivity, and clinical presentation, including lytic bone lesions, of multiple myeloma can aid in making the correct diagnosis.

Plasmacytoid/plasmacytic differentiation is a well-described feature in a subset of mature low-grade B-cell lymphomas, particularly in lymphoplasmacytic lymphoma (LPL) where plasmacytic differentiation is a diagnostic requirement, marginal zone lymphoma (MZL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Less commonly, follicular lymphoma (FL) and mantle cell lymphoma (MCL) may also demonstrate plasmacytic differentiation. B-lymphocyte differentiation into long-lived plasma cells is an antigen mediated process that is derived from activated B-cells in the germinal center whereas short-lived plasma cells can arise from naïve B-cells in extrafollicular areas of lymphoid tissue. As a result of these processes, post-germinal center B-cell lymphomas more often exhibit plasmacytic differentiation.23 An integrated diagnostic approach can aid in distinguishing these entities from multiple myeloma.

Lymphoplasmacytic lymphoma (LPL) is a mature B-cell lymphoma that has the most clinical, morphologic, and immunophenotypic overlap with plasma cell neoplasms. LPL, by definition, is a proliferation of mature B-lymphocytes that demonstrate a spectrum of plasmacytic differentiation.24 The neoplastic cells consist of mature B-lymphocytes, plasmacytoid B-lymphocytes, and mature plasma cells. LPL lesions may show a predominance of one cell type, where a predominance of plasma cells can mimic a true plasma cell neoplasm. The clinical presentation of LPL may mimic multiple myeloma in that most patients will present with monoclonal gammopathy, though most LPL paraproteins are of the IgM isotype (Table 2). When IgM monoclonal gammopathy and bone marrow involvement by LPL are present, the clinical diagnostic criteria for Waldenstrom macroglobulinemia (WM) is met. Most patients with LPL (∼90 %) meet the criteria for Waldenstrom macroglobulinemia. The remaining LPL variants include non-IgM/ non-Waldenstrom variants where the LPL may generate other monoclonal immunoglobulin isotypes (e.g., IgG, IgA) or may not generate a paraprotein (non-secretory LPL).25 Of note, <1 % of plasma cell neoplasms produce IgM (Table 2).26 An IgM paraproteinemia may also be associated with hyperviscosity, coagulopathy, hemolytic anemia, cryoglobulinemia, and peripheral neuropathy.27 Non-Waldenström LPL is more likely to involve extramedullary sites at diagnosis and may mimic multiple myeloma due to detection of non-IgM monoclonal gammopathy, but morphologic, immunophenotypic, and molecular genetic findings in LPL are distinct from true plasma cell neoplasms.

The lesional cells consist of a spectrum of mature small B-cells, plasmacytoid B-cells, and mature plasma cells (Fig. 4). The plasmacytoid cells are characterized by overlapping mature B-cell and plasma cell morphology that include eccentric nuclei, round to slightly irregular nuclear contours, clumped chromatin that does not quite yet resemble the “clockface” chromatin of mature plasma cells, moderate cytoplasm compared to the scant cytoplasm of mature lymphocytes, light basophilic cytoplasm that stains less intensely than mature plasma cells on Romanosky stains (e.g., Diff Quik), and absence of a prominent Golgi hof. A subset of lesional cells may contain nuclear pseudoinclusions, aka “Dutcher bodies” that occur when the immunoglobulin-packed cytoplasm invaginates into the nuclear membrane. Inclusions can be further highlighted on histologic sections with immunoglobulin light chain immunohistochemistry (Fig. 4).

The pattern of LPL infiltration in bone marrow and tissues is variable. The bone marrow is the most common site of involvement where LPL typically demonstrates an interstitial pattern of infiltration with paratrabecular aggregate formation, which can mimic follicular lymphoma on H&E stain given that bone marrow involvement by follicular lymphoma is classically associated with paratrabecular aggregates. This pattern can help distinguish LPL from mimics such as splenic marginal zone lymphoma that share similar morphology and immunophenotype in the bone marrow but more consistently form non-paratrabecular nodular aggregates.28 (Table 2)

The cellular milieu of LPL lesions has been well characterized but can vary across patient samples. The lymphoid proliferations are frequently associated with scattered, mature, round, mast cells that contribute to B-cells signaling and proliferation via interactions between CD154 (CD40 ligand) on mast cells and CD40 on LPL B-lymphocytes.29 Scattered hemosiderin laden macrophages may also be seen.30 This constellation of morphologic findings can help distinguish LPL from multiple myeloma.

The lesional cells demonstrate a non-specific B-cell and plasma cell immunophenotype but should demonstrate immunoglobulin light chain restriction. Most LPL cells lack expression of CD5 and CD10, though either marker may be present in up to 10–20 % of LPL cases and can make distinguishing these lesions from other low-grade B-cell lymphomas with plasmacytic differentiation a challenge. The mature B-cell component should express B-cell antigens CD19, CD20, PAX5 and CD22. The neoplastic plasmacytic component should express mature plasma cell markers CD19, CD38, CD45, CD138, MUM1, and typically lack aberrant CD56 expression (Fig. 2). Retained expression of CD19 and CD45 can help distinguish LPL plasma cells from multiple myeloma. The plasmacytoid B-cells typically demonstrate retained but diminished expression of mature B-cell antigens CD20, CD22, PAX5, CD19, and variable expression of CD38 and MUM1. Broad B-lineage antigens CD19 and CD79a can help highlight the spectrum of LPL cells, including the neoplastic plasma cells (Fig. 4).

Myeloid differentiation factor 88 gene (MYD88) hotspot activating mutation MYD88 p.L265P is present in ∼90 % of LPL/WM and is a useful diagnostic target that can aid in distinguishing LPL from other BCL-SM.31 It can also aid in distinguishing LPL from MM, which typically lack MYD88 p.L265P. Other MYD88 non-L265P mutations have also been reported in LPL. Loss of function mutations affecting the C-X-C chemokine receptor type 4 gene (CXCR4) are detected in 27–36 % of LPL, are less common in other BCL-SM and plasma cell neoplasms, and are associated with resistance to ibrutinib therapy.30,32

Marginal zone lymphoma (MZL) subtypes include extranodal MZL of mucosa-associated lymphoid tissue (MALT), nodal MZL, splenic MZL (SMZL), primary cutaneous MZL, and pediatric nodal MZL. For the interest of this review, the emphasis will be on MALT lymphoma and splenic MZL which share the most clinical overlap with multiple myeloma and other low-grade B-cell lymphomas with plasmacytic differentiation. Nodal marginal zone lymphoma with plasmacytic differentiation can mimic multiple myeloma with lymph node involvement when there is a prominent plasma cell component, though true plasma cell neoplasms are infrequently limited to lymph nodes at presentation and should prompt an evaluation to rule out a B-cell lymphoma.

Splenic MZL shares the most morphologic and immunophenotypic similarities with LPL compared to other low-grade B-cell lymphomas with plasmacytic differentiation and may demonstrate similar diagnostic challenges in distinguishing it from multiple myeloma. SMZL frequently involves the spleen, bone marrow, peripheral blood, and splenic hilar lymph nodes. At initial bone marrow evaluation, a prominent plasmacytic component of SMZL may suggest involvement by a plasma cell neoplasm. However, morphologic features in the bone marrow that favor SMZL over a true plasma cell neoplasm or LPL are the presence of nodular interstitial lymphoid aggregates and intrasinusoidal distributed lymphoid cells, which are not expected in multiple myeloma, whereas paratrabecular aggregates are more common in LPL. Though not entirely specific, few to absent mast cells favor MZL over LPL.28 Small to medium-sized lymphocytes with abundant pale eosinophilic cytoplasm with monocytoid morphology (“monocytoid lymphocytes”) can aid in rendering a MZL diagnosis when present. Plasmacytic differentiation has been reported in 20–70 % of SMZL.33 The neoplastic B-lymphocytes in SMZL have a non-specific immunophenotype that are CD19(+), CD20(+), CD79a(+), CD5(-), CD10(-), CD23(-), LEF(-), Cyclin D1(-), BCL2(+), and BCL6(-). The SMZL B-cells frequently lack expression of CD43 and express surface IgM and IgD. The plasmacytic component is expected to retain expression of CD19 and CD45, but lack expression of CD56 that is often seen in MM. Mutations in KLF2 and NOTCH2 in SMZL, occur in ∼40 % and 6–25 % of cases, respectively and can aid in the diagnosis when considering plasma cell neoplasms and other low-grade B-cell lymphomas in the differential diagnosis.34

Extranodal MZL (MALT) arise in extranodal sites such as the gastrointestinal tract, salivary glands, and lungs that can demonstrate plasmacytic differentiation and may show some overlapping features with plasmacytoma and extramedullary multiple myeloma, including production of AL-amyloid (Fig. 5). MALT lymphomas are associated with chronic inflammatory conditions, including chronic infection (i.e., Helicobacter pylori gastritis in the stomach) and autoimmunity (i.e., Sjogren syndrome in salivary glands). These clinical associations can help aid in the diagnosis of challenging MALT lymphomas when there is a prominent plasmacytic component, particularly in small/limited biopsies. The neoplastic B-lymphocytes show morphologic and immunophenotypic overlap with other marginal zone lymphomas, including SMZL as described above. Unlike SMZL, aberrant expression of CD43 can be expressed in up to ∼50 % of MALT that can aid in the diagnosis, but also poses a diagnostic challenge when plasma cell neoplasms are considered in the differential diagnosis because plasma cells can also express CD43.35,36 Several chromosomal rearrangements have been described in MALT lymphoma involving MALT1 (18q21), BIRC3 (11q21), BCL10 (1p22), and FOXP1 (3p13) that can help distinguish MALT lymphomas from plasma cell neoplasms and other lymphomas.37

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with plasmacytic differentiation is a well-recognized phenomenon, though rare with unclear etiology.30,38 Approximately 15 % of CLL/SLL express weak PRDM1/BLIMP1, a key regulator of B-cell differentiation that is expressed in plasma cells and CLL/SLL immunoglobulin-secreting cells.39 In most instances, the differential diagnosis predominantly includes other B-cell lymphomas with plasmacytic differentiation as opposed to multiple myeloma, particularly when there is overt lymphocytosis.

The atypical B-cells are expected to demonstrate morphologic and immunophenotypic features of CLL/SLL in the majority of cells (Fig. 6). These features include lymphocytic morphology, proliferation center formation, expression of B-cell markers CD20 and PAX5, and aberrant expression of CD5 and LEF1. The plasmacytoid populations express CD5(±), LEF1(±), PAX5, MUM1, and shared light chain-restriction with the lymphoid population that is suggestive of a clonal relationship. The plasmacytoid cells lack usual plasma cell features such as CD138 positivity and may be associated with prior ibrutinib and venetoclax therapy for CLL/SLL.38 A mature clonally related plasma cell component can also be seen without a prominent plasmacytoid B-cell component (Fig. 6, Fig. 7). Key features to aid in distinguishing CLL/SLL with plasmacytic differentiation from multiple myeloma include lack of frank plasma cell neoplasm immunophenotypic aberrations and lack of CD138 expression on plasmacytoid populations when present. LEF1 expression and lack of MYD88 L265P mutation can aid in distinguishing CLL/SLL with plasmacytic differentiation from LPL and other B-cell lymphomas.30

Follicular lymphoma (FL) with plasmacytic differentiation, characterized by the presence of clonally related light chain-restricted plasmacytoid cells, is a rare phenomenon that accounts for <5 % of follicular lymphoma cases.40 Like normal germinal center B-cells, FL B-cells can demonstrate post-follicular maturation (plasma cells and memory B-cells) that down regulate expression of germinal center markers CD10 and BCL6. Two distinct types of follicular lymphoma with plasmacytic differentiation have been described.41 One type shows typical FL morphology with t(14;18) IGH::BCL2, with post-follicular maturation of plasma cells distributed in interfollicular areas. The second type shows FL lacking t(14;18) IGH::BCL2, with plasma cells distributed in perifollicular and intrafollicular areas. In such cases, the neoplastic B-lymphocytes show variable expression of germinal center markers, including frequent lack of CD10 and retained BCL6 expression. In cases with BCL2 rearrangement, the aberration is expected in both CD138-positive plasma cells and CD138-negative lymphoid cell populations.

In most cases described in the literature, the predominant population are mature lymphocytes typical of follicular lymphoma with a smaller subset of light-chain restricted plasma cells. Typical multiple myeloma clinical presentation is not expected in the setting of FL with plasmacytic differentiation and nodal disease is expected. The neoplastic plasma cells in follicular lymphoma with plasmacytic differentiation should lack the common multiple myeloma aberrations (e.g., CD19-, CD45-, CD56+).41 Rare cases have been reported of FL with plasmacytic differentiation that initially presented with numerous light chain-restricted plasma cells on initial iliac crest biopsy that was originally misdiagnosed as a plasma cell neoplasm, but ultimately showed FL with plasmacytic differentiation on subsequent lymph node biopsy.41

Most MCL are thought to arise from pre-germinal center naïve B-cells that localize to primary lymphoid follicles and mantle zones of B-cells that harbor t(11;14)(q13;q32) CCND1::IGH. MCL with plasmacytic differentiation has been reported in few case reports and small case series. Most cases present with typical MCL pathology such as nodal involvement by neoplastic small lymphocytes with nodular and mantle-zone growth patterns.23 Clonal plasma cells are expected in MCL with plasmacytic differentiation to be present in clusters within tumor nodules and within reactive germinal centers. The lymphoma B-cells and plasma cells are clonally related and harbor t(11;14)(q13;q32) CCND1::IGH.

In the era of targeted therapy (e.g., monoclonal antibodies, CAR-T, bispecific T-cell engager, etc.), diagnostic challenges may arise when B-cell directed agents are utilized, especially in follow-up samples. In patients with B-cell lymphomas with plasmacytic differentiation who are treated with agents such as anti-CD20 (e.g., rituximab, obinutuzumab, etc.) following initial diagnosis may have limited effects on the plasmacytic component (Fig. 7). At follow-up, samples may only show residual neoplastic, CD19(+), light chain-restricted plasma cells that can mimic a plasma cell neoplasm. Careful review of clinical history and immunophenotype is important in order to render an accurate diagnosis, particularly if the patient is new to your practice following prior diagnosis and therapy. These plasma cells are expected to lack aberrant biomarker expression typically seen in multiple myeloma as previously described (Fig. 2).