How I diagnose B-cell lymphoproliferative disorders with plasmacytic differentiation

Abstract

Objectives

B-cell lymphomas with plasmacytic differentiation is a broad category that includes small and large B-cell lymphomas. In this review, we focus on the small B-cell lymphomas, which include lymphoplasmacytic lymphoma and marginal zone lymphomas, among others. We aimed to review the diagnostic criteria of each entity and the features that distinguish them from each other.

Methods

We discuss the clinical presentation, morphology, immunophenotype, molecular features, and potential pitfalls of diagnosing B-cell lymphomas with plasmacytic differentiation and provide 2 illustrative cases.

Results

In some instances, small B-cell lymphomas with plasmacytic differentiation, particularly lymphoplasmacytic lymphoma and certain marginal zone lymphomas, have overlapping morphologic and immunophenotypic features. As a result, differentiating them may be difficult.

Conclusions

In cases where classification is challenging, integration with clinical, radiologic, and laboratory findings may be helpful in arriving at a specific diagnosis. Instances remain, however, in which classification is difficult.

Defining B-Cell Lymphomas With Plasmacytic Differentiation

B-cell lymphomas with plasmacytic differentiation encompasses a variety of entities, including small and large B-cell lymphomas. In fact, most small B-cell lymphomas can show plasmacytic differentiation, although it is rare in entities such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), or follicular lymphoma (FL). This review focuses on B-cell lymphoproliferative disorders with small cell morphology, particularly lymphoplasmacytic lymphoma (LPL) and marginal zone lymphoma (MZL), and discusses potential pitfalls and diagnostic challenges. A differential diagnosis and general diagnostic algorithm is illustrated in FIGURE 1.

Case Presentations

Case 1

A 65-year-old man presented with fevers, night sweats, and weight loss. Complete blood cell count results revealed a white blood cell count of 45.02 ×10³/µL (reference range, 4.23-9.07 ×10³/µL), a hemoglobin level of 12 g/dL (reference range, 13.7-17.5 g/dL), a hematocrit level of 37.1% (reference range, 40.1%-51%), a mean corpuscular volume of 87.3 fL (range, 79.0-92.2 fL), and a platelet count of 123 ×10³/µL (reference range, 163-337 ×10³/µL). On manual differential diagnosis, testing revealed 9% polys, 0% bands, 85% lymphocytes, 5% monocytes, 0% eosinophils, and 0% basophils. The lactate dehydrogenase level was elevated, at 422 U/L (reference range, 100-190 U/L). There was clinical concern for an aggressive B-cell lymphoma. Positron emission tomography/computed tomography imaging revealed mildly ¹⁸F-fludeoxyglucose avid lymph nodes in the neck, chest, and abdomen and a hypermetabolic spleen. Peripheral blood flow cytometry revealed a monoclonal κ population of B lymphocytes that was negative for CD5 and CD10.

A bone marrow study was performed. Morphologic findings from review of peripheral blood smear and bone marrow histologic sections are shown in FIGURE 2. Flow cytometric analysis of bone marrow showed that B cells represented 91% of lymphocytes (65% of analyzed cells) and expressed CD19 and CD20 (moderate) and were essentially negative for CD5, CD10, and CD23, with weak cytoplasmic surface κ expression. Cytogenetic studies revealed deletion of 6q and t(9;14)(p13;q32.3). No rearrangements of BCL6, MYC, IGH::BCL2, or BIRC::MALT1 were detected. Next-generation sequencing revealed MYD88 L265P (27.4% variant allele frequency) and POT1 R80H (25.4% variant allele frequency) pathogenic variants.

Case 2

A 58-year-old woman with a medical history of irritable bowel syndrome, Raynaud phenomenon, and worsening chronic normocytic anemia presented with dyspnea on exertion. Vitamin B₁₂ and folate levels were within normal limits. Gastrointestinal endoscopy and colonoscopy were unrevealing. Additional labs revealed an immunoglobulin M (IgM) level above 5000 mg/dL (reference range, 45-281 mg/dL), elevated free κ light chains at 35.08 mg/dL (reference range, 0.33-1.94 mg/dL), a κ/λ free light chain ratio of 28.29 (reference range, 0.26-1.65), an M-spike of 3.4 g/dL, and serum viscosity at 2.7 (reference range 1.5-1.9). Computed tomographic scanning of the chest, abdomen, and pelvis showed no evidence of mediastinal, hilar, or axillary lymphadenopathy or splenomegaly. The complete blood cell count showed a white blood cell count of 5.2 ×10³/µL (reference range, 4.0-10.5 ×10³/µL), a hemoglobin level of 8.3 g/dL (reference range, 12.5-16.0 g/dL), a hematocrit level of 26.7% (reference range, 37%-47%), a mean corpuscular volume of 82.4 fL (reference range, 78-100 fL), and a platelet count of 237 ×10³/µL (reference range, 150-450 ×10³/µL). On differential diagnosis, testing revealed 39% neutrophils, 45.2% lymphocytes, 13.5% monocytes, 0.8% eosinophils, and 0.2% basophils.

A bone marrow biopsy was then performed; the histology with immunohistochemistry (IHC) is shown in FIGURE 3. Flow cytometric analysis of the bone marrow revealed monoclonal B cells, with expression of CD19, CD20, partially CD38, and κ light chain restriction; testing was negative for CD5 and CD10; and there were monoclonal plasma cells with expression of CD38, CD19, CD45, and cytoplasmic κ light chain restriction. Cytogenetic studies revealed a normal karyotype, and fluorescence in situ hybridization studies for CCND1::IGH t(11;14) were negative. Single-gene sequencing assays did not detect pathogenic variants in MYD88 or CXCR4.

Clinical Features

Commonly encountered entities of B-cell lymphomas with plasmacytic differentiation are LPL and MZLs, which are the focus of this review. Mantle zone lymphoma encompasses 3 subtypes: extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma), nodal MZL, and splenic MZL. In the sections that follow, both LPL and MZLs are compared and contrasted in terms of their clinical features, morphology and immunophenotype, and molecular features. Other lymphoproliferative disorders with a plasmacytic component are discussed in the differential diagnosis of LPL and MZL.

Lymphoplasmacytic lymphoma is related to Waldenstrom macroglobulinemia, which is defined as the presence of an IgM paraprotein and bone marrow involvement by LPL. Lymphoplasmacytic lymphoma predominantly affects the bone marrow and can be asymptomatic in its early phases. Less commonly, it can also involve lymph nodes and the spleen. Lymphoplasmacytic lymphoma is typically associated with an IgM paraprotein and can also present with elevated serum free light chains. Symptoms may be related to the IgM monoclonal component, including hyperviscosity (ie, vision or sensory changes) or bleeding as a result of interruption of platelet and clotting factor function. The IgM paraprotein can precipitate in the cold, leading to cryoglobulinemia; associated symptoms include skin manifestations, such as acrocyanosis, Raynaud phenomenon, purpura, and livedo reticularis. Neurologic symptoms, such as peripheral neuropathy with paresthesias, are also seen and may be due to IgM acting as an autoantibody against myelin-associated glycoprotein. In rare cases of LPL, there may be a non-IgM paraprotein or even no paraprotein at all.

In contrast, the various types of MZLs (ie, extranodal, nodal, splenic) have distinct clinical manifestations. Marginal zone lymphoma, particularly MALT lymphoma, is classically associated with chronic inflammation and autoimmune disorders. In the stomach, MALT lymphoma is associated with chronic Helicobacter pylori infection, while involvement of the salivary glands or thyroid is associated with Sjogren syndrome or Hashimoto thyroiditis, respectively.¹ Extranodal MZL can present in nearly any anatomic location, with the presentation generally related to the site of involvement—for instance, epigastric pain or diarrhea in the case of gastrointestinal involvement. Nodal MZL can exhibit a variety of clinical manifestations and can be asymptomatic, with painless lymphadenopathy; classically, the head and neck lymph nodes are involved.² Splenic MZL involves the spleen, leading to splenomegaly, and can present with cytopenias and symptoms related to splenomegaly; lymph nodes local to the spleen, bone marrow, and peripheral blood can also be involved. Lymphocytosis is uncommon in extranodal and nodal MZL, while lymphocytosis is often seen in splenic MZL.

Clinicopathologic integration is often important in distinguishing the MZLs and LPL; in particular, the level of serum paraprotein, splenomegaly, and lymphadenopathy are all helpful features. Multistation lymphadenopathy would be more in keeping with nodal MZL, and marked splenomegaly would also be more fitting with a splenic MZL. Although MZL can have a monoclonal gammopathy, it is typically at lower levels,³ and the presence of a significant IgM serum paraproteinemia in concert with the associated symptoms described above (ie, bleeding diathesis, neuropathy, hyperviscosity) would be more suggestive of LPL. Proposals for a serum paraprotein level cutoff to distinguish LPL from other lymphomas have ranged from as high as 3 g/dL down to 1.5 g/dL.^4,5 A survey of 356 patients with Waldenstrom macroglobulinemia revealed IgM levels ranging from 0.3 to 12 g/dL (median, 2.6 g/dL).⁶

Morphology and Immunophenotype

The morphologic architecture in both bone marrow and lymph node, in conjunction with the immunophenotype, can be diagnostic of a specific B-cell lymphoma with plasmacytic differentiation FIGURE 4. In difficult cases, integration with clinical findings (discussed earlier) or other ancillary studies (discussed later) are needed. Careful note should be made of architectural features (ie, diffuse pattern of involvement in lymph nodes; paratrabecular or intrasinusoidoidal distribution in bone marrow). Immunohistochemical panels vary with practice and should be informed by flow cytometric findings, when available.

In LPL, the bone marrow infiltrate is composed of B cells, often with plasmacytoid morphology, and plasma cells. The infiltrate is characteristically nonparatrabecular and interstitial in a diffuse pattern. Nodular aggregates may be seen, although they are uncommon in LPL. Additional supporting features include the presence of Dutcher bodies, mast cells associated with lymphoplasmacytic proliferation, and hemosiderin deposition. In the setting of lymph node involvement, the appearance of LPL can be variable; typically, there is preservation of normal architecture with patent sinuses, but architectural effacement by a vague nodular growth pattern can also be seen. There is no single defining immunohistochemical marker for LPL. The clonal B cells are typically negative for CD5 and CD10. Immunohistochemistry or in situ hybridization for κ and λ light chains will reveal light chain restriction of the plasma cell component and often the B cells, as well. By flow cytometry, the immunophenotype of B cells in LPL typically is positive for CD19, CD20, CD22, and CD38 and negative for CD5, CD10, and CD23(1). Flow cytometry is useful in establishing the clonality of B lymphocytes and plasma cells; both the B cells and plasma cells will show the same light chain restriction in LPL.

As in LPL, the clonal B cells of MZL are negative for CD5 and CD10. In MZL (particularly nodal and splenic forms), the bone marrow infiltrate typically shows an interstitial or intertrabecular nodular distribution, while splenic MZL can also show an intrasinusoidal infiltrate (eg, within vessels highlighted by CD34 IHC). A notable finding in splenic MZL is the presence of polar villous lymphocytes in peripheral blood FIGURE 2A. An important characteristic feature to recognize in MZL is the presence of pale-appearing areas due to the presence of monocytoid B cells.^7,8 In the setting of lymph node involvement, nodal MZL can also show a range of morphologic architecture, displaying diffuse (most common), nodular, parafollicular, or even perifollicular patterns of involvement. Nodal MZL also often shows follicular colonization, where IHC can highlight BCL2-positive, CD10-negative, and BCL6-negative cells (characterized by obscured mantle zones and a “moth-eaten” appearance of follicles). Marginal zone lymphoma also involves expanded or disrupted follicular dendritic cell meshworks, highlighted by CD21. Although MZL is typically composed mainly of small and medium-sized lymphoid cells, occasional large cells are often admixed, and the appearance is more polymorphous than in LPL. Although MZL may show a similar immunophenotype to LPL by many flow cytometric panels, by IHC, myeloid nuclear differentiation antigen and immune receptor translocation-associated protein 1 have emerged as markers that are positive in the majority of nodal MZL cases.^9,10 Caution should be exercised, though, given that data regarding their specificity are still somewhat limited, and a minority of LPLs have also been reported to express MDNA.¹¹ Of note, myeloid nuclear differentiation antigen can also highlight primary follicles.¹²

Conventional Cytogenetic Analysis

Many B-cell lymphomas with plasmacytic differentiation show abnormal karyotypes, although in most cases they are not specific. Studies examining a large cohort have reported that LPL tends to show more alterations, with a more complex karyotype than MZLs.¹³ Lymphoplasmacytic lymphoma and MZLs can all exhibit gains of chromosomes 3, 12, and 18 and loss of 6q23-24. Copy number alterations involving loss of 17p13 have been reported in up to 23% of LPL cases and splenic MZL cases and were not detected in either nodal or extranodal MZL cases; 7q deletion is seen in up to 40% of splenic MZL cases. The t(11;18)(q21;q21); API2::MALT1 translocation is strongly associated with gastric extranodal MZL.¹³ Extranodal MZL involving the lung is also associated with the t(11;18) translocation and has been reported to have the t(14;18)(q32;q21); IGH::MALT1 and t(1;14)(p22;q32); IGH::BCL10 translocations, although the latter translocation is rare.^14,15 Fluorescence in situ hybridization probes are available for most of the genes, making interphase fluorescence in situ hybridization on paraffin-embedded tissue a suitable (and in some cases the only) alternative to conventional karyotype.

Molecular Testing

The discovery of the MYD88 L265P pathogenic variant in more than 90% of LPL cases¹⁶ and development of clinical assays for its detection³ were major advances in the diagnosis of LPL. The detection of the MYD88 L265P variant is a key differentiating feature in the diagnosis of LPL,^2,17 but it has been reported in up to 15% of splenic MZL cases, rarely in nodal MZL cases, and up to 3% of CLL/SLL cases.¹⁸ Thus, although the presence of MYD88 L265P is helpful, it should be interpreted carefully, especially as studies have shown that it does not necessarily define a unique entity, even among B-cell lymphomas with plasmacytic differentiation primarily involving bone marrow with IgM paraprotein.¹⁹ Moreover, cases of LPL without the MYD88 variant, although rare, do occur and can present a diagnostic challenge, as discussed later. CXCR4 variants are also seen in LPL and are typically present with an MYD88 L265P variant.²⁰ The MYD88 L265P variant can be detected in peripheral blood and bone marrow samples with high sensitivity through a single-gene digital droplet polymerase chain reaction assay.²¹ Such assays may offer greater advantages over next-generation sequencing assays in terms of cost and sensitivity.²²

Beyond the MYD88 L265P variant, other molecular findings may be useful in the diagnosis of B-cell lymphoproliferative disorders with plasmacytic differentiation. The detection of NOTCH2 and KLF2 pathogenic variants has been reported in up to 25% of splenic MZL cases, and these variants were not found in LPL.²³ In the diagnosis of extranodal MZL, reactive lymphoid hyperplasia can be in the differential; IgH clonality studies can be helpful in some cases but could pose a potential pitfall because up to 13% of non-neoplastic, reactive cases of gastritis can show clonal rearrangements.²⁴

Diagnostic and Interpretive Challenges

Challenges in precisely classifying B-cell lymphoproliferative disorders with plasmacytic differentiation occur when classic or typical features are not present. In particular, distinguishing LPL from nodal MZL can be difficult, especially when no MYD88 L265P variant is detected. MYD88-negative (MYD88 wild-type) LPLs do occur but are uncommon (up to 10% of cases). Diagnostic pitfalls can occur with incomplete clinicopathologic correlation. In particular, the level of paraprotein, presence of symptoms related to paraproteinemia (ie, hyperviscosity syndrome), and presence of lymphadenopathy should be assessed before arriving at a final diagnosis to avoid misdiagnosing an LPL for a nodal or extranodal MZL, for example. If MYD88 is wild type and paraproteinemia is either absent or small or the patient has varying degrees of lymphadenopathy (can be “reactive-appearing” on the imaging studies), then MZL should be favored, even if substantial plasmacytic differentiation is noted. Distinguishing between an extranodal MZL of MAST type and LPL can also be challenging, particularly because the former can show marked plasmacytic differentiation and clonal plasma cells with Dutcher bodies. The presence of high IgM paraproteinemia and bone marrow involvement would be more in keeping with LPL. It is also worth noting that although LPL is usually negative for CD5 and CD10, there are uncommon cases of CD5 positivity, which could be confused for CLL/SLL. In these cases, the detection of an MYD88 pathogenic variant and the histomorphology, as discussed earlier, should aid in the diagnosis.

Other diagnostic pitfalls can occur with lymphoproliferative disorders that exhibit a marked degree of plasmacytoid cytomorphology, where there are several possibilities. There may be involvement by a small B-cell lymphoma with plasmacytic differentiation, a plasma cell neoplasm, or—in rare cases—concurrent involvement by both a B-cell lymphoproliferative disorder and a plasma cell neoplasm. In such instances, the immunophenotype can guide diagnosis FIGURE 5. Plasma cell neoplasms are invariably negative for CD19, show dim or negative CD45, and often have aberrant expression of CD56 or CD117. CD79a staining is variable in plasma cell neoplasms, while CD38 can be positive in both mature B-cell lymphomas and plasma cell neoplasms. Of note, CD20 can be positive in plasma cell neoplasms with t(11;14)(q13;q32); IGH::CCND1 rearrangement (which can show plasmacytoid morphology and have no clonal CD20-positive B cell component),^25,26 which can be useful in distinguishing it from LPL, where CD20 is usually negative in the plasma cell component. Here, flow cytometric analysis can be helpful by gating on background lymphocytes (low side scatter vs bright CD45); these lymphocytes should be polytypic, in contrast to the monotypic B cells seen in LPL FIGURE 6. This approach may also be helpful in differentiating plasma cell neoplasms from MCL if the plasma cells happen to be positive for CD20 and show a lymphocytic morphology. Studies have shown the utility of CD19 and CD56 as well in differentiating a plasma cell neoplasm from neoplastic plasma cells within a B-cell lymphoma: The latter will typically express CD19 and CD45 but not CD56, while plasma cell myeloma is typically negative for CD19 and CD45 but often positive for CD56.²⁷

Questions for the Expert

1. Are there small B-cell lymphomas other than LPL and MZL to consider when plasmacytic differentiation is seen?

Virtually all commonly encountered small B-cell lymphomas—in particular, CLL/SLL, MCL, and FL—have been reported to show plasmacytic differentiation, although it is uncommon. In particular, plasmacytic differentiation is rare in FL and extremely rare in MCL. These categories have distinct immunophenotypes; thus, integration with IHC or flow cytometry as well as genetic findings should help differentiate among these categories. In the spleen, splenic diffuse red pulp small B-cell lymphoma often shows plasmacytic differentiation and is characterized by involvement of the red pulp with a monotonous population of plasmacytoid lymphocytes and atrophy of the white pulp.

1. Are there histologic or molecular findings in B-cell lymphomas with plasmacytic differentiation that are prognostically significant?

Although LPL and MZL are generally considered indolent lymphomas, histologic transformation to a more aggressive lymphoma, such as diffuse large B-cell lymphoma, can uncommonly occur. MYD88–wild-type LPL may portend a more aggressive course with worse clinical outcome. Generally no histologic or molecular features are predictors for large cell transformation, however, although recent studies have suggested that the presence of increased large cells in MZL may portend a higher risk of transformation,²⁸ and more studies are needed. Established prognostication indices for MZL and LPL are all generally based on clinical findings. Of note, the presence of a CXCR4 pathogenic variant with an MYD88 L265P variant confers greater resistance to ibrutinib treatment than having the MYD88 L265P variant alone.^28,29

1. What are the differences in clinical management between MZL and LPL?

The treatment for either MZL or LPL is often influenced by symptomatic severity and extent of disease. Radiation therapy for nodal MZL can be offered if disease is localized, or rituximab with or without bendamustine can be considered if symptoms are more pronounced. Symptomatic LPL can in some instances also be treated with rituximab plus bendamustine, but many other chemotherapy regimens are available. In particular, ibrutinib has proven effective for Waldenstrom macroglobulinemia through targeting of Bruton tyrosine kinase, which drives pro-survival signaling in the setting of an MYD88 L265P variant.³⁰ More recently, the newer-generation Bruton tyrosine kinase inhibitor zanubrutinib has been approved for Waldenstrom macroglobulinemia, with an improved side effect profile compared with ibrutinib. Zanubrutinib is also approved for patients with relapsed/refractory MZL who received another anti-CD20 therapeutic agent.³¹

Case Diagnosis

1. The core biopsy showed a lymphocytic infiltrate (80% of total cellularity) composed predominantly of CD20-positive B cells in an interstitial and nodular pattern, with mildly irregular nuclei, condensed chromatin, indistinct nucleoli, and scant amphophilic cytoplasm. Admixed are rare CD138-positive, MUM1-positive plasma cells that show monotypic expression of IgM FIGURE 7. The remaining background bone marrow was unremarkable. The finding of a clonal, CD5-negative, CD10-negative B-cell population with an MYD88 L265P pathogenic variant raised the possibility of LPL, but several features, including the architecture of the lymphocytic infiltrate in an interstitial, nodular pattern, as well as little to no plasmacytic differentiation would be unusual for LPL. Notably, there is marked lymphocytosis, with circulating atypical lymphocytes with occasional cytoplasmic villi. In the context of the imaging findings, the morphologic and immunophenotypic findings taken together were more in keeping with splenic MZL than LPL. Of note, an MYD88 L265P variation was not specific for LPL and can be uncommonly seen in other B-cell lymphomas, including MZL. The reported findings of a POT1 pathogenic variant and t(9;14)(p13;q32.2) were nonspecific and can be seen in other low-grade B-cell lymphomas. This translocation is a rare recurrent cytogenetic abnormality exclusively detected in B-cell neoplasms and involves rearrangement of the PAX5 and IGH genes. Unlike the other 14q32 rearrangements, no fusion gene is created by the translocation, and the genomic rearrangement leads to forced PAX5 expression. Additional workup, including serum protein electrophoresis (not available for review), would have been helpful to evaluate for a paraprotein. Because of clinical concern for an occult transformation to an aggressive B-cell lymphoma, the patient received rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, and prednisone chemotherapy, which was well tolerated, and the patient has had no evidence of disease to date following completion of therapy.

2. The presence of both a clonal CD5-negative, CD10-negative B-cell population and a clonal plasma cell population raises a differential diagnosis of LPL and an MZL. The core biopsy showed a lymphoplasmacytic infiltrate composed of plasma cells (60% of total cellularity) that were highlighted by CD138, MUM1, and IgM and were negative for CD20, cyclin D1, CD117, and CD56. In addition, the infiltrate included CD20-positive, PAX5-positive B lymphocytes (20% of total cellularity) that formed discrete, nonparatrabecular aggregates. The background bone marrow was unremarkable. The nonparatrabecular B-cell aggregates are less commonly seen in LPL but can occur and are not specific to MZL. Dutcher bodies and mast cells are often seen in LPL. Of note, approximately 10% of LPL cases are negative for MYD88 variation; therefore, the variation’s absence does not rule out LPL. The imaging findings showed no lymphadenopathy or splenomegaly, which also makes MZL less likely. In the context of a high IgM paraprotein level, serum viscosity, and the history of Raynaud phenomenon, the overall findings raise the possibility of classification as LPL. The morphologic features (robust plasma cell infiltrate making up the majority of the bone marrow space with discrete, multifocal, nonparatrabecular aggregates of B cells, including larger forms) are quite atypical, however, as is the absence of an MYD88 L265P variation. Alternative considerations other than MZL include 2 distinct processes (B-cell lymphoma and plasma cell neoplasm), although there are no plasma cells markers typical of plasma cells in multiple myeloma (eg, cyclin D1, CD20, CD56, CD117), making this diagnosis less likely. Clinically, the patient was deemed to have LPL and responded well to treatment with rituximab and bendamustine but relapsed 1 year later and is currently being treated in a clinical trial. In difficult cases such as this one, it may be best to provide a descriptive top-line diagnosis (ie, extensive involvement by κ-restricted plasma cells and multiple aggregates of κ-restricted B cells) and discuss the differential diagnosis.

Conclusions

The entities that make up B-cell lymphoproliferative disorders with plasmacytic differentiation often have characteristic morphologic, immunophenotypic, and molecular features that distinguish them. It is not uncommon in practice, however, to encounter cases where 1 or several of the features are atypical or do not neatly fit into a classic presentation. In this review, we have discussed the clinical presentation, morphology, immunophenotype, and molecular features of commonly encountered B-cell lymphomas with plasmacytic differentiation—in particular, MZL and LPL. We have emphasized the importance of clinicopathologic integration, especially in cases with an atypical or nonclassic presentation. We have also discussed cases that illustrate the concept of understanding B-cell maturation in classifying B-cell lymphomas with plasmacytic differentiation and navigating the difficulty encountered at times in the differential diagnosis between MZL and LPL. For challenging cases where precise classification is difficult, providing a general top-line diagnosis of B-cell lymphoma with plasmacytic differentiation, followed by a note discussing the differential diagnoses, can be considered. Continuing research on the molecular and genetic mechanisms of these entities may lead to the discovery of biomarkers that may 1 day better assist with classifying B-cell lymphomas with plasmacytic differentiation.

Conflict of Interest Disclosure

The authors have nothing to disclose.

Funding

None.

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References