Lymphoplasmacytic lymphoma (LPL) is a low-grade, B-cell neoplasm composed of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that typically involve the bone marrow, and it is associated with an immunoglobulin M (IgM) gammopathy. The definition of Waldenström macroglobulinemia (WM) and its relationship to LPL has been confusing in the past. In addition, the diagnosis of LPL itself can be challenging because LPL lacks disease-specific morphologic, immunophenotypic, and genetic features to differentiate it from other mature B-cell neoplasms. Accurate diagnosis of LPL/WM rests on recognition of the differential diagnostic features between LPL and other diagnostic possibilities and the use of the recently refined definition of WM and its relationship with LPL: The presence of an IgM monoclonal gammopathy of any level in the setting of bone marrow involvement by LPL. This review summarizes the clinical, laboratory, and histologic features of LPL/WM, with particular emphasis on unique aspects of LPL/WM that may aid in accurate diagnosis.
Lymphoplasmacytic lymphoma (LPL) is a chronic, lymphoproliferative neoplasm characterized by small B lymphocytes, plasmacytoid lymphocytes, and plasma cells typically involving the bone marrow, lymph nodes, and spleen. The 2008 World Health Organization criteria for classification of hematologic diseases characterizes Waldenström macroglobulinemia (WM) as a subset of LPL that has a detectable level of monoclonal immunoglobulin (Ig) M gammopathy, with bone marrow involvement by LPL.1,2 Waldenström macroglobulinemia was originally described in 1944 by Jan G. Waldenström, MD, DSc, who reported on 2 patients with oronasal bleeding, anemia, lymphadenopathy, hypergammaglobulinemia, an elevated sedimentation rate, hyperviscosity, normal bone survey, cytopenias, and bone marrow involvement by a predominantly lymphoid infiltration.3 Although most cases of LPL are WM, there are exceptions where the diagnosis of WM does not apply. Examples are rare, primary, lymph node-based presentations of LPL or lymphoplasmacytic B-cell proliferations in the bone marrow associated with IgA or IgG gammopathies.
Lymphoplasmacytic lymphoma/WM is a rare disease, with an annual incidence of 3 to 4 cases per million people, most commonly affecting older, white men.2,4,5 Infiltration of the bone marrow and extramedullary sites, such as lymph nodes, spleen, and liver, by malignant B cells and elevated IgM levels contribute to symptoms associated with pancytopenia, organomegaly, and hyperviscosity. Most patients are either asymptomatic or present with anemia; presenting with symptoms of hyperviscosity is uncommon.6 In rare instances, diffuse lymphoplasmacytic infiltration of the lung, stomach, or bowel may occur. Associated with rare cases of WM is a clinical presentation of diffuse urticaria and IgM paraproteinemia called Schnitzler syndrome. Characteristic symptoms of hyperviscosity syndrome include mucosal bleeding, visual disturbance, and headache. More severe neurologic manifestations include mental confusion, focal neurologic deficits, and stroke. Hyperviscosity syndrome occurs in up to 30% of patients, with symptoms of hyperviscosity usually appearing when the reference range serum viscosity of 1.4 to 1.8 cP reaches 4 to 5 cP (corresponding to a serum IgM level of at least 3.0 g/dL).7,8 The paraprotein may also have autoantibody or cryoglobulin activity resulting in autoimmune phenomena or cryoglobulinemia. The deposition of IgM can lead to peripheral neuropathies and renal impairment. Most cases of LPL are WM with an IgM paraprotein, however, a few cases are IgA-secreting, IgG-secreting, or nonsecreting LPL. Symptoms can vary considerably among individual patients, and many patients are asymptomatic at diagnosis.
Cell counts in patients with LPL/WM typically demonstrate mild anemia and thrombocytopenia. Severe thrombocytopenia is usually only encountered late in the disease course. Characterization of the paraprotein is essential in the laboratory workup of LPL/WM. Serum protein electrophoresis, typically represented by a densitometry tracing of the pattern, should demonstrate a monoclonal immunoglobulin that is visualized as a peak (M-spike) in the γ-globulin region (Figure 1, A). Immunofixation is recommended to further characterize the type of heavy and light chain present (Figure 1, B). Densitometry of the M-spike can be combined with serum nephelometry to monitor IgM levels. Because of the unique physicochemical characteristics of paraproteins, different patients with the same IgM levels can have strikingly divergent viscosities. Most patients with LPL/WM are symptomatic when serum or whole-blood viscosity is above 3.0 and 8.0 cP, respectively.7,8 Measuring whole-blood viscosity is complex because the viscosity is affected by the hematocrit and does not behave as a Newtonian fluid, like serum or plasma, where viscosity is independent of flow rate. Accordingly, measurement of serum or plasma viscosity is preferred.9
Up to 80% of patients with LPL/WM will have monoclonal immunoglobulin light chains (Bence-Jones proteins) in the urine. Laboratory evaluation should include 24-hour urine collection for urine protein electrophoresis. Because of their correlation with clinical outcomes, levels of serum free light chains and β2 microglobulin should also be assessed.10,11
In the peripheral blood, anemia is the most common finding in symptomatic patients with LPL/WM. The anemia is probably multifactorial and may be due to the expansion of clonal cells in the bone marrow, increased plasma volume, reduced erythropoietin production because of hyperviscosity, and elevated levels of interleukin 6.12 The anemia is usually normocytic and normochromic, and rouleaux formation is often present in WM. Lymphocytosis may be present, and the circulating neoplastic cells are primarily small with condensed nuclear chromatin and inconspicuous nucleoli. A subset of plasmacytoid lymphocytes is usually present, characterized by eccentric nuclei and more-abundant basophilic cytoplasm (Figure 2, A).
In the bone marrow, the pattern of marrow infiltration may be diffuse, interstitial, or focal nonparatrabecular (Figure 2, B). A solely paratrabecular pattern of infiltration is unusual and should raise the possibility of follicular lymphoma.1 The bone marrow infiltrate of LPL is composed of small lymphocytes admixed with variable numbers of plasmacytoid lymphocytes and plasma cells (Figure 2, B and C). Increased mast cells are often present, and they may support the growth of LPL.13 Accumulation of cytoplasmic or pseudonuclear immunoglobulin in the plasma cells, known as Russell bodies and Dutcher bodies, respectively, are other typical findings (Figure 2, D).
In the lymph node, the classic pattern is that of a subtle, paracortical expansion of small lymphocytes associated with varying numbers of plasma cells, often demonstrating Dutcher bodies. Most lymphocytes are small with monocytoid, centroblastic, or immunoblastic lymphocytes comprising only a small subset of the neoplastic cells. This pattern does not typically efface the nodal architecture, leaving the sinuses intact, and is associated with small, benign B-cell follicles and hemosiderosis. Alternatively, nodal LPL can be associated with hyperplastic follicles and vaguely nodular or diffuse effacement of nodal architecture by the same population of small, mature lymphocytes associated with plasma cells. Epithelioid histiocytes can be abundant in this pattern.14 Most LPL cases demonstrate frank plasmacytic differentiation rather than only lymphoplasmacytoid cells. That said, other B-cell lymphomas, such as marginal zone lymphoma (MZL), follicular lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), and occasionally, mantle cell lymphoma, can also demonstrate frank plasmacytic differentiation. Overall, LPL in the bone marrow and lymph node is a diagnostic challenge, demonstrating a wide spectrum of findings that can overlap with other B-cell lymphomas with plasmacytic differentiation, and LPL needs to be approached as a diagnosis of exclusion. More details regarding diagnostic strategies are presented in the “Differential Diagnosis” section.
The typical immunophenotype of LPL demonstrates expression of CD19, CD20, CD22, FMC7, BCL2, CD38, and CD79a with monotypic surface light chain. Staining with CD5, CD10, and CD23 is usually absent.15 However, up to 20% of cases may express CD5, CD10, or CD23.16 Immunoglobulin light-chain restriction can usually be demonstrated in both the small lymphocytes and plasma cells on tissue sections by immunohistochemistry. The plasma cells in LPL have been reported to have a unique immunophenotype, when compared with plasma cells found in marginal-zone lymphoma or plasma cell myeloma, with coexpression of PAX5 and CD45 with CD19, respectively.17
The immunophenotypic profile of LPL/WM in combination with the presence of somatic mutations of genes in the immunoglobulin heavy-chain variable region without intraclonal diversity suggests that the malignant cells originate from cells at a late stage of differentiation derived from a B cell arrested after somatic hypermutation in the germinal center and before terminal differentiation to a plasma cell.18 The causes of LPL/WM are poorly understood; however, there are emerging data to support a role for immune-related and genetic factors in the etiology of LPL/WM. A few studies have reported evidence of frequent somatic immunoglobulin gene mutations, suggesting chronic antigen stimulation might play an etiologic role.19,20 Population-based studies from the United States have found autoimmunity and hepatitis C viral infection to be associated with an increased risk of developing WM,21,22 although that is not supported by other studies.23
GENETIC AND MOLECULAR FINDINGS
Like all B-cell neoplasms, the B cells in LPL have clonally rearranged immunoglobulin genes. Somatic hypermutation is present in more than 90% of LPL/WM cases, and biased use of the immunoglobulin heavy-chain variable region has been documented, suggesting antigenic selection is involved in the development of this mature B-cell lymphoma.24 Despite plasmacytic differentiation, there is evidence of deregulated transition of the LPL B cells to plasma cells with aberrant gene expression patterns and a lack of heavy-chain class switching in LPL.25 Earlier reports of the association of LPL/WM with t(9;14)(p13;q32) IGH/PAX5 have not been supported in more-recent studies.26,27 Recent interest has focused on the presence of 6q deletions, reported in up to 63% of LPL/WM.28 Although 6q deletion is relatively nonspecific, it may have an oncogenic role in LPL/WM, having been found to be associated with features of adverse prognosis, possibly via inactivation of negative regulators of the nuclear factor κB (NF-κB) signaling pathway.28,29 Similarly, a set of recent reports suggests that LPL may be dependent on constitutive NF-κB signaling, with a large proportion of LPL cases found to contain a somatic variant in the MYD88 gene that constitutively activates NF-κB. Interestingly, although 90% of LPL cases demonstrated that mutation, it was found in only 6% of MZL cases.30–32 The genetic abnormalities 13q− and trisomy 12, typically associated with CLL, are uncommon in LPL/WM. Trisomy 4, however, appears to be specific for LPL/WM and has been reported in 20% of cases.33
Accurate diagnosis of LPL/WM can be difficult because of the absence of specific morphologic, immunophenotypic, or chromosomal markers, making differentiation from other small B-cell lymphomas challenging. Additionally, with current criteria, there is diagnostic overlap among WM, IgM-monoclonal gammopathy of undetermined significance, and smoldering WM.
The 2008 World Health Organization criteria for classification of hematologic diseases characterizes WM as a subset of LPL that has a detectable level of monoclonal IgM gammopathy with bone marrow involvement by LPL.1,2 That definition overlaps with the diagnosis of IgM-monoclonal gammopathy of undetermined significance, which is characterized by a serum IgM paraprotein of less than 3 g/dL, less than 10% lymphoplasmacytic marrow infiltration, and an absence of the constitutional symptoms, anemia, hyperviscosity, lymphadenopathy, and hepatosplenomegaly.34 Cases with an IgM paraprotein of more than 3 g/dL and/or more than 10% marrow infiltration, but still without constitutional symptoms, symptomatic anemia, and hyperviscosity have been classified as smoldering WM.34 If patients are divided into symptomatic WM and asymptomatic WM, those with IgM-monoclonal gammopathy of undetermined significance have a 262-fold increased risk for the development of symptomatic WM, and patients with smoldering WM have a 55% risk of progression to symptomatic WM at 5 years.3,21,34
Lymphoplasmacytic lymphoma is a diagnosis of exclusion. The differential diagnosis includes mantle cell lymphoma, CLL/SLL, MZL, and plasma cell myeloma.
Differentiating LPL from MZL can be especially difficult because both are low-grade B-cell lymphomas that share the nonspecific CD5−/CD10− immunophenotype and lack disease-defining molecular-genetic markers. However, this may be changing with the recent discoveries of the MYD88 mutation in LPL and the finding that, unlike the plasma cells in MZL, some plasma cells in LPL aberrantly express PAX5.17 Marginal zone lymphoma is divided into 3 categories: (1) extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma), (2) splenic MZL, and (3) nodal MZL. Of the 3, differentiating LPL/WM from MALT lymphoma is probably the most straightforward. Typically, MALT lymphoma is not associated with a monoclonal gammopathy, and, conversely, extranodal involvement by LPL/WM, especially at sites such as the gastrointestinal tract and salivary gland favored by MALT lymphoma, is uncommon in LPL/WM. Histologically, distinguishing features of MALT lymphomas are lymphoepithelial lesions and “monocytoid” B cells.
Distinguishing LPL/WM from splenic MZL can be very challenging. Like LPL/WM, splenic MZL consistently involves the bone marrow and is often associated with an IgM paraprotein. To further complicate matters, splenic MZL frequently exhibits plasma cell differentiation. Accordingly, distinguishing LPL/WM from splenic MZL on a bone marrow biopsy alone can be virtually impossible, and histologic evaluation of the spleen may be necessary to confirm the diagnosis. The identification of circulating, villous lymphocytes, although frequently nonspecific, may add support for the diagnosis of splenic MZL.
Nodal MZL is more aggressive than MALT lymphoma and splenic MZL. Patients frequently have a disseminated presentation with multifocal adenopathy, bone marrow involvement, and an IgM gammopathy in up to one-third of cases but, by definition, lack extranodal or splenic involvement. Histologically, the findings of a marginal-zone growth pattern, follicular colonization, scattered germinal center remnants, and disrupted follicular dendritic-cell meshworks, highlighted by immunohistochemical staining for CD21, are helpful features to suggest a diagnosis of nodal MZL rather than LPL.35 The presence of monocytoid B cells in the lymph node may not be especially helpful as a distinguishing feature of nodal MZL because monocytoid cells have been described in LPL/WM. The problem with distinguishing nodal MZL with plasmacytic differentiation from LPL/WM is well recognized, especially in non-WM cases where there is no bone marrow involvement and/or IgM gammopathy to help support the diagnosis of LPL. In those cases, rather than making an arbitrary decision, the diagnosis of small B-cell lymphoma with plasmacytic differentiation should be rendered.
Both mantle cell lymphoma and SLL/CLL typically express CD5 and usually pose less of a diagnostic dilemma. Mantle cell lymphoma can also be distinguished by the expression of cyclin D1. The distinctive immunophenotype of SLL/CLL, including expression of CD23 without FMC7, can be combined with morphologic identification of the proliferation centers to aid in differentiation from LPL.
Plasma cell myeloma expressing IgM is extremely rare. Differentiating LPL/WM from plasma cell myeloma hinges on identification of a pure plasma cell population, without lymphoid marrow infiltration, which is associated with osteolytic lesions and hypercalcemia. At the cytogenetic level, the IGH translocations frequently found in plasma cell myeloma are extremely rare in LPL.31,36
Rare cases of LPL that present primarily with extramedullary disease and are not WM remain poorly characterized, which is likely related to the reproducibility of the diagnosis of LPL being highest in the setting of IgM gammopathy with bone marrow involvement (WM), and, conversely, diagnosis of extramedullary LPL lacks sufficient criteria for adequate reproducibility and is frequently indistinguishable from cases of MZL.37
PROGNOSIS AND MANAGEMENT
Like many other mature, small B-cell lymphomas, LPL/WM is an indolent, incurable disease with a median survival of 5 to 10 years.2 The most frequent causes of death related to LPL/WM are progressive disease, transformation to a higher-grade lymphoma, and infection. Poor prognostic factors include advanced age, low hemoglobin, low serum albumin, and high β2-microglobulin levels. Quantitative serum IgM levels, leukopenia, thrombocytopenia, and organomegaly have also been associated with adverse outcome.38–40 Deletion of chromosome arm 6q has been associated with features of adverse prognosis.28
As an incurable, indolent B-cell lymphoma, treatment of LPL/WM is generally expectant in asymptomatic patients. Symptomatic patients with modest hematologic abnormalities, IgM-related neuropathy, hemolytic anemia, or glomerulonephritis can be treated with single-agent rituximab therapy without maintenance. Patients with advanced disease consisting of bulky disease, profound cytopenias, constitutional symptoms, and hyperviscosity syndrome are typically treated with a regimen of rituximab, cyclophosphamide, and dexamethasone.38 Symptoms of hyperviscosity can be dramatically improved by plasmapheresis, although that does not affect tumor burden. Novel agents that target deregulated signaling pathways, such as proteasome and PI3K/Akt/mTOR inhibitors, are currently being evaluated in patients with LPL/WM.41
Lymphoplasmacytic lymphoma is a B-cell neoplasm composed of small lymphocytes, plasmacytoid lymphocytes, and plasma cells, which typically affects older adults. Most cases of LPL are WM, which is defined as bone marrow involvement with LPL and a detectable monoclonal IgM serum paraprotein. Patients with LPL/WM can present with distinctive symptoms associated with hyperviscosity syndrome, including visual disturbance and neurologic compromise. Diagnosis of LPL/WM can be challenging because LPL lacks disease-specific morphologic, immunophenotypic, and genetic features that readily differentiate it from other small B-cell lymphomas, all of which are capable of plasma cell differentiation. Using 2008 World Health Organization diagnostic criteria for WM, there is diagnostic overlap among WM, IgM monoclonal gammopathy of undetermined significance, and smoldering WM. Management of LPL/WM is expectant. Systemic chemotherapy is typically reserved for patients with advanced disease, and plasmapheresis is used to treat patients with hyperviscosity syndrome.
The authors have no relevant financial interest in the products or companies described in this article.