Learn Lymphoplasmacytic Lymphoma, Waldenstrom’s Macroglobulinemia

Lymphoplasmacytic Lymphoma

Lymphoplasmacytic lymphoma (LPL), the lymphoma prototypically associated with Waldenstrom’s macroglobulinemia, can exhibit some morphologic overlap with other low-grade B-cell lymphomas with plasmacytic differentiation, in particular MZL and CLL, and it has often been considered a diagnosis of exclusion. However, the detection of an MYD88 L265P mutation that is present in more than 90% of lymphoplasmacytic lymphoma is a most useful diagnostic tool in the appropriate context. 

The mutation is also frequently seen in IgM monoclonal gammopathy of undetermined significance (MGUS), in which it is associated with greater disease burden and increased risk of disease progression. CXCR4 mutations are also seen in a subset of cases of lymphoplasmacytic lymphoma and appear to portend more aggressive behavior. Detection of MYD88 L265P in the peripheral blood of patients with lymphoplasmacytic lymphoma or IgM MGUS has also been shown to be useful in determining disease burden in the bone marrow and may obviate the need for bone marrow aspiration or biopsy-based monitoring in the future. Provides a list of recurrent somatic mutations and associated pathways in small B-cell lymphoma/leukemia.

Introduction Of Lymphoplasmacytic Lymphoma

Lymphoplasmacytic lymphoma (LPL) is defined in the WHO Classification of Tumours of Haematopoetic and Lymphoid Tissues, fourth edition, as a small B-cell neoplasm composed of lymphocytes, plasma cells, and plasmacytoid lymphocytes, which does not meet the criteria for any of the other small B-cell lymphomas that may also exhibit plasmacytic differentiation. It typically involves the bone marrow, but peripheral blood, lymph nodes, and spleen may also be involved. Waldenstrom macroglobulinemia (WM) is defined as lymphoplasmacytic lymphoma involving bone marrow associated with an IgM monoclonal paraprotein of any concentration and is found in the majority of patients with lymphoplasmacytic lymphoma.

Cases that express IgG or IgA heavy chain may fulfill criteria for lymphoplasmacytic lymphoma but are less common. Most lymphoplasmacytic lymphoma cases lack expression of a specific immunophenotype related to antigens commonly assessed in the workup of B-cell malignancies, including CD5, CD10, CD23, and CD103. Because of this feature and because plasmacytic differentiation may be seen in a number of small B-cell lymphomas, most commonly one of the subtypes of marginal-zone lymphoma, a specific diagnosis of lymphoplasmacytic lymphoma may not always be possible, and some cases are best diagnosed as a small B-cell lymphoma with plasmacytic differentiation with a differential diagnosis provided. However, the recent identification of the MYD88 L265P somatic mutation as a recurrent finding is greater than 90% of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia may aid in establishing this diagnosis with greater certainty. 

Epidemiology Of Lymphoplasmacytic Lymphoma

lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia is an uncommon lymphoid neoplasm, representing approximately 2% of non-Hodgkin’s lymphoma cases diagnosed in the United States between 1988 and 2007 according to Surveillance, Epidemiology and End Results (SEER) registry data. The median age at diagnosis is 73 years with a male predominance. The overall age-adjusted incidence is 3.8 per 1 million persons per year. Incidence increases sharply with age and is higher in Caucasians compared with other races. A role for genetic factors in the pathogenesis of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia is suggested based on numerous reports of familial occurrence in case-control and larger cohort studies.

A study from Asia found lower incidence rates in Japan and Taiwan compared with rates reported in the literature for Asians living in the United States, suggesting that both environmental and genetic factors are involved in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia development. Among environmental factors, chronic antigenic stimulation secondary to various autoimmune diseases or other inflammatory conditions has been implicated. An etiologic role for hepatitis C virus (HCV) has also been suggested; however, this has not been shown in all studies and a large study with both serologic and molecular genetic methods for HCV detection found no association with lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia

Clinical Features Of Lymphoplasmacytic Lymphoma And WM

The clinical manifestations of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia can be attributed to two main factors: the effects of the monoclonal IgM paraprotein and tissue infiltration by neoplastic cells. The monoclonal IgM paraprotein causes morbidity via several mechanisms related to its biochemical and immunologic properties, non-specific interactions with other proteins, antibody activity, and propensity to deposit in tissues.16 The high concentration of monoclonal IgM molecules and their tendency to form pentamers can lead to serum hyperviscosity through the binding of water and erythrocyte aggregation.

Symptoms Of Lymphoplasmacytic Lymphoma

Symptomatic hyperviscosity is seen in 10% to 30% of Waldenstrom’s macroglobulinemia patients, and serum viscosity increases sharply at IgM concentrations of greater than 3 g/ dL, with most patients manifesting symptoms at levels greater than 5 g/dL. Symptoms of hyperviscosity include headaches,  visual disturbances, mental status changes, and, in severe cases, intracranial hemorrhage. Coprecipitation of the monoclonal IgM (typecryoglobulinemia) may be seen in up to 20% of patients, with a minority of such patients exhibiting symptoms of Raynaud phenomenon, acrocyanosis, or, less frequently, renal manifestations.

In other patients, the monoclonal IgM may behave as a type II cryoglobulin and demonstrate IgG autoantibody activity, leading to symptoms of purpura, arthralgias, renal insufficiency, and peripheral neuropathy. Other autoantibody effects of the monoclonal IgM against red blood cell antigens may result in cold agglutinin hemolytic anemia, whereas binding of peripheral nerve constituents may lead to sensorimotor neuropathy. The latter manifestation is relatively common in Waldenstrom’s macroglobulinemia, reported in 25% to nearly 50% of patients in some series.

Peripheral neuropathy may also be mediated by non-autoimmune effects of the monoclonal IgM protein, secondary to fibrillar or tubular deposits in the endoneurium, amyloid deposition within the nerve, or direct infiltration of nerve structures. The monoclonal protein may also deposit in various other tissues as amorphous aggregates leading to dysfunction of affected organs. Deposition of monoclonal light chain in the form of amyloid (primary AL amyloidosis) is much less common in patients with Waldenstrom’s macroglobulinemia but may lead to similar types of organ dysfunction.

Monoclonal Of Lymphoplasmacytic Lymphoma

Symptoms related to direct tissue infiltration by neoplastic cells are most commonly due to bone marrow involvement, which leads to peripheral cytopenias. At the time of presentation, the degree of anemia is typically more profound than other cytopenias, because the anemia in Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma is multifactorial in nature and due in large part to increased plasma viscosity leading to inappropriately low erythropoietin production. Other factors contributing to anemia include hemolysis, plasma volume expansion, and gastrointestinal blood loss in patients with the involvement of that site.

Nodal and splenic involvement may be present, but bulky lymphadenopathy is uncommon and splenomegaly, if present, is typically mild to moderate in degree. Extramedullary and extranodal sites of disease involvement by lymphoplasmacytic lymphoma that have been reported include lung, soft tissue, skin, gastrointestinal and hepatobiliary tracts, kidney, and central nervous system (CNS).

Pulmonary involvement, seen in less than 5% of patients, may be in the form of nodules, masses, diffuse infiltrates, or pleural effusions, and results in symptoms of cough (most commonly), dyspnea, and chest pain. The gastrointestinal disease may involve the stomach, duodenum, or small intestine, resulting in malabsorption, bleeding, or obstruction, whereas cutaneous involvement may result in chronic urticaria or in the formation of plaques or nodules.

Direct infiltration of the CNS, known as Bing-Neel syndrome, is a rare complication of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia that is characterized clinically by a variety of neurologic signs and symptoms, including mental status changes, headache, motor dysfunction, vertigo, impaired hearing, and, in some cases, coma. Unlike in plasma cell myeloma, lytic bone lesions are not seen, and hypercalcemia is rare.

Morphology Of lymphoplasmacytic lymphoma AND WN

Lymphocytosis may be present, but the absolute lymphocyte count is usually lower than in chronic lymphocytic leukemia (CLL). Circulating neoplastic cells may have plasmacytoid features with clumped chromatin, eccentric nuclei, and moderately abundant basophilic cytoplasm, occasionally with a para nuclear hof. Red cell agglutination and rouleaux formation may be present in patients with serum hyperviscosity due to elevated IgM paraprotein.

Bone marrow aspirate smears demonstrate lymphocytosis with a morphologic spectrum that includes small, round lymphocytes; plasmacytoid lymphocytes; and plasma cells. Varying patterns of bone marrow involvement may be observed in core biopsy specimens, with interstitial and nodular infiltrates most commonly reported. Less frequently, pure paratrabecular or diffuse patterns of marrow involvement may be seen.

The lymphoid aggregates are composed mainly of small lymphocytes with variable numbers of plasmacytoid lymphocytes and plasma cells. Plasmacytic differentiation may be reflected by the presence of Russell or Dutcher bodies. Increased mast cells are almost always present in association with the lymphoid aggregates, and their identification may be facilitated by tissue Giemsa stain or CD117 immunohistochemistry; however, this finding is not considered specific for the diagnosis of lymphoplasmacytic lymphoma.

Peripheral Blood and Bone Marrow

The pattern of bone marrow involvement may raise the differential diagnosis of other small B-cell neoplasms that more commonly involve the bone marrow, including CLL and follicular lymphoma. Distinction from these entities can be made readily on the basis of the immunophenotype of the neoplastic cells as noted later. In addition, although nodular aggregates may extend to paratrabecular locations and infrequent lymphoplasmacytic lymphoma cases with predominant paratrabecular patterns of involvement have been described, these paratrabecular aggregates are generally not associated with linear growth along bony trabeculae or fibrosis, as seen in bone marrow involvement by follicular lymphoma.

Bone marrow involvement by marginal-zone lymphoma presents a more challenging distinction, given its shared immunophenotype with lymphoplasmacytic lymphoma. Interstitial involvement is more commonly seen in lymphoplasmacytic lymphoma compared with marginal-zone lymphoma. In contrast to bone marrow involvement by splenic marginal zone lymphoma (SMZL), intrasinusoidal involvement is rare in lymphoplasmacytic lymphoma. Assessment for the presence of the MYD88 L265P mutation may be helpful in difficult cases.

Cases with prominent plasmacytic differentiation may raise the differential diagnosis of plasma cell myeloma, particularly the small lymphocytic variant with lymphoplasmacytic morphology. The latter is distinguishable from lymphoplasmacytic lymphoma on the basis of its CD45-negative, CD19-negative, CD56-positive immunophenotype, and frequent cyclin D1 positivity by immunohistochemistry corresponding to an underlying CCND1 rearrangement detectable by FISH.

Lymph Nodes Of Lymphoplasmacytic Lymphoma And WN

In the past, two main patterns of nodal involvement have been described. In the classic pattern, there is subtotal architectural effacement with retention of small primary or enlarged reactive follicles and patent or dilated sinuses. The interfollicular areas contain a relatively monomorphous infiltrate of small lymphocytes, plasmacytoid lymphocytes, and plasma cells, without prominent follicular colonization.

Only rare large transformed cells are present. Dutcher bodies, increased numbers of mast cells, or hemosiderin deposition may be present. Other cases demonstrate more complete architectural effacement with a vaguely nodular to diffuse polymorphous infiltrate consisting of small lymphocytes, plasmacytoid lymphocytes, and plasma cells, with greater numbers of large transformed cells resembling immunoblasts. The latter may be numerous in some cases, but should not form large aggregates or sheets, in which case a diagnosis of transformation to diffuse large B-cell lymphoma (DLBCL) should be considered. 

Clusters of epithelioid histiocytes may be conspicuous in the so-called polymorphous pattern, sometimes termed polymorphous immunocytes in previous classification systems. In both the classic and polymorphous patterns, extracellular deposits of immunoglobulin, in the form of amyloid or amorphous Congo red–negative amyloid-like material, may be present, or crystal-storing histiocytes may be identified. Pseudofollicles or proliferation centers, as seen in small-lymphocytic lymphoma (SLL), are not a typical feature. 

Lymphoplasmacytic Lymphoma MYD88

More recently, studies of MYD88 L265P mutation analysis in nodal lymphomas initially diagnosed as lymphoplasmacytic lymphoma, nodal marginal zone lymphoma (NMZL), and small B-cell lymphoma with plasmacytic differentiation has helped to refine the morphologic spectrum of nodal lymphoplasmacytic lymphoma. These studies show that some MYD88 L265P–mutated cases demonstrate complete nodal architectural effacement, a vaguely nodular growth pattern, variably prominent follicular colonization, or focal areas containing pale monocytoid or marginal-zone B cells.

Cases harboring the MYD88 L265P mutation had significantly more common bone marrow involvement, elevated serum IgM levels, and presence of a serum M component, suggesting that they represent true lymphoplasmacytic lymphoma cases despite the presence of morphologic features previously thought to be more characteristic of NMZL. Conversely, cases initially diagnosed as lymphoplasmacytic lymphoma with a polymorphous pattern of nodal involvement containing prominent histiocytes and occasional immunoblasts were all negative for the MYD88 L265P mutation, suggesting that they may represent a B-cell neoplasm distinct from lymphoplasmacytic lymphoma.

Therefore, at this time, it may be best to classify the latter cases as B-cell lymphoma with plasmacytic differentiation until additional studies are undertaken to characterize them further. 

Spleen and Other Tissues Of Lymphoplasmacytic Lymphoma

Splenic involvement by lymphoplasmacytic lymphoma has not been well described, but older published series and illustrated reviews support the presence of nodular and diffuse infiltrates of lymphoplasmacytic cells involving the red pulp, in a similar distribution to other small B-cell neoplasms with a leukemic pattern of dis- semination. The morphologic spectrum of the lymphoma cells, including small lymphocytes, plasma cells, and intermediate forms, is analogous to that seen in the bone marrow and lymph node specimens.

This cytologic appearance may give rise to the differential diagnosis of SMZL, which may demonstrate plasmacytic differentiation in some cases. Pathologic features favoring a diagnosis of lymphoplasmacytic lymphoma over SMZL include relative sparing of the white pulp with the absence of a marginal-zone growth pattern, absence of monocytoid or marginal-zone–type cytology, and conspicuous plasmacytic differentiation that is usually readily apparent by both morphologies and on immunohistochemical or in situ hybridization studies of tissue sections.

In addition, lymphoplasmacytic lymphoma patients typically have higher IgM paraproteinemia and more extensive disease involving the bone marrow or lymph nodes, with secondary splenic involvement resulting in a milder degree of splenic enlargement compared with SMZL. Other small B-cell lymphoma entities with diffuse red pulp involvement that may enter into this differential diagnosis include hairy cell leukemia (HCL) and splenic diffuse red pulp small B-cell lymphoma (SDRPSBL).

The distinction between lymphoplasmacytic lymphoma and HCL is usually straightforward on clinical, morphologic, and immunophenotypic grounds. Although SDRPSBL cases may show subtle plasmacytoid features, they usually lack strong features of plasmacytic differentiation such as cytoplasmic immunoglobulin deposition by immunohistochemistry or in situ hybridization. Common sites of extramedullary and extranodal disease were described earlier.

Nodular Diffuse Of Lymphoplasmacytic Lymphoma

Among the few histologic descriptions in the literature, lymphoplasmacytic lymphoma involving extramedullary sites may show some features that overlap with extranodal marginal zone lymphoma (EMZL), including the presence of nodular and diffuse infiltrates of lymphoplasmacytic cells, focal clusters of monocytoid B cells, and the presence of Dutcher bodies. However, in gastrointestinal sites such as the stomach and colon, lymphoepithelial lesions and colonization of preexisting follicles have not been described.

Skin biopsies have been reported to show interstitial, nodular, or diffuse dermal infiltration by lymphoplasmacytic cells with perinodal and periadnexal accentuation; focal epidermal ulceration may be present in rare cases. Hepatic involvement, reported in cases with the splenic disease, has been reported to show expansion of portal tracts and sinusoids by small plasmacytoid lymphocytes.

In cases of CNS involvement (Bing-Neel syndrome), cytologic evaluation of cerebrospinal fluid (CSF) specimens may show a lymphocytic pleocytosis consisting of plasmacytoid lymphocytes and plasma cells, similar to the spectrum of cell populations seen in other tissues. Laboratory evaluation of such specimens via flow cytometry, electrophoresis, immunofixation, and, more recently, MYD88 L265P mutation analysis may help confirm the diagnosis.

Immunophenotype Of Lymphoplasmacytic Tissue

The lymphocytic component of lymphoplasmacytic lymphoma expresses moderate levels of the pan–B-cell antigens, including CD19, CD20, CD22, CD79a, PAX5, and FMC7, as well as the monoclonal surface light chain. The plasmacytic component of the tumor expresses cytoplasmic immunoglobulin, as well as other markers of plasma cell differentiation, including CD138 (variable) and MUM1 (IRF4). Unlike the neoplastic plasma cells of plasma cell myeloma, CD19 expression is usually retained on the plasmacytic component and CD56 is negative.

CD25 and CD38 are frequently, though not always, expressed, and neoplastic cells are typically negative for other phenotypically distinctive markers, including CD5, CD10, CD23, and CD103. Occasional CD5- positive cases have been reported, which can generally be distinguished from CLL/SLL and mantle cell lymphoma by the presence of strong cytoplasmic immunoglobulin expression in a significant subset of cells and the absence of cyclin D1 expression.

Similarly, rare CD10-positive cases can be distinguished from follicular lymphoma based on the degree of plasmacytic differentiation, absence of other germinal- center–associated antigens such as BCL6, and pattern of staining with follicular dendritic cell antigens (CD21 and/or CD23).

Postulated Normal Counterpart And Pathogens

The lymphocytes of lymphoplasmacytic lymphoma are post–germinal-center B cells capable of spontaneous differentiation to plasma cells in vitro. Molecular genetic analyses of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia and IgM MGUS have demonstrated the presence of extensive somatic hypermutation within the IGH gene, consistent with derivation from a post–germinal-center B cell. There is little evidence of intraclonal variation, and most reports indicate that the tumor cells have failed to undergo heavy chain class switching, with some suggestion that they may be defective in this capacity.

These findings suggest that the tumor derives from an IgM- positive memory B cell whose normal counterpart localizes in the bone marrow to mature to an IgM-secreting plasma cell, and that the transformation event occurs following affinity maturation prior to isotype switching. Mast cells, which are often increased in tissues involved by lymphoplasmacytic lymphoma, are thought to play a permissive role in lymphoplasmacytic lymphoma development via the elaboration of inflammatory cytokines and CD40 ligand–dependent signaling.

Which ultimately leads to phosphorylation of IκBα and release and activation of nuclear factor (NF)κB.3 L265P is a gain-of-function mutation that promotes cell survival by allowing spontaneous MYD88 homodimerization, BTK activation, and IRAK complex assembly, leading to constitutive NFκB activation. Inhibition of MYD88 signaling has been shown to decrease NFκB nuclear translocation and activity in both MYD88 L265P–mutated ABC-type DLBCL and Waldenstrom's macroglobulinemia cell lines.

Mutation Of Waldenstrom’s Macroglobulinemia

Blockade of IκBα by proteasome inhibitors is associated with high response rates in Waldenstrom’s macroglobulinemia patients,111-114, and ibrutinib, a selective BTK inhibitor, has shown high activity in MYD88 L265P–mutated cell lines and promising early results in patients with relapsed or refractory Waldenstrom’s macroglobulinemia. The next most common gene target of somatic point mutations in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia is CXCR4.

CXCR4 stimulation by its ligand activates AKT and mitogen-activated protein (MAP) kinase signaling and facilitates Waldenstrom’s macroglobulinemia cell migration, adhesion, and homing. WHIM-like CXCR4 mutations result in impaired receptor internalization and have an activating role in Waldenstrom’s macroglobulinemia, as shown by tumor growth, extramedullary dissemination, and decreased survival in transfected mouse models, effects that were abrogated following the use of an anti-CXCR4 monoclonal antibody.

ARID1A, the third most common single nucleotide variant target in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia, encodes for a chromatin-remodeling protein, and its family member, ARID1B, resides on chromosome 6q and is frequently lost lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia. Both ARID1A and ARID1B mutations have been described in other malignancies, and are thought to exert their effects via p53 and cyclin-dependent kinase inhibitor 1A (CDKN1A) regulation, important mediators in cell-cycle control and DNA damage response.

TP53 itself has been found to be mutated in approximately 7% of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia cases. Together, these findings imply that multiple somatic mutations exist in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia that cooperates to promote lymphomagenesis via a variety of mechanisms, including NFκB– dependent prosurvival signaling, cell migration, and homing, and cell-cycle dysregulation. 

Clinical Course, Treatment, And Prognosis Of Lymphoplasmacytic Lymphoma

Like most other low-grade B-cell lymphomas, the clinical course in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia is generally indolent, with most patients experiencing slowly progressive disease and treatment refractoriness. The median overall survival in large series ranges from 5 to 10 years, with variability in outcome reported based on a number of clinical and laboratory prognostic factors.

An International Prognostic Scoring System for Waldenstrom’s macroglobulinemia has been developed that takes into account the following five adverse characteristics in determining prognosis and optimizing initial therapy: age greater than 65 years, hemoglobin less than or equal to 11.5 g/dL, platelet count less than or equal to 100 × 109 /L, β2-microglobulin greater than 3 mg/L, and serum monoclonal protein concentration greater than 7.0 g/dL. Five-year survival for low-risk patients with zero or one adverse characteristic and age less than or equal to 65 years is 87% versus 36% for high-risk patients with more than two adverse characteristics.

Lymphoplasmacytic Lymphoma Of Prognosis

The remaining patients with two adverse characteristics or age greater than 65 years belong to an intermediate-risk group with a 5-year overall survival of 68%.In terms of pathologic characteristics important in determining prognosis, the presence of polymorphous morphology, a complex karyotype, or a cytogenetic 6q deletion abnormality has all been associated with an adverse prognosis in various reports.

In addition, the low prevalence of MYD88 L265P mutation in cases with polymorphous morphology suggests that such cases may represent a distinct clinicopathologic entity from lymphoplasmacytic lymphoma demonstrating more classical morphology with MYD88 L265P mutations.

MYD88 Lymphoplasmacytic Lymphoma

Transformation to DLBCL has been reported in 13% of cases in one series and is associated with an aggressive clinical course and poor prognosis. Largescale genomic approaches have identified somatic mutations in addition to MYD88 L265P that may be important for prognosis in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia. For example, patients with both MYD88 L265P and ARID1A mutations had a significantly greater degree of bone marrow involvement, anemia, and thrombocytopenia than patients with MYD88 L265P alone.

In a separate study, the same authors found that patients whose tumors harbor both MYD88 L265P and CXCR4 non-sense mutations show a more aggressive disease course, with significantly greater bone marrow involvement, higher serum IgM levels, and more symptomatic disease (including hyperviscosity syndrome) requiring therapy, whereas patients wild type for both MYD88 and CXCR4 exhibit the lowest degree of bone marrow involvement. Interestingly, in the same study,  CXCR4 mutant versus wild-type status did not affect overall survival, but patients with MYD88 wild-type tumors had a significantly lower overall survival compared with patients with MYD88 L265P–mutated tumors, suggesting that other genetic determinants of disease prognosis may be important in the MYD88 L265P–negative subgroup.

Finally, CXCR4- mutated Waldenstrom’s macroglobulinemia cells have shown resistance in vitro to BTK, mammalian target of rapamycin (mTOR), and phosphatidylinositol 3-kinase (PI3K) inhibitors, but not proteasome inhibitors. It is likely that as our understanding of the genetic basis of lymphoplasmacytic lymphoma improves, more sophisticated prognostic scoring systems encompassing both clinicopathologic and genomic variables will emerge, allowing for the development of targeted and more effective therapies in patients with this neoplasm.

Current consensus criteria for initiation of therapy and treatment recommendations are based on a series of International Workshops on Waldenstrom’s macroglobulinemia (IWWM) that has convened over the last decade. These guidelines were last updated in 2012 based on the results of several phase 2 studies. Initiation of therapy is appropriate in patients with constitutional symptoms, progressive symptomatic lymphadenopathy or splenomegaly, severe cytopenias secondary to marrow infiltration, or symptomatic complications of the disease, such as hyperviscosity syndrome, peripheral neuropathy, amyloidosis, renal insufficiency, or cryoglobulinemia.

The decision to initiate therapy is not based solely on the serum IgM level, which may not correlate with symptom severity. Combination therapies that include rituximab (e.g., bendamustine and rituximab; dexamethasone, rituximab, and cyclophosphamide; or bortezomib and rituximab) are typically used in the frontline setting, whereas fludarabine-containing regimens, everolimus, or alemtuzumab may be considered in the relapsed or refractory setting or in patients with limited treatment options. High-dose chemotherapy with autologous stem cell rescue is an option for salvage therapy in patients with chemosensitive disease.

Limiting exposure to alkylating agents and nucleoside analogs is recommended in younger patients due to complications of myelosuppression and increased risk for secondary myelodysplastic syndrome and acute myeloid leukemia. In many patients with Waldenstrom’s macroglobulinemia, an increase in serum IgM level (a so-called IgM flare) is seen following the initiation of rituximab and other anti-CD20 monoclonal antibody therapies that do not imply disease progression.

However, this elevation may last several weeks in some patients, necessitating additional diagnostic studies to rule out the possibility of progressive disease and limiting the utility of these drugs in patients with paraprotein-related symptoms of hyperviscosity,  cryoglobulinemia, or cold agglutinin hemolytic anemia. Plasmapheresis may be beneficial in some patients with severe paraprotein-related symptoms at baseline or when done preemptively, prior to the initiation of rituximab, in order to avoid symptom exacerbations.

Neoplastic Conditions Of Lymphoplasmacytic Lymphoma

The main neoplastic entities in the differential diagnosis of lymphoplasmacytic lymphoma include other small B-cell lymphomas with plasmacytic differentiation, particularly the various subtypes of marginal zone lymphoma, due to the non-specific immunophenotype that they share with lymphoplasmacytic lymphoma. EMZL and SMZL have relatively distinct clinical presentations and disease distributions from lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia, and can usually be distinguished from lymphoplasmacytic lymphoma on this basis.

In addition, lymphoplasmacytic lymphoma has been shown to lack translocations involving MALT1 and BCL10 that are frequently detected in EMZL involving the stomach and lung. The distinction between NMZL and nodal involvement by lymphoplasmacytic lymphoma is perhaps the most challenging, particularly on small biopsy specimens. NMZL may exhibit significant plasmacytic differentiation, whereas some lymphoplasmacytic lymphoma cases contain focal monocytoid or marginal-zone cytology and prominent follicular colonization. The presence of increased mast cells and dilated sinuses has traditionally been thought to favor lymphoplasmacytic lymphoma, but these features are not present in all cases. 

Findings of two recent studies have highlighted the utility of MYD88 L265P mutation analysis in helping to establish the diagnosis of lymphoplasmacytic lymphoma in nodal biopsy specimens. Because the presence of this mutation is neither entirely sensitive nor specific to lymphoplasmacytic lymphoma, correlation with other clinical, laboratory, and pathologic features is still necessary to help establish a diagnosis of lymphoplasmacytic lymphoma.

In cases lacking the MYD88 L265P mutation and in which supporting clinical and laboratory data are limited (e.g., cases without a recent or concurrent bone marrow biopsy or corroborating serum immunoglobulin levels or serum protein and immunofixation electrophoresis studies), a diagnosis of small B-cell lymphoma with plasmacytic differentiation with the provision of a differential diagnosis is most appropriate. Another neoplastic entity that may enter into the differential diagnosis of lymphoplasmacytic lymphoma is gamma heavy chain disease, a very rare B-cell lymphoproliferative disorder characterized by the secretion of an abnormal truncated gamma heavy chain that is unable to bind light chains.

The median age of presentation ranges from 51 to 68 years, and a substantial proportion of patients have an underlying autoimmune disease, most commonly rheumatoid arthritis, which may precede the onset of lymphoma by several years. The associated lymphoma typically involves the bone marrow, lymph nodes, and spleen, but patients may also present with localized extranodal disease involving the skin, thyroid, salivary glands, gastrointestinal tract, and conjunctiva. 

Examination of involved tissues usually demonstrates a mixed population of lymphocytes, plasmacytoid lymphocytes, and plasma cells that is morphologically similar to lymphoplasmacytic lymphoma. Due to its clinical and morphologic overlap with lymphoplasmacytic lymphoma, gamma heavy chain disease has traditionally been considered a variant of lymphoplasmacytic lymphoma, but it can usually be readily distinguished from lymphoplasmacytic lymphoma on the basis of its immunophenotype, demonstrating positivity for IgG heavy chain with absent staining for light chains by immunohistochemistry or in situ hybridization.

Moreover, the neoplastic infiltrate of gamma heavy chain disease is often more polymorphous than that typically seen in lymphoplasmacytic lymphoma, with variable numbers of immunoblasts, eosinophils,  and histiocytes identified, and a hypervascular background may be present. Rarely, atypical Reed-Sternberg–like cells suggest a morphologic differential diagnosis of Hodgkin’s lymphoma or certain types of peripheral T-cell lymphoma. Other cases may demonstrate clinicopathologic features of other small B-cell neoplasms, including EMZL, SMZL, or other splenic small B-cell neoplasms.

This histologic diversity, with many cases demonstrating features, unlike lymphoplasmacytic lymphoma, along with a recent study demonstrating that cases of gamma heavy chain disease lack the MYD88 L265P mutation associated with lymphoplasmacytic lymphoma suggest that gamma heavy chain disease is pathogenetically distinct from lymphoplasmacytic lymphoma despite some overlapping clinical and morphologic features.

Disorders Of Waldenstrom’s Macroglobulinemia

The differential diagnosis of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia includes disorders in which the presence of a serum IgM paraprotein is a key disease manifestation, including IgM MGUS and asymptomatic or smoldering Waldenstrom’s macroglobulinemia. IgM MGUS is defined by serum IgM monoclonal protein less than 3 g/dL, absent or minor lymphoplasmacytic infiltrates on bone marrow evaluation comprising less than 10% marrow cellularity, and absence of symptoms of Waldenstrom’s macroglobulinemia.

This diagnosis is warranted if flow cytometry demonstrates a clonal B-cell or plasma cell population or molecular genetic studies reveal a clonal IGH rearrangement, but no lymphoplasmacytic infiltrates are evident by morphology. MYD88 L265P mutation analysis is not helpful in the distinction between IgM MGUS and lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia because the mutation has been identified in approximately half of IgM MGUS cases. IgM MGUS patients with the MYD88 L265P mutation have a higher risk for progression to lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia independent of serum M protein concentration, pointing to the potential utility of MYD88 L265P as a marker of prognosis and disease progression in patients with IgM MGUS.

Symptoms Of Waldenstrom's Macroglobulinemia

Patients with smoldering or asymptomatic Waldenstrom’s macroglobulinemia have histopathologic evidence of marrow involvement by lymphoplasmacytic lymphoma (lymphoplasmacytic infiltrates composing at least 10% of marrow cellularity) and/or serum IgM monoclonal protein greater than or equal to 3 g/dL but remain without symptoms of Waldenstrom’s macroglobulinemia or evidence of end-organ damage (i.e., anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly).

Treatment Of Waldenstrom's Macroglobulinemia

Therefore, the distinction between asymptomatic and symptomatic lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia requires correlation with clinical and laboratory data. IgM MGUS and asymptomatic Waldenstrom’s macroglobulinemia patients need to be followed but do not require treatment until symptoms develop. IgM MGUS patients have an elevated long-term risk for progression to lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia or, to a lesser extent, CLL or primary AL amyloidosis over time, with a cumulative incidence of progression of 10% at 5 years, whereas the risk for progression is significantly greater for asymptomatic Waldenstrom’s macroglobulinemia patients, the majority of who develop symptoms requiring treatment at 5 years or more of follow-up.

IgM-Secreting Disorders Of Lymphoplasmacytic Lymphoma

Primary chronic cold agglutinin disease is autoimmune hemolytic anemia mediated by the binding of complement-fixing monoclonal IgM kappa cold agglutinins to the I antigen on the surfaces of red blood cells. Diagnostic criteria are based on clinical and laboratory findings of chronic hemolysis, the cold agglutinin titer, and characteristic abnormalities on direct Coombs testing, as well as the absence of overt lymphoma by clinical or radiologic assessment.

Despite the latter feature, lymphoid aggregates are frequently identified on pathologic examination of bone marrow specimens, and clonal B cells may be detected by flow cytometry of peripheral blood or bone marrow, leading to a diagnosis of an associated B-cell lymphoma in approximately 75% of cases that have often been classified as lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia in prior studies. 

However, a recent detailed analysis of bone marrow findings in a relatively large number of patients with primary chronic cold agglutinin disease revealed several key differences from lymphoplasmacytic lymphoma/ Waldenstrom’s macroglobulinemia, including relatively limited bone marrow infiltration by monomorphous B cells without lymphoplasmacytic morphology, lack of expression of plasma cell-associated markers such as MUM1, and absence of the MYD88 L265P mutation.

These findings suggest that the underlying lymphoproliferative disorder in cases of primary chronic cold agglutinin the disease is distinct from that found in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia, but one that requires further study at this time for more complete characterization.

Myeloma Of Waldenstrom’s macroglobulinemia

Plasma cell myeloma of the IgM subtype is exceedingly rare, accounting for approximately 1% of cases, and affected patients often present with hypercalcemia and lytic bone lesions, symptoms typical of non-IgM plasma cell myeloma and not seen in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia. However, because not all patients with plasma cell myeloma have these symptoms at presentation and because plasma cell myeloma and lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia share some clinical features, such as anemia and renal insufficiency, the diagnosis of IgM plasma cell myeloma should be made only after carefully excluding the presence of peripheral lymphadenopathy, splenomegaly, or a monoclonal B-cell component by histopathologic examination or by flow cytometry.

The CD19-negative, CD56-positive immunophenotype of clonal plasma cells in myeloma may be an additional clue to the diagnosis, as the plasmacytic component of lymphoplasmacytic lymphoma should show the opposite pattern of staining. Rare cases of primary AL amyloidosis associated with a monoclonal IgM paraprotein have been described. These patients appear to have distinct clinicopathologic features, including older age at diagnosis, more frequent kappa light chain production, and less severe organ dysfunction.

Mu heavy chain disease, the rarest of the three heavy chain diseases with only 30 to 40 cases described in the literature, is a lymphoid neoplasm resembling CLL/SLL associated with splenomegaly, lymphadenopathy, lytic bone lesions, and kappa Bence Jones proteinuria. Serum immunofixation studies show monoclonal IgM without associated light chains, and examination of bone marrow aspirate specimens reveals small, round lymphocytes and admixed plasma cells containing prominent cytoplasmic vacuoles.

Conditions Of Lymphoplasmacytic Lymphoma

The presence of residual reactive follicles, patent sinuses, and a significant interfollicular plasma cell component in nodal lymphoplasmacytic lymphoma may give rise to the differential diagnosis of the plasma cell variant of Castleman’s disease.

The distinction may be particularly challenging, as up to 50% of cases of the plasma cell variant of Castleman’s disease contain clonal plasma cells. The diagnosis of lymphoplasmacytic lymphoma can usually be established on the basis of clinical and laboratory features supporting lymphoplasmacytic lymphoma/ Waldenstrom’s macroglobulinemia, as well as the immunophenotype of the plasmacytic component, because the clonal plasma cells in the plasma cell variant of Castleman’s disease, when present, are almost always IgG or IgA lambda restricted.

Among non-neoplastic conditions, the findings of nodal lymphoplasmacytic lymphoma may mimic lymph nodes biopsied in the setting of rheumatoid arthritis or syphilitic (luetic) lymphadenitis, due to overlapping features of follicular hyperplasia and increased interfollicular plasma cells. In addition, lymphadenopathy-associated with IgG4-related disease may show features that overlap with lymphoplasmacytic lymphoma. 

The diagnosis of rheumatoid arthritis, syphilis, or IgG4-related disease can be readily established on the basis of clinical and laboratory features, and by demonstration of polyclonality of the plasmacytic component by stains for immunoglobulin light chains. In addition, lymphoplasmacytic lymphoma lacks the inflamed vasculature seen in syphilis, in which spirochetes can be identified with special histochemical stains or antitreponemal immunohistochemistry.