Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia

INTRODUCTION — The term "macroglobulinemia" refers to the production of excess IgM monoclonal protein that occurs in certain clonal lymphoproliferative disorders and plasma cell dyscrasias. This broad definition includes patients with monoclonal gammopathy of undetermined significance of the IgM type (IgM MGUS), smoldering Waldenström macroglobulinemia, Waldenström macroglobulinemia (WM), and a number of related disorders in which an IgM monoclonal protein is detected, such as chronic lymphocytic leukemia (CLL), a number of lymphoma variants, and primary (AL) amyloidosis.

WM is a distinct clinicopathologic entity demonstrating lymphoplasmacytic lymphoma (LPL) in the bone marrow with an IgM monoclonal gammopathy in the blood. Patients may present with symptoms related to the infiltration of the hematopoietic tissues or the effects of monoclonal IgM in the blood.

This topic review will limit discussion to the clinical manifestations and diagnosis of WM. The pathologic features of LPL and the prognosis and treatment of WM are discussed separately.

●(See "Treatment and prognosis of Waldenström macroglobulinemia".)

●(See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma".)

●(See "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Non-IgM MGUS'.)

EPIDEMIOLOGY — WM is a rare disorder with an incidence of approximately three per million people per year with 1400 new cases diagnosed in the United States each year [1,2]. The median age at diagnosis is 70 years; less than 10 percent of patients are under 50 years of age, and approximately 60 percent are males [3,4]. WM is much more common in White populations compared with other groups [5]. Specifically, it is uncommon in Black populations, who make up approximately 5 percent of cases, and individuals from or with families from Mexico [1].

First-degree family members of patients with WM have a higher than expected frequency of developing WM, although the absolute risk remains low. In one large database, the diagnosis of WM was 15.8-fold higher among first-degree relatives than among the general population [6].

ETIOLOGY — The etiology of WM is unknown. No obvious causative or predisposing factor has been identified. In a case-control study of 65 cases of WM compared with 213 hospital controls, no differences in sociodemographic factors, prior medical conditions, medication use, alcohol consumption, employment in any particular industry or occupation, specific occupational exposures (including radiation), or familial cancer history were found [7].

However, larger studies have suggested an association with chronic immune stimulation and autoimmune disorders [8-11]. As an example, a retrospective report of users of United States Veterans Affairs health care facilities from 1997 to 2004, reported that hepatitis C virus infection conferred a threefold higher risk of WM (adjusted hazard ratio 2.8, 95% CI 2.0-3.8) [9]. Another study suggested a possible association with exposure to farming, pesticides, and wood dust, but not for solvents, hair dye, or asbestos [8]. More studies are needed to determine if there is a causal relationship between these host and environmental factors and WM.

Although WM appears to be a sporadic disease in the majority of cases, a familial predisposition is present in up to 20 percent [8,12-20]. The nature and course of disease for patients with a family history appears to be similar to that of sporadic cases [8].

Since there are no proven preventative approaches, there is no role for screening asymptomatic relatives at this time. A large population-based study evaluated 6177 first-degree relatives of 2749 patients with WM or lymphoplasmacytic lymphoma (LPL) and 24,609 first-degree relatives of 8279 controls [17]. First-degree relatives of patients with WM or LPL had a 20-fold increased risk of developing WM/LPL. They also had an increased risk of developing non-Hodgkin lymphoma, chronic lymphocytic leukemia, and MGUS (relative risks of 3, 3, and 5, respectively). No association was found for multiple myeloma or Hodgkin lymphoma.  

PATHOGENESIS — Both somatic mutations and chromosomal abnormalities have been identified in the malignant B cells of WM. A recurrent mutation of the MYD88 gene (MYD88 L265P) is present in the vast majority of patients with WM [21,22]. Although highly associated with WM, MYD88 mutations are not entirely specific. About 40 percent of WM patients have recurrent mutations in the CXCR4 gene [23]. The genetic findings in WM are discussed in more detail separately. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma", section on 'MYD88 mutations'.)

The pattern of somatic mutations in WM suggests selection by antigenic stimulation at a relatively late stage of B cell differentiation [24-26], such as a post-germinal center IgM memory B cell that has undergone somatic hypermutation but has failed to undergo isotype class switching (table 1) [27,28]. Sensitive flow cytometry and gene expression profiling studies suggest a CD25⁺CD22^+low activated B lymphocyte [29]. Further discussion of the pathogenesis of the underlying malignant clone, lymphoplasmacytic lymphoma, is presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma", section on 'Pathogenesis'.)

This population of clonal B cells results in the production of abnormal monoclonal IgM. This monoclonal IgM may manifest itself clinically via several mechanisms, either in the setting of clinical WM, or in a patient who only has IgM monoclonal gammopathy of undetermined significance (IgM MGUS):

●The IgM can act as an autoantibody directed against myelin-associated glycoprotein or other nerve components resulting in neuropathy [30,31]. (See 'Neuropathy' below.)

●The IgM may be directed against antigens on the patient's own red blood cells resulting in a Coombs-positive autoimmune cold hemolytic anemia [32]. (See 'Complete blood count' below.)

●Amorphous material consisting of the monoclonal IgM protein (alone or in combination with amyloid) may be deposited in the extracellular space of the kidneys, gastrointestinal tract, or skin. (See 'Kidney involvement' below and 'Gastrointestinal symptoms' below and 'Other' below.)

●The IgM protein may precipitate out of the serum in cold temperatures resulting in symptoms of cryoglobulinemia [33,34]. (See 'Cryoglobulinemia' below.)

●The pentameric configuration of IgM molecules increases serum viscosity thereby slowing the passage of blood through capillaries [35]. IgM levels high enough to cause hyperviscosity syndrome almost always denote underlying WM rather than IgM MGUS. (See 'Hyperviscosity syndrome' below.)

●In patients with WM, the malignant B cells may directly infiltrate the hematopoietic tissues resulting in cytopenias (eg, anemia, thrombocytopenia, neutropenia), lymphadenopathy, hepatomegaly, and/or splenomegaly. Anemia associated with WM can also be due to increased hepcidin [36]. (See 'Overview' below.)

●Rarely, the plasmacytoid lymphocytes may infiltrate the central nervous system (ie, Bing-Neel syndrome) or meninges.

CLINICAL PRESENTATION

Overview — During the course of their disease, patients with WM can develop symptoms related to infiltration of hematopoietic or other tissues (eg, anemia, lymphadenopathy, hepatosplenomegaly) and/or symptoms related to the IgM monoclonal protein in their blood (eg, hyperviscosity, peripheral neuropathy) [37,38]. Most patients with WM present with nonspecific constitutional symptoms, but up to one-quarter of patients may be asymptomatic at diagnosis. The most common presenting features include weakness, fatigue, weight loss, and chronic oozing of blood from the nose or gums. Recurrent infections may also occur due to a relative decrease in other immunoglobulins.

As an example, a series of 217 patients with WM reported the following symptoms and physical findings at presentation [39]:

●Funduscopic abnormalities – 34 percent

●Constitutional "B" symptoms – 23 percent

●Bleeding – 23 percent

●Neurologic symptoms – 22 percent

●Symptoms secondary to hyperviscosity – 31 percent

●Lymphadenopathy – 25 percent

●Hepatomegaly – 24 percent

●Splenomegaly – 19 percent

No osteolytic bone lesions were found at presentation in this series, and involvement of the lung, kidney, gut, and skin were each seen in approximately 4 percent of patients. Cold agglutinins were present in 5 percent of patients, but only 1.5 percent had symptoms attributable to cold agglutinins.

Tissues may be involved in WM through infiltration with malignant cells (extramedullary involvement [40]) or via deposition of IgM or amyloid fibrils. The following sections describe involvement of specific organs in more detail.

Hyperviscosity syndrome — Symptoms related to hyperviscosity are present in up to 30 percent of patients, producing neurologic complaints such as blurring or loss of vision, headache, vertigo, nystagmus, dizziness, tinnitus, sudden deafness, diplopia, or ataxia [39]. Marked hyperviscosity can rarely lead to confusion, dementia, disturbances of consciousness, stroke, or coma [41,42]. When accompanied by anemia, hyperviscosity and the associated plasma volume expansion may precipitate or aggravate heart failure [43]. Symptomatic hyperviscosity is a medical emergency. (See "Treatment and prognosis of Waldenström macroglobulinemia", section on 'Emergency management of hyperviscosity'.)

Clinical manifestations are rarely attributable to hyperviscosity if serum viscosity is <4 centipoise (CP, normal value 1.5 CP). Although the correlation between serum viscosity and clinical manifestations is not precise, symptoms often begin when serum viscosity is >4 CP, and most patients are symptomatic when serum viscosity is >6 CP. As an example, in a compilation of two different series, zero, 67, and 75 percent of patients had symptoms of hyperviscosity when the serum viscosity was less than 3, greater than 4, and greater than 5 CP, respectively [44]. Higher serum IgM levels at presentation are associated with a shorter time to the development of symptomatic hyperviscosity. Specifically, serum IgM level >6000 mg/dL was associated with a median time to symptomatic hyperviscosity of three months in one study [45]. (See 'Serum viscosity' below.)

Neuropathy — Approximately 20 percent of patients may present with symptoms of neuropathy at the time of diagnosis. The most frequent neurologic abnormality is a distal, symmetric, and slowly progressive sensorimotor peripheral neuropathy causing paresthesias and weakness [30,31,46,47]. The lower extremities are usually more involved than the upper extremities. Anti-myelin-associated glycoprotein (MAG) activity is found in about one-half of these patients, but there is no correlation between these antibodies and the severity of symptoms [30]. Other autoantibodies of uncertain pathogenetic significance have also been described, including those directed against GM1 ganglioside and asialo-GM1 ganglioside [31].

Other neurologic manifestations can occur but are less common. These include cranial nerve palsies, mononeuropathy, mononeuritis multiplex, multifocal leukoencephalopathy, and sudden deafness. Infiltration of the central nervous system (ie, Bing-Neel syndrome) or meninges by plasmacytoid lymphocytes is rare, but may require evaluation with cerebrospinal fluid analysis and magnetic resonance imaging (MRI) of the brain and spinal axis [48-50].

Physical examination and electromyography (EMG) may be helpful in differentiating between neuropathy due to WM, multiple myeloma (MM), or monoclonal gammopathy of undetermined significance (MGUS) from that due to other causes such as amyloid or POEMS syndrome. As mentioned above, the neuropathy in WM, MM, and MGUS is usually demyelinating with sensory involvement more common than motor involvement. In contrast, the neuropathy in amyloid is usually axonal and the neuropathy in POEMS syndrome, while also demyelinating, more commonly involves the motor neurons. (See "POEMS syndrome", section on 'Peripheral neuropathy' and "Overview of polyneuropathy", section on 'Diagnostic evaluation'.)

Nerve biopsies should be considered a last diagnostic resource and only performed in challenging cases [51]. Among patients with a peripheral neuropathy, sural nerve biopsy may reveal myelin degeneration, cellular infiltration of the nerve, or IgM deposits on the myelin sheath. However, it is impossible to determine whether the presence of IgM in the biopsy specimen is a causative factor or whether it represents passive deposition of IgM in an already damaged nerve [30,52]. Amyloid deposition in the nerve may be responsible for the sensorimotor peripheral neuropathy in some patients. Amyloid may be investigated using Congo red staining of a subcutaneous fat pad aspirate and/or bone marrow biopsy.

Funduscopic abnormalities — Funduscopic abnormalities were noted in 34 percent of patients in one series [39]. A classic finding in WM associated with hyperviscosity is the presence of dilated, segmented, and tortuous retinal veins, giving a "sausage link" appearance (picture 1). Other retinal lesions, including hemorrhages, exudates, and papilledema may be impressive, and central retinal vein thrombosis can occur. Funduscopic examination is recommended in patients with serum IgM level >3000 mg/dL and indicated for patients with suspected hyperviscosity related symptoms [53].

Cryoglobulinemia — Approximately 10 percent of macroglobulins in WM precipitate in the cold (cryoglobulins), but are rarely responsible for cold hypersensitivity. However, if the cryoglobulin precipitates at temperatures greater than 22°C, serious symptoms can occur and may include Raynaud phenomenon, urticaria, purpura, acral cyanosis, and/or tissue necrosis [33,34]. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

Kidney involvement — Renal insufficiency is seen in about 3 percent of patients with WM [54]. Despite this, deposits of IgM in the glomerular basement membrane may be prominent and infiltration of lymphocytes or plasmacytoid cells can occur [40,55,56]. Light chain cast nephropathy and nephrotic syndrome (commonly due to amyloid deposition) have also been described in WM [54]. Immune-mediated glomerulonephritis, which is typically due to IgM deposition or cryoglobulinemia, and nonamyloid nephrotic syndrome (with a minimal change-like picture), have been described [56,57]. A renal biopsy may be needed in patients who have recent unexplained renal dysfunction. (See "Monoclonal immunoglobulin deposition disease" and "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

Urinary monoclonal light chains (Bence Jones protein) can be detected by immunofixation in 70 percent of patients, but the quantity is much less than in multiple myeloma [55]. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)

Gastrointestinal symptoms — The monoclonal IgM protein may rarely be deposited as extracellular amorphous material in the lamina propria of the gastrointestinal tract and produce severe malabsorption with diarrhea and steatorrhea [58,59]. Lymphangiectasia is seen on intestinal biopsy in some cases. Patients may also develop protein-losing enteropathy and be at increased risk of thrombosis due to the enteric loss of anticoagulant proteins. Possible contributing factors include the infiltration by malignant cells, amyloid deposition, or increased viscosity of the interstitial fluid due to high concentrations of IgM [59]. (See "Protein-losing gastroenteropathy".)

Other — Other clinical presentations, such as lytic bone lesions, pulmonary involvement, and skin lesions are uncommon.

●In contrast to multiple myeloma, bone pain is rare in WM. Fewer than 5 percent of patients with otherwise classical WM have lytic bone lesions. When present, these patients are usually classified as having IgM multiple myeloma, rather than WM [60].

●Pulmonary involvement is rarely a prominent feature of WM [40,61]. It is manifested by cough and dyspnea and the presence of a pleural effusion, diffuse pulmonary infiltrates, or an isolated mass. These pulmonary manifestations often respond to WM-directed therapy.

●Skin lesions are uncommon, occurring in approximately 3 percent of patients at presentation. More commonly, the skin may show dependent purpura secondary to abnormalities in platelet function and hyperviscosity.

Lymphoplasmacytoid cells may infiltrate the dermis and produce macular or papulonodular lesions. Multiple flesh-colored pruritic papules on extensor surfaces may be present and are secondary to deposition of IgM reacting with epidermal basement membrane proteins [62-64]. The presence of an IgM monoclonal protein and erythematous urticarial skin vasculitis (Schnitzler syndrome) has been described [65]. (See "Cutaneous manifestations of internal malignancy", section on 'Vasculitis' and "Urticarial vasculitis", section on 'Differential diagnosis'.)

LABORATORY FINDINGS — Approximately 25 percent of patients with WM will be asymptomatic when a diagnosis is made. These patients may be brought to attention based on abnormal laboratory tests performed for other reasons.

As an example, a series of 217 patients with WM reported the following laboratory abnormalities at presentation [39]:

●Anemia – 38 percent

●Neutropenia (absolute neutrophil count ≤1000/microL) – 4 percent

●Thrombocytopenia (platelet count ≤50,000/microL) – 2 percent

●Elevated lactate dehydrogenase (LDH) – 11 percent

●Elevated beta-2 microglobulin level – 54 percent

The erythrocyte sedimentation rate is usually greatly increased but may be normal. Further evaluation of a patient suspected of having WM includes a bone marrow aspiration with biopsy and serum protein electrophoresis (SPEP).

Complete blood count — Anemia can be seen in approximately 40 percent of patients with newly diagnosed WM. A moderate to severe degree of anemia is found in about 80 percent of patients with symptomatic WM, and the peripheral blood smear typically shows striking rouleaux formation (picture 2).

The genesis of anemia in WM is multifactorial, and includes:

●Inadequate red cell synthesis due to bone marrow replacement

●Iron deficiency due to decreased gastrointestinal absorption

●Chronic inflammation with increased hepcidin

●Decreased erythrocyte survival, which may rarely be due to an autoimmune hemolytic anemia

The hemoglobin and hematocrit levels are often spuriously lower than expected in WM patients with high IgM levels from the reduction in red cell mass because of an increase in plasma volume. In one series, the Coombs test was positive in 10 percent of patients, but only 3 percent developed significant hemolysis [39].

Lymphocytosis and monocytosis are also common findings in WM. Leukopenia and thrombocytopenia (due to marrow infiltration) may be present initially but the platelet count is rarely less than 50,000/microL. Thrombocytopenia may be due to bone marrow infiltration, autoimmune destruction, and/or hypersplenism.

Platelet function and blood coagulation — A clinically important bleeding diathesis is common in WM and is secondary to hyperviscosity, and an interference with clotting factor and platelet function. While chronic oozing of blood from the nose or gums is common, bleeding may occur from the gastrointestinal tract during and/or after surgery [39].

The most frequent laboratory abnormality related to coagulation is prolongation of the thrombin time, a reflection of the inhibition of fibrin polymerization by the IgM paraprotein [66]. Alterations in platelet function, probably due to an interaction between the IgM paraprotein and platelet surface membrane glycoproteins, can result in prolongation of the bleeding time, impaired clot retraction, defective in vivo platelet aggregation, and decreased in vitro platelet adhesion [67]. (See "Platelet function testing".)

Routine studies to test bleeding and clotting function are not necessary in WM in the absence of clinical bleeding. In patients who have clinical bleeding, unexplained by hyperviscosity, the evaluation should include prothrombin time, partial thromboplastin time, thrombin time, and factor X activity. Acquired von Willebrand disease can develop in patients with WM with high IgM levels [68]. (See "Acquired von Willebrand syndrome", section on 'Lymphoproliferative disorders'.)

Bone marrow examination — A bone marrow aspirate and biopsy demonstrating lymphoplasmacytic lymphoma is an essential component of the diagnosis of WM. While the bone marrow aspirate is frequently hypocellular, the biopsy specimen is usually hypercellular and extensively infiltrated with lymphoid and plasmacytoid cells (picture 3). Intranuclear vacuoles containing IgM monoclonal protein (Dutcher bodies) within the malignant cells of WM are common (picture 4).

Details on the morphologic, immunophenotypic, and genetic abnormalities seen in lymphoplasmacytic lymphoma are presented separately (table 2). (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma".)

Serum protein electrophoresis — The detection of a monoclonal IgM protein in the serum is a key diagnostic criterion for WM. Serum protein electrophoresis (SPEP) reveals a sharp, narrow spike or dense band of monoclonal IgM, usually migrating in the gamma area (figure 1).

While SPEP is a good screening test for monoclonal protein, additional studies, usually serum immunofixation, must be performed in order to confirm the presence of a monoclonal protein and to determine its type. The quantitative IgM level obtained by nephelometry may be 2 or 3 g/dL more than that found in the serum protein electrophoretic spike [69]. Consequently, the method used to measure the serum protein abnormality must be consistent during diagnosis and follow-up. Immunodiffusion methods should not be used in WM (or multiple myeloma), because this technique is inaccurate with IgA and IgM [70]. In the setting of cryoglobulins or cold agglutinins, the sample should be warmed prior to quantitation of the monoclonal protein in order to minimize interference by these entities.

In each individual case, immunoperoxidase staining detects either kappa or lambda light chains, but not both. Seventy-five percent of the IgM proteins are of the kappa light chain type. Reciprocal reductions in the concentrations of IgG and IgA are often present, but are not as profound as in multiple myeloma.

Serum viscosity — Serum viscosity should be performed in any patient with a monoclonal gammopathy and signs and symptoms suggesting the hyperviscosity syndrome. Serum viscosity should also be determined whenever the monoclonal IgM protein spike is >4 g/dL. (See 'Hyperviscosity syndrome' above.)

The relationship between serum viscosity and IgM protein concentration is nonlinear. Thus, with low serum IgM concentrations, an increase of 1 to 2 g/dL produces only a small increase in serum viscosity, but with IgM levels of 4 to 5 g/dL, an increment of 1 to 2 g/dL greatly increases viscosity.

The normal value for serum viscosity is 1.5 centipoise (CP), but hyperviscosity symptoms are rarely present unless the viscosity is >4 CP. Many laboratories report viscosity in relative terms (eg, relative to distilled water or saline) rather than in absolute terms (ie, CP). Because relative and absolute viscosities of serum are similar, these two units can be used interchangeably. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Blood viscosity'.)

Serum free light chain assay — The serum free light chain (FLC) assay measures serum kappa and lambda light chain levels, which can then be expressed as a FLC kappa to lambda ratio. Patients without proliferative disorders of plasma cells or B-lymphocytes have normal FLC ratios [71]. In comparison, patients with plasma cell disorders will have greater than expected proportions of kappa or lambda light chains resulting in an abnormal ratio. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)

There is a paucity of data regarding serum FLC assays in patients with WM. While initial studies suggest that FLC levels correlate with other markers of tumor burden [72-74], the role of FLC assays in the diagnosis and determination of treatment response need further clarification in prospective trials.

Laboratory artifacts — Circulating monoclonal protein may interfere with one or more laboratory tests performed on liquid-based automated analyzers, either by precipitating during the analysis, or by virtue of specific binding properties. The most common artifacts are a low value for HDL cholesterol, a high value for bilirubin, as well as altered measurement of inorganic phosphate. Other examples include interference with measurement of LDL cholesterol, C-reactive protein, antistreptolysin-O, creatinine, glucose, urea nitrogen, iron, and inorganic calcium. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Interference with laboratory tests'.)

DIAGNOSIS — The diagnosis of WM is made based on an evaluation of a bone marrow biopsy specimen, analysis of the serum protein components, and consideration of the clinical scenario [75-78].

To make a diagnosis of WM, the following criteria must be met [76,77]:

●An IgM monoclonal gammopathy (of any size) must be present in the serum.

●≥10 percent of the bone marrow biopsy sample must demonstrate infiltration by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation (lymphoplasmacytic features or lymphoplasmacytic lymphoma) with an intertrabecular pattern [77]. The requirement for ≥10 percent marrow infiltration is to differentiate patients with WM from patients with IgM MGUS. Studies show that patients with less than 10 percent marrow involvement have an overall survival similar to or better than the general population, and thus are not served well with a label of malignancy [79]. They have a low risk of progression to symptomatic WM of approximately 1.5 percent per year [80]. It is based on this rationale that these criteria differ from the 2^nd International Workshop criteria, which allows any level of marrow involvement as sufficient to establish a diagnosis of WM [76]. These criteria are also consistent with the International Myeloma Working Group definitions, which consider bone marrow infiltration less than 10 percent as IgM MGUS rather than WM [81].

●This infiltrate should express a typical immunophenotype (eg, surface IgM+, CD5-/+, CD10-, CD11c-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138-). The plasmacytic component will be CD138+, CD38+ and CD45- or dim.

The MYD88 L265P gene mutation has been identified in over 90 percent of patients with WM, and can be of help on differentiating WM from other conditions [21].

Variations from the typical immunophenotype may occur, but the goal is to satisfactorily exclude other lymphoproliferative disorders, including chronic lymphocytic leukemia, marginal zone and mantle cell lymphoma. Details on the morphologic, immunophenotypic, and genetic abnormalities seen in lymphoplasmacytic lymphoma are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma".)

The majority of patients with the histopathologic finding of lymphoplasmacytic lymphoma (LPL) have a circulating monoclonal IgM consistent with the diagnosis of WM. In the past, LPL and WM have been arbitrarily differentiated from each other based on the level of the monoclonal IgM protein. Currently, the preferred terminology in cases of LPL with circulating monoclonal IgM is WM, rather than lymphoplasmacytic lymphoma, regardless of the size of the monoclonal IgM protein.

DIFFERENTIAL DIAGNOSIS — WM must be differentiated from other monoclonal gammopathies and lymphomas. Specifically, WM must be differentiated from IgM monoclonal gammopathy of undetermined significance, multiple myeloma, chronic lymphocytic leukemia, marginal zone lymphoma, and mantle cell lymphoma (table 2 and table 3).

In addition, WM can transform into a more aggressive disease akin to Richter's transformation, typically with elevated serum lactate dehydrogenase levels, chromosomal abnormalities, aneuploid DNA content, immunoblastic morphology, and poor response to therapy [82]. This subject is discussed separately. (See "Histologic transformation of follicular lymphoma".)

Marginal zone lymphoma — The differentiation between WM and IgM-secreting marginal zone lymphoma (MZL) is sometimes difficult as the immunohistochemical features of MZL and WM are similar. In addition, MYD88 mutations can be seen in 5 to 10 percent of patients with MZL. Clinically, MZL is more likely to present with prominent lymphadenopathy, splenomegaly, or extranodal involvement, while WM can exclusively affect the marrow without extramedullary involvement. IgM levels in MZL tend to be lower than in WM, typically lower than 1000 mg/dL. (See "Nodal marginal zone lymphoma".)

IgM monoclonal gammopathy of undetermined significance (MGUS) — Patients with IgM MGUS are diagnosed based on the following criteria [81]:

●Serum IgM concentration <3.0 g/dL.

●The absence of anemia, hepatosplenomegaly, lymphadenopathy, and systemic symptoms.

●Minimal or no lymphoplasmacytic infiltration of the bone marrow. When applying the Mayo Clinic criteria, the overall marrow involvement by such cells should be <10 percent [77].

Detection of MYD88 L265P mutations is not helpful in this distinction; MYD88 mutations are seen in over 90 percent of WM and about 50 percent of patients with IgM MGUS [22].

This subject is discussed in depth separately. (See "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Non-IgM MGUS'.)

Schnitzler syndrome — Schnitzler syndrome is a form of chronic urticaria associated with monoclonal gammopathy of the IgM class, and most often kappa, plus additional features, which may include bone pain, skeletal hyperostosis, arthralgias, lymphadenopathy, and intermittent fevers. There is no specific test for Schnitzler syndrome and clinicians must maintain a high index of suspicion in patients with chronic urticaria and an IgM monoclonal protein in their serum. Identification of these patients is important because many will have resolution of their symptoms following inhibition of the interleukin (IL)-1 pathway. Patients with Schnitzler syndrome have minimal or no lymphoplasmacytic infiltration of the bone marrow; overall marrow involvement by such cells should be <10 percent [83]. (See "Urticarial vasculitis", section on 'Differential diagnosis'.)

Smoldering WM — Patients who meet criteria for WM but do not have any clinical symptoms and lack evidence of anemia, hepatosplenomegaly, lymphadenopathy, or hyperviscosity are considered to have smoldering Waldenström macroglobulinemia. These patients do not require therapy but need to be monitored for disease progression [84]. (See "Treatment and prognosis of Waldenström macroglobulinemia", section on 'Asymptomatic patients'.)

IgM multiple myeloma — Classical multiple myeloma (MM) with an IgM paraprotein is extremely rare, comprising only 0.5 percent of a Mayo Clinic series [85]. IgM MM needs to be distinguished from WM based on clinical and cytogenetic features. A diagnosis of IgM MM requires demonstration of osteolytic lesions and/or a t(11;14) translocation [86]. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Monoclonal proteins'.)

Less than 2 to 3 percent of patients with otherwise classical WM have lytic bone lesions. When present, these patients are usually classified as having IgM MM, rather than WM.

Often, the lymphoplasmacytic lymphoma seen in the bone marrow of patients with WM can be distinguished from plasma cells seen in the bone marrow of patients with MM by the absence of CD56 and the presence of a substantial small lymphocytic component that expresses a clonal surface immunoglobulin.

Cytogenetic abnormalities are helpful making the distinction between IgM MM and WM. MYD88 mutations are seen in WM, and not in MM. In contrast, the t(11;14) translocation is not seen in WM, and its presence is diagnostic of IgM MM. In one study, this translocation was seen in seven of eight patients with IgM MM and in none of 74 patients with WM [87]. (See "Multiple myeloma: Staging and prognostic studies", section on 'Cytogenetic abnormalities'.)

Chronic lymphocytic leukemia — Polyclonal increases in gamma globulins can be seen in up to 15 percent of patients with chronic lymphocytic leukemia (CLL). CLL can be easily differentiated from WM by its immunophenotype.

In contrast to WM, the abnormal B cells in CLL are CD5 positive, CD23 positive, and FMC7 negative. Gene expression profiling studies of WM cells reveal a phenotype more akin to CLL than MM [88]. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Mantle cell lymphoma — In contrast to WM and other indolent non-Hodgkin lymphomas, nuclear staining for cyclin D1 (bcl-1) is present in more than 70 percent of cases of mantle cell lymphoma (MCL). Most MCLs also have t(11;14)(q13;q32), a translocation seen in some cases of MM, but not in WM. In MCL, the clonal cells are characteristically CD5 positive, CD23 negative. In contrast, in WM the clonal population is typically C5 negative and CD23 negative. (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis".)

Amyloidosis — On occasion, patients may have both WM and an IgM-related systemic amyloidosis. The clinical presentation in primary (AL) amyloidosis depends on the number and nature of the organs affected and may include nephrotic syndrome, restrictive cardiomyopathy, peripheral neuropathy, hepatomegaly, macroglossia, or purpura. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Clinical presentation'.)

●One series described 50 patients with an IgM monoclonal protein and systemic amyloidosis [89]. Six (12 percent) had a serum IgM protein concentration >3 g/dL. The majority had an increase of lymphocytes and plasma cells in the bone marrow. In the eight patients in whom it was studied, the amyloid deposits consisted of a monoclonal immunoglobulin light chain, indicating that the amyloidosis was of the primary (AL) type. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

●A retrospective French collection of patients with IgM-related systemic AL amyloidosis has been reported; 53 of the 64 patients (83 percent) had a prior diagnosis of either WM or lymphoplasmacytic non-Hodgkin lymphoma [90]. The median elapsed time between diagnosis of the IgM-related disorder and amyloidosis was eight months (range: 0 to 192 months). (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'IgM-associated AL amyloidosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Waldenström macroglobulinemia".)

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SUMMARY

●Epidemiology – Waldenström macroglobulinemia (WM) is a rare clinicopathologic entity demonstrating infiltration of the bone marrow by clonal lymphoplasmacytic cells and a monoclonal IgM gammopathy in the blood. Patients usually present in their seventh decade with symptoms related to the infiltration of the hematopoietic tissues or the effects of monoclonal IgM in the blood. (See 'Epidemiology' above.)

●Clinical presentation

•Common presentations – WM most commonly presents with symptoms associated with anemia (eg, pallor, weakness, fatigue), systemic complaints (eg, weight loss, fever, night sweats), and organomegaly (eg, enlarged lymph nodes, spleen, and/or liver). In contrast to patients with multiple myeloma, involvement of the bone or kidneys is uncommon. (See 'Overview' above.)

Up to 25 percent of patients may be asymptomatic at diagnosis; such patients are considered to have smoldering WM.

•Hyperviscosity syndrome – An important presentation includes central nervous system signs and symptoms due to the hyperviscosity syndrome (eg, blurring or loss of vision, headache, ataxia, dementia, stroke, or coma). This may be severe enough to constitute a medical emergency, requiring urgent plasmapheresis. (See 'Hyperviscosity syndrome' above and "Treatment and prognosis of Waldenström macroglobulinemia", section on 'Emergency management of hyperviscosity'.)

Classic findings associated with hyperviscosity in WM is the presence of oronasal bleeding and dilated, segmented, and tortuous retinal veins, giving a "sausage link" appearance (picture 1). (See 'Funduscopic abnormalities' above.)

•Neurologic presentations – Another major presentation is that of peripheral neurologic symptoms such as paresthesias and weakness. Other neurologic complaints may include Bing-Neel syndrome and present with cranial nerve palsies, atypical neuropathic complaints, headaches, low back pain and motor deficits, and others. (See 'Neuropathy' above.)

●Diagnosis – The diagnosis of WM is made based on an evaluation of a bone marrow biopsy specimen, analysis of the serum protein components, and consideration of the clinical scenario. (See 'Diagnosis' above.)

The diagnosis of WM is made when the following criteria are met:

•Presence of an IgM monoclonal paraprotein on serum immunofixation. (See 'Serum protein electrophoresis' above.)

•The bone marrow biopsy sample must demonstrate ≥10 percent infiltration by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation (lymphoplasmacytic features or lymphoplasmacytic lymphoma) with an intertrabecular pattern. This infiltrate should express a typical immunophenotype (eg, surface IgM+, CD5-/+, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138-). (See 'Bone marrow examination' above.)

•MYD88 L265P mutations can also be seen in over 90 percent of patients with WM and can help differentiating WM from other conditions. MYD88 L265P mutations can also be seen in about 50 percent of patients with monoclonal gammopathy of undetermined significance (MGUS).

●Differential diagnosis – The differential diagnosis includes other monoclonal gammopathies and lymphomas. Specifically, WM must be differentiated from IgM MGUS, multiple myeloma, chronic lymphocytic leukemia, marginal zone lymphoma, and mantle cell lymphoma (table 3). (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who contributed to an earlier version of this topic review.