Recommendations for the diagnosis and initial evaluation of patients with Waldenström Macroglobulinemia: A Task Force from the 8^th International Workshop on Waldenström Macroglobulinemia

Abstract

The diagnosis of Waldenström macroglobulinemia (WM) can be challenging given the variety of signs and symptoms patients can present. Furthermore, once the diagnosis of WM is established, the initial evaluation should be thorough as well as appropriately directed. During the 8th International Workshop for WM in London, United Kingdom, a multi-institutional task force was formed to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, we present the results of the deliberations taken place to address these issues. We provide recommendations for history taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis and imaging studies. We also provide guidance on the initial evaluation of special situations such as anemia, hyperviscosity, neuropathy, Bing-Neel syndrome and amyloidosis. We hope these recommendations serve as a practical guidance to clinicians taking care of patients with a suspected or an established diagnosis of WM.

Introduction

Waldenström Macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the accumulation of malignant immunoglobulin Type M (IgM)-producing lymphocytes, and lymphoplasmacytic and plasma cells [1]. WM is a rare lymphoma with incidence estimated at 3 new cases per 1 million individuals, or approximately 1,000 new cases per year in the United States [2]. Despite an incurable disease course, there have been improvements in survival in patients with WM, in whom the median survival has increased from 5 to 8 years over the last decade [3, 4]. Some WM patients can experience prolonged survival times measuring up to decades. It is important to mention, however, that clinical factors such as age and hemoglobin levels, among others, can help identify patients with WM who will have better and worse prognosis [4].

In patients with WM, the clinical presentation can be highly variable [5]. The signs and symptoms of the disease are due to the infiltration of the bone marrow and/or other lymphoid organ by the lymphoplasmacytic cells but also due to the specific immunological and physicochemical properties of the monoclonal IgM. The clinical presentation is variable, and may include symptomatic cytopenias, peripheral neuropathy, hyperviscosity, extramedullary disease, or cryoglobulinemia, cold agglutinemia, among other clinical findings. In addition, a substantial proportion of patients are asymptomatic at the time of diagnosis.

Given the heterogeneous clinical presentation, it is paramount to evaluate patients with WM appropriately at diagnosis in order to guide management decisions. During the 8^th International Workshop for WM (IWWM-8) in London, UK (www.wmworkshop.org), a Task Force was formed with the purpose of providing guidance for the initial evaluation of patients with suspected or established diagnosis of WM. This evaluation aims to define disease characteristics accurately and to recognize disease-related complications.

Essential evaluation

A summary of the Task’s recommendation for essential tests to be performed in patients with WM is shown in Table 1.

Table 1.

Essential evaluation of patients with Waldenström Macroglobulinemia.

Evaluation
History & physical examination
Include funduscopic examination
Laboratory studies:
Complete blood count
Complete metabolic panel
Serum immunoglobulin levels (IgA, IgG, IgM)
Serum and urine electrophoresis with immunofixation
Serum viscosity
Serum beta-2-microglobulin level
If clinically indicated:
Cryoglobulins
Cold agglutinin titer
Von Willebrand screening
24-hour urine protein quantification
Bone marrow aspiration and biopsy
Immunohistochemistry
Flow cytometry
Include testing for MYD88 L265P gene mutation
Computed tomography scans of the chest, abdomen and pelvis with IV contrast
In patients being considered for therapy

History and physical

History-taking and physical examination are essential components of the initial evaluation of patients with WM

Appropriate and careful history taking should provide valuable information regarding the presence of constitutional symptoms such as fevers, night sweats or unintentional weight loss. Additional symptoms commonly reported by patients with WM include fatigue, malaise and shortness of breath, usually associated with anemia, and increased bleeding or bruising that can be associated with thrombocytopenia or acquired von Willebrand disease (vWD) [6]. Symptoms associated with hyperviscosity can include spontaneous epistaxis, new-onset headaches, blurred vision that does not correct with glasses, vertigo and tinnitus [7]. Funduscopic examination should be performed during the initial physical examination to evaluate for the presence of hyperviscosity. WM-related peripheral neuropathy is usually characterized by bilateral and symmetrical reduction of sensory function of the feet and hands and, if advanced, may contribute to gait disorder, difficulties in handling small objects or writing [8]. A history of rash may be indicative of cryglobulinemia, while complaints of urticarial rash may also raise the suspicion of Schnitzler’s syndrome. A family history of WM or other lymphoproliferative disorders should also be sought as it may have negative prognostic implications [9, 10]. Recommended actions based on findings in the review of systems are shown in Table 2.

Table 2.

Review of systems in patients with Waldenström macroglobulinemia

Symptom/Complaint	Implications	Action
Fatigue, lack of energy	Anemia	Evaluate for anemia, including iron, folate or cobalamin deficiency, hemolytic anemia (warm and cold antibodies), etc. Patients with iron deficiency may benefit with parenteral iron.
Constitutional symptoms	Disease progression	Obtain serum IgM levels and SPEP. Evaluate other causes of fever, night sweats and unintentional weight loss.
Recurrent sinus and bronchial infections	Hypogammaglobulinemia	Antibiotic support. If patient refractory to antibiotics, required hospitalization, or infections were life threatening, consider IVIG replacement
Headaches, blurry vision or visual loss, confusion, epistaxis	Hyperviscosity	Funduscopic examination, obtain serum IgM and serum viscosity levels. Consider emergent plasmapheresis for symptomatic hyperviscosity.
Easy bruising, bleeding diathesis	Thrombocytopenia; acquired Von Willebrand disease (vW	Complete blood count, evaluate for immune thrombocytopenia or hypersplenism if indicated; consider evaluation for VWD; consider amyloidosis. Evaluate other bleeding diathesis.
Progressive symmetrical numbness, tingling, burning, pain feet and hand	IgM-related neuropathy; amyloidosis	Obtain EMG studies and neurology consult. Obtain anti-MAG, and if negative anti-GM1 and anti-sulfatide IgM antibody studies. Consider fat pad biopsy and Congo red stain for amyloidosis. Evaluate other causes of neuropathy: diabetes, thyroid dysfunction, HIV infection, cobalamin deficiency, etc.
Raynaud-like symptoms, acrocyanosis, ulcerations on extremities	Cryoglobulinemia; cold agglutinemia	Obtain cryoglobulins and cold agglutinins. In patients suspected of having cryoglobulins, IgM should be obtained in a warm bath to avoid cryoprecipitation. Consider emergent plasmapheresis
Diarrhea, gastrointestinal cramping	Malabsorption	Endoscopy to evaluate small bowel, biopsy to evaluate for amyloidosis, IgM deposition, tumor involvement. Evaluate other causes of diarrhea.
Foamy urine, bipedal edema	Kidney dysfunction	Obtain serum free light chains, 24-hour urine protein, and consider kidney biopsy. Evaluate other causes of kidney dysfunction.
Urticaria, papules, dermatitis	Schnitzler’s syndrome, IgM or tumor cell infiltration, amyloid deposition	Skin biopsy, histological examination for tumor cell infiltration, stain for IgM, Congo-red staining for amyloid. Evaluate other causes of rash.

The physical examination may reveal lymphadenopathy as well as hepatosplenomegaly, which can produce upper quadrant abdominal discomfort and/or early satiety. Rarely, Raynaud’s phenomenon or ulcers of the legs or tip of the nose and ears can be manifestations of cryoglobulinemia [7]. Also rarely, darkening of the urine after exposure to cold may be a manifestation of cold agglutinemia [11]. Skin should be surveyed looking for rash, purpura or bruising. A neurological examination should be performed to evaluate for sensory and/or motor neuropathy. However, this task force would like to emphasize that no sign or symptom is pathognomonic of WM. Nonetheless, the presence of particular signs or symptoms can be helpful on directing additional workup.

Laboratory studies

Essential initial laboratory studies include complete blood count (CBC), complete metabolic panel (CMP), quantitative immunoglobulins, serum and urine protein electrophoresis (SPEP and UPEP) with immunofixation, serum viscosity and beta-2-microglobulin

The CBC may identify anemia, leucopenia/neutropenia and/or thrombocytopenia. Thrombocytopenia can be secondary to bone marrow involvement, autoimmune destruction and/or hypersplenism. Peripheral blood evaluation shows rouleaux formation, and in some cases lymphoplasmacytoid cells can be observed. Lymphocytosis, however, is an infrequent event in WM patients. Macrocytosis may be due to rouleaux or associated with hemolysis due to cold agglutinin disease or autoimmune hemolytic anemia. In some cases, a high IgM level can be associated with artificially low hemoglobin levels due to volume expansion [12], in which cases transfusions of red blood cells should be avoided as it can dangerously increase serum viscosity. CMP can indicate abnormal kidney function, which can be associated with deposition of LPL cells, IgM, light chains, cryoglobulins or amyloid [13], as well as hepatic dysfunction.

The measurement of serum IgM levels is a helpful indirect marker of LPL infiltration of the bone marrow, and can be used to follow progression or response to therapy [5]. However, serum IgM does not correlate perfectly with tumor burden. In about 70% of WM patients, subnormal levels of uninvolved serum immunoglobulin (IgA and/or IgG) can be seen at diagnosis [14]. SPEP with immunofixation can identify an IgM monoclononal (M) protein. It is essential that immunofixation be obtained in all cases, since small quantities of IgM may be overlooked if only quantitative measurements are performed. In a few patients, two M-spikes can be identified, which may represent monomeric and pentameric forms of IgM and not necessarily true biclonality. In other cases, the IgM M-spike might migrate into the beta region rather than the gamma region and could be difficult to quantitate. Finally, in a minority of cases, true bi- or triclonality can be observed as well as class switching with corresponding IgG or IgA M-spikes. Serum viscosity can be useful in specific situations, especially in cases with high IgM or if hyperviscosity is suspected clinically [15]. The role of serum free light chain measurement in patients with WM is under investigation [16], and is recommended only in special situations (i.e. suspicion of light chain amyloidosis).

A 24-hour urine analysis with measurement of the total 24h protein and electrophoresis should be considered in the initial evaluation. Urine electrophoresis and immunofixation may reveal Bence Jones proteinuria (free monoclonal light chains), although this is observed less frequently than in multiple myeloma. Cases of cast nephropathy due to light chain proteinuria have been described [13, 17]. Significant albuminuria may indicate AL amyloidosis (and rarely AA amyloidosis) and serum free light chains should be measured and followed.

Serum beta-2-microglobulin level should be obtained, as it is a prognostic marker for survival and a component of the International Prognostic Scoring System for WM (IPSSWM) [4]. The IPSSWM also includes age, hemoglobin, platelet count and M-spike size, and is used to classify patients with symptomatic disease requiring therapy into low, intermediate and high-risk groups. If clinically indicated, vWD screening (i.e. VW antigen, ristocetin cofactor and FVIII level) should be obtained, as acquired vWD has been identified in some cases of WM. High von Willebrand factor levels have been associated with worse prognosis in patients with WM [18].

Serum viscosity might be useful in assessing patients with hyperviscosity symptoms [15, 19]. However, serum viscosity levels may be slow to be reported, not reproducible or lack correlation to serum IgM levels. Serum IgM levels are more expedient and reliable for assessing patients with suspected hyperviscosity syndrome. Funduscopic examination should be done in all patients with serum IgM >3,000 mg/dl and in those patients with suspected hyperviscosity syndrome.

Bone marrow aspiration and biopsy

Bone marrow aspiration and biopsy is essential for the diagnosis of WM, and should be evaluated by immunohistochemistry and flow cytometry as well as the presence of the MYD88 L265P gene mutation

The presence of elevated IgM levels or an IgM M-spike is not sufficient for the diagnosis of WM [20]. IgM monoclonal gammopathy of undetermined significance (MGUS), IgM myeloma, AL amyloidosis, and other B-cell malignancies with plasmacytic differentiation, such as marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL) or mantle cell lymphoma (MCL), are all included in the differential diagnosis of WM. Bone marrow aspiration and biopsy must be performed in case of IgM monoclonal gammopathy to make the diagnosis of WM and exclude other IgM-related diseases. Conversely, a diagnosis of LPL in the absence of a monoclonal IgM paraprotein does not fulfill the criteria for WM. The typical appearance of WM in a bone marrow biopsy includes the presence of an excess of kappa or lambda light chain restricted lymphocytes, lymphoplasmacytoid forms and plasma cells [1]. The pattern of infiltration on trephine biopsy sections is typically interstitial, nodular or diffuse while a purely paratrabecular pattern is unusual. The presence of mast cells in the marrow microenvironment favors a diagnosis of WM. In addition to its use in the initial evaluation, tissue biopsy is recommended in all WM patients with suspected histological transformation.

Immunophenotypic evaluation must be performed on bone marrow samples. Based on immunohistochemistry and flow cytometry, which are considered complementary, lymphocytes and lymphoplasmacytic cells express IgM, kappa or lambda, CD19, CD20 and weak CD22 as well as homogeneous CD25 [21, 22]. In approximately 10%-20% of the cases, WM cells can express CD5 (typically seen in CLL and MCL), CD23 (typically seen in CLL) or CD10 (typically seen in FL). Immunophenotyping should also demonstrate the presence of a monoclonal plasma cell component that expresses CD38 or CD138, lacks typical myelomatous antigenic aberrancies, and shows the same restricted light chain expression (kappa or lambda) as the lymphoplasmacytic component. WM plasma cells lack the phenotypic characteristics of myeloma plasma cells (e.g., WM plasma cells express CD19), which is helpful in the differential diagnosis [23]. Cytogenetic analysis is not required for the routine diagnostic assessment of WM patients as it is difficult to obtain tumour metaphases in vitro [24]. There are no disease-defining cytogenetic abnormalities. Deletion 6q and trisomy 4 are frequent cytogenetic abnormalities described in WM [24–27]. Conventional cytogenetic or FISH studies may be useful, however, in the differential diagnosis. For example, IgM myeloma is characterized by high incidence of t(11;14) [28, 29].

The bone marrow aspirate should be evaluated for the MYD88 L265P gene mutation, which is present in over 90% of patients with WM [30], and can help in cases in which a diagnosis of WM is suspected but uncertain. The presence of the MYD88 L265P mutation, however, is not diagnostic of WM, as approximately 50–80% of patients with IgM MGUS also carry the mutation [31, 32]. Importantly, a minority (5–10%) of patients who fulfill the immunophenotypic and clinical criteria of WM may not have the MYD88 L265P gene mutation (wild-type MYD88). In these patients, the diagnosis of WM should not be excluded based only on the absence of the MYD88 L265P mutation. Rare MYD88 non-L265P mutations have been reported by using MYD88 gene sequencing [33]. The absence of MYD88 mutation may be associated with an inferior survival outcome [34]. No standardized method for the detection of the mutation yet exists. For example, allele-specific and reverse transcriptase PCR, among other methodologies, are used by different laboratories with various primers and detection limits. The use of CD19+ selected cells from peripheral blood has also been investigated but not standardized, and some false negative cases can be expected [35]. Physicians should use the method with which their laboratory is most experienced, and the method and detection limits should be reported.

More recently, somatic mutations in the CXCR4 gene, similar to the mutations seen in the Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome, have been described in approximately 30–40% of patients with WM [36–39]. In contrast to the MYD88 L265P recurrent point mutation, there are multiple CXCR4-WHIM mutations, making the development of a PCR-based assay difficult. There is evidence that CXCR4 mutations can confer resistance to ibrutinib [34, 40]. The task force does not support routine testing for CXCR4-WHIM mutations at this time, but recommends to do it in the context of clinical trials in order to assess the impact of CXCR4-WHIM mutation status on treatment outcomes.

Computed tomography

Computed tomography (CT) of the chest, abdomen and pelvis with the intravenous administration of contrast is essential for the initial staging of patients with WM who are being considered for treatment initiation

WM is typically a disease of the bone marrow. Approximately, 10–15% of patients, however, may have extramedullary disease such as lymphadenopathy, hepatosplenomegaly or pleural effusions on physical examination at time of diagnosis. The presence of adenopathy may be present in up to 60% of patients at time of relapse [12]. The presence of splenomegaly based on measurements using CT should be interpreted cautiously in patients with modest increases in splenic size. Baseline evaluation and re-assessment may be useful if an IgM flare needs to be differentiated from disease progression [41, 42]. The panel recommends an initial assessment of the presence of extramedullary disease by imaging. If lymphadenopathy or organomegaly are found, then imaging during or after completion of therapy is advised. The role of positron emission tomography (PET)/CT imaging has not been established in WM and only a single published study exists [43]. Thus, the task force does not currently support the routine use of PET/CT for diagnosis or follow-up of the disease. However, PET/CT scanning can be useful in cases of aggressive transformation of WM, since the most common histology is diffuse large B-cell lymphoma (DLBCL) [44, 45]. If aggressive transformation is suspected, biopsy for pathological evaluation is essential to exclude other pathologies such as solid malignancies, reactive processes or clonally unrelated lymphomas [45]. Staging and therapy should follow current DLBCL management guidelines.

Special situations

Anemia

Anemia occurring in patients with WM can be multifactorial and needs to be evaluated appropriately, with specific attention to absolute and functional iron deficiency states

Anemia is the most common reason patients with WM seek medical attention and the most common reason to initiate treatment. In patients with WM, anemia can occur due to the replacement of the bone marrow by malignant cells, iron deficiency and hemolysis. In some cases, high IgM levels can induce plasma volume expansion generating a “dilutional” anemia. In some cases of anemia, the picture is consistent with an absolute iron deficient state (low iron saturation and low serum ferritin levels). In other cases, the picture is consistent with functional iron deficiency (low iron saturation and normal or high serum ferritin levels). When absolute iron deficiency is identified in patients with WM for whom anemia is the only criterion for initiation of therapy, gastrointestinal bleeding should be excluded. Since many patients with WM are elderly, a second malignancy (e.g. colon cancer) could co-exist. There are data describing excess secretion of hepcidin by WM cells [46]. Hepcidin is a regulator of the content of serum iron content, and its excess results in decreased iron absorption, increased iron storage, and inability to reutilize the stored iron. Since hepcidin blocks the absorption of iron, intravenous supplementation of iron may be useful [47].

Rarely, anemia may be due to an autoimmune hemolytic process. The Coombs test is positive in about 10% of WM patients overall, but less than 5% of patients develop significant hemolysis [48]. In such cases, performing a hemolytic workup including reticulocyte counts, lactate dehydrogenase, haptoglobin and direct Coombs test are useful to evaluate for warm or cold autoimmune hemolytic anemia. Cold agglutinins should also be measured, if clinically indicated by the presence of hemoglobinuria after cold exposure. Other causes of anemia such as cobalamin and folate deficiency, chronic renal, hepatic or thyroid dysfunction, non-autoimmune hemolytic anemia, or other primary bone marrow processes should be pursued, if clinically suspected, especially in elderly patients. Recommendations on the evaluation of anemia in WM patients are shown in Table 3.

Table 3.

Initial evaluation of anemia in patients with Waldenström Macroglobulinemia

Evaluation
Laboratory studies:
Iron, TIBC, ferritin*
Creatinine and estimated GFR
Liver function tests
Thyroid stimulating hormone
Cobalamin (vitamin B12)
Folate
Reticulocyte count, LDH, haptoglobin
In special situations:
Cold agglutinin titer
Direct Coombs test
Erythropoietin

^*In iron deficiency, esophagogastroduodenoscopy and/or colonoscopy should be considered.

Hyperviscosity

Symptomatic hyperviscosity can herald catastrophic events such as CNS or retinal bleeding resultin in loss of vision, and should be promptly managed with plasmapheresis and WM-directed therapy

Symptomatic hyperviscosity is not a rare complication of WM and is characterized by an increased serum viscosity due to high serum IgM levels. The clinical presentation of hyperviscosity is variable but symptoms may include spontaneous epistaxis, new-onset headaches, blurred vision that does not correct with glasses, hearing loss, tinnitus and vertigo [15]. Measurement of serum viscosity should be obtained by the Oswalt method and carefully evaluated along with clinical symptoms and signs. However, serum viscosity levels may be slow to be reported, and often are not reproducible or lack correlation to serum IgM levels. Serum IgM levels are more expedient and reliable for assessing patients with suspected hyperviscosity syndrome. The presence of cryoglobulins (discussed below) may further aggravate serum viscosity levels, and should be examined in any patient suspected of hyperviscosity. Although routine funduscopic examination is highly encouraged in any patient with WM at first evaluation, this panel recommends that patients with WM and serum IgM levels higher than 3,000 mg/dL should also undergo a formal funduscopic evaluation by an experienced ophthalmologist to identify vessel tortuosity, “sausaging” or retinal hemorrhages. These findings would strongly suggest the need for immediate therapy. Retinal evaluation should be performed every 6–12 months as clinically indicated.

In some cases, the presence of cryoglobulins might render falsely low serum IgM levels [7]. In this situation, maintaining the serum sample in a 37°C warm bath might provide a more reliable serum IgM level measurement. Cryoglobulinemia can often manifest through acrocyanosis, palpable purpura, livedo reticularis, non-healing ulcers in the lower extremities and discoloration of the tip of the nose and ears upon cold exposure. Type I cryoglobulinemia is usually associated with lymphoproliferative disorders. Type II cryoglobulinemia is often associated with hepatitis C virus infection. When suspected, a test for cryoglobulins should be obtained. Plasmapheresis will rapidly remove cryoglobulins and IgM and decrease the serum viscosity.

Neuropathy

WM-associated peripheral neuropathy (PN) can have multiple etiologies, and the panel strongly recommends consultation with neurologist with expertise in neuropathy for evaluation and co-management of WM patients with PN

It is important to note that patients with WM can have other unrelated causes for neuropathy that need to be appropriately evaluated. The differential diagnosis for PN includes radiculopathy, diabetic neuropathy, cobalamin deficiency, thyroid dysfunction, HIV infection, Lyme disease, autoimmune processes such as systemic lupus erythematosus, vasculitis or CIDP. Up to 20% of patients with WM may have PN, which may be due to lymphoplasmacytic infiltration of the nerve fibers, IgM deposition, autoantibodies, cryoglobulinemia or amyloidosis. The most common clinical presentation is a sensory PN presenting with slowly progressing bilateral and symmetrical numbness of the feet, associated with a demyelinating process [8]. In a portion of patients with demyelinating PN, anti-myelin-associated globulin (MAG) antibodies are detectable in the serum and should be evaluated [49]. Anti-GM1 antibodies should also be evaluated in WM patients with motor neuropathy [50]. Axonal degeneration has also been described in patients with WM with sensorimotor PN, and can be secondary to long-standing demyelinating processes. Amyloidosis is typically associated with axonal degeneration. Small fiber neuropathy (SFN) can also be seen in WM patients, and is characterized by a sensation of burning or electrical shocks of soles and palms, especially at night. In these patients, physical examination and appropriate laboratory studies, neurological evaluation and electromyography/nerve conduction studies (EMG/NCS) should be performed. Skin biopsies are sometimes performed to diagnose SFN. However, these have low sensitivity, and the diagnosis of SFN remains largely clinical. Nerve biopsies are associated with permanent neurological deficits. This task force discourages clinicians from routinely performing skin or nerve biopsies in patients with WM-associated PN.

Bing-Neel syndrome (BNS)

BNS refers to involvement of the central nervous system (CNS) with lymphoplasmacytic cells, and is recognized in approximately 1% of patients with WM

Approximately 50% of the patients diagnosed with BNS will succumb due to disease progression within 2 years of diagnosis [51, 52]. BNS should be suspected in patients with WM who develop central neurological deficits. These symptoms include motor deficits, altered mental status, cranial nerve deficits, seizures, headaches and atypical PN. Based on recent case series, BNS can present at any time during the course of the disease [51, 52]. BNS can also present when patients are receiving WM-directed therapy, and even when in apparent complete response. The evaluation of these patients should include brain and whole spine MRI with gadolinium enhancement, and lumbar puncture to obtain cerebrospinal fluid (CSF). CSF should be sent for cytology, flow cytometry and molecular studies including PCR for IGH gene rearrangement and MYD88 L265P gene mutation. In patients with focal brain lesions without CSF involvement, a biopsy should be performed, whenever possible, to rule out other malignancies.

Amyloidosis

Amyloidosis is an uncommon complication seen in patients with WM and is associated with higher rates of morbidity and mortality

Amyloidosis consists of the accumulation of amyloid fibrils, which are composed of misfolded proteins. Amyloid fibrils can deposit in many organs, but most commonly in the kidneys, heart, liver and peripheral nerves. There are several types of amyloidosis [53]. The most commonly associated with WM is light chain amyloidosis (AL); however, although infrequent (4%), WM and other IgM-secreting lymphomas can be associated with reactive, AA amyloidosis, not AL amyloidosis, with important practical implications [54]. Amyloidosis can present as a systemic disease and, when suspected, material obtained from a fat pad biopsy or a bone marrow biopsy should be stained with Congo Red. Amyloid produces an apple-green birefringence on microscopic examination under polarized light. In a few cases, however, obtaining a biopsy of the affected organ might be necessary. With the exception of cases with a clinical presentation clearly suggesting AL-type amyloidosis (e.g. soft tissue involvement, or combination of nephrotic syndrome and heart involvement), amyloid typing is recommended. Amyloid typing should be performed preferably using mass spectrometry [55, 56]. If mass spectrometry is not available, immunoelectron microscopy or immunohistochemistry performed in specialized laboratories may be used [57, 58]. Once a diagnosis of amyloidosis is obtained, appropriate workup includes 24-hour urine protein analysis to evaluate for previously non-apparent renal involvement, and serum free light chain concentration, which can serve as a marker for response and/or progression. Obtaining troponin and brain natriuretic peptide levels is necessary to evaluate cardiac involvement and for prognostic assessment.

Conclusion

WM patients can have a wide variety of clinical signs and symptoms as well as laboratory findings. This Task Force aimed to present complete but concise data to help clinicians to diagnose and evaluate patients with WM. Because WM is a rare disease, most of the recommendations presented here arise from expert consensus opinion. We therefore hope that this report will instigate research focused on improving the diagnostic accuracy as well as identifying areas for improvement in the evaluation of patients with WM.