Approach

The diagnostic workup of Waldenström macroglobulinemia (WM) includes a full history and physical exam, laboratory tests (including studies to detect and quantify monoclonal immunoglobulin M [IgM] in the serum), bone marrow evaluation (including morphologic, immunophenotypic, and genetic analysis), and imaging.

History

A careful history should be taken to identify signs/symptoms associated with WM, especially as these may be nonspecific. It is important to take a thorough family history as familial clustering has been observed.[11][26]

Patients may be asymptomatic, or have signs/symptoms associated with tumor infiltration (in the bone marrow or other organs) and/or monoclonal IgM.

Common presenting signs/symptoms include:[4][29]​​[30][31]

  • Fatigue, weakness, and shortness of breath (due to anemia caused by bone marrow infiltration, or less commonly cold hemolytic anemia [cold agglutinin disease] caused by autoimmune activity of monoclonal IgM to red blood cells at cooler temperatures)

  • Anorexia

  • Infections

  • Peripheral neuropathy.

Fatigue and anorexia are the most common presenting symptoms of WM.[4]

Less common presenting signs/symptoms include:

  • B-symptoms (weight loss, fevers, night sweats)

  • Hyperviscosity (e.g., skin and/or mucosal bleeding, headache, blurred vision, dizziness, vertigo, tinnitus, thrombosis [stroke, angina, myocardial infarction, pulmonary embolism, deep vein thrombosis]).

​Serum viscosity is raised in patients with WM due to elevated IgM in the serum.[30][32]​​​​[33]​​ However, symptoms of hyperviscosity are observed in a minority of patients at diagnosis, and usually appear when serum IgM level is ≥3 g/dL.[34] 

Other presenting features

Interaction of IgM with coagulation factors can disturb clotting and bleeding times (e.g., resulting in acquired von Willebrand disease). IgM may also coat platelets, thereby impairing their function. This can give rise to bleeding from mucous membranes.[32]

Raynaud syndrome, arthralgia, purpura, and skin ulcers may occur due to cryoglobulinemia caused by circulating IgM undergoing precipitation at cooler temperatures. Cryoglobulins may be detected in 20% of WM patients, but less than 5% of patients present with symptoms.[32]​ Raynaud syndrome may also be associated with cold hemolytic anemia (cold agglutinin disease).

High-output cardiac failure may develop because of the expanded plasma volume arising from increased osmotic pressure, but this is rare.

IgM deposition can occur in glomerular loops (presenting as proteinuria), in the intestine (presenting as diarrhea), and in the skin (presenting as macroglobulinemia cutis papules and nodules), but this is rare. Primary amyloidosis (due to deposition of monoclonal light chains in tissue and organs) is rare and occurs mainly in the heart, peripheral nerves, kidneys, soft tissues, liver, and lungs (in descending order of frequency).

Physical exam

Although nonspecific, physical findings that support the diagnosis of WM include:[35]

  • Lymphadenopathy, usually low volume (i.e., not bulky)

  • Retinal changes caused by hyperviscosity (e.g., dot and blot hemorrhages, tortuous blood vessels, venous "sausaging," and/or optic disk edema).

  • Hepatomegaly (clinically significant hepatomegaly is rare)

  • Splenomegaly (rarely palpable)

  • Purpura (uncommon)

Initial laboratory workup

The following baseline laboratory tests are recommended:[30][36][37]​​

  • CBC with differential: includes evaluation of mean corpuscular volume (MCV) and reticulocyte count for evidence of autoimmune hemolysis

  • Assessment of hematinics (iron, vitamin B12, and folate levels): to exclude other common causes of anemia

  • Peripheral blood smear

  • Comprehensive metabolic panel (including serum blood urea nitrogen [BUN], serum creatinine, electrolytes, serum albumin, and liver function tests [LFTs])

  • Serum lactate dehydrogenase (LDH)

  • Serum beta-2 microglobulin

  • Serum uric acid.

These baseline tests can help guide diagnosis and inform prognostication and risk stratification.

Important prognostic markers used for risk stratification include serum albumin, serum LDH, and serum beta-2 microglobulin. See Criteria.

Confirmatory diagnostic tests

A definitive diagnosis of WM requires confirmation of monoclonal IgM in the serum (any concentration) and bone marrow infiltration by malignant lymphoplasmacytic cells.[38]

The following laboratory tests should be carried out to confirm monoclonal IgM in the serum:

  • Serum quantitative immunoglobulins: to quantify the amount of immunoglobulins in the serum. The concentration of serum IgM is not in itself a criterion for diagnosis but can guide diagnosis and must be interpreted in the context of the other clinical and laboratory findings.

  • Serum protein electrophoresis with immunofixation: to detect and confirm monoclonal IgM (and the type of light chain: kappa or lambda) in the serum.

Bone marrow evaluation

A bone marrow aspirate and biopsy should be carried out, followed by careful morphologic assessment and immunophenotypic analysis of the biopsy specimens (using flow cytometry and immunohistochemistry).

Diagnosis is confirmed if there is bone marrow infiltration by malignant lymphocytes with morphologic and immunophenotypic features consistent with lymphoplasmacytic lymphoma (LPL).[1][2]​​[39][40]

The diagnosis of LPL and WM overlap, with the presence of monoclonal IgM in the serum differentiating WM from LPL (according to the WHO classification). See Classification.

Morphologic features of LPL/WM include infiltrating small lymphocytes, lymphoplasmacytes, and plasma cells.[39][40][41]​ The pattern of bone marrow infiltration may be diffuse, interstitial, or nodular, and is usually intertrabecular.

Typical immunophenotypic markers include: CD5±, surface immunoglobulin (sIgM)+/intermediate, CD20+, CD19+, CD22+, CD23-, CD10-, CD38+, CD25+, CD27+, FMC7+, CD103-, and CD138-.[30][37]​​​ Because of ambiguity of CD5, special care must be taken to exclude CD5+ entities such as chronic lymphocytic leukemia and mantle cell lymphoma.[38][42]

Genetic mutation testing

Testing of biopsy samples for the MYD88 L265P mutation (e.g., using allele-specific polymerase chain reaction) is recommended in all patients as it has diagnostic, prognostic, and therapeutic implications.[36][37]​​[43]​​​ This mutation occurs in over 90% of patients with WM and can be used to differentiate WM from other B-cell lymphomas.[17]​​[24][43]​​​ The minority of patients who lack the MYD88 mutation have a worse prognosis and are less responsive to treatment with Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib, zanubrutinib).[18][24]

Testing for the CXCR4 mutation may be considered if treatment with a BTK inhibitor is planned.[36][37] This mutation occurs in approximately 30% of patients with WM.[20][22]​​ It is thought to be an activating mutation in WM, and is found in WM patients who have a MYD88 mutation.[21] Patients with the MYD88 mutation who lack the CXCR4 mutation may have the best response to BTK inhibitors.[18]

If there are existing genetic test results, do not order a duplicate test unless there is uncertainty about the existing result, for example, the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[44]

Imaging

CT scans of the chest, abdomen, and pelvis should be obtained at diagnosis to detect splenomegaly and lymphadenopathy, and to stage the patient.[36][37]

18F-fluorodeoxyglucose PET/CT scan of the chest, abdomen, and pelvis is valuable in assessing patients with suspected high-grade transformation where avid PET uptake is seen at sites of possible transformed disease; however, a biopsy is required to confirm disease transformation. It may also be used to better determine tumor burden and monitor response to therapy.[45]

Skeletal surveys and bone scans are not necessary in the absence of symptoms because lytic bone lesions are not a feature of WM.[35]​​

Additional tests to consider

The following tests may be considered as part of the diagnostic workup:[35][36][37]

  • Twenty-four-hour urine for total protein and urine protein electrophoresis with immunofixation, if renal dysfunction or amyloidosis is suspected.

  • Serum free light chain assay, if renal dysfunction (e.g., cast nephropathy) or amyloidosis is suspected.

  • Serum viscosity (SV), if symptoms of hyperviscosity are present or if IgM is high.

  • Cold agglutinins and cryoglobulins, if clinically suspected.

  • Viral serology for hepatitis B and C, and HIV. It is important to test for these infections before initiating treatment with chemotherapy and targeted therapies (e.g., rituximab, ibrutinib) because these treatments can lead to reactivation of hepatitis and worsen the infective risk with HIV.

  • Neurologic antibody testing (including antimyelin-associated glycoprotein [anti-MAG] antibodies, antiganglioside M1 [anti-GM1] antibodies, antisulfatide IgM antibodies), nerve conduction study/electromyography, and referral to a neurologist are indicated if peripheral neuropathy is suspected. The presence of anti-MAG, anti-GM1, or antisulfatide IgM antibodies supports the diagnosis of IgM-related neuropathy. Their absence does not exclude the diagnosis.

  • Fat pad biopsy with Congo red staining, if amyloidosis is suspected (e.g., those presenting with unexplained cardiac problems, neuropathy, renal dysfunction). Amyloid typing (e.g., using mass spectrometry) may be warranted to confirm amyloid type. See Amyloidosis.

  • Retinal exam, if IgM level is ≥3.0 g/dL or if hyperviscosity is suspected.

  • Clotting assays (including prothrombin time and activated partial thromboplastin time) to assess for acquired von Willebrand disease, if significant bruising or bleeding is present.

  • Lymph node biopsy, if there is concern for high-grade transformation.

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