Tests
1st tests to order
CBC with differential
Test
Used for baseline assessment and for follow-up of disease course and treatment.
Includes evaluation of MCV and reticulocyte count for evidence of autoimmune hemolysis.
Result
anemia; other cytopenias are less common
iron, vitamin B12, and folate
Test
Important to exclude other common causes of anemia (e.g., iron deficiency, vitamin B12 deficiency, and folate deficiency).
Result
normal iron, vitamin B12, and folate levels
peripheral blood smear
Test
May show stacked red blood cells (Rouleaux formation) due to elevated serum proteins.
Result
Rouleaux formation
serum BUN, creatinine, electrolytes
Test
Used for baseline assessment and periodically during treatment and follow-up.
Result
usually normal (indicating normal renal function); patients may have renal dysfunction due to cast nephropathy or infiltration but this is rare
LFTs
Test
Liver can be infiltrated by malignant lymphoplasmacytic cells, causing organ dysfunction.
Result
usually normal
serum albumin
serum LDH
serum beta-2 microglobulin
serum uric acid
Test
Used for baseline assessment and periodically during treatment and follow-up.
A marker for tumor cell proliferation and turnover.
Result
may be elevated
serum quantitative immunoglobulins
Test
Confirms presence of monoclonal IgM in the serum.[38][39]
Densitometry is more reliable than nephelometry.[51]
Quantifies 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.
Result
increased concentration of IgM (in proportion with tumor burden)
serum protein electrophoresis with immunofixation
Test
Confirms presence of monoclonal IgM in the serum, including type of light chain (kappa or lambda).[38][39]
Immunofixation can also be used to document complete response to therapy (in which case it should be reconfirmed after 6 weeks) and to follow up on disease remission.
Result
positive for kappa or lambda IgM monoclonal component; kappa is more common (80%)
bone marrow evaluation
Test
Mandatory test to confirm the diagnosis of Waldenström macroglobulinemia (WM).[38][39] Also used to document response to therapy.
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/or immunohistochemistry).[38][39]
Diagnosis is confirmed if there is bone marrow infiltration by malignant lymphocytes with morphologic and immunophenotypic features consistent with lymphoplasmacytic lymphoma (LPL).[1][2][41][42]
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).[1][2] See Classification.
Morphologic features include infiltrating small lymphocytes, plasmacytoid lymphocytes, and plasma cells.[39] The pattern of bone marrow infiltration may be diffuse, interstitial, or nodular, and is usually intertrabecular.[37][39]
Typical immunophenotypic markers include: CD19+, CD20+, and surface immunoglobulin M (sIgM)+.[39] CD5, CD10, CD23 may be expressed in 10% to 20% of WM cases, but this should not exclude a diagnosis of WM.[39] Care must be taken to exclude CD5+ entities such as chronic lymphocytic leukemia and mantle cell lymphoma.[40][43]
Result
intertrabecular monoclonal lymphoplasmacytic infiltrate, ranging from predominantly lymphocytic to lymphoplasmacytic to overt plasma cells; immunophenotypic markers for LPL/WM (e.g., CD19+, CD20+, sIgM+; CD5, CD10, CD23 may be expressed in 10% to 20% of WM cases, but this should not exclude a diagnosis of WM)
genetic mutation testing
Test
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.[38][39][44] This mutation occurs in over 90% of patients with Waldenström macroglobulinemia (WM) and can be used to differentiate WM from other B-cell lymphomas, and from IgM multiple myeloma.[18][25][39][44][45] 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 and zanubrutinib).[19][25]
Testing for the CXCR4 mutation may be considered.[38][39] This mutation occurs in up to 40% of patients with WM.[21][23] It is thought to be an activating mutation in WM, and is found in WM patients who have a MYD88 mutation.[22] Patients with the MYD88 mutation who lack the CXCR4 mutation may have the best response to BTK inhibitors.[19]
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.[46]
Result
may be positive for MYD88 L265P and CXCR4 mutations
CT chest, abdomen, and pelvis
Test
Should be obtained at diagnosis to assess for splenomegaly, lymphadenopathy, other extramedullary disease sites, and to stage the patient.[38][39]
Repeated as clinically indicated: for example, to document response to therapy.
Result
may show splenomegaly, lymphadenopathy, or other extramedullary disease
Tests to consider
24-hour urine for total protein and urine protein electrophoresis with immunofixation
serum free light chain assay
Test
Consider if renal dysfunction or amyloidosis is suspected.[4][38]
Serum free light chains may be elevated in proportion with tumor burden, therefore a potentially useful marker for tumor burden.[52] May be grossly elevated in patients with cast nephropathy (a rare occurrence).
Can be used to document disease response to therapy and to follow up remission if initial test was positive.[53]
Result
may be elevated
serum viscosity (SV)
Test
Considered if symptoms of hyperviscosity are present (e.g., mucosal bleeding) or if IgM level is high.[4][38][39]
Hyperviscosity is a distinguishing feature of Waldenström macroglobulinemia. However, symptoms of hyperviscosity are observed in a minority of patients at diagnosis, and usually appear when serum IgM level is ≥3 g/dL.[35]
Result
normal or elevated
cold agglutinins and cryoglobulins
Test
Considered if clinically suspected.
Cold agglutinins and cryoglobulins should be checked before IgM measurement. If cold agglutinins or cryoglobulins are present, serum sample should be warmed to 98.6°F (37°C) before IgM determination.[51][54]
Result
confirms presence of cold agglutinins and cryoglobulins; often these are asymptomatic
viral serology (hepatitis B and C, and HIV)
Test
It is important to test for hepatitis B and C and HIV 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.[38][39]
Hepatitis C should be ruled out if cryoglobulinemia is suspected.[39]
Result
may be positive for hepatitis B, hepatitis C, or HIV
antimyelin-associated glycoprotein (MAG) antibodies
Test
Ordered if peripheral neuropathy is suspected.[30] Referral to a neurologist is important.
Presence of MAG antibodies supports the diagnosis of IgM-related neuropathy. Their absence does not exclude the diagnosis.
Result
may be positive
antiganglioside M1 (anti-GM1) antibodies
Test
Ordered if peripheral neuropathy is suspected.[30] Referral to a neurologist is important.
Presence of anti-GM1 antibodies supports the diagnosis of IgM-related neuropathy. Their absence does not exclude the diagnosis.
Result
may be positive
antisulfatide IgM antibodies
Test
Ordered if peripheral neuropathy is suspected.[30] Referral to a neurologist is important.
Presence of antisulfatide IgM antibodies supports the diagnosis of IgM-related neuropathy. Their absence does not exclude the diagnosis.
Result
may be positive
nerve conduction study/electromyography
Test
May be ordered if peripheral neuropathy is suspected.[30] Referral to a neurologist is important.
Presence of demyelinating pattern may support the diagnosis of IgM-related neuropathy. Presence of axonal degeneration may suggest amyloid or cryoglobulinemic involvement.
Result
may show demyelinating pattern or axonal degeneration
Congo red staining of bone marrow biopsy and/or tissue biopsy (e.g., fat pad)
Test
Ordered if amyloidosis is suspected (e.g., those presenting with unexplained cardiac problems, neuropathy, renal dysfunction).[38][39]
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).
Amyloid tissue subtyping (e.g., using mass spectrometry) may be warranted to confirm amyloid type. See Amyloidosis.
Result
positive green birefringence when stained with Congo red
retinal exam
Test
Considered if IgM level is ≥3 g/dL or if hyperviscosity is suspected.[38][39]
Hyperviscosity is a distinguishing feature of Waldenström macroglobulinemia. However, symptoms of hyperviscosity are observed in a minority of patients at diagnosis, and usually appear when serum IgM level is ≥3 g/dL.[35]
Result
may show dot and blot hemorrhages, tortuous blood vessels, venous 'sausaging', and/or optic disc edema
prothrombin time (PT) and activated partial thromboplastin time (APTT)
Test
May be carried out to assess for acquired von Willebrand disease (VWD) if excess bruising or bleeding is present, or if clinically indicated.[39]
Result
may show PT within the reference range for VWD, and prolonged APTT
von Willebrand disease (VWD) screening test
Test
May be carried out to assess for acquired VWD if excess bruising or bleeding is present, or if clinically indicated.[39]
Result
may show low levels of von Willebrand factor suggesting acquired VWD
lymph node biopsy
Test
Lymph node biopsy is not required for diagnosis but may be indicated if there is concern for high-grade transformation.
Flow cytometry and immunohistochemistry may reveal immunophenotype markers consistent with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (WM; e.g., CD19+, CD20+, surface immunoglobulin M [sIgM]+). CD5, CD10, CD23 may be expressed in 10% to 20% of WM cases, but this should not exclude a diagnosis of WM.[39]
Because of the ambiguity of CD5, special care must be taken to exclude CD5+ entities such as chronic lymphocytic leukemia and mantle cell lymphoma.[40][43]
Result
monoclonal lymphoplasmacytic infiltrate
18F-fluorodeoxyglucose PET/CT (FDG-PET/CT) chest, abdomen, and pelvis
Test
Can be used to assess patients with suspected high-grade transformation where avid FDG uptake is seen at sites of possible transformed disease; however, a biopsy is required to confirm disease transformation.[38]
May also be used to monitor response to therapy.[47]
Result
may show high-grade disease transformation, lymphadenopathy, and hepatosplenomegaly
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