Laboratory and clinical evaluations that can be performed in the initial workup of all WM patients and those with particular disease-related features
| Examination . | WM patient population . | Remarks . |
|---|---|---|
| β-2-Microglobulin (B2M) | All patients. | Serum B2M >3.0-3.5 mg/L associated with poor prognosis.105,106 Serum B2M is a determinant in WM International Prognostic Staging System.107 Value of B2M in making treatment decisions remains to be clarified. |
| Blood urea nitrogen (BUN), creatinine | All patients. | If moderate to severe azotemia is present, additional work-up including renal biopsy for deposition of light and heavy chains, amyloid fibrils, and cryoglobulins, and tumor infiltration can be considered. |
| BM biopsy and aspiration | All patients. | Morphological evaluation for lymphoplasmacytic cells. Immunohistochemistry and/or flow cytometry demonstrating clonal population. sIgM, CD19, CD20, CD22, and CD79 expression consistent with WM.108,109 Up to 20% of WM cases may be CD5, CD10, or CD23 positive.110 MYD88 mutated >90% of cases, and can support WM diagnosis.3-9,69 |
| Cold agglutinins (CAGG) | Select patients with anemia, reticulocytosis, Raynaud-like symptoms, and/or acrocyanosis. | Present in up to 5% of WM patients. |
| Complete blood counts (CBC) | All patients. | Hb <10 g/dL and/or PLT count of <100 000/mm3 related to WM disease can be used to support initiation of therapy based on consensus guidelines.30,33 |
| Cryoglobulins | Select patients with Raynaud-like symptoms, acrocyanosis, peripheral non-healing ulcerations, acrocyanosis, peripheral sensory neuropathy, or erratic serum IgM readings. | Present in 10-15% of WM patients. Patients with cryoglobulinemia should have serum IgM levels obtained on warm bath. |
| CT scans of chest, abdomen, pelvis | All patients. | Follow-up CT scans are only necessary for patients with baseline extramedullary disease or who later are suspected of having extr-medullary disease. Repeat CT scans should be considered in patients with relapse or progression.30,33 |
| Cytogenetic analysis | Select patients with bone lytic lesions, ambiguous bone marrow or laboratory findings concerning for myeloma. | 14q32 translocations present in most IgM myeloma cases with t11;14 being most common, but are absent in WM.111 MYD88 mutation can also be evaluated in BM specimens in ambiguous cases, as present in >90% of WM but absent in IgM myeloma cases.4,112 6q deletions common in WM, but prognostic significance and clinical utility is unclear.113-115 |
| Electromyography (EMG) | Patients with peripheral sensory neuropathy. | EMG typically shows de-myelinating pattern with anti-myelin IgM-related peripheral sensory neuropathy. Axonal degeneration can be present with amyloid or cryoglobulinemic involvement.116 |
| Fat-pad biopsy | Select patients with suspected amyloidosis, peripheral neuropathy, nephropathy, unexplained arrhythmias, cardiomegaly or heart failure. | Congo-red staining on fat pad and/or bone marrow biopsy may be used to establish presence of amyloid. Cardiac and renal work-up should be considered if Congo-red staining is positive to clarify extent of amyloid deposition. |
| Funduscopic examination | All patients. | Indirect ophthalmoscopy with scleral depression should also be considered in patients with hyperviscosity symptoms, and/or elevated serum IgM levels (>3000 mg/dL).117 |
| Hepatitis testing | Select patients with cryoglobulinemia, and who are being considered for rituximab. | Hepatitis C implicated in some cases of type II cryoglobulinemia.118 Hepatitis B testing should be evaluated in all patients who are being considered for rituximab. HBsAg-positive WM patients may be also be candidates for prophylactic anti-viral therapy during rituximab therapy.119 |
| Iron, total iron binding capacity (TIBC) | Select patients with anemia. | Hepcidemia is common in WM and can impact iron absorption and re-utilization.31 If iron saturation (iron/TIBC) is <10-12% and not related to GI blood loss may be candidate for parenteral iron therapy.32 |
| Liver function tests (LFTs) | All patients. | |
| Lumbar puncture with CSF examination | Select patients with suspected Bing-Neel Syndrome. | Brain MRI with gadolinium should first be done to evaluate for parenchymal and meningeal involvement, and evaluate risk for herniation. Cytological examination, white cell count with differential, flow cytometry, PCR for IgH rearrangements, as well as evaluation for MYD88L265P can be obtained to identify WM cells in CSF.120 If CSF positive, and Brain MRI is negative, MRI of entire spinal axis can be considered to evaluate for tumor presence if brain MRI is negative. |
| MYD88 genotyping | MYD88L265P positive >90% of cases by AS-PCR, and can support WM diagnosis.4-8 MYD88WT is associated with inferior overall survival; and lower response rates and progression free survival to ibrutinib in WM patients.14,69 Sanger sequencing for non-L265P MYD88 mutations can be considered in WM patients who by AS-PCR are negative for MYD88L265P as other types of MYD88 mutations can occur in WM.69,121 | |
| Positron emission tomography (PET) scan | Select patients. | No role for routine PET scans in WM unless disease transformation is suspected.30,33 |
| Serum IgM, IgA, IgG levels (quantitative) | All patients. | Obtain on warm bath for patients suspected of having cryoglobulinemia. Serum IgM levels can flare following rituximab, and should be carefully monitored in WM patients with high serum IgM levels (>4000 mg/dL).30,33 Quantitative serum IgM levels can be used as surrogate marker for disease burden assessment.82 Serum IgA, IgG levels are subnormal in most WM patients and impacted by certain treatments.78 Patients with severely depressed IgG and recurring sino-bronchial infections may benefit with IVIG infusions. |
| Reticulocyte count (RC) | Select patients with anemia. | For patients with high reticulocyte counts, consider hemolysis work-up. Extravascular hemolysis is common in WM, and LDH, and haptoglobin levels may be normal. Consider cold agglutinin testing, and if negative obtain direct and indirect Coombs evaluation. Splenic capture may also be etiological for reticulocytosis in WM patients with hypersplenism. |
| Serum free light chains (SFLC) | Select patients with light-chain nephropathy, amyloidosis. | May be useful for serial assessment of treatment impact in patients with amyloidosis or light chain deposition disease. |
| Serum myelin associated glycoprotein (MAG) titers | Select patients with peripheral sensory neuropathy, some forms of ataxia. | Positive in 25-50% of WM patients with disease related peripheral neuropathy.68,122 If negative, may consider further testing for anti-ganglioside M1 (GM1) and anti-sulfatide IgM antibodies. |
| Serum protein electrophoresis (SPEP) | All patients. | Demonstration of serum monoclonal IgM protein required for diagnosis of WM. Monoclonal IgM protein may be used as surrogate marker for assessing disease burden.82 Migration pattern of serum IgM and formation of higher order complexes on gels can complicate serial IgM protein assessment in some patients.83 Absence of serum IgM monoclonal protein by SPEP and immunofixation studies following therapy can be used to support attainment of a complete response (Table 6).81 |
| Serum viscosity | Select patients with suspected hyperviscosity symptoms and findings. | May be useful in assessing patients with hyperviscosity symptoms, though slow to be resulted and erratic readings commonly occur.62,63 Serum viscosity levels may be slow to be resulted, 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 hyperviscosity syndrome.117 |
| Examination . | WM patient population . | Remarks . |
|---|---|---|
| β-2-Microglobulin (B2M) | All patients. | Serum B2M >3.0-3.5 mg/L associated with poor prognosis.105,106 Serum B2M is a determinant in WM International Prognostic Staging System.107 Value of B2M in making treatment decisions remains to be clarified. |
| Blood urea nitrogen (BUN), creatinine | All patients. | If moderate to severe azotemia is present, additional work-up including renal biopsy for deposition of light and heavy chains, amyloid fibrils, and cryoglobulins, and tumor infiltration can be considered. |
| BM biopsy and aspiration | All patients. | Morphological evaluation for lymphoplasmacytic cells. Immunohistochemistry and/or flow cytometry demonstrating clonal population. sIgM, CD19, CD20, CD22, and CD79 expression consistent with WM.108,109 Up to 20% of WM cases may be CD5, CD10, or CD23 positive.110 MYD88 mutated >90% of cases, and can support WM diagnosis.3-9,69 |
| Cold agglutinins (CAGG) | Select patients with anemia, reticulocytosis, Raynaud-like symptoms, and/or acrocyanosis. | Present in up to 5% of WM patients. |
| Complete blood counts (CBC) | All patients. | Hb <10 g/dL and/or PLT count of <100 000/mm3 related to WM disease can be used to support initiation of therapy based on consensus guidelines.30,33 |
| Cryoglobulins | Select patients with Raynaud-like symptoms, acrocyanosis, peripheral non-healing ulcerations, acrocyanosis, peripheral sensory neuropathy, or erratic serum IgM readings. | Present in 10-15% of WM patients. Patients with cryoglobulinemia should have serum IgM levels obtained on warm bath. |
| CT scans of chest, abdomen, pelvis | All patients. | Follow-up CT scans are only necessary for patients with baseline extramedullary disease or who later are suspected of having extr-medullary disease. Repeat CT scans should be considered in patients with relapse or progression.30,33 |
| Cytogenetic analysis | Select patients with bone lytic lesions, ambiguous bone marrow or laboratory findings concerning for myeloma. | 14q32 translocations present in most IgM myeloma cases with t11;14 being most common, but are absent in WM.111 MYD88 mutation can also be evaluated in BM specimens in ambiguous cases, as present in >90% of WM but absent in IgM myeloma cases.4,112 6q deletions common in WM, but prognostic significance and clinical utility is unclear.113-115 |
| Electromyography (EMG) | Patients with peripheral sensory neuropathy. | EMG typically shows de-myelinating pattern with anti-myelin IgM-related peripheral sensory neuropathy. Axonal degeneration can be present with amyloid or cryoglobulinemic involvement.116 |
| Fat-pad biopsy | Select patients with suspected amyloidosis, peripheral neuropathy, nephropathy, unexplained arrhythmias, cardiomegaly or heart failure. | Congo-red staining on fat pad and/or bone marrow biopsy may be used to establish presence of amyloid. Cardiac and renal work-up should be considered if Congo-red staining is positive to clarify extent of amyloid deposition. |
| Funduscopic examination | All patients. | Indirect ophthalmoscopy with scleral depression should also be considered in patients with hyperviscosity symptoms, and/or elevated serum IgM levels (>3000 mg/dL).117 |
| Hepatitis testing | Select patients with cryoglobulinemia, and who are being considered for rituximab. | Hepatitis C implicated in some cases of type II cryoglobulinemia.118 Hepatitis B testing should be evaluated in all patients who are being considered for rituximab. HBsAg-positive WM patients may be also be candidates for prophylactic anti-viral therapy during rituximab therapy.119 |
| Iron, total iron binding capacity (TIBC) | Select patients with anemia. | Hepcidemia is common in WM and can impact iron absorption and re-utilization.31 If iron saturation (iron/TIBC) is <10-12% and not related to GI blood loss may be candidate for parenteral iron therapy.32 |
| Liver function tests (LFTs) | All patients. | |
| Lumbar puncture with CSF examination | Select patients with suspected Bing-Neel Syndrome. | Brain MRI with gadolinium should first be done to evaluate for parenchymal and meningeal involvement, and evaluate risk for herniation. Cytological examination, white cell count with differential, flow cytometry, PCR for IgH rearrangements, as well as evaluation for MYD88L265P can be obtained to identify WM cells in CSF.120 If CSF positive, and Brain MRI is negative, MRI of entire spinal axis can be considered to evaluate for tumor presence if brain MRI is negative. |
| MYD88 genotyping | MYD88L265P positive >90% of cases by AS-PCR, and can support WM diagnosis.4-8 MYD88WT is associated with inferior overall survival; and lower response rates and progression free survival to ibrutinib in WM patients.14,69 Sanger sequencing for non-L265P MYD88 mutations can be considered in WM patients who by AS-PCR are negative for MYD88L265P as other types of MYD88 mutations can occur in WM.69,121 | |
| Positron emission tomography (PET) scan | Select patients. | No role for routine PET scans in WM unless disease transformation is suspected.30,33 |
| Serum IgM, IgA, IgG levels (quantitative) | All patients. | Obtain on warm bath for patients suspected of having cryoglobulinemia. Serum IgM levels can flare following rituximab, and should be carefully monitored in WM patients with high serum IgM levels (>4000 mg/dL).30,33 Quantitative serum IgM levels can be used as surrogate marker for disease burden assessment.82 Serum IgA, IgG levels are subnormal in most WM patients and impacted by certain treatments.78 Patients with severely depressed IgG and recurring sino-bronchial infections may benefit with IVIG infusions. |
| Reticulocyte count (RC) | Select patients with anemia. | For patients with high reticulocyte counts, consider hemolysis work-up. Extravascular hemolysis is common in WM, and LDH, and haptoglobin levels may be normal. Consider cold agglutinin testing, and if negative obtain direct and indirect Coombs evaluation. Splenic capture may also be etiological for reticulocytosis in WM patients with hypersplenism. |
| Serum free light chains (SFLC) | Select patients with light-chain nephropathy, amyloidosis. | May be useful for serial assessment of treatment impact in patients with amyloidosis or light chain deposition disease. |
| Serum myelin associated glycoprotein (MAG) titers | Select patients with peripheral sensory neuropathy, some forms of ataxia. | Positive in 25-50% of WM patients with disease related peripheral neuropathy.68,122 If negative, may consider further testing for anti-ganglioside M1 (GM1) and anti-sulfatide IgM antibodies. |
| Serum protein electrophoresis (SPEP) | All patients. | Demonstration of serum monoclonal IgM protein required for diagnosis of WM. Monoclonal IgM protein may be used as surrogate marker for assessing disease burden.82 Migration pattern of serum IgM and formation of higher order complexes on gels can complicate serial IgM protein assessment in some patients.83 Absence of serum IgM monoclonal protein by SPEP and immunofixation studies following therapy can be used to support attainment of a complete response (Table 6).81 |
| Serum viscosity | Select patients with suspected hyperviscosity symptoms and findings. | May be useful in assessing patients with hyperviscosity symptoms, though slow to be resulted and erratic readings commonly occur.62,63 Serum viscosity levels may be slow to be resulted, 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 hyperviscosity syndrome.117 |