History and exam

Key diagnostic factors

common

age >70 years

More common in those ages >70 years.[7][10]​

In one US study using Surveillance Epidemiology and End Results (SEER) data (1980-2016), the annual Waldenström macroglobulinemia incidence rate increased with age, from 0.06 per 100,000 in those ages under 50 years to 3.2 per 100,000 in those ages 80 years and over.[6]​​

In the US, median age at diagnosis is 73 years.[7]​​​

male sex

More common in men.[6]​​[8][9]

In one US study using Surveillance Epidemiology and End Results (SEER) data (1980 to 2016), the annual WM incidence rate was 0.65 per 100,000 in men compared with 0.36 per 100,000 in women.[6]​​

white ancestry

More common in white people than in black people.[6]​​

In one US study using Surveillance Epidemiology and End Results (SEER) data (1980 to 2016), the annual WM incidence rate was 0.52 per 100,000 in white people compared with 0.29 per 100,000 in black people.[6]​​

Other diagnostic factors

common

history of IgM monoclonal gammopathy of undetermined significance (MGUS)

MGUS is a risk factor for WM.

In a study of 1384 patients with MGUS, the relative risk of progression to WM was increased by a factor of 46 compared with the general population.[12]

family history of B-cell lymphoproliferative disease

Family history of B-cell lymphoproliferative disease is associated with WM.

In one study of 257 WM patients, 48 (18.7%) had a family history of B-cell lymphoproliferative disease (including 13 [5.1%] with a history of WM; 9 [3.5%] non-Hodgkin lymphoma; 8 [3.1%] multiple myeloma; 7 [2.7%] chronic lymphocytic leukemia; 5 [1.9%] MGUS; 3 [1.2%] acute lymphoblastic leukemia; and 3 [1.2%] Hodgkin lymphoma).[13]

family history of WM (or related monoclonal gammopathies)

Familial clustering has been observed.[11][26]

Studies have reported families with multiple cases of WM, multiple myeloma, or MGUS.[14][15]

fatigue, weakness, shortness of breath

Due to anemia resulting from 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.[4][30]​​[32]

Fatigue is the most common symptom in WM.[4]

anorexia

Anorexia is the second most common symptom in WM, after fatigue.[4]

infections

Infections, particularly recurrent sinus and bronchial infections, are common due to a weakened immune system.[29]

peripheral neuropathy

Present in 20% of patients at diagnosis.[4][31]​​​​

uncommon

B symptoms (weight loss, fevers, night sweats)

Weight loss is present in 17% of patients.[4]​ Fever is present in 15% of patients.[4]

Raynaud syndrome

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]

May also be associated with cold hemolytic anemia (cold agglutinin disease) caused by autoantibody activity of IgM to red blood cells at cooler temperatures.[32]

splenomegaly

Uncommon in WM.[35]​ Rarely palpable.

Presence of splenomegaly (along with absence of lytic bone lesions) can differentiate WM from multiple myeloma.

lymphadenopathy

Uncommon in WM.[35]​ Usually low volume (i.e., not bulky).

Presence of lymphadenopathy (along with absence of lytic bone lesions) can differentiate WM from multiple myeloma.

hepatomegaly

Uncommon in WM.[35] Clinically significant hepatomegaly is ​rare.

skin and/or mucosal bleeding (purpura, epistaxis)

Purpura is present in approximately 9% of patients.[4]​ Mucosal bleeding (including epistaxis) is present in approximately 7% of patients.[4]

Bleeding is a sign of hyperviscosity. Observed in a minority of patients at diagnosis, and usually appears when serum IgM level is ≥3 g/dL.[34]​​

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]

ophthalmologic symptoms

Includes blurring or loss of vision, and retinal changes caused by hyperviscosity such as dot and blot hemorrhages, tortuous blood vessels, venous 'sausaging', and/or optic disc edema. Observed in a minority of patients at diagnosis, and usually appears when serum IgM level is ≥3 g/dL.[34]

headache

Potential symptom of hyperviscosity. Observed in a minority of patients at diagnosis, and usually appears when serum IgM level is ≥3 g/dL.[34] ​

dizziness and/or vertigo

Potential symptom of hyperviscosity. Observed in a minority of patients at diagnosis, and usually appears when serum IgM level is ≥3 g/dL.[34]​

tinnitus

Potential symptom of hyperviscosity.[30]​ Observed in a minority of patients at diagnosis, and usually appears when serum IgM level is ≥3 g/dL.[34]

thrombosis

Potential sign of hyperviscosity and may manifest as stroke, angina, myocardial infarction, pulmonary embolism, or deep vein thrombosis. Observed in a minority of patients at diagnosis, and usually appears when serum IgM level is ≥3 g/dL.[34]

Risk factors

strong

IgM monoclonal gammopathy of undetermined significance (MGUS)

In a study of 1384 patients with MGUS, the relative risk of progression to WM was increased by a factor of 46 compared with the general population.[12]​​

family history of B-cell lymphoproliferative disease

In a study of 257 WM patients, 48 (18.7%) had a family history of B-cell lymphoproliferative disease (including 13 [5.1%] with a history of WM; 9 [3.5%] non-Hodgkin lymphoma; 8 [3.1%] multiple myeloma; 7 [2.7%] chronic lymphocytic leukemia; 5 [1.9%] MGUS; 3 [1.2%] acute lymphoblastic leukemia; and 3 [1.2%] Hodgkin lymphoma).[13]

Additional findings in these patients included younger age at diagnosis and more extensive bone marrow infiltration by WM.[13]

family history of WM

Familial clustering has been observed.[11][26]​​ 

Pathogenic variants in highly penetrant genes may only constitute a modest proportion of deleterious variants.[26]​

weak

hepatitis C virus (HCV)

In one retrospective cohort study, HCV infection was associated with increased risk for WM (HR 2.76) compared with uninfected patients.[27] However, another study did not report an association between HCV infection and WM.[28]

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