Waldenström macroglobulinemia (WM)

ALSO KNOWN AS: Lymphoplasmacytic lymphoma

DEFINITION Waldenström macroglobulinemia (WM) is a rare and indolent form of non-Hodgkin’s lymphoma and is one of the malignant monoclonal gammopathies. In WM, lymphoplasmacytic cells that are in the process of maturing from B cells into plasma cells multiply abnormally and produce large amounts of monoclonal immunoglobulin M antibody (IgM). High levels of IgM create hyperviscosity of the serum, and lymphoplasmacytic cells infiltrate into the bone marrow, spleen, and lymph nodes.

Risk Factors

The most significant risk factor for WM is age. Median age at diagnosis is sixty-three. Men are at greater risk than women, and White men are at higher risk than African Americans. People who have monoclonal gammopathy of undetermined significance (MGUS) have a higher risk of developing non-Hodgkin’s lymphoma and WM within twenty years. Having a first-degree relative with WM may also increase the risk.

Etiology and Genetics

The cause of WM remains unknown, although mutations in gene MYD88 have been observed in over 90 percent of patients. There is some evidence that IgM in some patients with WM may have specificity for the same myelin-associated glycoprotein that has been associated with demyelinating diseases such as multiple sclerosis. This may explain why some patients with WM develop peripheral neuropathy before the onset of neoplastic disease. Speculation exists that this immunologic response may be triggered by viral infection. Hepatitis C, hepatitis G, and human herpes virus 8 have been suspected in the of WM, but the data are not strong enough for these viruses to be considered causative at this time.

Evidence of a genetic etiology for WM comes from reports of family history. In one study, approximately 20 percent of people with WM were found to have a first-degree relative with WM or a similar B cell-associated disease. Various other studies have documented immunoglobulin abnormalities in first-degree relatives of people diagnosed with WM, including monoclonal gammopathy, polyclonal gammopathy, and decreased levels of immunoglobulins. In a recent report published in Clinical Cancer Research, a follow-up study of twenty-two first-degree relatives of patients with WM found that IgM macroglobulinemia seems to be a phenotypic marker of WM in some families and carries a high risk of progression to WM. The frequency of IgM macroglobulinemia was found to be greater than thirty times what would normally be expected in a general population. Of five relatives who initially had IgM monoclonal gammopathy, after a median time period of seventeen years, all had persisted or progressed and three had gone on to develop WM.

Several types of chromosomal abnormalities have been observed in patients with WM. Deletions of chromosome 6q, including 6q21-22, have been reported in about 75 percent of patients with WM. Prognostic indications of these findings is uncertain, and there is not enough evidence to link WM with any consistent chromosomal or genetic change.

Symptoms

Signs and symptoms of WM are caused by secretion of IgM, which causes hyperviscosity and vascular complications because of the physical, chemical, and immunologic properties of the IgM paraprotein, and by direct infiltration of neoplastic lymphoplasmacytic cells into bone marrow, spleen, and lymph nodes.

The onset of WM may be gradual and nonspecific, and many asymptomatic patients are diagnosed by routine blood work abnormalities. The most common presenting symptoms are weakness, severe fatigue, anorexia, peripheral neuropathy, weight loss, fever, and Raynaud’s phenomenon. Common symptoms due to hyperviscosity may include abnormal bleeding from the nose, gums, or gastrointestinal tract, headache, blurred vision, dizziness, or hearing loss.

Common signs of WM found on physical examination include enlargement of the spleen and liver as well as generalized lymphadenopathy. Examination of the skin may reveal signs of increased bleeding tendency such as bruising or purpura. Ophthalmoscopic evaluation may reveal dilation of retinal veins, which is characteristic of hyperviscosity.

Infiltration of the central nervous system can cause Bing-Neel syndrome, which is characterized by lethargy, stupor, confusion, memory loss, and motor abnormalities. The neuropathy of WM is typically distal, sensorimotor, symmetrical, and slowly progressive. The constellation of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes is known as POEMS syndrome and can be seen in patients with WM.

The signs and symptoms of WM are most similar to multiple myeloma (MM). WM can be differentiated from MM by enlargement of the spleen and liver, which is common in WM but rare in MM. Lytic bone lesions and renal disease that are commonly seen in MM are rarely seem in WM.

Screening and Diagnosis

WM is a rare condition with about 1,500 cases diagnosed each year in the United States, accounting for about 2 percent of hematologic malignancies. Diagnosis is based on finding evidence of a monoclonal spike on serum electrophoresis. Immunoelectrophoresis and immunofixation studies can help identify the spike as M component. About 80 percent of patients will present with a normocytic normochromic anemia. Thrombocytopenia and leukopenia are also common.

Malignant are usually present in peripheral blood. About 10 percent of macroglobulins in WM are cryoglobulins, but unlike the mixed cryoglobulins seen in rheumatoid arthritis or other autoimmune diseases, the cryoglobulins seen in WM are purely composed of IgM. Like the mixed cryoglobulins, the cryoglobulins of WM may cause Raynaud’s phenomenon or other vascular symptoms precipitated by cold.

Bone marrow aspiration and biopsy are needed to confirm the diagnosis of WM. Bone marrow examination will show lymphoplasmacytic and small lymphocyte infiltration. Infiltration may be described on histology as diffuse, nodular, or packed. Nodular infiltration has the best prognosis and packed infiltration has the poorest prognosis.

Urinary immunoglobulins are usually light chain kappa type. Proteinuria is found in 40 percent of patients but exceeds 1 gram per day in only 3 percent of patients. Imaging studies including chest radiographs, computed tomography (CT), and magnetic resonance imaging (MRI) may be done to rule out infiltrates and organomegaly. Mental status symptoms should be evaluated by obtaining cerebrospinal fluid to rule out the presence of IgM.

Treatment and Therapy

Although there is no cure for WM, treatment can be effective and there are many treatment options available. Treatment for symptomatic hyperviscosity is considered to be a medical emergency and should be instituted promptly. The treatment of choice is plasmapheresis since 80 percent of IgM is confined in the intravascular space. Treatment of macroglobulinemia is by alkylating agents, analogues, monoclonal antibodies, or combination therapy. The alkylating agent chlorambucil has been used for more than forty years. The response rate is about 60 percent when chlorambucil is used with or without prednisone. In patients who are resistant to alkylating agents, the nucleosides fludarabine or cladribine are often effective. The monoclonal rituximab produces response rates of 20 to 50 percent. Combination therapies have reached response rates of 75 percent in some studies.

Other therapies that have been effective for WM include thalidomide, autologous blood cell transplantation, and interferon alpha. Autologous transplantation is reserved for younger patients who have not responded to other treatment. Interferon alpha given for six months has shown a response rate of 50 percent for a duration of more than two years. In cases where other treatments are not effective, splenectomy is occasionally performed because it removes a major reservoir of IgM.

Prevention and Outcomes

There is no way to prevent WM. Some patients meet the diagnostic criteria for WM but remain asymptomatic. These patients are considered to have smoldering or indolent disease and can be followed carefully without treatment for many years. Complications of WM include renal disease, amyloidosis, cardiac failure, infections, and increased risk for lymphomas, myelodysplasia, and leukemia.

Median survival for all patients with WM is 78 months. About 80 percent of patients respond to some type of chemotherapy, and their median survival rate exceeds three years. In patients whose macroglobulin level can be reduced by 75 percent, median survival increases to 7.7 years. Incidence of WM rises sharply with age. Half of all patients with WM are diagnosed after the age of sixty-three. Older age, male sex, general symptoms, and cytopenia are associated with a worse prognosis.

Bibliography

Cashen, Amanda F., and Brian Van Tine, eds. The Washington Manual Hematology and Oncology Subspecialty Consult. 3rd ed. Philadelphia: Kluwer/Lippincott, 2012. Print.

Fauci, Anthony S., et al. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw, 2012. Print.

Gertz, Morie A. "Waldenström Macroglobulinemia: 2023 Update on Diagnosis, Risk Stratification, and Management." American Journal of Hematology, vol. 98, no. 2, Feb. 2023, pp. 348-358, doi.org/10.1002/ajh.26796. Accessed 9 Sept. 2024.

"Macroglobulinemia of Waldenstrom." MedlinePlus. Natl. Lib. of Medicine, 30 Apr. 2012. Web. 2 Sept. 2014.