Waldenstrom Macroglobulinemia

Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD more...

Updated: Jan 31, 2012

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Background
Pathophysiology
Etiology
Epidemiology
Prognosis
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Background

Waldenström macroglobulinemia, one of the malignant monoclonal gammopathies, is a chronic, indolent, lymphoproliferative disorder.^[1]It is characterized by the presence of a high level of a macroglobulin (immunoglobulin M [IgM]), elevated serum viscosity, and the presence of a lymphoplasmacytic infiltrate in the bone marrow. (See Pathophysiology, Etiology, and Workup.)

A clonal disease of B lymphocytes, Waldenström macroglobulinemia is considered to be a lymphoplasmacytic lymphoma, as defined by the Revised European American Lymphoma Classification (REAL) and World Health Organization (WHO) classification.

The clinical manifestations of Waldenström macroglobulinemia result from the presence of the IgM paraprotein and malignant lymphoplasmacytic cell infiltration of the bone marrow and other tissue sites. The clinical presentation is similar to that of multiple myeloma except that (1) organomegaly is common in Waldenström macroglobulinemia and is uncommon in multiple myeloma and (2) lytic bony disease and renal disease are uncommon in Waldenström macroglobulinemia but are common in multiple myeloma. (See Pathophysiology, Presentation, and Workup.)

Complications

Complications of Waldenström macroglobulinemia include the following:

Hyperviscosity syndrome
Visual disturbances secondary to hyperviscosity syndrome
Diarrhea and malabsorption secondary to gastrointestinal (GI) involvement
Renal disease (less common)
Amyloidosis of the heart, kidney, liver, lungs, and joints
Bleeding manifestations secondary to platelet dysfunction and coagulation factor and fibrinogen abnormalities due to interaction with plasma IgM
Raynaud phenomenon secondary to cryoglobulinemia
Increased predisposition to infection due to B-cell dysfunction (disease related) or T-cell dysfunction (therapy related, particularly after nucleoside analogues)
Cardiac failure
Increased incidence of lymphomas, myelodysplasia, and leukemias

Pathophysiology

The clinical manifestations of this disorder result from 2 important factors. First, secretion of the IgM paraprotein leads to hyperviscosity and vascular complications because of physical, chemical, and immunologic properties of the paraprotein. Monoclonal IgM causes hyperviscosity syndrome, cryoglobulinemia types 1 and 2, coagulation abnormalities, sensorimotor peripheral neuropathy, cold agglutinin disease and anemia, primary amyloidosis, and tissue deposition of amorphous IgM in the skin, GI tract, kidneys, and other organs.

Second, neoplastic lymphoplasmacytic cells infiltrate the bone marrow, spleen, and lymph nodes. Less commonly, these cells can infiltrate the liver, lungs, GI tract, kidneys, skin, eyes, and central nervous system (CNS). Infiltration of these organs causes numerous clinical symptoms and signs.

Occasionally, IgM paraprotein has (1) rheumatoid factor activity, (2) antimyelin activity that can contribute to peripheral neuropathy, and (3) immunologically related lupus anticoagulant activity.

A study by Pasricha et al found that bone marrow features, particularly the degree of plasma cell infiltration, correlates with IgM paraprotein concentration at diagnosis. Thus, evaluation of the plasma cell compartment in the bone marrow at baseline and after therapy may be helpful.^[2]

Etiology

No definite etiology exists for Waldenström macroglobulinemia. Environmental, familial, genetic, and viral factors have been reported. IgM monoclonal gammopathies of undetermined significance (MGUS) are considered a precursor of Waldenström macroglobulinemia.

A possible role for genetic factors has been suggested by reports of familial clustering of Waldenström macroglobulinemia. In one study, approximately 20% of 181 serial Waldenström macroglobulinemia patients presenting to a tertiary referral had a first-degree relative with either Waldenström macroglobulinemia or another B-cell lymphoproliferative disease. Reports of familial cases suggest a genetic predisposition.^{[3, 4]}

Hepatitis C, hepatitis G, and human herpesvirus 8 have been implicated, but as yet, no strong data support a causative link between these viruses and Waldenström macroglobulinemia.

Epidemiology

Waldenström macroglobulinemia is a relatively rare condition, with the 1500 cases diagnosed per year in the United States accounting for approximately 2% of hematologic malignancies. The incidence rate for Waldenström macroglobulinemia in the United States is higher among whites, with people of African descent representing only 5% of all patients. In the United Kingdom, the annual incidence of the disease is 10.3 per million.^[5]

Waldenström macroglobulinemia is a disease of elderly individuals. Most patients present in the seventh or eighth decade of life. The median age at diagnosis in the United States is 65 years, with a slight male predominance.

Prognosis

Waldenström macroglobulinemia is an indolent disorder, and patients survive for a median of approximately 78 months. Kaplan-Meier survival curves of patients with Waldenström macroglobulinemia do not show a plateau.^[6]

Different studies have been performed to assess prognosis. Patients with a nodular type of bone marrow involvement tend to do better than those with diffuse involvement.

Poor prognostic factors include the following:

Age older than 65 years
Hemoglobin value of less than 10 g/dL
Albumin level less than 4.0 g/dL
Elevated beta-2-microglobulin level

A study by Kastritis et al found that despite the evolution of treatment to include nucleoside analogues and other novel agents, no significant improvement in the outcome of patients with Waldenström macroglobulinemia has been noted since the late 20th century.^[7]

Morbidity and mortality

The most important causes of death in Waldenström macroglobulinemia include progression of the proliferative process, infection, cardiac failure, renal failure, strokes, and GI bleeding. Transformation to a more aggressive immunoblastic variant is less common (6% of cases).

Proceed to Clinical Presentation

Contributor Information and Disclosures

Author

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology

Disclosure: Novartis Honoraria Speaking and teaching; Novartis Consulting fee Speaking and teaching; Eisai Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching

Coauthor(s)

Doris Ponce, MD Fellow, Department of Hematology/Oncology, New York Medical College

Doris Ponce, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Wendy Hu, MD Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center

Wendy Hu, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Physicians for Social Responsibility