eMedicine Specialties > Hematology > Plasma Cell Disorders

Waldenstrom Hypergammaglobulinemia

Author: Doris Ponce, MD, Fellow, Department of Hematology/Oncology, New York Medical College
Coauthor(s): Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College; Vijay Ramu, MBBS, Staff Physician, Department of Internal Medicine, East Tennessee State University; Harsha Vyas, MD, Fellow, Section of Hematology and Oncology, Wake Forest University School of Medicine; Koyamangalath Krishnan, MD, FRCP, FACP, Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University
Contributor Information and Disclosures

Updated: Aug 29, 2009

Introduction

Background

Waldenström macroglobulinemia (WM) is one of the malignant monoclonal gammopathies.1 Waldenström macroglobulinemia is a condition 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. Waldenström macroglobulinemia is a clonal disorder of B lymphocytes. This condition is considered to be lymphoplasmacytic lymphoma as defined by the Revised European American Lymphoma Classification (REAL) and World Health Organization (WHO) classification.

The clinical manifestations of this condition result from the presence of the IgM paraprotein and malignant lymphoplasmacytic cell infiltration of the bone marrow and other tissue sites. The clinical presentation of Waldenström macroglobulinemia is similar to that of multiple myeloma (MM) 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.

Pathophysiology

The clinical manifestations of this disorder result from two important factors.

First, secretion of the IgM paraprotein leads to hyperviscosity and vascular complications because of physical, chemical, and immunological 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 CNS. Infiltration of these organs causes numerous clinical symptoms and signs (see Clinical).

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

Frequency

United States

Waldenström macroglobulinemia is a relatively rare condition, with 1500 cases diagnosed per year, accounting for approximately 2% of hematologic malignancies. The incidence rate for Waldenström macroglobulinemia is higher among whites, with African descendants representing only 5% of all patients. The median age at diagnosis is 65 years, with a slight male predominance.

International

In the United Kingdom, the annual incidence is 10.3 per million.

Mortality/Morbidity

Waldenström macroglobulinemia is a chronic indolent lymphoproliferative disorder. Median survival time is approximately 78 months. Kaplan-Meier survival curves of patients with Waldenström macroglobulinemia do not show a plateau.

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

Race

See Frequency.

Sex

See Frequency.

Age

Waldenström macroglobulinemia is a disease of elderly individuals. Most patients present in the seventh or eighth decade of life.

Clinical

History

  • Onset is insidious and nonspecific. Many patients are asymptomatic at presentation and are diagnosed incidentally from routine blood work.
  • Weakness, anorexia and weight loss are the most common symptoms. Merlini et al reported presenting features in 215 patients with Waldenström macroglobulinemia as follows:
    • Weakness - 66%
    • Anorexia - 25%
    • Peripheral neuropathy - 24%
    • Weight loss - 17%
    • Fever - 15%
    • Raynaud phenomenon - 11% (Raynaud phenomenon is due to cryoglobulinemia and may precede other serious symptoms for several years.)
  • Symptoms due to hyperviscosity syndrome include bleeding, dizziness, headache, blurry vision, and hearing or visual problems and can be life threatening.2
    • Visual changes, such as blurred vision or double images, and spontaneous bleeding with minor trauma could be presenting features.
    • Patients often present with a history of abnormal bleeding.
  • GI system findings may include malabsorption, GI bleeding, and diarrhea.

Physical

The physical findings result from tissue infiltration by the malignant clone, hyperviscosity state cause by antigen-antibody reactions triggered by the paraprotein, and derangement of the hemostatic system by the paraprotein.

  • Merlini et al3 also reported physical findings in 215 patients evaluated for Waldenström macroglobulinemia, including the following:
    • Hepatomegaly - 20%
    • Splenomegaly - 19%
    • Lymphadenopathy - 15%
    • Purpura - 9%
    • Hemorrhagic manifestations - 7%
  • Mental status changes include lethargy, stupor, or even coma. Infiltration of the CNS by the malignant clone can cause a syndrome of confusion, memory loss, disorientation, and motor abnormalities called the Bing-Neel syndrome.
  • Papilledema, ie, sausage-shaped (distended and tortuous) retinal veins, and hemorrhages may be evident on funduscopic examination.
  • Neuropathy is typically slowly progressive, distal, symmetric, and sensorimotor. Other variants, including a chronic ataxic neuropathy known as Miller-Fisher syndrome (a variant of Guillain-Barré syndrome), have been described. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) also may be associated with Waldenström macroglobulinemia.
  • Hepatosplenomegaly and lymphadenopathy are common.
  • Skin manifestations include purpura, bullous skin disease, papules on extremities, cutaneous plaques and nodules, chronic urticaria (Schnitzler syndrome), Raynaud phenomenon, livedo reticularis, and acrocyanosis.
  • Pulmonary involvement is rare (3-5%), with nodules, masses, parenchymal infiltrates, or pleural effusion.
  • Congestive heart failure is an unusual manifestation, presenting with jugular venous distention, displaced apical impulse, S3 gallop, rales at lung auscultation, and peripheral edema.
  • Periorbital masses resulting from infiltration into retro-orbital structures and the lacrimal gland have been described. This can cause proptosis and ocular nerve palsies. Osseous lesions and amyloidosis are rare.

Causes

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 a recent 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.4,5
  • Hepatitis C, hepatitis G, and the human herpes virus 8 have been implicated, but, as yet, no strong data support a causative link between these viruses and Waldenström macroglobulinemia.

More on Waldenstrom Hypergammaglobulinemia

Overview: Waldenstrom Hypergammaglobulinemia
Differential Diagnoses & Workup: Waldenstrom Hypergammaglobulinemia
Treatment & Medication: Waldenstrom Hypergammaglobulinemia
Follow-up: Waldenstrom Hypergammaglobulinemia
References
Further Reading
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References

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Keywords

Waldenström hypergammaglobulinemia, macroglobulinemia, Waldenström's hypergammaglobulinemia, malignant lymphoproliferative disease, monoclonal gammopathy, malignant monoclonal gammopathies, Waldenström macroglobulinemia, Waldenström's macroglobulinemia, Waldenstrom macroglobulinemia, WM,

lymphoproliferative disorder, clonal disorder, B-lymphocyte disorder, blood malignancy, hematologic malignancy, blood cell cancer, plasmacytoid lymphocytic lymphoma, lymphoplasmacytoid lymphoma, primary macroglobulinemia, plasma cell neoplasms hemostatic disorders, paraproteinemias

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Contributor Information and Disclosures

Author

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.

Coauthor(s)

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; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

Vijay Ramu, MBBS, Staff Physician, Department of Internal Medicine, East Tennessee State University
Vijay Ramu, MBBS is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Harsha Vyas, MD, Fellow, Section of Hematology and Oncology, Wake Forest University School of Medicine
Harsha Vyas, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Koyamangalath Krishnan, MD, FRCP, FACP, Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University
Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians
Disclosure: Nothing to disclose.

Medical Editor

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, 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 Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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