eMedicine Specialties > Hematology > Plasma Cell Disorders

Waldenstrom Hypergammaglobulinemia: Differential Diagnoses & Workup

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

Differential Diagnoses

Chronic Lymphocytic Leukemia
Lymphoma, Non-Hodgkin
Monoclonal Gammopathies of Uncertain Origin
Multiple Myeloma

Workup

Laboratory Studies

  • The laboratory diagnosis of Waldenström macroglobulinemia is contingent on demonstrating a significant monoclonal IgM spike and identifying malignant cells consistent with Waldenström macroglobulinemia (usually found in bone marrow biopsy samples and aspirates).6
  • General studies include a CBC count, red cell indices, platelet count, and a peripheral smear.
    • Normocytic normochromic anemia, leukopenia, and thrombocytopenia may be observed. Anemia is the most common finding, present in 80% of patients with symptomatic Waldenström macroglobulinemia.
    • The peripheral smear may reveal plasmacytoid lymphocytes, normocytic normochromic red cells, and rouleaux formation.
    • Neutropenia can be found in some patients.
    • Thrombocytopenia is found in approximately 50% of patients with bleeding diathesis.
  • Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), renal and hepatic function, total protein levels, and an albumin-to-globulin ratio.7
    • The ESR and uric acid level may be elevated.
    • Creatinine is occasionally elevated and electrolytes are occasionally abnormal. Hypercalcemia is noted in approximately 4% of patients.
    • The LDH level is frequently elevated, indicating the extent of Waldenström macroglobulinemia–related tissue involvement.
    • Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive.
  • Beta-2-microglobulin and C-reactive protein test results are not specific for Waldenström macroglobulinemia. Beta-2-microglobulin is elevated in proportion to tumor mass.
  • Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional.
  • Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström macroglobulinemia.
  • Immunoelectrophoresis and immunofixation studies help identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein.
    • High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein.
    • The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström macroglobulinemia may exhibit more than one M protein.
  • Plasma viscosity must be measured.
  • Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, are found in the urine.
    • Urine collections should be concentrated.
    • Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1 g/d in approximately 3% of patients.
  • Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology.

Imaging Studies

  • Chest radiographs should be obtained, to evaluated for pulmonary infiltrates, nodules or effusion, and congestive heart failure.
  • Computed tomography images of the abdomen and pelvis may show evidence of abdominal adenopathy, hepatosplenomegaly, or both.
  • Magnetic resonance imaging (MRI) is not essential; however, MRI of the spine shows findings of bone marrow involvement in 90% of patients.
  • Cerebrospinal fluid analysis for patients with change in mental status may demonstrate elevated protein concentration and cerebrospinal fluid IgM paraprotein.

Procedures

  • Bone marrow aspiration and biopsy are required to establish the diagnosis.
    • Bone marrow examination findings show infiltration by small lymphocytes showing plasma cell differentiation.
    • The pattern of infiltration is diffuse or interstitial in most cases. A paratrabecular pattern should raise the possibility of follicular lymphoma.
    • Periodic acid-Schiff (PAS) staining results are often positive because of the high polysaccharide content in the cells.
    • Three patterns of marrow involvement are described, as follows: (1) lymphoplasmacytoid cells (ie, predominantly lymphoplasmacytic and small lymphocytes) in a nodular pattern, (2) lymphoplasmacytic cells (ie, small lymphocytes, mature plasma cells, mast cells) in an interstitial/nodular pattern, and (3) a polymorphous infiltrate (ie, small lymphocytes, plasma cells, plasmacytoid cells, immunoblasts with mitotic figures).
    • The abnormal cells may have PAS-positive intranuclear inclusions called Dutcher bodies (deposits of IgM around the nucleus).
  • Flow cytometry results show B-cell features with surface expression of IgM and B-cell differentiation markers. Waldenström macroglobulinemia is characterized in most cases by a surface IgM+ sIgD+/- CD5- CD10- CD19+ CD20+ CD22+ CD23- CD25+ CD27+ CD75- CD79+ CD103- CD138- FMC7+ BCL- 2+ BCL- 6- PAX- 5+ immunophenotype. In practice, a sIgM+ CD5- CD10- CD19+ CD20+ CD23- immunophenotype in association with a nonparatrabecular pattern of infiltration is diagnostic of Waldenström macroglobulinemia.
  • Various chromosomal abnormalities are common in patients with Waldenström macroglobulinemia. Deletions of 6q encompassing 6q21-22 have been observed in 40-90% of patients. However, although no evidence to date links Waldenström macroglobulinemia with consistent chromosomal or genetic changes, and prognostic implications are uncertain, a recent French study suggests a polymorphism may be a prognostic factor following initiation of treatment for this disease.8 Poulain et al evaluated the distribution and clinical influence of the CXCL12 (-801GA) polymorphism in 114 patients with Waldenstrom macroglobulinemia and found the CXCL12 (-801AA) genotype occurred more commonly in affected patients than control subjects (P = 0.01).8 However, patients with CXCL12 (-801GG) had a shorter median survival following administration of first-line therapy than the remaining patients. The investigators suggested the CXCL12 (-801GA) polymorphism may be associated with a higher incidence of Waldenstrom macroglobulinemia or may influence clinical outcome.8
  • Primary amyloidosis is a rare complication of IgM gammopathies. If suspected because of neuropathy, nephrotic syndrome, or cardiac failure, abdominal fat-pad needle aspiration, along with bone marrow biopsy, may help demonstrate amyloid deposits on Congo red staining (ie, apple-green birefringence under polarized light).

Histologic Findings

Bone marrow analysis reveals lymphoplasmacytoid cells. Plasma cells are fewer in number than in multiple myeloma. PAS staining results are often positive because of the high polysaccharide content in the cells. Lymphoid infiltration is either diffuse or nodular; however, some authors differentiate infiltration into 3 types: nodular, interstitial/nodular, and a "packed" marrow pattern. Nodular infiltration indicates the best prognosis among the other types of bone marrow infiltration. Packed marrow indicates the worst prognosis.

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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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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