Waldenström's macroglobulinemia

Overview
Waldenström macroglobulinemia (WM) is cancer involving a subtype of white blood cells called lymphocytes. The main attributing antibody is IgM. It is a type of lymphoproliferative disease, and shares clinical characteristics with the indolent non-Hodgkin lymphomas.

Etymology
It is named after the Swedish physician Jan G. Waldenström (1906-1996), who first identified the condition.

History and classification
WM was first described by Jan G. Waldenström (1906-1996) in 1944 in two patients with bleeding from the nose and mouth, anemia, decreased levels of fibrinogen in the blood (hypofibrinogenemia), swollen lymph nodes, neoplastic plasma cells in bone marrow, and increased viscosity of the blood due to increased levels of a class of heavy proteins called macroglobulins.

For a period of time, WM was considered to be related to multiple myeloma due to the presence of monoclonal gammopathy and infiltration of the bone marrow and other organs by plasmacytoid lymphocytes. The new World Health Organization (WHO) classification, however, places WM under the category of lymphoplasmacytic lymphomas, itself a subcategory of the indolent (low-grade) non-Hodgkin lymphomas.

Epidemiology
WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually. The median age of onset of WM is between 60 and 65 years.

Symptoms
Symptoms of WM include weakness, fatigue, weight loss and chronic oozing of blood from the nose and gums. Peripheral neuropathy can occur in 10% of patients. Lymphadenopathy, splenomegaly, and/or hepatomegaly are present in 30-40% of cases. Some symptoms are due to the effects of the IgM paraprotein, which may cause autoimmune phenomenon or cryoglobulinemia. Other symptoms of WM are due to the hyperviscosity syndrome, which is present in 6-20% of patients. This is attributed to the IgM monoclonal protein increasing the viscosity of the blood. Symptoms of this are mainly neurologic and can include blurring or loss of vision, headache, and (rarely) stroke or coma.

Diagnosis
A distinguishing feature of WM is the presence of an IgM monoclonal protein (or paraprotein) that is produced by the cancer cells, and a concurrent decrease in levels of uninvolved immunoglobulins (i.e., IgG and IgA).

Laboratory Tests

 * The laboratory diagnosis of Waldenström's macroglobulinemia is contingent on demonstrating a significant monoclonal IgM spike and identifying malignant cells consistent with Waldenström's macroglobulinemia (usually found in bone marrow biopsy samples and aspirates).


 * General studies include a CBC, 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's 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 tests, total protein levels, and an albumin-to-globulin ratio. 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's 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's 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's 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's 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

Prognosis
Current medical treatments result in survival some longer than 10 years. In part this is because better diagnostic testing means early diagnosis and treatments. Older diagnosis and treatments resulted in published reports of median survival of approximately 5 years from time of diagnosis. New treatments have made longer term survival a reality for many with this condition. In rare instances, WM progresses to multiple myeloma.

Treatment
There is no single accepted treatment for WM. Indeed, in 1991, Waldenström himself raised the question of the need for effective therapy. In the absence of symptoms, many clinicians will recommend simply monitoring the patient.

In 2002, a panel at the International Workshop on Waldenström's Macroglobulinemia agreed on criteria for the initiation of therapy. They recommended starting therapy in patients with constitutional symptoms such as recurrent fever, night sweats, fatigue due to anemia, weight loss, progressive symptomatic lymphadenopathy or splenomegaly, and anemia due to bone marrow infiltration.

Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia were also suggested as indications for therapy.

Treatment includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or vincristine. Corticosteroids may also be used in combination. Plasmapheresis can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood, although it does not address the underlying disease.

Recently, autologous bone marrow transplantation has been added to the available treatment options.