Waldenstrom's macroglobulinemia overview
Mirdula Sharma, MBBS ; Grammar Reviewer: Natalie Harpenau, B.S.

# Overview
Waldenstrom's macroglobulinemia is an uncommon mature B cell lymphoma usually involving the bone marrow and, less commonly, the spleen and/or lymph nodes.The term "macroglobulinemia" refers to the production of excess IgM monoclonal protein that occurs in certain clonal lymphoproliferative disorders and plasma cell dyscrasias. The broad definition of lymphoplasmacytic lymphoma includes patients with monoclonal gammopathy of undetermined significance of the IgM type (IgM MGUS), smoldering Waldenstrom macroglobulinemia, Waldenstrom macroglobulinemia (WM), and a number of related disorders in which an IgM monoclonal protein is detected, such as chronic lymphocytic leukemia (CLL), a number of lymphoma variants, and primary (AL) amyloidosis. According to new 2016 WHO classification, when hyperviscosity occurs in lymphoplasmacytic lymphoma patients due to excess IgM paraprotein, it is termed as Waldenstrom macroglobulinemia (WM). Hence, now WM is considered as a rare distinct subtype/clinicopathologic entity demonstrating lymphoplasmacytic lymphoma (LPL), with symptoms associated with presence of a serum IgM paraprotein due to infiltration of the hematopoietic tissues and the effects of monoclonal IgM in the blood. Waldenstrom macroglobulinemia is a type of lymphoproliferative disease involving lymphocytes with IgM as the main attributing antibody and shares clinical characteristics with the indolent non-Hodgkin lymphomas.  Waldenstrom's macroglobulinemia was first discovered by Jan G. Waldenstrom and represents 1% of all hematological cancers. Common causes of WM include genetic, environmental, and autoimmune factors. While common risk factors include monoclonal gammopathy of undetermined significance, age >50 year old, white ethnicity, heredity, hepatitis C, and immune disorders. Genes involved in the pathogenesis of Waldenstrom's macroglobulinemia include: MYD88-L265P, CXCR4 and chromosomes 6q, 13q, 3q, 6p and 18q. The hallmark of Waldenstrom's macroglobulinemia is hyper-viscosity syndrome. If left untreated, patients with asymptomatic Waldenstrom's macroglobulinemia may progress to develop a symptomatic disease. Common complications of Waldenstrom's macroglobulinemia include: hyperviscosity syndrome, cold haemagglutinin disease, cryoglobulinemia, peripheral neuropathy, venous thromboembolism, primary amyloidosis, malabsorptive diarrhea, and bleeding manifestations. Less common but more severe complications include Schnitzler syndrome, Richter syndrome, and Bing-Neel syndrome. Prognosis varies depending on the multiple factors involved. Five year survival rate is 87% for low-risk disease and 36% for high-risk disease. Signs and symptoms of patients with Waldenstrom's macroglobulinemia depend on the degree of tissue infiltration by malignant tumor cells, hyperviscosity syndrome, and accumulation of paraprotein. The diagnosis of Waldenstrom's macroglobulinemia is based on bone marrow biopsy and serum protein analysis. Risk stratification determines the protocol of management used for Waldenstrom's macroglobulinemia patients. Watchful waiting is recommended for asymptomatic Waldenstrom's macroglobulinemia. Symptomatic Waldenstrom's macroglobulinemia is treated with Rituximab +/- Chemotherapy. Ibrutinib with or without concurrent rituximab, is considered as a drug of choice for the treatment of Bing-Neel syndrome.

# Historical Perspective
Waldenstrom macroglobulinemia was first discovered by Jan G. Waldenstrom, a Swedish physician in 1944. Bing-Neel syndrome, a late and rare complication of Waldenstrom's macroglobulinemia, was first discovered in 1936 by Jens Bing and Axel Valdemar Neel. First report on familial aggregation of Waldenstrom macroglobulinemia was published in 1962. In 1944, Revised European-American classification of lymphoid neoplasms (REAL) and WHO in 2001, placed Waldenstrom macroglobulinemia in the category of lymphoplasmacytic lymphoma. A diagnostic criteria for Waldenstrom macroglobulinemia was proposed by a consensus group at the Second International Workshop in Athens, Greece in 2002. A report published in 2013 showed that a patient of Bing-Neel syndrome who discontinued the treatment in 2009 remained asymptomatic.

# Classification
There is no established system for the classification of Waldenstrom's macroglobulinemia. However, according to a devised criteria based upon patient's symptoms, Waldenstrom's macroglobulinemia can be further classified into smoldering/asymptomatic and symptomatic WM.

# Pathophysiology
Waldenstrom's macroglobulinemia is an uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which are normally involved in humoral immunity. Two main factors mediating this disease include IgM paraprotein secretion and tissue infiltration with neoplastic lymphoplasmacytic cells. Genes involved in the pathogenesis of WM include MYD88-L265P, and CXCR4 alongwith various other cytogenetic and epigenetic abnormalities. In patients of Waldenstrom's macroglobulinemia, there is an increased incidence of diffuse large B-cell lymphoma, myelodysplastic syndrome (acute myeloid leukemia), brain tumor, and renal MALT lymphoma. Two histologic subtypes include lymphoplasmacytoid and lymphoplasmacytic which invade the lymphoid organs such as spleen, lymph nodes and bone marrow. Bone marrow is infiltrated by small lymphocytes, well-formed plasma cells, and plasmacytoid lymphocytes in diffuse, interstitial, nodular, paratrabecular, nodular-interstitial and mixed paratrabacular-nodular patterns. Lymph nodes infiltration shows Dutcher and Russell bodies, mast cells, and hemosiderin-laden macrophages. Peripheral smear shows circulating malignant cells with a plasmacytoid appearance, having basophilic cytoplasm, perinuclear halo, and nucleus with "clock-face" chromatin without nucleoli. Immunohistochemistry shows pan B-cell surface antigens such as Ig+CD19+, CD20+, CD22+, CD79A+ and variable expression of some other antigens.

# Causes
The exact cause of Waldenstrom's macroglobulinemia has not been identified; however, the disease has been highly-associated with somatic mutations in MYD88 and CXR4 genes. In addition, less possible common cause of the disease includes chromosomal abnormalities.

# Differentiating Lymphoplasmacytic lymphoma from Other Diseases
Waldenstrom's macroglobulinemia must be differentiated from multiple myeloma, chronic lymphocytic leukemia/small lymphocytic lymphoma, b-cell prolymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

# Epidemiology and Demographics
The prevalence of Waldenstrom's macroglobulinemia is estimated to be 1000-1500 cases in United States annually. Waldenstrom's macroglobulinemia represents 1-2% of all hematological cancers. Overall age-adjusted incidence of Waldenstrom's macroglobulinemia  is 0.38 cases per 100,000 persons annually, increasing with age to 2.85 in patients above 80 years. Incidence of Waldenstrom's macroglobulinemia increases after 50 years of age with median age at diagnosis to be 65 years. Men are twice more likely than women to develop WM and there is higher incidence of WM in whites than blacks.

# Risk Factors
Common risk factors for the development of Waldenstrom's macroglobulinemia  are monoclonal gammopathy of undetermined significance, inherited immune disorders,heredity, hepatitis C and other autoimmune disorders, age >50 years, male gender, white race, allergic conditions like hay fever, multiple environmental factors, Human T-lymphotrophic virus type I or Epstein-Barr virus, history of Helicobacter pylori infection, history of immunosuppressant drug therapy after an organ transplant, diet rich in meat and fat and history of past treatment for Hodgkin lymphoma.

# Screening
According to the the United States Preventive Services Task Force (USPSTF), there is insufficient evidence to recommend routine screening for Waldenstrom's macroglobulinemia.

# Natural History, Complications, and Prognosis
If left untreated, patients with asymptomatic disease may progress to develop fatigue, weight loss, peripheral neuropathy, shortness of breath, purpura, raynaud's phenomenon, and vision problems. Common complications of Waldenstrom's macroglobulinemia include: hyperviscosity syndrome, cold haemagglutinin disease, cryoglobulinemia, peripheral neuropathy, primary amyloidosis, renal insufficiency, malabsorptive diarrhea, visual abnormalities, congestive heart failure, and schnitzler syndrome. Late and rare severe complications include richter syndrome, and bing-Neel syndrome. Prognosis varies depending on the various factors involved. Five year survival rate is 87% for low-risk disease and 36% for high-risk disease. A standardized scoring system known as the International Prognostic Staging System for Waldenstrom's Macroglobulinemia (IPSSWM) risk stratifies the patients with Waldenstrom's macroglobulinemia.

# Diagnostic Study of Choice
The diagnosis of Waldenstrom's macroglobulinemia is based on bone marrow aspiration and biopsy and serum protein analysis studies such as immunohistochemistry, flow cytometry and cytogenetics to distinguish WM from other types of B-cell lymphomas. CSF flow cytometry, protein electrophoresis and immunofixation is done for the diagnosis of Bing-Neel syndrome (a late, but severe, rare complication).

# History and Symptoms
Many patients with Waldenstrom's macroglobulinemia  are asymptomatic. The disease is subtle and symptoms are nonspecific and are caused by tumor infiltration, circulating monoclonal IgM, IgM deposition into tissues, amyloidogenic properties of IgM, and autoantibody activity of IgM. The most common symptoms of Waldenstrom's macroglobulinemia include weakness, anorexia, unexplained weight loss, fever, heavy sweating, blurry vision, peripheral neuropathy, and abdominal pain. Less common symptoms of the disease include enlarged lymph nodes, abdominal distension, headache, painless lumps, raynaud phenomenon, altered mental status, mucosal bleeding, vision problems, kidney issues, heart problems, infections, GIT problems, and other symptoms due to cryoglobulinemia, cold agglutinin disease, hyperviscosity syndrome, and bing-neel syndrome.

# Physical Examination
Patients with Waldenstrom's macroglobulinemia usually appear oriented to time, place, and person. Physical examination of patients with Waldenstrom's macroglobulinemia is usually remarkable for various findings depending on the degree of tissue infiltration by malignant tumor cells, hyperviscosity syndrome, and accumulation of paraprotein. Common physical exam findings include maculopapular lesions, purpura, petechiae, raynaud's phenomenon, skin ulcers, skin necrosis, cold urticaria, macroglobulinemia cutis, pallor, papilledema, retinopathy, lymphadenopathy, jugular venous distension, pleural effusion, lung rales, pulmonary infiltrates, displaced apical impulse, S3 gallop, hepatosplenomegaly causing abdominal distension, peripheral edema due to congestive heart failure, and distal, symmetric, sensorimotor peripheral neuropathy.

# Laboratory Findings
Laboratory findings consistent with the diagnosis of Waldenstrom's macroglobulinemia  include any cytopenia, lymphocytosis, monocytosis, elevated levels of LDH, Beta-2 microglobulin, uric acid, and urea & creatinine, elevated ESR, hypercalcemia, hyponatremia, positive rheumatoid factor, positive cryoglobulins, positive direct anti-globulin test, positive cold agglutinin titre, proteinuria, prolonged bleeding time, prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time and peripheral smear shows plasmacytoid lymphocytes, normocytic normochromic red blood cells and rouleaux formation.

# Electrocardiogram
There are no ECG findings associated with Waldenstrom's macroglobulinemia.

# Bone Marrow Aspiration and Biopsy
A bone marrow aspiration and biopsy is essential in the diagnosis of Waldenstrom macroglobulinemia and shows hypercellular bone marrow, Dutcher bodies, and three patterns of bone marrow infiltration including lymphoplasmacytoid cells, lymphoplasmacytic cells in an interstitial/nodular pattern, and a polymorphous infiltrate.

# Electrophoresis and Immunofixation
Serum protein electrophoresis and immunofixation are important for the diagnosis of Waldenstrom's macroglobulinemia and shows sharp, narrow spike and dense band of monoclonal IgM paraprotein. CSF flow cytometry, protein electrophoresis and immunofixation are done for the diagnosis of Bing-Neel syndrome and shows a lambda light chain-restricted population of B-cells consistent with a CD5+ CD10+ B-cell lymphoma.

# Chest X-ray
On chest x-ray, Waldenstrom's macroglobulinemia may be characterized by enlarged lymph nodes, pulmonary infiltrates, nodules, effusion, and cardiomegaly due to congestive heart failure.

# CT scan
In Waldenstrom's macroglobulinemia, CT scan imaging of chest, abdomen, and pelvis may show evidences of lymphadenopathy and hepatomegaly. CT of the lungs or abdomen can also be diagnostic for infection, which is particularly relevant to immunocompromised patients.

# MRI
There are no specific MRI findings associated with Waldenstrom's macroglobulinemia. However, MRI of the brain, spinal cord and orbits is especially important while assessing hyperviscosity and for diagnosing Bing-Neel syndrome.

# Echocardiography and Ultrasound
There are no specific echocardiography and ultrasound findings associated with Waldenstrom's macroglobulinemia. However, ultrasound can be used to look at enlarged spleen, liver, kidneys, lymph nodes and to help guide a biopsy needle into an enlarged lymph node.

# Other Imaging Findings
A PET scan can be helpful in spotting small collections of cancer cells, to detect whether an enlarged lymph node has lymphoma or not, to see the response of treatment, and to help decide whether an enlarged lymph node still contains lymphoma or is merely scar tissue after treatment.

# Other Diagnostic Studies
Other diagnostic studies for Waldenstrom's macroglobulinemia include nerve conduction study, electromyography, funduscopy, plasma viscosity, and mutational analysis.

# Medical Therapy
Risk stratification determines the protocol of management used for Waldenstrom's macroglobulinemia. There is no treatment for asymptomatic Waldenstrom's macroglobulinemia. The mainstay of treatment for symptomatic Waldenstrom's macroglobulinemia is Rituximab +/- Chemotherapy. Hyperviscosity syndrome is a medical emergency and requires prompt treatment with plasmapheresis. Drug of choice for the treatment of bing-neel syndrome is Ibrutinib with or without concurrent rituximab. Other treatment options include targeted therapy, immunotherapy and radiation therapy.

# Surgery
Surgery is not the first-line treatment option for patients with Waldenstrom's macroglobulinemia. Stem cell transplant is usually reserved for patients with either relapseor refractory Waldenstrom's macroglobulinemia. In very rare cases, laporotomy or laproscopy might be required.

# Primary Prevention
Primary prevention of Waldenstrom's macroglobulinemia depends on avoiding the type of modifiable risk factor causing the disease such as hepatitis C, HIV, rickettsiosis, hay fever, human T-lymphotrophic virus type 1 infection, epstein-Barr virus infection, environmental factors, history of helicobacter pylori infection, history of immunosuppressant drug therapy after an organ transplant, diet rich in meat and fat and history of past treatment for hodgkin lymphoma.

# Secondary Prevention
There are no established measures for the secondary prevention of Waldenstrom's macroglobulinemia.