Lymphoplasmacytic lymphoma overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]
Overview
Lymphoplasmacytic lymphoma(LPL, previously termed lymphoplasmacytoid lymphoma) 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. This broad definition includes patients with monoclonal gammopathy of undetermined significance of the IgM type (IgM MGUS), smoldering Waldenström macroglobulinemia, Waldenström 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 LPL patients. it is termed as Waldenström 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. Waldenström 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. Waldenström's macroglobulinemia was first discovered by Jan G. Waldenström and represents 1% of all hematological cancers. Common causes of this disease 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 Lymphoplasmacytic lymphoma include: MYD88-L265P, CXCR4 and chromosomes 6q, 13q, 3q, 6p and 18q. The hallmark of Waldenström's macroglobulinemia is hyper-viscosity syndrome. If left untreated, patients with asymptomatic Waldenström's macroglobulinemia may progress to develop a symptomatic disease. Common complications of Waldenström'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 lymphoplasmacytic lymphoma depend on the degree of tissue infiltration by malignant tumor cells, hyperviscosity syndrome, and accumulation of paraprotein. The diagnosis of lymphoplasmacytic lymphoma is based on bone marrow biopsy and serum protein analysis. Risk stratification determines the protocol of management used for lymphoplasmacytic lymphoma patients. Watchful waiting is recommended for asymptomatic Waldenström's macroglobulinemia. Symptomatic Waldenström's macroglobulinemia is treated with Rituximab +/- Chemotherapy. Ibrutinib with or without concurrent rituximab, is considered as a drug of choice for treatment of Bing-Neel syndrome.
Historical Perspective
Waldenström macroglobulinemia was first discovered by Jan G. Waldenström, a Swedish physician in 1944.
Classification
There is no established system for the classification of lymphoplasmacytic lymphoma. However, according to a devised criteria based upon patient's symptoms, Waldenström's macroglobulinemia can be further classified into smoldering/asymptomatic and symptomatic WM .
Pathophysiology
Lymphoplasmacytic lymphoma (LPL) is an uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which are normally involved in humoral immunity. Genes involved in the pathogenesis of LPL include MYD88-L265P, and CXCR4.
Causes
The exact cause of lymphoplasmacytic lymphoma has not been identified; however, the disease has been highly-associated with somatic mutations in MYD88 and CXR4 genes. In addition, less possible, common causes of the disease include chromosomal abnormalities and environmental factors.
Differentiating Lymphoplasmacytic lymphoma from Other Diseases
Lymphoplasmacytic lymphoma 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 lymphoplasmacytic lymphoma is estimated to be 1000-1500 cases in United States annually. Lymphoplasmacytic lymphoma represents 1-2% of all hematological cancers.
Risk Factors
Common risk factors in the development of lymphoplasmacytic lymphoma are monoclonal gammopathy of undetermined significance, heredity, hepatitis C, autoimmune disorders and allergic conditions.
Screening
According to the the United States Preventive Services Task Force (USPSTF), there is insufficient evidence to recommend routine screening for lymphoplasmacytic lymphoma.
Natural History, Complications, and Prognosis
If left untreated, patients with asymptomatic disease may progress to develop fatigue, weight loss, peripheral neuropathy and other symptoms of the disease. Common complications of lymphoplasmacytic lymphoma include: hyperviscosity syndrome, cold haemagglutinin disease, cryoglobulinemia, peripheral neuropathy, primary amyloidosis, renal insufficiency, malabsorptive diarrhea, and visual abnormalities. Prognosis varies depending on the various factors involved. Five year survival rate is 87% for low-risk disease and 36% for high-risk disease.
Diagnostic Study of Choice
The diagnosis of lymphoplasmacytic lymphoma is based on bone marrow biopsy and serum protein analysis.
History and Symptoms
Many patients with lymphoplasmacytic lymphoma are asymptomatic. The disease is subtle and symptoms are nonspecific. The most common symptoms of lymphoplasmacytic lymphoma include weakness, anorexia, blurry vision, peripheral neuropathy, and weight loss. Less common symptoms of the disease include bleeding and Raynaud phenomenon.
Physical Examination
Patients with lymphoplasmacytic lymphoma usually appear oriented to time, place, and person. Physical examination of patients with lymphoplasmacytic lymphoma is usually remarkable for various findings depending on the degree of tissue infiltration by malignant tumor cells, hyperviscosity syndrome, and accumulation of paraprotein.
Laboratory Findings
Patients with lymphoplasmacytic lymphoma usually appear oriented to time, place, and person. Physical examination of patients with lymphoplasmacytic lymphoma is usually remarkable for various findings depending on the degree of tissue infiltration by malignant tumor cells, hyperviscosity syndrome, and accumulation of paraprotein.
Electrocardiogram
There are no ECG findings associated with lymphoplasmacytic lymphoma.
Chest X-ray
On chest x-ray, lymphoplasmacytic lymphoma may be characterized by pulmonary infiltrates, nodules, effusion, and congestive heart failure.
Echocardiography and Ultrasound
There are no specific echocardiography and ultrasound findings associated with lymphoplasmacytic lymphoma. 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.
CT scan
In lymphoplasmacytic lymphoma, CT scan imaging of chest, abdomen, and pelvis may show evidences of lymphadenopathy and hepatomegaly.
MRI
There are no specific MRI findings associated with lymphoplasmacytic lymphoma. However, MRI of the brain, spinal cord and orbits is especially important while assessing hyperviscosity and for diagnosing Bing-Neel syndrome.
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.