Waldenström's macroglobulinemia (lymphoplasmacytic lymphoma) is a chronic lymphoproliferative disorder of indolent type that can manifest in life-threatening complications.
The onset of WM is not specific for a typical clinical picture. In fact, in many patients, it is discovered through routine blood tests. Commonly observed symptoms are anorexia, weight loss and weakness. Furthermore, one study investigated the frequency of symptoms in WM patients. It reported that weakness was the most common feature (66%) followed by anorexia (25%), peripheral neuropathy (24%), fever (15%), weight loss (17%), and Raynaud phenomenon (11%) caused by cryoglobulinemia [7].
Other manifestations include mental status changes such as confusion and memory loss, which result from CNS infiltration. Lethargy, stupor, and coma are other possible occurrences.
Hyperviscosity syndrome is potentially fatal as it presents with spontaneous bleeding, headache, dizziness, hearing impairment and visual abnormalities [8]. Furthermore, blurred vision and diplopia can be presenting features in this condition. GI manifestations may include bleeding, malabsorption, and diarrhea.
Physical exam findings may include lymphadenopathy, hepatomegaly and splenomegaly.
In the elderly patients, WM is presented with nonspecific symptoms such as anorexia, weakness, and weight loss. A thorough history of the patient (and of the family) as well as a physical exam are important. This is followed by an extensive workup.
Diagnostic and evaluation tests
Bone marrow samples and aspirates are necessary studies for the diagnosis of WM. The characteristic findings are a monoclonal IgM spike and lymphoplasmacytic cells [9]. Bone marrow analysis also reveals plasmacytic differentiation and the pattern of infiltration. Further critical studies include protein electrophoresis, viscosity measurements, and serum immunoglobulin levels. Specifically, electrophoresis with immunofixation can identify and quantify IgM. Flow cytometry may exhibit IgM markers on B cells. Another helpful test is a peripheral smear, which may display normocytic normochromic red cells, plasmacytoid lymphocytes, and rouleaux formation. Finally, if a chromosomal defect is present, genetic testing will identify deletion of 6q from chromosomes 6q21-22.
Laboratory tests
A complete blood count in WM exhibits leukopenia, normocytic normochromic anemia, and thrombocytopenia. The latter is observed in almost half of patients with bleeding disorders. Further lab testing includes lactate dehydrogenase (LDH) (usually elevated in WM), uric acid, erythrocyte sedimentation rate (ESR), renal and liver functions tests, rheumatoid factor, coagulation studies, and others as well [10]. Urinary immunoglobulin analysis demonstrates light chains known as Bence Jones protein.
Imaging
Chest X-ray is performed to detect infiltrates or effusions. This is also useful to determine if congestive heart failure is present. Additionally, CT of chest, abdomen, and pelvis can identify lymphadenopathy, and/or hepatosplenomegaly. Finally, MRI of spine exhibits evidence of bone marrow disease.
Therapy is tailored to the patient’s age, the presence of coexisting diseases, and severity of WM. The medical team will also take into consideration if the patient has cytopenia, hyperviscosity or any other complications. Additionally, the clinicians will also ascertain whether the patient is a candidate for autologous stem cell transplantation.
As a guide for disease management, the International Workshops on Waldenström Macroglobulinemia offered treatment recommendations [11].
Asymptomatic patients do not require treatment. They should undergo close surveillance consisting of immunoglobulin, viscosity, and M component measurements.
Surveillance
Close follow up is prudent. The medical team will monitor for symptoms of recurrence and side effects of the chemotherapy drugs. Periodic complete blood counts, IgM, and beta-2 microglobulin levels are also obtained. Depending on the medications used, further testing such as liver function tests is considered. Also, CT scans or other imaging may be warranted.
WM develops gradually and slowly. The median survival is 78 months. Poor prognosis is associated with older age (above 65 years old), hemoglobin level below 10g/dL, albumin level below 4g/dL, and increased beta-2-microglobulin level.
Studies have investigated types of bone marrow involvement and their correlation to prognosis. Patients with nodular bone marrow disease exhibit a better prognosis than those with diffuse bone marrow involvement.
The majority of deaths are attributed to the progression of the lymphoproliferative process, infection, stroke, and gastrointestinal bleeding. Also renal and cardiac failure contributes to mortality.
According to WHO classification, the affected LPL/WM cells are characterized by the presence of monotypic surface light chain immunoglobulin, IgM, CD19 and CD20 but are negative for CD5, CD10 and CD23. Immunophenotype for LPL/WM is however variable among cases with about 20% of patients showing CD5 or CD23.
One study demonstrated that there has been no improvement in WM since late 20th century despite new treatments [4]. However, another investigation observed that there are better survival rates in those diagnosed during 2001-2010 versus 1980-2000. Furthermore, the 10-year survival rate was 66% in the former group versus 49% in the latter. In white and other races, the survival rate relatively improved much better than in black individuals [5].
Mutations in genes (MYD88 and CXCR4) are indicative of the clinical manifestation and prognosis. Specific mutations are associated with increased bone marrow involvement and systemic disease such as hyperviscosity syndrome [6].
WM is associated with risk factors, but their role in developing the disease is not established. There is a genetic component to the cause as well. The implicated mutation, found in the MYD88 gene, is observed in 90% of patients. Normally, this gene is essential in the signalling pathway in the immune system as it promotes immune cell survival. If MYD88 is mutated, it remains activated and, therefore, enables longer survival of WM cells. This mutation is not inherited but occurs more often during the aging process, which provides clarity on why WM develops in the elderly.
Genetic mutation is not the only abnormality associated with WM cells. A partial deletion on chromosome 6 has been identified in some WM cells while others have shown chromosomal translocation caused due to attachment of a segment of one chromosome to another. It is believed that such changes could switch on oncogenes and inhibit tumor suppressor genes creating favorable conditions for the disease.
Another etiology involves the dendritic cells of the bone marrow, which normally produce interleukin-6 (IL-6) for maturation of plasma cells and certain lymphocytes. Hence, excess levels of IL-6 may have a role contributing to the pathogenesis of WM.
There are 1500 new cases of WM annually in the United States which amounts to about 2% of hematological cancers. The incidence of WM is higher in the white population as compared to people of African descent. In England the annual incidence is 10.3 per million population [2].
The risk factors are older age, male gender, white race, and a positive family history. It is unknown why there are gender and race preferences. Additionally, approximately 20% of these patients have a relative with the same disease or a B cell pathology.
WM mostly affects the elderly. Specifically, it manifests in the 7th or 8th decade in most patients. Furthermore, the median age for diagnosis is 65 years of age. The disease is unusual in individuals under the age of 50 years old.
Progress of WM is based on genetic factors. The clinical picture and survival of patients is determined by the somatic mutations in MYD88 and CXCR4 genes. Patients with MYD88 and CXCR4 and certain other comorbidities showed higher involvement of bone marrow disease and hyperviscosity syndrome. CXCR4 mutation did not affect risk to death as much as the wild type MYD88 status.
Genome sequencing in WM patients has demonstrated mutations in genes, MYD88 (90% cases), CXCR4 (27% cases) and ARID1A (17% cases). Genetic determinants underline the pathophysiology of the disease and its seriousness.
The pathogenesis of WM stems from two main processes as described below.
Infiltration
Infiltration of spleen, bone marrow and lymph nodes with neoplastic lymphoplasmacytic cells is a factor in the pathogenesis. These cells can occasionally infiltrate other organs such as the skin, gastrointestinal tract, kidneys, liver, lung, CNS as well. This infiltration manifests in clinical sequel. The level of plasma cell infiltration in the bone marrow reflects IgM concentration at diagnosis. Therefore, bone marrow plasma cells can be monitored before and after treatment [3].
IgM secretion
Due to the physical, chemical, and immunologic characteristics of IgM, the release of this protein results in hyperviscosity and other complications such as cryoglobulinemia, coagulopathy, peripheral neuropathy, primary amyloidosis, and anemia. Furthermore, IgM accumulates and deposits in multiple organs including the skin, gastrointestinal tract, kidneys, etc. In addition, IgM proteins can function similarly to rheumatoid factor, lupus anticoagulant, and antimyelin hence resulting in symptoms.
The risk factors of WM, which include older age, white race, male gender, and positive family history cannot be controlled or modified.
It is thought that hepatitis C is associated with the development of WM. Hepatitis open link C is preventable by avoiding the risk and causes of the virus such as intravenous drug use and unprotected sex act with several partners. Hepatitis C is treatable, but the impact of this on WM has not been elucidated.
Waldenström macroglobulinemia (WM) is an indolent lymphoproliferative disease characterized by elevated levels of plasma immunoglobulin M (IgM) and lymphoplasmacytic infiltrate in the patient's bone marrow [1]. This disorder is one among several malignant monoclonal gammopathies and hence shares similar features with multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS).
This B cell lymphoma is primarily found in the elderly and is thought to occur through genetic and chromosomal abnormalities in addition to other mechanisms.
While WM is usually discovered incidentally during routine blood tests, it can also be detected during a workup for nonspecific symptoms. The clinical picture consists of weakness, anorexia, weight loss and other symptoms as well. Work up includes a comprehensive history, physical exam, extensive blood studies including bone marrow biopsy and aspiration.
There are various chemotherapy regimens for symptomatic WM patients. The clinician will consider the patient’s age, the severity of symptoms, and any comorbidity when choosing the best option. Post-therapy surveillance includes test and possibly imaging.
Waldenstrom macroglobulinemia (WM) is a type of lymphoma that causes too much production immunoglobulin M, which is one of the main proteins the body uses for immunity. High levels of this cause the blood to become very thick. This makes it difficult for blood to flow smoothly through blood vessels. This disease occurs mostly in the elderly. In addition to age, it also is more common in white people, men, and those having a relative affected with this condition (or a similar disease).
The symptoms are usually weakness, anorexia, and unintentional weight loss. There are important blood tests that will determine the diagnosis. These will reveal the amount of different types of blood cells and immunologic proteins. Also, the clinician will perform a bone marrow biopsy to obtain a sample for further evaluation. Patients without symptoms do not require treatment but should be monitored closely with periodic testing. Patients with symptoms will most likely need to undergo treatment. The doctor and patient will discuss options, side effects, prognosis, and any question the patient has.
The treatment consists of different chemotherapy regimens. The best regimen depends on the patient’s age, symptoms, and whether the patient has any other health issues. After the patient is in remission, there is a period of monitoring during which the doctor will inquire about any side effects from the chemotherapy. Also, there are lab tests and possibly imaging techniques to monitor for return of disease.
A disease called hyperviscosity syndrome (thickened blood) can occur with WM. This disease leads to bleeding, dizziness, hearing problems, and blurred vision. Hyperviscosity syndrome is treated with plasmapheresis. This process removes the patient’s blood and passes it through a machine which extracts the component that makes the blood thick. The blood is then returned to the patient. This process helps relieve the disease and the symptoms.