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Ed Forum 2018

Signs and Symptoms

Because WM is indolent (slow growing), there may be no signs or symptoms of disease for years before and even after diagnosis. When signs or symptoms do occur, there may be no correlation between the level of monoclonal IgM and/or the amount of bone marrow infiltration with the degree of symptom severity. Patients with similar laboratory test results have markedly different types and degrees of symptoms. The following are conditions with typical recurring signs or symptoms that can occur in WM patients – depending on their severity, they may indicate the need for treatment. It is important to note that several of these signs and symptoms are also associated with other conditions, and one should not necessarily assume that WM is the only cause.

Anemia – decreased production of red blood cells, which carry oxygen from the lungs to the tissues. Although anemia has many causes, it is the most common manifestation of lymphoplasmacytic cell infiltration in the bone marrow, and its symptoms often initiate the process leading to a WM diagnosis. These symptoms include pallor, weakness, fatigue, lightheadedness, palpitations of the heart, and shortness of breath.

Lymphadenopathy, splenomegaly, and hepatomegaly – enlargement of the lymph nodes, spleen, and liver, respectively. Unless the enlargement is significant, it is frequently not noticeable.

Hyperviscosity – increased thickness of the blood, which in WM is caused by a high IgM level. Signs and symptoms of hyperviscosity include chronic bleeding from the nose, gums, and less commonly, the gastrointestinal tract; headache; ringing in the ears; dizziness; loss of coordination or balance, impaired hearing; blurring or loss of vision; distended, sausage-shaped veins in the retina; and swelling of the optic disk at the back of the eye. In severe cases, heart failure, sleepiness, stupor, and coma can develop. Symptoms of hyperviscosity occur most commonly at IgM concentrations greater than 4,000 mg/dL. However, such concentrations are not necessarily associated with hyperviscosity, as there is considerable variability in the amount of IgM that produces hyperviscosity symptoms in an individual.

Constitutional symptoms (also called B symptoms) – these include recurrent fever, night sweats, weight loss, and fatigue.

Peripheral neuropathy – characterized by numbness, tingling, burning, or prickling sensations that are commonly first noticed in the feet. The sensations are usually symmetrical, affecting both feet equally, and slowly progress to the upper legs, hands, and arms. Weakness of the legs and arms may develop. Peripheral neuropathy is seen in approximately 25% of WM patients and can occur because the monoclonal IgM targets specific components of the nerves or because of treatments that include bortezomib (Velcade), thalidomide, or other neurotoxic agents.

For a detailed discussion of the management of IgM-associated peripheral neuropathies, please see Investigation and management of IgM and Waldenström-associated peripheral neuropathies: recommendations from the IWWM-8 consensus panel by D'Sa, et al. (2017), Br J Haematol. doi:10.1111/bjh.14492.

Cold agglutinin disease – the presence of a high concentration of circulating antibody directed against the red blood cells. The antibody typically binds to the cells at low body temperatures and can cause hemolytic anemia (destruction of red blood cells). Signs and symptoms vary according to the severity of the disease and may include painful fingers and toes upon exposure to the cold, anemia, fatigue, shortness of breath, jaundice, Raynaud’s phenomenon (whiteness of the fingers, toes, nose, and/or ears) when cold, and dark urine caused by the presence of hemoglobin.

Cryoglobulinemia – a condition in which the circulating IgM has the properties of a cryoglobulin, which is a protein that precipitates at low body temperatures. When the IgM concentration reaches high levels, the precipitated antibody physically obstructs smaller blood vessels, leading to blueness of the fingers and toes when cold; Raynaud’s phenomenon; purpura (purple skin marks); and bleeding, ulcers, and gangrene of the fingers, toes, nose, and ears.

Amyloidosis – a group of rare diseases caused by the presence of an abnormal protein called amyloid in various tissues and organs of the body. The amyloid protein forms fibrils that may injure these body parts or interfere with their normal functioning. The protein may be deposited in a localized area or throughout the body. The most common tissues and organs involved are the kidneys, heart, gastrointestinal tract, peripheral nerves, and liver. Symptoms can vary widely based on which tissues and organs have the abnormal fibril deposits. Signs and symptoms of amyloidosis may be vague, such as weakness, fatigue, weight loss, shortness of breath, abnormal sensation in the feet, enlarged liver and/or spleen, bleeding under the skin, or anemia. More specific signs and symptoms might include swelling of the extremities, an enlarged tongue, carpal tunnel syndrome, food malabsorption, skin thickening, unexplained congestive heart failure, and unexplained kidney failure.

Thrombocytopenia – decreased production of platelets, which are important in blood clotting. Typical symptoms are bleeding, usually from the gums and nose, pinpoint flat red blotches on the skin called petechiae, and easy bruising.

Bing-Neel syndrome – characterized by the infiltration of lymphoplasmacytic cells or IgM in the central nervous system (brain and spinal cord). This is a very rare condition which can result in mental deterioration, confusion, visual disturbances, irritability, personality changes, convulsions, and coma.

For a detailed discussion of the management of Bing-Neel syndrome, please see "Guideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome" by Minnema, MC. et al. Haematologica, 2017 Volume 102 (1):43-51, obtained from the Haematologica Journal website www.haematologica.org.

Other signs and symptoms – recurrent infections, particularly of the sinuses and upper respiratory tract, may occur more often in WM patients than in the normal population. Occasionally the lymphoplasmacytic cells of WM will infiltrate the lung and produce masses or pleural effusion (fluid in the chest). Involvement of the kidneys and lesions in the bones are rare. Occasionally patients will have a rash or hives, and rarely the lymphoplasmacytic cells may infiltrate the skin. A small number of patients may exhibit masses of WM cells in various parts of the body, including the extremities, the spine, the breast, and the eye socket.  

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