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Waldenstrom Macroglobulinemia

Waldenström Macroglobulinemia

Waldenström's macroglobulinemia (lymphoplasmacytic lymphoma) is a chronic lymphoproliferative disorder of indolent type that can manifest in life-threatening complications.

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Presentation

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.

Easy Bruising
  • The covered platelet cells may not work right, resulting in bleeding and easy bruising. Every year, there are five new cases of macroglobulinemia per 1,000,000 people.[uihc.org]
  • bruising or bleeding (nosebleeds or bleeding from gums) Feeling very tired Pain or a feeling of fullness below the rib s on the left side Pain, tingling, or numbness, especially in the hands, feet, fingers, or toes Vision changes, such as blurred vision[seer.cancer.gov]
  • Some Of The Symptoms Of Waldenstrom Macroglobulinemia Are: Gum bleeding Visual impairment with diplopia or decreased vision Cyanotic skin Dizziness Easy bruising Severe fatigue Flank pain Headaches Alteration of mental status Nose bleeding Numbness or[epainassist.com]
  • Symptoms Symptoms of WM may include any of the following: Bleeding of the gums and nosebleeds Blurred or decreased vision Bluish skin Dizziness Easy bruising of the skin Fatigue Flank pain Headache Mental status changes Numbness , tingling, or burning[ufhealth.org]
  • Symptoms Symptoms of WM may include any of the following: Bleeding of the gums and nosebleeds Blurred or decreased vision Bluish skin in the fingers after cold exposure Dizziness or confusion Easy bruising of the skin Fatigue Diarrhea Numbness , tingling[mclaren.org]
Splenomegaly
  • Manifestations of macroglobulinemic lymphoma include lymphadenopathy, splenomegaly and bone marrow involvement. Renal presentations are unusual and complications of renal function are even less frequent.[ncbi.nlm.nih.gov]
  • CT-identified splenomegaly was reported in 6 of the 31 patients at baseline. Of the 6 patients with splenomegaly, 5 experienced a reduction in splenic enlargement and 1 patient discontinued treatment before response assessment.[onclive.com]
  • Signs and symptoms of the disease may include enlarged lymph nodes or spleen ( splenomegaly ), fatigue, headaches, weight loss, a tendency to bleed easily, visual problems, confusion, dizziness, and loss of coordination.[medicinenet.com]
  • Major Points Waldenström macroglobulinemia (lymphoplasmacytic lymphoma, WM) is an indolent B-cell lymphoma marked by adenopathy, splenomegaly, cytopenias, and hyperviscosity due to circulating monoclonal IgM antibodies.[wikijournalclub.org]
Generalized Lymphadenopathy
Massive Splenomegaly
Anemia
  • Surprisingly, the combination of lenalidomide with rituximab produced clinically significant anemia at 25 mg/day for 21/28 days, the highest possible dose, in Waldenström's Macroglobulinemia (WM).[ncbi.nlm.nih.gov]
  • Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Presence of IgM monoclonal protein associated with 10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis.[ncbi.nlm.nih.gov]
  • This case is unusual because the patient lacked all common clinical features of Waldenstrom macroglobulinemia with exception of anemia.[ncbi.nlm.nih.gov]
  • The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs.[ncbi.nlm.nih.gov]
Weight Loss
  • Commonly observed symptoms are anorexia, weight loss and weakness. Furthermore, one study investigated the frequency of symptoms in WM patients.[symptoma.com]
  • B means that a person has experienced the following symptoms: Unexplained weight loss Unexplained fever Heavy sweating, especially at night, which may drench one’s nightclothes or sheets on the bed.[cancer.net]
  • Fever, sweats, weight loss: WM, like other lymphomas, can cause fevers (without an infection), drenching night sweats, and weight loss (without trying). These are called B symptoms.[cancer.org]
  • If you notice swollen lymph nodes, unexplained weight loss and extreme fatigue, visit your doctor. Early detection and treatment is key to fighting lymphoma, which can be detected through blood work or a biopsy.[sharecare.com]
  • Signs and symptoms of the disease may include enlarged lymph nodes or spleen ( splenomegaly ), fatigue, headaches, weight loss, a tendency to bleed easily, visual problems, confusion, dizziness, and loss of coordination.[medicinenet.com]
Lymphadenopathy
  • The patient had no peripheral lymphadenopathy. On extensive investigation she was found to have pancreatic mass.[ncbi.nlm.nih.gov]
  • Manifestations of macroglobulinemic lymphoma include lymphadenopathy, splenomegaly and bone marrow involvement. Renal presentations are unusual and complications of renal function are even less frequent.[ncbi.nlm.nih.gov]
  • Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Presence of IgM monoclonal protein associated with 10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis.[ncbi.nlm.nih.gov]
  • The patient had lymphadenopathy and hepatosplenomegaly. Serum protein electrophoresis showed the presence of M band in the gamma globulin region, which, on immune fixation, showed a monoclonal band at the "IgM and K" region.[ncbi.nlm.nih.gov]
Asymptomatic
  • Patients typically present at an advanced age, and a substantial proportion are asymptomatic at diagnosis.[ncbi.nlm.nih.gov]
  • The most common symptoms at diagnosis were fatigue (77.8%) and bleeding (20%), while only 6 patients (6.7%) were asymptomatic.[ncbi.nlm.nih.gov]
  • Asymptomatic patients can be observed without therapy. First-line therapy should consist of the monoclonal anti-CD20 antibody, rituximab, given typically in combination with other agents.[ncbi.nlm.nih.gov]
  • Asymptomatic patients should be observed.[ncbi.nlm.nih.gov]
  • Given that 20-25 % of patients are asymptomatic at diagnosis and early intervention does not translate into survival benefit, we follow a risk-adapted approach and actively monitor this subset of "smoldering" patients.[ncbi.nlm.nih.gov]
Weakness
  • Commonly observed symptoms are anorexia, weight loss and weakness. Furthermore, one study investigated the frequency of symptoms in WM patients.[symptoma.com]
  • This can cause symptoms like weakness, trouble breathing, and fluid buildup in body tissues.[cancer.org]
  • This can result in anemia A shortage of red blood cells, causing weakness and fatigue. (low levels of red blood cells), neutropenia An abnormally low level of neutrophils.[lymphoma.org]
  • Fatigue Unexplained weight loss Enlarged lymph nodes or spleen Numbness, weakness or other nervous system problems, pain in the hands or feet, sometimes called peripheral neuropathy Abdominal swelling and diarrhea Weakness and shortness of breath Infections[cancer.net]
  • […] physician in Sweden by the name of Jan Waldenstrom and he noticed a peculiar constellation of symptoms in a few of his patients and these symptoms included bleeding, some visual changes, such as double vision and blurry vision, headaches, and generalized weakness[khanacademy.org]
Diarrhea
  • The patient was treated with cyclophosphamide, vincristine, and prednisone with rapid and complete resolution of the peripheral edema and diarrhea.[ncbi.nlm.nih.gov]
  • The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs.[ncbi.nlm.nih.gov]
  • Tiredness Bruising Diarrhea Mouth sores (Stomatitis) Muscle spasms Nausea Tiredness Mouth sores (Stomatitis) Pneumonia Bruising Muscle spasms Diarrhea Nausea Diarrhea is a common side effect in people who take IMBRUVICA .[imbruvica.com]
  • Other nonhematological toxicities were diarrhea (5%), fatigue (8%), stomatitis (8%) and pulmonary toxicity (5%).[ncbi.nlm.nih.gov]
  • Fatigue Unexplained weight loss Enlarged lymph nodes or spleen Numbness, weakness or other nervous system problems, pain in the hands or feet, sometimes called peripheral neuropathy Abdominal swelling and diarrhea Weakness and shortness of breath Infections[cancer.net]
Abdominal Pain
  • We report a case of Waldenstrom macroglobulinemia in an 60-year-old female who initially presented with intermittent abdominal pain. The patient had no peripheral lymphadenopathy. On extensive investigation she was found to have pancreatic mass.[ncbi.nlm.nih.gov]
  • Lymphoma cells can also grow in organs like the liver and spleen, causing these organs to swell and leading to abdominal pain. (For more on the symptoms of WM, see Signs and Symptoms of Waldenstrom Macroglobulinemia .)[cancer.org]
  • Case report We report a case of Waldenstrom macroglobulinemia in an 60-year-old female who initially presented with intermittent abdominal pain. The patient had no peripheral lymphadenopathy.[pancreas.imedpub.com]
Bleeding Gums
  • Symptoms of hyperviscosity include: Vision problems, especially blurred or double vision Confusion Dizziness Loss of coordination Headaches Nosebleeds or bleeding gums Fatigue If you are concerned about any changes you experience, please talk with your[cancer.net]
  • Abnormal bleeding: High levels of abnormal antibody can damage blood vessels, which can lead to problems like nosebleeds and bleeding gums.[cancer.org]
  • Some of these symptoms may include: Abnormal or unusual bleeding, such as bleeding gums, strange bruises, or nosebleeds Feeling unusually tired, even though you are getting enough sleep Shortness of breath with any exertion Frequent infections or illness[verywell.com]
  • gums Sometimes people have no symptoms and it is found by chance following a blood test.[lymphomation.org]
Hepatosplenomegaly
  • Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Presence of IgM monoclonal protein associated with 10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis.[ncbi.nlm.nih.gov]
  • Most commonly it presents with cytopenia, hepatosplenomegaly, lymphadenopathy, constitutional symptoms, and hyperviscosity syndrome.[ncbi.nlm.nih.gov]
  • The patient had lymphadenopathy and hepatosplenomegaly. Serum protein electrophoresis showed the presence of M band in the gamma globulin region, which, on immune fixation, showed a monoclonal band at the "IgM and K" region.[ncbi.nlm.nih.gov]
  • -ˌstrœmz- \ Medical Definition of Wal den ström's macroglobulinemia : lymphoplasmacytic lymphoma marked by an elevated serum concentration of a monoclonal antibody of the class IgM and characterized esp. by hyperviscosity of blood, lymphadenopathy, hepatosplenomegaly[merriam-webster.com]
Hepatomegaly
  • There was also mild hepatomegaly but no splenomegaly or ascites. Rest of the abdominal exam was unremarkable. Also, examination of other systems was unremarkable.[pancreas.imedpub.com]
  • Physical findings include: hepatomegaly, splenomegaly, fundic changes, adenopathy, neurologic abnormalities, and purpura. The most common laboratory finding is anemia.[icd10data.com]
  • For example, accumulation of these cells can lead to an enlarged liver (hepatomegaly), spleen (splenomegaly), or lymph nodes (lymphadenopathy).[ghr.nlm.nih.gov]
  • 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.[symptoma.com]
  • Merlini et al [16] reported the following occurrences of symptoms in 215 patients evaluated for Waldenström macroglobulinemia: Hepatomegaly - 20% Lymphadenopathy - 15% Purpura - 9% Hemorrhagic manifestations - 7% Papilledema, ie, sausage-shaped (distended[emedicine.medscape.com]
Hearing Problem
  • This disease leads to bleeding, dizziness, hearing problems, and blurred vision. Hyperviscosity syndrome is treated with plasmapheresis.[symptoma.com]
Hearing Impairment
  • Hyperviscosity syndrome is potentially fatal as it presents with spontaneous bleeding, headache, dizziness, hearing impairment and visual abnormalities. Furthermore, blurred vision and diplopia can be presenting features in this condition.[symptoma.com]
Purpura
  • Cutaneous manifestations are usually nonspecific such as purpura, ulcers, and urticarial lesions. These lesions are caused by hyperviscosity of the blood, immune complex-mediated vascular damage, paraprotein deposition, and amyloid deposition.[ncbi.nlm.nih.gov]
  • This suggests that the mechanism of immune thrombocytopenia in our case is different from that of idiopathic thrombocytopenic purpura.[pubs.sciepub.com]
  • It is also called hyperglobulinemic purpura, macroglobulinemia, Waldenstrom purpura, and Waldenstrom syndrome.[healthcentral.com]
  • Skin manifestations include the following: Purpura (see the image below) Bullous skin disease Papules on extremities Cutaneous plaques and nodules Chronic urticaria (Schnitzler syndrome) Raynaud phenomenon Livedo reticularis Acrocyanosis Purpura from[emedicine.medscape.com]
  • Visceral infiltration is rare but may target the stomach, small bowel, lungs, exocrine glands or skin, accounting for such symptoms as diarrhea, steatorrhea and purpura of the skin.[orpha.net]
Skin Lesion
  • Specific skin lesions occur rarely and generally consist of translucent, flesh-colored papules composed of monoclonal IgM deposits.[ncbi.nlm.nih.gov]
  • The most common symptoms of this disease are: weakness fatigue bleeding from the gums or nose weight loss bruises skin lesions skin discoloration swollen glands If the amount of IgM in your body becomes severely high, you may experience additional symptoms[healthline.com]
  • Hepatosplenomegaly and lymphadenopathy are found in 20% to 30% of patients with WM, accompanied by occasional fever, night sweats, and weight loss. 1 Patients may also develop Schnitzler’s syndrome, a term to describe skin lesions, fever, and arthralgia[academic.oup.com]
  • lesions of any type does not appear to affect outcome in this condition which often does not require treatment.[dermnetnz.org]
Petechiae
  • Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA . The mechanism for the bleeding events is not well understood.[jnj.com]
  • B-cells in the skin The most common of these is when there is so much paraprotein in the blood that it affects blood flow (hyperviscosity syndrome ) and this can present as: swelling of the feet bleeding from the gums purple spots on hands and feet ( petechiae[dermnetnz.org]
Blurred Vision
  • The following case study focuses on a 65-year-old woman with a history of Waldenström macroglobulinemia that has gone untreated who presents with a two-week history of headaches, blurred vision, and bruising.[hematology.org]
  • vision or blind spots Weight loss for no reason Progression and Transformation None Epidemiology and Mortality None Sources Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (Eds): WHO Classification of Tumours of Haematopoietic[seer.cancer.gov]
  • This disease leads to bleeding, dizziness, hearing problems, and blurred vision. Hyperviscosity syndrome is treated with plasmapheresis.[symptoma.com]
  • Vision problems: Bleeding around the small blood vessels inside the eyes or poor circulation in these vessels caused by thickened blood might lead to blurred vision or blind spots.[cancer.org]
  • Patients whose IgM levels exceed 4 g/dL with a serum viscosity measurement greater than 4 are more likely to develop hyperviscosity syndrome, which generally includes oronasal bleeding, gingival bleeding, and blurred vision due to retinal hemorrhages.[academic.oup.com]
Diplopia
  • Some Of The Symptoms Of Waldenstrom Macroglobulinemia Are: Gum bleeding Visual impairment with diplopia or decreased vision Cyanotic skin Dizziness Easy bruising Severe fatigue Flank pain Headaches Alteration of mental status Nose bleeding Numbness or[epainassist.com]
  • 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.[symptoma.com]
  • […] skull base and orbit has also been reported. 48 Bing-Neel syndrome (long-standing hyperviscosity altering the vascular permeability and leading to perivascular malignant infiltration) consists of headache, vertigo, impaired hearing, ataxia, nystagmus, diplopia[bloodjournal.org]
Visual Impairment
  • Complications Of Waldenstrom Macroglobulinemia Some Of The Complications Of Waldenstrom Macroglobulinemia Are: Altered mentation Congestive heart failure Gastrointestinal bleeding Visual impairment.[epainassist.com]
  • impairment (distended and tortuous retinal veins with hemorrhage and exudates), neurologic symptoms due to sluggish blood flow, bleeding due to IgM binding of clotting factors and cryoglobulinemia causing Raynaud phenomena and cold urticaria Laboratory[pathologyoutlines.com]
Epistaxis
  • A 71-year-old woman presented with malaise, skin bruising, epistaxis, and gingival bleeding of recent and prompt onset. There was no adenopathy. The liver and spleen were not enlarged.[ncbi.nlm.nih.gov]
  • He unfortunately continued to have bouts of epistaxis and his thrombocytopenia worsened. It was decided to add Rituximab at a dose of 375 mg/m 2 for steroid refractory ITP.[pubs.sciepub.com]
  • […] several months of therapy. 49 In the initial case descriptions, the initial paradoxical increases in serum IgM levels and the concomitant rise in viscosity lead to clinically significant events, including subdural hemorrhage, worsening -headaches, and/or epistaxis[hematologyandoncology.net]
  • The clinical presentation due to properties of circulating IgM includes hyperviscosity, which results in symptoms such as headache, blurring of vision, and recurrent epistaxis.[cancertherapyadvisor.com]
  • Manifestations are the result of shear forces which cause venous damage, and include visual changes resulting from retinal flame-shaped hemorrhages, epistaxis, gingival bleeding, headaches and dizziness; more severe manifestations include stupor and coma[nature.com]
Dizziness
  • Signs and symptoms of the disease may include enlarged lymph nodes or spleen ( splenomegaly ), fatigue, headaches, weight loss, a tendency to bleed easily, visual problems, confusion, dizziness, and loss of coordination.[medicinenet.com]
  • The thickened blood may clot in the fingers and toes, causing numbness, or in the brain, causing dizziness and confusion. The covered platelet cells may not work right, resulting in bleeding and easy bruising.[uihc.org]
  • These symptoms frequently occur as a result of hyperviscosity and include: vision changes, including blurry vision and vision loss headaches dizziness or vertigo changes in mental status Waldenstrom’s disease develops when your body overproduces IgM antibodies[healthline.com]
  • This disease leads to bleeding, dizziness, hearing problems, and blurred vision. Hyperviscosity syndrome is treated with plasmapheresis.[symptoma.com]
  • Tell your healthcare provider if you get any symptoms of heart rhythm problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, chest discomfort, or you faint High blood pressure (hypertension[imbruvica.com]
Headache
  • Symptoms of hyperviscosity include headaches, vision changes, mental status changes, seizures, and bleeding. Congestive heart failure and volume overload can also be seen.[hematology.org]
  • […] time there was a young physician in Sweden by the name of Jan Waldenstrom and he noticed a peculiar constellation of symptoms in a few of his patients and these symptoms included bleeding, some visual changes, such as double vision and blurry vision, headaches[khanacademy.org]
  • […] fatigue pale appearance rapid heart rate weakness Clotting Symptoms dizziness weight loss headaches visual changes lack of concentration confusion in speech numbness, tingling, or weakness in arms or legs pain or swelling in arms or legs shortness of[uihc.org]
  • Signs and symptoms of the disease may include enlarged lymph nodes or spleen ( splenomegaly ), fatigue, headaches, weight loss, a tendency to bleed easily, visual problems, confusion, dizziness, and loss of coordination.[medicinenet.com]
  • These symptoms frequently occur as a result of hyperviscosity and include: vision changes, including blurry vision and vision loss headaches dizziness or vertigo changes in mental status Waldenstrom’s disease develops when your body overproduces IgM antibodies[healthline.com]
Peripheral Neuropathy
  • Patients with disease-related hemoglobin 10 g/L, platelets 100 10(9)/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease should be considered[ncbi.nlm.nih.gov]
  • Occasionally, IgM paraprotein has (1) rheumatoid factor activity, (2) antimyelin activity that can contribute to peripheral neuropathy, and (3) immunologically related lupus anticoagulant activity.[emedicine.medscape.com]
  • Peripheral neuropathy is one of the adverse effects of bortezomib therapy which usually necessitates dose reductions.[cancertherapyadvisor.com]
  • 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 .[symptoma.com]
Confusion
  • The definition of Waldenström macroglobulinemia (WM) and its relationship to LPL has been confusing in the past.[ncbi.nlm.nih.gov]
  • Signs and symptoms of the disease may include enlarged lymph nodes or spleen ( splenomegaly ), fatigue, headaches, weight loss, a tendency to bleed easily, visual problems, confusion, dizziness, and loss of coordination.[medicinenet.com]
  • The thickened blood may clot in the fingers and toes, causing numbness, or in the brain, causing dizziness and confusion. The covered platelet cells may not work right, resulting in bleeding and easy bruising.[uihc.org]
  • Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with IMBRUVICA Decrease in blood cell counts.[imbruvica.com]
  • Symptoms of hyperviscosity include: Vision problems, especially blurred or double vision Confusion Dizziness Loss of coordination Headaches Nosebleeds or bleeding gums Fatigue If you are concerned about any changes you experience, please talk with your[cancer.net]
Stupor
  • 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.[symptoma.com]
  • - 66% Anorexia - 25% Peripheral neuropathy - 24% Weight loss - 17% Fever - 15% Raynaud phenomenon - 11%; Raynaud phenomenon is due to cryoglobulinemia and may precede other serious symptoms by several years Mental status changes, including lethargy, stupor[emedicine.medscape.com]
  • ., blurred vision, dizziness, headaches, paresthesias, oro-nasal bleeding, papilledema, retinal vein engorgement and flame-shaped hemorrhages, as well as stupor and coma), rather than on the magnitude of the viscosity measurement (Bachanova and Burns,[aetna.com]
  • Manifestations are the result of shear forces which cause venous damage, and include visual changes resulting from retinal flame-shaped hemorrhages, epistaxis, gingival bleeding, headaches and dizziness; more severe manifestations include stupor and coma[nature.com]

Workup

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.

Hyperviscosity
  • Because hyperviscosity syndrome can be lethal, it must be recognized and managed early. Hyperviscosity syndrome has a triad presentation: vision changes, neurologic abnormalities, and bleeding.[ncbi.nlm.nih.gov]
  • 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.[symptoma.com]
  • Plasmapheresis should be used for patients with symptomatic hyperviscosity and before rituximab for those with high serum IgM levels to preempt a symptomatic IgM flare.[ncbi.nlm.nih.gov]
  • An 84-year-old female presenting with proptosis and hyperviscosity syndrome was found to have Waldenström macroglobulinemia.[ncbi.nlm.nih.gov]
  • […] when, (i) there is a relative afferent papillary defect and central scotoma, (ii) the visual acuity is not consistent with the retinal pathology, and (iii) the visual defects persisted despite resolution of macular oedema following treatment of the hyperviscosity[ncbi.nlm.nih.gov]
Elevated Sedimentation Rate
  • In the original description of Waldenstrom macroglobulinemia, Waldenstrom described two patients with oronasal bleeding, lymphadenopathy, anemia, thrombocytopenia, and an elevated sedimentation rate [ 2 ].[pancreas.imedpub.com]
  • sedimentation rate, hyperviscosity, and cytopenia who showed lymphoproliferative disease in the bone marrow with normal findings on bone radiography. 4 Since the original description, Waldenström macroglobulinemia has become recognized as a distinct[academic.oup.com]
Lymphocytes Increased
  • As the numbers of abnormal lymphocytes increase, the spleen and lymph nodes “glands” will enlarge. The common lymph nodes affected are in the neck, armpits or in the groin.[leukaemia.org.au]

Treatment

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].

  • Therapy consists of different regimens 1) rituximab and cyclophosphamide/dexamethasone, 2) rituximab and bendamustine, or 3) rituximab and bortezomib/dexamethasone.
  • WM patients who are chemoresistant will likely receive an alternative regimen. Those with relapse could be treated with a previously used effective regimen or another option.
  • New drugs such as monoclonal antibodies, second generation proteasome inhibitors, Bruton's tyrosine kinase inhibitors, and rapamycin inhibitors may have a role in therapy as well.
  • Young chemosensitive patients may be candidates for autologous transplantation.
  • Patients suffering from hyperviscosity syndrome require emergent plasmapheresis [12]. Since 80% of IgM is located intravascularly, removal of at least 50% of the blood volume reduces the viscosity.

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.

Prognosis

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].

Etiology

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.

Epidemiology

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. 

Sex distribution
Age distribution

Pathophysiology

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. 

Prevention

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. 

Summary

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.

Patient Information

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 visionHyperviscosity 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.

References

Article

  1. Vogt RF, Marti GE. Overview of monoclonal gammopathies of undetermined significance. British Journal Haematology. 2007;139(5):687-9.
  2. Wang H, Chen Y, Li F, et al. Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: A large population-based study. Cancer. 2012;118 (15): 3793-3800.
  3. Pasricha SR, Juneja SK, Westerman DA, Came NA. Bone-marrow plasma cell burden correlates with IgM paraprotein concentration in Waldenstrom macroglobulinaemia. Journal of Clinical Pathology. 2011; 64(6):520-3.
  4. Kastritis E, Kyrtsonis MC, Hatjiharissi E, et al. No significant improvement in the outcome of patients with Waldenström's macroglobulinemia treated over the last 25 years. American Journal of Hematology. 2011; 86(6):479-83. 
  5. Castillo JJ, Olszewski AJ, Cronin AM, Hunter ZR, Treon SP. Survival trends in Waldenström macroglobulinemia: an analysis of the Surveillance, Epidemiology and End Results database. Blood. 2014; 123(25):3999-4000. 
  6. Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood. 2014;123(18):2791-6.
  7. Merlini G, Baldini L, Broglia C, et al. Prognostic factors in symptomatic Waldenstrom's macroglobulinemia. Seminars in Oncology. 2003; 30(2):211-5. 
  8. Menke MN, Feke GT, McMeel JW, Treon SP. Ophthalmologic techniques to assess the severity of hyperviscosity syndrome and the effect of plasmapheresis in patients with Waldenström's macroglobulinemia. Clinical Lymphoma Myeloma. 2009; 9(1):100-3.
  9. Varghese AM, Rawstron AC, Ashcroft AJ, Moreton P, Owen RG. Assessment of bone marrow response in Waldenstrom's macroglobulinemia. Clinical Lymphoma Myeloma. 2009; 9(1):53-5.
  10. Katzmann JA, Kyle RA, Benson J, et al. Screening panels for detection of monoclonal gammopathies. Clinical Chemistry. 2009; 55(8):1517-22.
  11. Dimopoulos MA, Kastritis E, Owen RG, et al. Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood. 2014; 124(9):1404-1411.
  12. Menke MN, Feke GT, McMeel JW, Treon SP. Effect of plasmapheresis on hyperviscosity-related retinopathy and retinal hemodynamics in patients with Waldenstrom's macroglobulinemia. Investigative Ophthalmology & Visual Science. 2008; 49(3):1157-60.

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Last updated: 2018-06-21 19:21