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 Headaches Hepatomegaly 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 Splenomegaly [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]

  When they do occur, signs and symptoms may include: Easy bruising Bleeding from the nose or the gums Fatigue Weight loss Numbness in your hands or feet Fever Headache Shortness of breath Changes in vision Confusion When to see a doctor Make an appointment [mayoclinic.org]

• Splenomegaly

  The presence of progressive, symptomatic lymphadenopathy or splenomegaly provide additional reasons to begin therapy. The presence of anemia with a hemoglobin value of [ncbi.nlm.nih.gov]

  In contrast to myeloma, Waldenstrom cells can infiltrate into lymphoid organs, yielding lymphadenopathy and splenomegaly in some patients. [pathwaymedicine.org]

  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]

• Generalized Lymphadenopathy

  lymphadenopathy is part of an HIV-related syndrome. [ijpmonline.org]

• Massive Splenomegaly

  Patient with WM and massive splenomegaly, refractory to chemo. [en.wikibooks.org]

• Anemia

  The presence of anemia with a hemoglobin value of [ncbi.nlm.nih.gov]

  For the typical patient, anemia is very important to keep in mind. There are many mechanisms under which anemia can be produced. [onclive.com]

• Fatigue

  The consensus panel agreed that initiation of therapy was appropriate for patients with constitutional symptoms such as recurrent fever, night sweats, fatigue due to anemia, or weight loss. [ncbi.nlm.nih.gov]

  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]

• Asymptomatic

  An algorithm is provided on the management of asymptomatic individuals and the sequence used for chemotherapeutic intervention of symptomatic patients. [ncbi.nlm.nih.gov]

  Currently, there are no data to help guide clinical decision making on whether to delay or commence therapy in asymptomatic patients. In these cases, enrollment into a clinical trial may be a suitable option. [hematologyadvisor.com]

• Lymphadenopathy

  The patient had no peripheral lymphadenopathy. On extensive investigation she was found to have pancreatic mass. [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]

  The consensus panel agreed that initiation of therapy was appropriate for patients with constitutional symptoms such as recurrent fever, night sweats, fatigue due to anemia, or weight loss. [ncbi.nlm.nih.gov]

  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]

• 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]

  Chemotherapy was begun with the rituximab-bortezomib regimen, resulting in a progressive decrease of fecal output at one week and resolution of diarrhea at 15 days. [revistagastroenterologiamexico.org]

  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]

• 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]

  The abnormal lymphocytes also grow in the liver and spleen, which can cause the organs to become enlarged and result in abdominal pain. [cancer.uams.edu]

  Seventy-two years ago, Waldenström first described 3 cases, one of which presented with intense abdominal pain and bloating.3 Later reports included symptoms of pseudo-obstruction, protein-losing enteropathy associated with duodenal lymphangiectasia, [revistagastroenterologiamexico.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

  Signs and symptoms of WM include: Vision problems Confusion Dizziness Loss of coordination Headaches Nosebleeds Bleeding gums Fatigue [primeoncology.org]

  Symptoms of hyperviscosity include: Vision problems, especially blurred or double vision Confusion Dizziness Loss of coordination Headaches Nosebleeds or bleeding gums Fatigue Shortness of breath If you are concerned about any changes you experience, [cancer.net]

  This can lead to symptoms such as: Vision problems Confusion Dizziness Loss of coordination Headache Nosebleeds or bleeding gums Fatigue In some people, the large proteins clump in cooler parts of the body — like the tip of the nose, the ears and the [seattlecca.org]

  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]

• Oral Bleeding

  In most cases the first clinical features are hemorrhagic manifestations with petechiae, bruising, purpura, epistaxis, oral bleeding, bloody diarrhea and intracranial bleeding. Acute or chronic eczema is the second characteristic finding of WAS. [orpha.net]

• Hepatosplenomegaly

  Most commonly it presents with cytopenia, hepatosplenomegaly, lymphadenopathy, constitutional symptoms, and hyperviscosity syndrome. [ncbi.nlm.nih.gov]

• 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]

  Corresponding ICD-10-CM Codes (U.S. only) C88.0 Waldenstrom's macroglobulinemia (effective October 01, 2015) Signs and Symptoms Adenopathy Confusion Dizziness Easy bruising or bleeding (nosebleeds or bleeding from gums) Feeling very tired Headaches Hepatomegaly [seer.cancer.gov]

  Physical findings include: hepatomegaly, splenomegaly, fundic changes, adenopathy, neurologic abnormalities, and purpura. The most common laboratory finding is anemia. [icd9data.com]

  Clinical manifestations are due to deposition of IgM in the liver, spleen, and/or lymph nodes, so it presents with anemia, hyperviscosity, lymphadenopathy, hepatomegaly, splenomegaly and neurologic symptoms. [hrcak.srce.hr]

  So it is advised to perform CT scans of the chest, abdomen, and pelvis in order to detect enlarged lymph nodes, hepatomegaly, or splenomegaly. [onclive.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]

  The patient was started on rituximab, with progressive decrease of proteinuria, remission of edema, polyarthralgia and disappearance of skin purpura, after the 2nd dose of the drug. [revistanefrologia.com]

• 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]

  Wiskott-Aldrich syndrome (WAS) is a rare immunodeficiency disease with a characteristic phenotype that includes: X-linked recessive petechiae, bloody diarrhea, epistaxis due to thrombocytopenia with small platelets eczema starts in the first month of [radiopaedia.org]

  In most cases the first clinical features are hemorrhagic manifestations with petechiae, bruising, purpura, epistaxis, oral bleeding, bloody diarrhea and intracranial bleeding. Acute or chronic eczema is the second characteristic finding of WAS. [orpha.net]

  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]

• 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]

  These Ig can precipitate on exposure to cold and in vivo such aggregates can obstruct the small vessels or initiate vasculitis causing Raynaud's phenomenon, arthralgia, skin lesions such as purpura and ulcers.[7] Erythematous macules and purpuric papules [mjdrdypu.org]

  lesions of any type does not appear to affect outcome in this condition which often does not require treatment. [dermnetnz.org]

• 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]

• Arthralgia

  A 68-year-old woman consulted for new-onset oedemas, arthralgias and purpuric lesions in lower limbs. [revistanefrologia.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]

  Adverse events of any grade that were substantially more frequent with ibrutinib–rituximab than with placebo–rituximab were diarrhea, arthralgia, and nausea, and those that were less frequent were IgM flare, infusion-related reactions, fatigue, asthenia [nejm.org]

  These Ig can precipitate on exposure to cold and in vivo such aggregates can obstruct the small vessels or initiate vasculitis causing Raynaud's phenomenon, arthralgia, skin lesions such as purpura and ulcers.[7] Erythematous macules and purpuric papules [mjdrdypu.org]

  Cryoglobulins may be detected in 20% of patients, but fewer than 5% present with symptoms such as Raynaud syndrome, arthralgia, purpura, and skin ulcers. 53 Priapism has also been described as an unusual complication. [bloodjournal.org]

• Blurred Vision

  Clinically, patients may present with fatigue, weight loss, peripheral neuropathy or symptoms of hyperviscosity, including headache, blurred vision or epistaxis. [ncbi.nlm.nih.gov]

  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]

  This disease leads to bleeding, dizziness, hearing problems, and blurred vision. Hyperviscosity syndrome is treated with plasmapheresis. [symptoma.com]

  vision or blind spots Weight loss for no reason Diagnostic Exams Flow cytometry Immunohistochemistry Immunophenotyping Peripheral blood smear Progression and Transformation None Epidemiology and Mortality None Sources Swerdlow SH, Campo E, Harris NL, [seer.cancer.gov]

  Related characteristics hyperviscosity syndrome include nasal and mouth bleeding, blurred vision or loss of vision, headache, dizziness and ataxia. [ivami.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]

  It presents with epistaxis, diplopia, headache, dyspnea and potentially macrovascular complications such as stroke AL Amyloidosis - Results from the deposition of amyloidogenic light chains in fibrillary structures in organs such as the heart, liver and [atlasgeneticsoncology.org]

  […] 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]

  In reviews of the literature, the incidence of retinopathy ranges from 30% to 67%. 1,2 Cagianut 3 reported 13 of 20 patients were severely incapacitated because of visual impairment. [jamanetwork.com]

  During physical examination, the patient was tachycardic on auscultation and had unilateral dysmetria on the finger-nose test, with no visual impairment and normal funduscopy. [hindawi.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]

  Fish-oil supplements contributed to both grade 2 epistaxis events, and these events resolved when these supplements were discontinued. [doi.org]

  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]

• Peripheral Neuropathy

  Peripheral neuropathy occurs in nearly half of patients with this condition, and hyperviscosity-related nervous system disorders are encountered in up to a third. [ncbi.nlm.nih.gov]

• Headache

  Clinically, patients may present with fatigue, weight loss, peripheral neuropathy or symptoms of hyperviscosity, including headache, blurred vision or epistaxis. [ncbi.nlm.nih.gov]

  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]

  […] 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 WM include: Vision problems Confusion Dizziness Loss of coordination Headaches Nosebleeds Bleeding gums Fatigue [primeoncology.org]

• 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]

  Signs and symptoms of WM include: Vision problems Confusion Dizziness Loss of coordination Headaches Nosebleeds Bleeding gums Fatigue [primeoncology.org]

  This disease leads to bleeding, dizziness, hearing problems, and blurred vision. Hyperviscosity syndrome is treated with plasmapheresis. [symptoma.com]

• Confusion

  Signs and symptoms of WM include: Vision problems Confusion Dizziness Loss of coordination Headaches Nosebleeds Bleeding gums Fatigue [primeoncology.org]

  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]

• Ataxia

  Features related to hyperviscosity syndrome include bleeding in the nose or mouth, blurring or loss of vision, headache, dizziness, and difficulty coordinating movements (ataxia). [ghr.nlm.nih.gov]

  Related characteristics hyperviscosity syndrome include nasal and mouth bleeding, blurred vision or loss of vision, headache, dizziness and ataxia. [ivami.com]

  The symptoms include skin and mucosal bleedings, visual disturbance secondary to retinopathy, neurological symptoms (headache, vertigo, dizziness, nystagmus, deafness, and ataxia), and, in rare cases, congestive cardiac failure [3]. [hindawi.com]

  Recently, it has been found that carriers of the premutation are at greater risk for a neurodegenerative disorder resembling Parkinson’s disease called Fragile X-associated Tremor Ataxia Syndrome. [waisman.wisc.edu]

  […] bowel as well as the 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 [bloodjournal.org]

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]

• Hyperglobulinemia

  References 1. (1944) Incipient myelomatosis or “essential” hyperglobulinemia with fibrinogenopenia—a new syndrome? Acta Med Scand 117 : 216–247 2. [doi.org]

  Incipient myelomatosis or ‘essential’ hyperglobulinemia with fibrinogenopenia a new syndrome?. Acta Med Scand, CXVII (1944), pp. 217-246 [4] R.E. Cooke, R.M. Kalnins, W.K. Ho. Waldenström macroglobulinaemia and intestinal lymphangiectasia. [revistagastroenterologiamexico.org]

  She had hyperglobulinemia with altered albumin/globulin ratio (total protein 8.2 g/dL and albumin 2.3 g/dL; reference ranges: 6.0-8.0 g/dL and 3.5-5.0 g/dL, respectively); his total calcium was 10.2 mEq/dL and phosphate was 4.3 mEq/dL. [pancreas.imedpub.com]

  Incipient myelomatosis or essentia hyperglobulinemia with fibrinogenopenia: a new syndrome? Acta Med Scand 1944; 117:216–247 [Google Scholar] 2. Owen RG, Johnson SA, Morgan GJ. Walden-ström's macroglobulinaemia: laboratory diagnosis and treatment. [ajronline.org]

• 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]

  Waldenström, MD, DSc, who reported on 2 patients with oronasal bleeding, anemia, lymphadenopathy, hypergammaglobulinemia, an elevated sedimentation rate, hyperviscosity, normal bone survey, cytopenias, and bone marrow involvement by a predominantly lymphoid [archivesofpathology.org]

  Diagnosis In the original description of WM, Jan Gösta Waldenström 20 described two patients with oronasal bleeding, lymphadenopathy, anemia, thrombocytopenia, and an elevated sedimentation rate. [onlinelibrary.wiley.com]

• Immunoglobulin A Decreased

  Normal immunoglobulins are decreased in half of patients. Immunofixation electrophoresis of concentrated urine frequently shows a monoclonal light chain (usually kappa [ κ ]), but gross Bence Jones proteinuria is unusual. [merckmanuals.com]

  Normal immunoglobulins are decreased in half of patients. Immunofixation electrophoresis of concentrated urine frequently shows a monoclonal light chain (more often kappa [κ]), but gross Bence Jones proteinuria is unusual. [msdmanuals.com]

• Hematocrit Decreased

  Acute decreases in hematocrit were observed during first 2 weeks of lenalidomide therapy in 13/16 (81%) patients with a median hematocrit decrease of 4.4% (1.7-7.2%). [clinicaltrials.gov]

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.

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.

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.