Waldenstrom macroglobulinemia is a chronic, slow-growing lymphoproliferative disorder. It usually affects older adults and is primarily found in the bone marrow . Waldenström macroglobulinemia (WM) is a distinct clinicopathologic entity demonstrating lymphoplasmacytic lymphoma (LPL) in the bone. Waldenström macroglobulinemia is often an indolent disorder, and many patients are candidates for observation with careful monitoring.

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The WM is a rare disease wsldenstrom a typically indolent clinical course, affecting mainly individuals aged between 63 and 68 years. The differential diagnosis with other lymphomas is essential for the assessment of prognosis and therapeutic approach.

Treatment of patients with asymptomatic WM does not improve the quality of life of patients, or increase their survival, being recommended, therefore, their follow-up. For the treatment of symptomatic patients, alkylating agents, purine analogs and anti-CD20 monoclonal antibodies are used.

Waldenström’s macroglobulinemia – a review

However, the disease is incurable and the response to therapy is not always favorable. Recent studies have shown promising waldensstrom with bortezomib, an inhibitor of proteasomes, and some patients respond to thalidomide. In patients with relapse or refractory to therapy, autologous transplantation may engermedad indicated.

The aim of this paper is to describe in detail the current knowledge on the pathophysiology of WM, main clinical waldenstrpm, diagnosis, prognosis and treatment. LPLs are rare and indolent cancers of mature B-lymphocytes, which predominantly involve the bone marrow and, less commonly, the spleen, lymph nodes, peripheral blood and other organs.

There is a higher incidence in individuals aged between 63 and 68 years. Its etiology is unknown, but several studies suggest a possible causal relationship with autoimmune diseases, exposure to environmental factors and chronic antigenic stimulation, such as infection with the hepatitis C virus HCV. Enfermedsd the high incidence of HCV infection in these patients, a statistically significant association between HCV infection and WM has not been found.

It is believed that WM originates in memory B-lymphocytes.

Thus, in most cases, the neoplastic B cells present somatic hyper-mutation in the genes coding the hypervariable regions of the immunoglobulin heavy chains V H genes.

In relation to the mechanisms involved in the pathophysiology of WM, the blocking of immunoglobulin isotype switching and the role of cytokines is noteworthy.

Although isotype switching is rarely seen in WM, according to some studies it is possible that it occurs ex vivo and in vivo.

Another study showed the possibility of isotype switching occurring in vivo. Mast cells and various cytokines play an important role in the development of the disease. In WM, malignant B-lymphocytes express awldenstrom receptor CD27, 13 which can be found in the membrane of memory B-lymphocytes and in soluble form sCD27 in high concentrations in the serum.

Activated mast cells secrete growth and survival factors for B-lymphocytes such as CD40L and APRIL proliferation-inducing ligand15 which may contribute to lymphoplasmocytoid differentiation of malignant cells in the bone marrow. The clinical presentation of WM varies. However, some patients do not enfermedd any clinical symptoms when diagnosis is made. The large size of the monoclonal IgM molecule and its high concentration contribute to increased blood viscosity and vascular enfermdad, compromising the blood flow to enfefmedad tissues.

Waldenström’s macroglobulinemia – Wikipedia

The wxldenstrom clinical manifestations associated with the hyperviscosity syndrome are bleeding epistaxis, bleeding gums and gastrointestinal bleedingocular changes papilledema, blindness, blurred vision and retinal changes: However, the serum viscosity is not always proportional to the concentration of IgM and its relationship to symptoms is not linear.

It is also responsible for the development of distal symmetrical sensorimotor polyneuropathy or multiple mononeuropathy with axonal degeneration. Monoclonal IgM can cause platelet dysfunction by binding to IIIa and Ib glycoproteins on the surface of platelets or due to nonspecific interactions with platelets. Monoclonal IgM may exhibit “cold agglutinin” activity, binding to erythrocyte antigens at a temperature lower than physiological temperature, determining the development of chronic cold antibody hemolytic anemia.


Type II cryoglobulinemia mono and polyclonal is characterized by the deposition of monoclonal IgM-polyclonal IgG immunocomplexes at the level of blood vessels, with consequent activation of the complement. The most frequent neurological disorder is a demyelinating distal symmetrical sensorimotor peripheral neuropathy, which manifests itself slowly and progressively, causing paresthesia and asthenia.

Monoclonal IgM can also connect nonspecifically to multiple antigens of the peripheral nerves, triggering axonal impairment. The deposition of monoclonal IgM in the basal membrane of the epidermis is associated with bullous skin disease.

Renal failure is not very common; however, monoclonal IgM may accumulate in the renal glomeruliforming subendothelial deposits that clog glomerular capillaries. In primary or light chain amyloidosis AL amyloidosisamyloid fibrils may be deposited in the heart, kidneys, liver, lungs and peripheral nerves. Patients experience pain, the sensation of “electric shocks” and thermal sensitivity in the lower limbs.

AL amyloidosis may further affect the autonomic nervous system, causing diarrhea, hypotension, impotence and bladder dysfunction.

The deposition of amyloid A protein AA amyloidosis has been documented, although rare, 3738 and may occur in the kidneys and intestines, causing nephrotic syndrome and intestinal malabsorption.

LPL primarily involves the bone marrow, but the disease can reach the lymph nodes, spleen and liver, among other organs. Other factors may contribute to its aggravation, such as gastrointestinal bleeding, hyperhemolysis, and hyperviscosity itself, which may cause a decrease in the erythropoietin synthesis. Extramedullary infiltration is uncommon, and may affect the articular and periarticular structures, gastrointestinal tract, lungs, kidneys, skin, eyes and central nervous system.

The symptoms of malabsorption, diarrhea, obstipation or bleeding may indicate involvement of the gastrointestinal tract. Renal infiltration has also been reported, 49 as well as cutaneous infiltration maculopapular lesions, plaques or nodules 750 and infiltration of periorbital structures, such as the tear gland and retro-orbital lymphoid tissue ocular tremors. The infiltration of malignant cells in the central nervous system is responsible for a rare neurological disorder called Bing-Neel syndrome.

Associated symptoms are nystagmus, diplopia, vertigo, memory loss, mental confusion, motor dysfunction and eventually coma. Table 1 presents the diagnostic criteria for WM. The detection of IgM monoclonal gammopathy is important for diagnosis, but the serum concentration presents a great variability between individuals.

Immunophenotypic variations may occur.

Other lymphoproliferative diseases, including marginal zone B-cell lymphoma, chronic lymphocytic leukemia and mantle cell lymphoma should be excluded. For diagnosis, a bone marrow biopsy is crucial to assess the extent of neoplastic infiltration, the infiltration pattern and cellular morphology.

In WM, medullary infiltrate consists of a monoclonal cellular population of small B-lymphocytes, in different maturation stages: A high number of mast cells in the medullary infiltrate is frequent, and this finding may help in the differential diagnosis.

LPL may eventually evolve into a more aggressive form of lymphoma such as as diffuse large B-cell lymphoma. In the peripheral blood, plasmacytoid lymphocytes are sometimes observed, but leukemic symptoms are rarely observed.

Immunophenotyping should be interpreted simultaneously, verifying its consistency with the results of a bone marrow biopsy. Some waldendtrom these markers are particularly useful for studying the bone marrow infiltrate in the bone biopsy through immunohistochemical and other studies for the immunophenotypic characterization of B-lymphocytes by flow cytometry.

The assessment of the clinical status of patients enfermedae several examinations and laboratory tests Table 2. When interpreting the results it is important to consider that some parameters could be altered because the monoclonal IgM may interfere in several measurements performed in automated analyzers, especially in the evaluation of HDL cholesterol, bilirubin, inorganic phosphate, LDL cholesterol, C-reactive protein, creatinine, glucose, urea, iron and calcium ions.

It is fundamental to distinguish WM from other disorders that could be clinically confused with this disease. Differential diagnosis Table 3 is important for the exclusion of neoplasms potentially secreting monoclonal IgM and which can also present lymphocytes with lymphoplasmocytoid differentiation in the bone marrow. In patients at low waldenstrim, the average survival time is 12 years, and treatment should involve low toxicity, preserving quality of life.

The use of this system in symptomatic patients that are candidates for treatment enables tailoring treatment to the patient, taking into account the estimated average survival. The treatment of asymptomatic patients does not improve their quality of life and survival; 3 biannual clinical observation is the recommended option in these cases if hematologic function is preserved.


In fact, the choice of treatment is a critical option and should not be taken so as to limit future options, since all patients will inevitably present relapses after initial treatment, requiring treatment.

First-line therapy includes alkylating agents, purine analogs and monoclonal anti-CD20 antibodies.

Waldenström’s macroglobulinemia

The Mayo Clinic has developed a therapeutic approach adapted to the clinical characteristics of the patient. Monotherapy is recommended in symptomatic patients with moderate hematological impairment, in patients with neuropathy associated with the IgM autoantibody, and in cases of hemolytic anemia resistant to corticosteroids.

Rituximab is an IgG1 anti-CD20 monoclonal antibody. The connection to the CD20 receptor on B-lymphocytes activates the complement cascade, leading to the formation of the membrane attack complex that induces cell lysis. At the start of rituximab treatment, some patients have a paradoxical and often transient increase in serum concentrations of IgM IgM flarewhich can persist for up to 4 months and is not indicative of treatment failure.

In patients requiring urgent control of the disease, plasmapheresis is indicated if they have clinical manifestations of moderate to severe hyperviscosity, cryoglobulinemia and cytopenias caused by the action of the monoclonal IgM autoantibody. The sessions should be repeated daily until symptoms subside or until normalization of serum viscosity.

Subsequent treatment should be started quickly, as the concentration of IgM will return to its initial level after 4 to 5 weeks. The main reasons for choosing this regimen in these patients are the good treatment tolerance, reduced myelosuppression and the lack of toxicity for stem cells.

The reuse of the first-line treatment is recommended if the response to initial treatment was maintained without maintenance for at least 12 months. Otherwise, another first-line agent or combination therapy should be used. In patients with short-term remission or resistance to initial treatment, therapy with a drug of different pharmacological class as monotherapy or combined is recommended. In association therapy, a regime using rituximab, fludarabine and cyclophosphamide is highlighted; however, the latter should be avoided in younger patients and candidates for autologous stem cell transplantation.

The use of bortezomib proteasome inhibitor has proven promising, as well as alemtuzumab anti-CD52 monoclonal antibody datalidomida, enzastaurin protein kinase C inhibitoreverolimus inhibitor of mammalian target of rapamycin – mTOR and perifosine Akt inhibitor. Transplantation of hematopoietic stem cells is indicated in younger patients with multiple recurrences or who have been refractory to previous treatments.

The concentration of monoclonal IgM is one of the parameters most commonly used among the criteria for assessing response to treatment. However, this biomarker is not always reliable, since its concentration can be affected by the treatment itself. The concentration of sCD27 and assessment of the amount of monoclonal free light chains have been presented as potential biomarkers for laboratory monitoring of therapy.

The WHO classification of lymphoid neoplasms and beyond: Guideline for diagnosis and treatment of Waldenstrom’s macroglobulinaemia. Diagnosis and management of Waldenstrom macroglobulinemia: Four brothers with Waldenstrom’s macroglobulinemia. Characterization of familial Waldenstrom’s macroglobulinemia. An overview of its clinical, biochemical, immunological and therapeutic features and our series of patients collected in a single center.

Crit Rev Oncol Hematol. Typical Waldenstrom macroglobulinemia is derived from a B-cell arrested after cessation of somatic mutation but prior to isotype switch events. Dnfermedad interactions in the pathogenesis of Waldenstrom macroglobulinemia. Guidelines on the management of Waldenstrom macroglobulinaemia. Diagnosis and management of Waldenstrom’s macroglobulinemia. Prognostic factors in symptomatic Waldenstrom’s macroglobulinemia.

Peripheral neuropathy in essential mixed cryoglobulinemia. J Dtsch Dermatol Ges. Pruzanski W, Shumak KH. Biologic activity of cold-reacting autoantibodies first of two parts.

N Engl J Med.

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