Waldenström's disease

Classification according to ICD-10
C88.0	Macroglobulinaemia Waldenström
ICD-10 online (WHO version 2019)

The Waldenstrom ( MW ), also macroglobulinemia or Immunocytoma called, is a malignant lymphoma . It is to the indolent (ie slowly progressive and symptoms causing little) B cell - non-Hodgkin's lymphoma counted, taking the top category of lymphoplasmozytischen lymphomas. The disease is typically associated with abnormal production of monoclonal immunoglobulin M (IgM) by lymphoma cells. In certain aspects, Waldenström's disease is similar to multiple myeloma (plasmacytoma) , but it shows a much more benign course.

The disease is named after Jan Gösta Waldenström (1906–1996), a Swedish internist who first scientifically described the disease in 1944.

Epidemiology

It is a rare disease with an incidence of around one new disease per 100,000 inhabitants per year. The mean age at occurrence is around 65 years, patients under 40 years of age are rarely affected. The disease tends to affect men and Europeans or their offspring.

Pathogenesis

The pathogenesis is not yet fully understood and may be similar to chronic lymphocytic leukemia . There is an uninhibited clonal proliferation of mature plasma-cellularly differentiated but dysfunctional B lymphocytes, as well as an infiltration of various tissues and an overproduction of IgM. The infiltration mainly affects the bone marrow , spleen and lymph nodes . Other organ systems such as the liver , eyes or the central nervous system , which is known as Bing-Neel syndrome , are more rarely affected. The infiltration of the bone marrow leads, among other things, to the displacement of the hematopoietic stem cells . This restricts the haematopoiesis , leading to anemia , and a tendency towards infection and bleeding . The overproduction of IgM can lead to hyperviscosity syndrome. Due to the increased viscosity of the blood, the tissue blood flow can be impaired and as a result microcirculation disorders occur, i.e. blood flow disorders especially in the small vessels.

In a 2012 study from Boston, over 90% of patients showed a point mutation in the MYD88 gene, with the amino acid leucine being replaced by proline at position 265 (L265P for short). In contrast, only 10% of patients with monoclonal gammopathy of unclear significance showed this mutation. The MYD88 protein is part of the NF-κB signaling pathway. It is activated as a homodimer when a ligand binds to the interleukin-1 receptor directly or when a ligand binds to the toll-like receptor TLR4 by interaction with TIRAP ( TIR domain containing adapter protein ) and Bruton's tyrosine kinase (BTK) . Furthermore, MYD88 activates a signal cascade via IRAK1, TRAF6, TAK1 and IKK with phosphorylation of IκBα and the release of NF-κB proteins, which migrate into the cell nucleus and have a proliferative and antiapoptotic effect.

Symptoms

Most patients are asymptomatic at the time of diagnosis and the disease is discovered more “by chance” on the basis of a blood test. In some patients, however, symptoms also lead to the diagnosis. The most common symptoms include tiredness , which affects two thirds of all WM patients, and peripheral neuropathy (polyneuropathy) , which affects around a quarter. The neuropathy is caused by the deposition of monoclonal IgM in the myelin sheaths , which can be detected by a nerve biopsy (e.g. in the area of ​​the easily accessible sural nerve ). The degree of polyneuropathy does not correlate with the level of the IgM level in the blood. Even very small amounts of IgM can cause significant PNP, while in other patients this can be completely absent despite very high IgM levels. In addition, there are seldom unspecific B symptoms such as fever , night sweats and unwanted weight loss . Also one can Raynaud's disease occur early. Destruction of the bone and the resulting pain or pathological fractures are - in contrast to plasmacytomas - very rare. The infiltration of the various organs leads to hepatosplenomegaly (enlargement of the liver and spleen) (in 20%), lymphadenopathy (swelling of the lymph nodes) (in 15%), purpura (punctiform skin bleeding) (in 9%) and some less common symptoms that result from tissue displacement can arise.

The overproduction of IgM and the resulting hyperviscosity of the blood can lead to a wide variety of other symptoms in the context of hyperviscosity syndrome . Such a bleeding tendency, which manifests itself among other things by frequent nosebleeds or bleeding after the slightest injuries , headaches , malaise, blurred vision and other visual and acoustic problems.

diagnosis

The diagnosis is made by a combination of clinical, laboratory, immunological, and genetic findings. Laboratory chemistry shows an increase in monoclonal immunoglobulin M in the serum. IgM monoclonality can be demonstrated using immunofixation electrophoresis . A histological and cytological examination of the bone marrow after bone marrow puncture shows an increase in the number of mature lymphocytes. Genetically, these lymphocytic cells usually have the MYD88 L265P mutation.

Other laboratory findings include anemia, which affects up to 80% of patients; Thrombocytopenia or neutropenia are less common . The sedimentation reaction , LDH and often also the uric acid content can be increased. The plasma viscosity must be determined in order to quantify the extent of paraproteinemia. In the urine of nearly half of the patients can Bence Jones proteins are detected.

Imaging techniques such as CT and MRI are used to determine the extent of tissue infiltration. Lung infiltrates, hepatosplenomegaly and the intestinal lymph nodes are assessed in particular .

therapy

Therapy only becomes necessary when WM symptoms appear. However, symptom-free patients should remain under regular medical control. There is no evidence that starting therapy early improves the patient's prognosis, that is, overall survival or disease-free survival. As a rule, the therapeutic goal is not curative, but purely palliative , ie the symptoms of the disease should be eliminated, but the primary goal is not complete healing. Therapy regimens include the drugs chlorambucil , fludarabine (as monotherapy or in combination with cyclophosphamide ), the CVP regimen (cyclophosphamide, vincristine , prednisolone ). Anthracyclines can also be used for more severe courses . The monoclonal antibody rituximab is effective, but not approved for this disease. In general it can be said that there are few data on the optimal therapy of these patients, since the disease is rare and patients are rarely included in therapy studies due to the relative benign nature of the disease . Therefore, whenever possible, patients should be treated in clinical trials.

The effect of chemotherapy on the IgM levels in the blood does not appear before a few days after therapy (the serum half-life of IgM is around five days). If the hyperviscosity syndrome is severe, plasmapheresis can be performed to rapidly lower the IgM level in the blood.

forecast

The disease typically progresses slowly if left untreated. The lack of functional leukocytes leads to an antibody deficiency syndrome with weak immune systems and more frequent infections. The course of the disease depends on many different factors and varies greatly from patient to patient. The median survival time is 7.7 years after initial diagnosis if timely treatment is carried out. Factors that lead to a worse course are:

• Age> 65 years
• Hemoglobin <10 g / dl
• Albumin <4.0 g / dl
• increased blood β2-microglobulin levels

In total, half of the patients are still alive seven years after the initial diagnosis , some with a high quality of life even after more than 20 years.

Others

A famous sufferer was Georges Pompidou . He died of this disease in 1974 - surprising to the public - while he was President of France. Also, Mohammad Reza Pahlavi , the former Shah of Iran, should have died in 1980 in Cairo from this disease. In 1978, Houari Boumedienne , the President of Algeria, died of Waldenström's disease.

literature

• G. Merlini: Waldenstrom's Macroglobulinemia-Clinical Manifestations and Prognosis. In: American Society of Hematogy. Washington, DC 1999.
• V. Rajkumar, A. Dispenzieri, R. Kyle: Monoclonal gammopathy of undetermined significance, waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. In: Mayo Clin Proc. 81, 2006, pp. 693-703.

Web links

• D. Ponce: Waldenstrom Hypergammaglobulinemia . eMedicine.com - last updated: October 17, 2011
• Self-help organization: Waldenstrom's Macroglobulinemia Foundation

Individual evidence

1. ↑ Oncology, hematology - data and information: 4 Lymphoplasmocytic lymphoma (including Waldenström's disease): 4.1 Definition, pathology, genetics , as of December 18, 2016 : "Lymphoplasmocytic lymphoma (LPL) is a mature-cell B-cell neoplasia of the small-cell type according to the WHO classification. Waldenström's disease or Waldenström's macroglobulinemia (MW) is used when a monoclonal IgM of any concentration and bone marrow infiltration are detected, which is the case in approx. 30% of LPL. "
2. ↑ JG Waldenström: Incipient myelomatosis or "essential" hyperglobulinemia with fibrinogenopenia - a new syndrome? In: Acta Medica Scandinavica. Stockholm, 117, 1944, pp. 216-247.
3. ↑ Steven P. Treon, Lian Xu, Guang Yang, Yangsheng Zhou, Xia Liu, Yang Cao, Patricia Sheehy, Robert J. Manning, Christopher J. Patterson, Christina Tripsas, Luca Arcaini, Geraldine S. Pinkus, Scott J. Rodig, Donald A. Skifter, Stephen E. Lincoln, Zachary R. Hunter: MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia. In: New England Journal. 2012, Volume 367, Issue 9 of August 30, 2012, pp. 826-833.
4. ^ L. Altman: Dr. Jean A. Bernard, 98, Dies; Found Cancer in Shah of Iran. In: New York Times. April 30, 2006. Retrieved April 16, 2015.

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