REVIEW ARTICLE COIMBRA S ET AL. Waldenström’s macroglobulinemia – a review SUSANA COIMBRA1,2*, RAFAEL NEVES3, MARGARIDA LIMA4, LUÍS BELO1,3, ALICE SANTOS-SILVA1,3 1Institute of Molecular and Cellular Biology (IBMC), University of Porto, Porto, Portugal. 2CESPU, Institute for Research and Advanced Training in Health Sciences and Technologies, Gandra-PRD, Portugal. 3Department of Biological Sciences, Biochemistry Laboratory, Faculty of Pharmacy, University of Porto, Porto, Portugal. 4Santo António General Hospital, Centro Hospitalar of Porto, Porto, Portugal. SUMMARY Waldenström’s macroglobulinemia (WM) is a lymphoproliferative disease of B lymphocytes, characterized by a lymphoplasmocytic lymphoma in the bone mar- row and by IgM monoclonal hypergammaglobulinemia. It was first described in 1944 by Jan Gösta Waldenström, reporting two patients with oronasal bleeding, lymphadenopathy, anemia, thrombocytopenia, high erythrocyte sedimentation rate and serum viscosity, normal radiography and bone marrow infiltrated by lymphoid cells. The WM is a rare disease with a typically indolent clinical course, affecting mainly individuals aged between 63 and 68 years. Most patients have clinical signs and symptoms related to hyperviscosity resulting from IgM monoclonal gammopa- thy, and/or cytopenias resulting from bone marrow infiltration by lymphoma. 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 Study conducted at the University of Porto, Porto, Portugal follow-up. For the treatment of symptomatic patients, alkylating agents, puri- ne analogs and anti-CD20 monoclonal antibodies are used. However, the disea- Article received: 6/4/2013 se is incurable and the response to therapy is not always favorable. Recent stu- Accepted for publication: 1/30/2014 dies have shown promising results with bortezomib, an inhibitor of proteasomes, *Correspondence: and some patients respond to thalidomide. In patients with relapse or refrac- Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto tory to therapy, autologous transplantation may be indicated. Address: Rua do Campo Alegre, 823 The aim of this paper is to describe in detail the current knowledge on the pa- Postal Code: 4150 Porto – Portugal thophysiology of WM, main clinical manifestations, diagnosis, prognosis and Phone: 351 962677495 treatment. [email protected] http://dx.doi.org/10.1590/1806-9282.60.05.019 Keywords: Waldenström’s macroglobulinemia, hypergammaglobulinemia, IgM, Conflict of interest: none lymphocytes B. prognosis. INTRODUCTION Waldenström’s macroglobulinemia (WM), described in There is a higher incidence in individuals aged between 1944 by Jan Gösta Waldenström, is a lymphoplasmacytic 63 and 68 years.3 Approximately 60% of patients are men, lymphoma (LPL) characterized by IgM monoclonal hy- and it is more common in caucasian indivuals.3 The ave- pergammaglobulinemia and bone marrow infiltration.1 rage survival is 5 years,3 however, approximately 10% of LPLs are rare and indolent cancers of mature B-lym- patients survive up to 15 years.4 As the disease is mainly phocytes, which predominantly involve the bone marrow diagnosed in old age, about 50% of patients die due to and, less commonly, the spleen, lymph nodes, peripheral comorbidities not related directly to WM.3 blood and other organs.1 ETIOLOGY EPIDEMIOLOGY Its etiology is unknown, but several studies suggest a pos- WM has an estimated incidence of 3 cases/million/year, sible causal relationship with autoimmune diseases, ex- accounting for about 2% of all hematological cancers.2 posure to environmental factors and chronic antigenic 490 REV ASSOC MED BraS 2014; 60(5):490-499 WALDENSTRÖM’S maCROGLOBULINEMIA – A REVIEW stimulation, such as infection with the hepatitis C virus such as CD40L and APRIL (proliferation-inducing li- (HCV). Despite the high incidence of HCV infection in gand),15 which may contribute to lymphoplasmocytoid these patients, a statistically significant association differentiation of malignant cells in the bone marrow. between HCV infection and WM has not been found.5 In relation to familial predisposition, an association CLINICAL SYMPTOMS is estimated in 20% of cases.6,7 In first degree family rela- The clinical presentation of WM varies. Most of the pa- tions there is a high risk of developing lymphoprolifera- tients present clinical signs/symptoms related to IgM hy- tive diseases, which is twenty times higher for WM/LPL.8 pergammaglobulinemia and/or LPL infiltration in or- gans and tissues, especially bone marrow. However, some PATHOPHYSIOLOGY patients do not exhibit any clinical symptoms when diag- It is believed that WM originates in memory B-lymphocy- nosis is made.16 tes.9,10 These lymphocytes descend from B-lymphocytes Blood hyperviscosity determines hemorheological that proliferate in the germinal centers of lymph nodes changes and is one of the most important characteristics (post-germinal center B-lymphocytes), accumulating all of WM; however, it is observed in less than 15% of pa- the genetic changes that occur in these centers. Thus, in tients upon diagnosis. The large size of the monoclonal most cases, the neoplastic B cells present somatic hyper- IgM molecule and its high concentration contribute to mutation in the genes coding the hypervariable regions of increased blood viscosity and vascular resistance, com- 11,12 17 the immunoglobulin heavy chains (VH genes). Howe- promising the blood flow to oxygenate tissues. ver, in some cases, the neoplastic B-cells are derived from The main clinical manifestations associated with the B-lymphocytes which have undergone somatic mutation hyperviscosity syndrome are bleeding (epistaxis, bleeding outside of germinal centers.13 In other cases, there is no gums and gastrointestinal bleeding), ocular changes (pa- evidence of somatic mutations in the VH genes, which may pilledema, blindness, blurred vision and retinal changes: indicate that they are derived from pre-germinal center B- hemorrhage, exudates, dilatation and segmentation of -lymphocytes, such as “virgin” B-lymphocytes.12 the retinal veins, venous thrombosis), neurological chan- In relation to the mechanisms involved in the patho- ges (headache, dizziness, syncope, deafness, ataxia, diplo- physiology of WM, the blocking of immunoglobulin isoty- pia, drowsiness and even seizures) and cardiac changes pe switching and the role of cytokines is noteworthy. (heart failure).18 Most malignant cells in WM express surface IgM and The symptoms of hyperviscosity generally manifest IgD, suggesting an intrinsic incapacity to switch isoty- when the concentration of monoclonal IgM is greater pes.13 This “block” may be related to the absence/dysfunc- than 5000 mg/dL or when the serum viscosity reaches 4-5 tion of the activation-induced cytidine deaminase (AID) cP (reference range: 1.4 to 1.8 cP). However, the serum vis- enzyme, which is involved in somatic hypermutation and cosity is not always proportional to the concentration of the immunoglobulin isotype switching process.11,13 IgM and its relationship to symptoms is not linear.16 Although isotype switching is rarely seen in WM, ac- Type I cryoglobulinemia (monoclonal IgM cryoglo- cording to some studies it is possible that it occurs ex vivo bulinemia) is associated with lymphoproliferative disea- and in vivo. Kriangkum et al.11 demonstrated that AID ses such as WM, and is detected in approximately 20% of may be induced ex vivo, by stimulation with CD40L and patients, while symptomatic in only 5% of cases.19 The interleukin-4 (IL-4). Another study showed the possibi- precipitation of monoclonal IgM cryoglobulin is also res- lity of isotype switching occurring in vivo.14 ponsible for some clinical symptoms, such as Raynaud’s Mast cells and various cytokines play an important phenomenon, acrocyanosis, purpura and necrosis of body role in the development of the disease.15 Cytokines may regions most exposed to the cold. It is also responsible be important for angiogenesis, increased bone resorption, for the development of distal symmetrical sensorimotor proliferation, survival of malignant cells, and secretion polyneuropathy or multiple mononeuropathy with axo- of monoclonal IgM. nal degeneration.20,21 In WM, malignant B-lymphocytes express the recep- Monoclonal IgM can cause platelet dysfunction by tor CD27,13 which can be found in the membrane of me- binding to IIIa and Ib glycoproteins on the surface of pla- mory B-lymphocytes and in soluble form (sCD27) in high telets or due to nonspecific interactions with platelets.9 concentrations in the serum.15 sCD27 activates bone mar- It may also neutralize the activity of several coagulation row mast cells by binding to CD70. Activated mast cells factors (fibrinogen, prothrombin, factors V, VII, VIII, IX, secrete growth and survival factors for B-lymphocytes X, and Von Willebrand factor),9,22 triggering hemostatic REV ASSOC MED BraS 2014; 60(5):490-499 491 COIMBRA S ET AL. disorders that are the source of hemorrhagic manifesta- The deposition of monoclonal IgM in the lamina pro- tions. pria and/or submucosa of the intestine can be associated Monoclonal IgM may exhibit “cold agglutinin” acti- with diarrhea, malabsorption and gastrointestinal blee- vity, binding to erythrocyte antigens at a temperature lo- ding.33 wer than physiological temperature, determining the de- Renal