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Epidemiology, pathogenesis, clinical manifestations and diagnosis of Waldenström macroglobulinemia

S Vincent Rajkumar, MD
Section Editor
Robert A Kyle, MD
Deputy Editor
Rebecca F Connor, MD


The term "macroglobulinemia" refers to the production of excess IgM monoclonal protein that occurs in certain clonal lymphoproliferative disorders and plasma cell dyscrasias. This broad definition includes patients with monoclonal gammopathy of undetermined significance of the IgM type (IgM MGUS), smoldering Waldenström macroglobulinemia (SWM), Waldenström macroglobulinemia (WM), and a number of related disorders in which an IgM monoclonal protein is detected, such as chronic lymphocytic leukemia (CLL), a number of lymphoma variants, and primary (AL) amyloidosis.

WM is a distinct clinicopathologic entity demonstrating lymphoplasmacytic lymphoma (LPL) in the bone marrow with an IgM monoclonal gammopathy in the blood. Patients may present with symptoms related to the infiltration of the hematopoietic tissues or the effects of monoclonal IgM in the blood.

This topic review will limit discussion to the clinical manifestations and diagnosis of WM. The pathologic features of lymphoplasmacytic lymphoma and the prognosis and treatment of WM are discussed separately. (See "Treatment and prognosis of Waldenström macroglobulinemia" and "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma" and "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'IgM MGUS'.)


WM is a rare disorder with an incidence of approximately three per million people per year with 1400 new cases diagnosed in the United States each year [1,2]. The median age at diagnosis is 64 years; less than 1 percent of patients are under 40 years of age, and approximately 60 percent are males [3]. WM is much more common in Caucasians than in other ethnic groups [4]. Specifically, it is uncommon in Blacks, who make up approximately 5 percent of cases, and those of Mexican descent [1].

The majority of patients with the histopathologic finding of lymphoplasmacytic lymphoma (LPL) have a circulating monoclonal IgM consistent with the diagnosis of WM. In the past, LPL and WM have been arbitrarily differentiated from each other based on the level of the monoclonal IgM protein. Currently, the preferred terminology in cases of LPL with circulating monoclonal IgM is WM, rather than lymphoplasmacytic lymphoma, regardless of the size of the monoclonal IgM protein. (See 'Diagnosis' below.)

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Literature review current through: Sep 2017. | This topic last updated: Mar 30, 2017.
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  1. Fonseca R, Hayman S. Waldenström macroglobulinaemia. Br J Haematol 2007; 138:700.
  2. Groves FD, Travis LB, Devesa SS, et al. Waldenström's macroglobulinemia: incidence patterns in the United States, 1988-1994. Cancer 1998; 82:1078.
  3. García-Sanz R, Montoto S, Torrequebrada A, et al. Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases. Br J Haematol 2001; 115:575.
  4. Benjamin M, Reddy S, Brawley OW. Myeloma and race: a review of the literature. Cancer Metastasis Rev 2003; 22:87.
  5. Renier G, Ifrah N, Chevailler A, et al. Four brothers with Waldenstrom's macroglobulinemia. Cancer 1989; 64:1554.
  6. McMaster ML, Csako G, Giambarresi TR, et al. Long-term evaluation of three multiple-case Waldenstrom macroglobulinemia families. Clin Cancer Res 2007; 13:5063.
  7. McMaster ML, Goldin LR, Bai Y, et al. Genomewide linkage screen for Waldenstrom macroglobulinemia susceptibility loci in high-risk families. Am J Hum Genet 2006; 79:695.
  8. Treon SP, Hunter ZR, Aggarwal A, et al. Characterization of familial Waldenstrom's macroglobulinemia. Ann Oncol 2006; 17:488.
  9. Altieri A, Bermejo JL, Hemminki K. Familial aggregation of lymphoplasmacytic lymphoma with non-Hodgkin lymphoma and other neoplasms. Leukemia 2005; 19:2342.
  10. Kristinsson SY, Björkholm M, Goldin LR, et al. Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden. Blood 2008; 112:3052.
  11. Liang XS, Caporaso N, McMaster ML, et al. Common genetic variants in candidate genes and risk of familial lymphoid malignancies. Br J Haematol 2009; 146:418.
  12. Royer RH, Koshiol J, Giambarresi TR, et al. Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation. Blood 2010; 115:4464.
  13. Landgren O, Kristinsson SY, Goldin LR, et al. Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood 2009; 114:791.
  14. Roccaro AM, Sacco A, Shi J, et al. Exome sequencing reveals recurrent germ line variants in patients with familial Waldenström macroglobulinemia. Blood 2016; 127:2598.
  15. Linet MS, Humphrey RL, Mehl ES, et al. A case-control and family study of Waldenstrom's macroglobulinemia. Leukemia 1993; 7:1363.
  16. Giordano TP, Henderson L, Landgren O, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA 2007; 297:2010.
  17. Koshiol J, Gridley G, Engels EA, et al. Chronic immune stimulation and subsequent Waldenström macroglobulinemia. Arch Intern Med 2008; 168:1903.
  18. Kristinsson SY, Koshiol J, Björkholm M, et al. Immune-related and inflammatory conditions and risk of lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. J Natl Cancer Inst 2010; 102:557.
  19. Wagner SD, Martinelli V, Luzzatto L. Similar patterns of V kappa gene usage but different degrees of somatic mutation in hairy cell leukemia, prolymphocytic leukemia, Waldenstrom's macroglobulinemia, and myeloma. Blood 1994; 83:3647.
  20. Aoki H, Takishita M, Kosaka M, Saito S. Frequent somatic mutations in D and/or JH segments of Ig gene in Waldenström's macroglobulinemia and chronic lymphocytic leukemia (CLL) with Richter's syndrome but not in common CLL. Blood 1995; 85:1913.
  21. Ciric B, VanKeulen V, Rodriguez M, et al. Clonal evolution in Waldenstrom macroglobulinemia highlights functional role of B-cell receptor. Blood 2001; 97:321.
  22. Schop RF, Kuehl WM, Van Wier SA, et al. Waldenström macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions. Blood 2002; 100:2996.
  23. Kriangkum J, Taylor BJ, Treon SP, et al. Clonotypic IgM V/D/J sequence analysis in Waldenstrom macroglobulinemia suggests an unusual B-cell origin and an expansion of polyclonal B cells in peripheral blood. Blood 2004; 104:2134.
  24. Paiva B, Corchete LA, Vidriales MB, et al. The cellular origin and malignant transformation of Waldenström macroglobulinemia. Blood 2015; 125:2370.
  25. Nobile-Orazio E, Marmiroli P, Baldini L, et al. Peripheral neuropathy in macroglobulinemia: incidence and antigen-specificity of M proteins. Neurology 1987; 37:1506.
  26. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 16-1999. A 71-year-old man with progressive weakness and a gammopathy. N Engl J Med 1999; 340:1661.
  27. Stone MJ, Merlini G, Pascual V. Autoantibody activity in Waldenstrom's macroglobulinemia. Clin Lymphoma 2005; 5:225.
  28. Letendre L, Kyle RA. Monoclonal cryoglobulinemia with high thermal insolubility. Mayo Clin Proc 1982; 57:629.
  29. Michael AB, Lawes M, Kamalarajan M, et al. Cryoglobulinaemia as an acute presentation of Waldenstrom's macroglobulinaemia. Br J Haematol 2004; 124:565.
  30. Gertz MA, Kyle RA. Hyperviscosity syndrome. J Intensive Care Med 1995; 10:128.
  31. MacKenzie RM. Macroglobulinemia. In: Neoplastic Diseases of the Blood, Wiernick PH, Canellos GP, Dutcher JD (Eds), Churchill-Livingstone, New York 1996. Vol 3, p.601.
  32. Dimopoulos MA, Panayiotidis P, Moulopoulos LA, et al. Waldenström's macroglobulinemia: clinical features, complications, and management. J Clin Oncol 2000; 18:214.
  33. Banwait R, Aljawai Y, Cappuccio J, et al. Extramedullary Waldenström macroglobulinemia. Am J Hematol 2015; 90:100.
  34. Pavy MD, Murphy PL, Virella G. Paraprotein-induced hyperviscosity. A reversible cause of stroke. Postgrad Med 1980; 68:109.
  35. Mueller J, Hotson JR, Langston JW. Hyperviscosity-induced dementia. Neurology 1983; 33:101.
  36. Bloch KJ, Maki DG. Hyperviscosity syndromes associated with immunoglobulin abnormalities. Semin Hematol 1973; 10:113.
  37. Crawford J, Cox EB, Cohen HJ. Evaluation of hyperviscosity in monoclonal gammopathies. Am J Med 1985; 79:13.
  38. Rudnicki SA, Harik SI, Dhodapkar M, et al. Nervous system dysfunction in Waldenström's macroglobulinemia: response to treatment. Neurology 1998; 51:1210.
  39. Baehring JM, Hochberg EP, Raje N, et al. Neurological manifestations of Waldenström macroglobulinemia. Nat Clin Pract Neurol 2008; 4:547.
  40. Richards AI. Response of meningeal Waldenström's macroglobulinemia to 2-chlorodeoxyadenosine. J Clin Oncol 1995; 13:2476.
  41. Simon L, Fitsiori A, Lemal R, et al. Bing-Neel syndrome, a rare complication of Waldenström macroglobulinemia: analysis of 44 cases and review of the literature. A study on behalf of the French Innovative Leukemia Organization (FILO). Haematologica 2015; 100:1587.
  42. Dalakas MC, Flaum MA, Rick M, et al. Treatment of polyneuropathy in Waldenström's macroglobulinemia: role of paraproteinemia and immunologic studies. Neurology 1983; 33:1406.
  43. Morel-Maroger L, Basch A, Danon F, et al. Pathology of the kidney in Waldenström's macroglobulinemia. Study of sixteen cases. N Engl J Med 1970; 283:123.
  44. Veltman GA, van Veen S, Kluin-Nelemans JC, et al. Renal disease in Waldenström's macroglobulinaemia. Nephrol Dial Transplant 1997; 12:1256.
  45. Lindström FD, Hed J, Eneström S. Renal pathology of Waldenström's macroglobulinaemia with monoclonal antiglomerular antibodies and nephrotic syndrome. Clin Exp Immunol 1980; 41:196.
  46. Veloso FT, Fraga J, Saleiro JV. Macroglobulinemia and small intestinal disease. A case report with review of the literature. J Clin Gastroenterol 1988; 10:546.
  47. Pratz KW, Dingli D, Smyrk TC, Lust JA. Intestinal lymphangiectasia with protein-losing enteropathy in Waldenstrom macroglobulinemia. Medicine (Baltimore) 2007; 86:210.
  48. Takahashi K, Yamamura F, Motoyama H. IgM myeloma--its distinction from Waldenström's macroglobulinemia. Acta Pathol Jpn 1986; 36:1553.
  49. Cobb MW, Domloge-Hultsch N, Frame JN, Yancey KB. Waldenström macroglobulinemia with an IgM-kappa antiepidermal basement membrane zone antibody. Arch Dermatol 1992; 128:372.
  50. Lowe L, Fitzpatrick JE, Huff JC, et al. Cutaneous macroglobulinosis. A case report with unique ultrastructural findings. Arch Dermatol 1992; 128:377.
  51. Gressier L, Hotz C, Lelièvre JD, et al. Cutaneous macroglobulinosis: a report of 2 cases. Arch Dermatol 2010; 146:165.
  52. Schnitzler L, Schubert B, Boasson M, et al. Urticaire chronique, lésions osseuses, macroglobulinémie IgM: Maladie de Waldenstrom? Bulletin de la Societe Francaise Dermatologica Sypholologie 1974; 81:363.
  53. Coleman M, Vigliano EM, Weksler ME, Nachman RL. Inhibition of fibrin monomer polymerization by lambda myeloma globulins. Blood 1972; 39:210.
  54. Penny R, Castaldi PA, Whitsed HM. Inflammation and haemostasis in paraproteinaemias. Br J Haematol 1971; 20:35.
  55. Riches PG, Sheldon J, Smith AM, Hobbs JR. Overestimation of monoclonal immunoglobulin by immunochemical methods. Ann Clin Biochem 1991; 28 ( Pt 3):253.
  56. Virella G, Fundenberg HH. Comparison of immunoglobulin determinations in pathological sera by radial immunodiffusion and laser nephelometry. Clin Chem 1977; 23:1925.
  57. Katzmann JA, Abraham RS, Dispenzieri A, et al. Diagnostic performance of quantitative kappa and lambda free light chain assays in clinical practice. Clin Chem 2005; 51:878.
  58. Itzykson R, Le Garff-Tavernier M, Katsahian S, et al. Serum-free light chain elevation is associated with a shorter time to treatment in Waldenstrom's macroglobulinemia. Haematologica 2008; 93:793.
  59. Leleu X, Moreau AS, Weller E, et al. Serum immunoglobulin free light chain correlates with tumor burden markers in Waldenstrom macroglobulinemia. Leuk Lymphoma 2008; 49:1104.
  60. Leleu X, Xie W, Bagshaw M, et al. The role of serum immunoglobulin free light chain in response and progression in waldenstrom macroglobulinemia. Clin Cancer Res 2011; 17:3013.
  61. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
  62. Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol 2003; 30:110.
  63. Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP. Diagnosis and management of Waldenstrom's macroglobulinemia. J Clin Oncol 2005; 23:1564.
  64. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127:2375.
  65. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014; 15:e538.
  66. Jain T, Offord CP, Kyle RA, Dingli D. Schnitzler syndrome: an under-diagnosed clinical entity. Haematologica 2013; 98:1581.
  67. Kyle RA, Benson JT, Larson DR, et al. Progression in smoldering Waldenstrom macroglobulinemia: long-term results. Blood 2012; 119:4462.
  68. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78:21.
  69. Schuster SR, Rajkumar SV, Dispenzieri A, et al. IgM multiple myeloma: disease definition, prognosis, and differentiation from Waldenstrom's macroglobulinemia. Am J Hematol 2010; 85:853.
  70. Avet-Loiseau H, Garand R, Lodé L, et al. Translocation t(11;14)(q13;q32) is the hallmark of IgM, IgE, and nonsecretory multiple myeloma variants. Blood 2003; 101:1570.
  71. Chng WJ, Schop RF, Price-Troska T, et al. Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma. Blood 2006; 108:2755.
  72. Gertz MA, Kyle RA, Noel P. Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenström's macroglobulinemia. J Clin Oncol 1993; 11:914.
  73. Terrier B, Jaccard A, Harousseau JL, et al. The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients. Medicine (Baltimore) 2008; 87:99.