Macroglobulinemia, Waldenstrom 1 C88.0

Blattner et al (1980) found macroglobulinemia, Waldenström (WM) in one father and 3 children. Clinical and subclinical autoimmune diseases were also common in the family.

Waldenström macroglobulinemia (WM) is a malignant B-cell neoplasia characterized by lymphoplasmacytic infiltration of the bone marrow and hypersecretion of monoclonal immunoglobulin M (IgM) (Vijay A et al 2007). The importance of genetic factors is suggested by the observation of a familial clustering of WM (McMaster ML et al. 2003; Ngo VN et al. 2011)

Royer et al (2010) analyzed 103 WM patients and 272 unaffected relatives from 35 families with WM and 46 families with mixed WM/B-cell disease and from 28 patients with sporadic disease. The nature and course of the disease process did not differ between patients with and without significant family history. The mean age at diagnosis was 59 years in familial cases and 62.2 years in sporadic cases. Patients with a family history of the disease were more likely than unaffected relatives to report a history of autoimmune disease and infection. Furthermore, a greater likelihood of exposure to pesticides, wood dust, and organic solvents was reported (Royer et al. 2010). This study suggests chronic immune stimulation in the development of WM and suggests that both genetic and environmental factors may influence susceptibility to the development of the disease.

By microRNA expression profiling of bone marrow-derived CD19(+) WM cells, Roccaro et al. (2009) identified a specific microRNA signature characterized by increased expression of 6 microRNAs, including MIR155 (609337), MIR363, MIR206 (611599), MIR494 (616036), MIR184 (613146), and MIR542-3p. Furthermore, it was shown that therapeutic agents commonly used in WM, including rituximab, perifosine, and bortezomib, decreased the expression of 5 of the elevated miRNAs. These data suggest that microRNAs play a central role in the biology of WM and provide the basis for the development of new microRNA-based targeted therapies in WM (Roccaro et al. 2009).

Treon et al. (2012) performed whole-genome sequencing of lymphoplasmacytic lymphoma (LPL) cells from the bone marrow of 30 patients with Waldenstrom macroglobulinemia, sequencing normal tissue and tumor tissue in 10 patients. Among the patients with Waldenstrom macroglobulinemia, a somatic mutation, L265P (602170,0004), was identified in samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This mutation predicted an amino acid change that triggers IRAK (300283)-mediated NF-kappa B signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenstrom macroglobulinemia and in 3 of 3 patients with nonIgM-secreting LPL (91% of all patients with LPL). MYD88 L265P is thus a frequently recurring mutation in patients with Waldenstrom macroglobulinemia. It is diagnostically useful.

Roccaro et al (2009) presented evidence that WM is associated with activation of NF-kappa B metabolism. Braggio et al (2009) identified biallelic inactivation of TNF receptor-associated factor 3 (TRAF3; 601896) in 3 (5.3%) of 57 WM samples. TRAF3 inactivation was associated with transcriptional activation of NF-kappa-B. These results suggest that mutational activation of the NF-kappa-B pathway plays a role in the development of WM.

The clinical features of Waldenstrom macroglobulinemia are variable. Many patients have asymptomatic or indolent disease. Symptoms are due to the extent of tumor infiltration and result in anemia or cytopenia when the bone marrow is infiltrated, and organomegaly or pulmonary infiltrates. The most common symptom is fatigue, which is due to anemia. Increased concentrations of circulating IgM can lead to increases in vascular resistance and viscosity and cause abnormalities in bleeding and clotting times. IgM can be deposited in renal glomerular loops, intestine, and skin. Furthermore, it is shown that IgM protein can cause various autoimmune symptoms, such as peripheral neuropathy.

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The cutaneous manifestations are divided into:

Specific lesions:

• Infiltration of the bone marrow by lymphoplasmacytic lymphoma.
• Cutaneous infiltrations by neoplastic cells: Chronic, solitary or even disseminated, red or brown, usually asymptomatic papules, plaques or nodules with a smooth surface (usually on the face or trunk).
• Lymph nodes or spleen are enlarged in about 20-40% of patients.
• Renal involvement (myeloma kidney, cast nephropathy).
• Macroglobulinemia (see also MGUS) may be absent at an early stage of development. These clinical phenomena become clinically evident only at a critical tumor mass.
• Cutaneous lesions due to homogeneous IgM deposits: formation of vesicles and blisters and, less frequently, of small, asymptomatic skin-colored papules on the buttocks and trunk (macroglobulinosis cutis).

Nonspecific lesions:

• Paraprotein may cause a hyperviscosity syndrome with purpura, cyanotic discoloration of the acras (fingers, toes, earlobes), Raynaud's phenomenon, dizziness, mucosal hemorrhage, and visual disturbances.
• Other clinical symptoms include:
• Symptoms due to cold agglutinins (anemia, livedovasculitis, Raynaud's syndrome, acrocyanosis, digital ulcers).
• polyneuropathy 8
• with prolonged disease progression secondary IgM amyloidosis, occasionally renal dysfunction.
• vasculitic ulcers and livedovasculopathy.

Therapy is deferred in asymptomatic patients. Usually, progressive anemia is the most common indication for starting treatment.

While familial Waldenström macroblobulinemia-1 is rare, asymptomatic elevation of IgM monoclonal protein, termed "IgM monoclonal gammopathy of undetermined significance " (MGUS), is more common. Patients with "IgM MGUS" may develop WM at a rate of 1.5% to 2% per year (Kyle et al. 2003).

1. Braggio E et al (2009) Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappa-B signaling pathways in Waldenstrom's macroglobulinemia. Cancer Res 69: 3579-3588.
2. Kyle RA et al (2003) Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood 102: 3759-3764.
3. McMaster ML et al (2006) Genomewide linkage screen for Waldenstrom macroglobulinemia susceptibility loci in high-risk families. Am J Hum Genet 79: 695-701.
4. McMaster ML et al (2003) Familial Waldenstrom's macroglobulinemia. Semin Oncol 30: 146-152.
5. Ngo VN et al (2011) Oncogenically active MYD88 mutations in human lymphoma. Nature 470: 115-119.
6. Renier G et al (1989) Four brothers with Waldenstrom's macroglobulinemia. Cancer 64: 1554-1559.
7. Roccaro AM et al (2009) microRNA expression in the biology, prognosis, and therapy of Waldenstrom macroglobulinemia. Blood 113: 4391-4402.
8. Royer RH et al (2010) Differential characteristics of Waldenstrom macroglobulinemia according to patterns of familial aggregation. Blood 115: 4464-4471.
9. Treon SP et al (2015) MYD88 mutations and response to ibrutinib in Waldenstrom's macroglobulinemia. (Letter) New Eng J Med 373: 584-586.
10. Treon SP et al (2012) MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. New Eng J Med 367: 826-833.
11. Vijay A et al (2007) Waldenstrom macroglobulinemia. Blood 109: 5096-5103.