Waldenstrom macroglobulinemia

Digital case

 JRC:7796 : Waldenstrom’s macroglobulinemia.

Definition: Waldenstrom macroglobulinemia (WM) is a clinicopathologic syndrome in which a B-cell neoplasm involving the bone marrow, usually lymphoplasmacytic lymphoma (LPL), is associated with immunoglobulin M paraprotein in the serum.

See also: lymphoplasmacytic lymphoma (LPL)

Etiology

 lymphoplasmacytic lymphoma
 lymphoplasmacytoid lymphoma
 small lymphocytic lymphoma/chronic lymphocytic leukemia
 mantle cell lymphoma
 follicular lymphoma

Transformation

 transformation of Waldenstrom macroglobulinemia

• diffuse large B-cell lymphoma (22184531, 12931555)
• anaplastic large cell lymphoma
• acute lymphoblastic leukemia (2511104)
• osteolytic myeloma (16827885)

Physiopathology

Waldenstrom’s macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes.

The underlying etiology is not yet known but a number of risk factors have been identified. There has been an association demonstrated with the locus 6p21.3 on chromosome 6.

There is a 2- to 3-fold risk increase of developing WM in people with a personal history of autoimmune diseases with autoantibodies and particularly elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis.

There are genetic factors, with first-degree relatives shown to have a highly increased risk of also contracting Waldenstrom’s.

The following molecular pathways have been implicated:

 CD154/CD40
 Akt
 ubiquitination, p53 activation, cytochrome c release
 NF-KB
 WNT/beta-catenin
 mTOR
 ERK
 MAPK
 Bcl-2

MicroRNAs

 increased expression of miRNAs

• miRNA-363
• miRNA-206
• miRNA-494
• miRNA-155
• miRNA-184
• miRNA-542
• miRNA–3p

 decreased expression

• miRNA-9

MicroRNA-155 regulates the proliferation and growth of WM cells in vitro and in vivo, by inhibiting MAPK/ERK, PI3/AKT, and NF-kappaB pathways.

Open References

 Development of diffuse large B-cell lymphoma in a patient with Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma: clonal identity between two B-cell neoplasms. Shiseki M, Masuda A, Watanabe N, Fujii M, Kimura T, Yoshinaga K, Mori N, Teramura M, Motoji T. Hematol Rep. 2011 Aug 31;3(2):e10. PMID: 22184531 (Free)

 Typical Waldenstrom macroglobulinemia is derived from a B-cell arrested after cessation of somatic mutation but prior to isotype switch events. Sahota SS, Forconi F, Ottensmeier CH, Provan D, Oscier DG, Hamblin TJ, Stevenson FK. Blood. 2002 Aug 15;100(4):1505-7. PMID: 12149241[Free]

References

 Lin P, Bueso-Ramos C, Wilson CS, Mansoor A, Medeiros LJ. Waldenstrom macroglobulinemia involving extramedullary sites: morphologic and immunophenotypic findings in 44 patients. Am J Surg Pathol. 2003 Aug;27(8):1104-13. PMID: 12883242