Waldenström's macroglobulinemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Roukoz A. Karam, M.D.[3] Mirdula Sharma, MBBS [4]
Overview
Waldenström macroglobulinemia is an uncontrolled clonal proliferation of terminally differentiated B lymphocytes (plasma cells), which are normally involved in humoral immunity. Genes involved in the pathogenesis of Waldenström macroglobulinemia include MYD88-L265P, and CXCR4.
Pathophysiology
- Waldenström macroglobulinemia arises from terminally differentiated B lymphocytes, which are normally involved in humoral immunity.
- It is understood that Waldenström macroglobulinemia is mediated by 2 major factors:
- The secretion of IgM paraprotein
- Causes symptoms of hyperviscosity syndrome
- The infiltration of tissues with neoplastic lymphoplasmacytic cells
- Mainly the bone marrow, spleen,and lymph nodes
- Sometimes the liver, gastrointestinal tract, lungs, kidneys, skin, eyes, and central nervous system
- The secretion of IgM paraprotein
Genetics
- The exact pathogenesis of Waldenström macroglobulinemia is not completely understood; however, its familial pattern of involvement supports the role played by genetic factors in the pathogenesis of this disease.[1][2]
- Development of Waldenström macroglobulinemia is the result of multiple genetic mutations.[3]
- Somatic mutations as well as chromosomal abnormalities play a part in the pathogenesis of this disease:
- A mutation of the MYD88 gene (L265P) has been found in more than 90% of patients with Waldenström macroglobulinemia, while it has rarely presented in patients with other types of mature B-cell tumors.[4][5][6][7][8][9][10][11]
- MYD88: The activating point mutation of MYD88 augments growth and survival of both normal and neoplastic B cells by preventing apoptosis. Point mutation of MYD88 leads to leucine to proline substitution in codon 265 (L265P) of MYD88 and produces constantly overactive protein causing proliferation of malignant cells that should normally undergo apoptosis.
- Monoclonal gammopathy of undetermined significance patients found to have MYD88 L265P mutation have significantly higher risk of progression to Waldenström macroglobulinemia or to other lymphoproliferative disorders.
- Less commonly (30-35%), nonsense or frameshift mutations in the C-X-C chemokine receptor type 4 (CXCR4) 5338X gene have also been reported in patients with Waldenström macroglobulinemia.[12]
- Patients with Waldenström's macroglobulinemia with co-existing mutation of MYD88 & CXCR4 are more likely to have hyper-viscosity syndrome and bone marrow involvement.[3]
- A mutation of the MYD88 gene (L265P) has been found in more than 90% of patients with Waldenström macroglobulinemia, while it has rarely presented in patients with other types of mature B-cell tumors.[4][5][6][7][8][9][10][11]
Cytogenetics
- Many cytogenetic abnormalities were reported in Waldenström macroglobulinemia patients including:
- Deletion (genetics) of the long arm of chromosome 6q21-22.1 (most common,50%).[13]
- Deletion of long arm of chromosome 20.
- t(9;14)(p13;q32)(50%).[14]
- Trisomy 4(20%).[14]
- Trisomy 5.
- Monosomy 8.[15]
Epigenetics
- Three most common epigenetic causes are DNA methylation, histone acetylation, and non-coding RNAs such as miRNAs.[16]
- Up-regulation of miRNAs 155, 184, 206, 363, 494, and 542-3p occurs in Waldenström macroglobulinemia; among which miRNA-155 has a crucial role in tumor cell growth and proliferation in Waldenström macroglobulinemia.
- Gene transcription through histone acetylation occurs following increased expression of miRNA-206 and reduced expression of miRNA-9.
Associated Conditions
Several studies showed an increased incidence of following second cancers in patients with Waldenström macroglobulinemia:[17]
- Diffuse large B-cell lymphoma
- Myelodysplastic syndrome/Acute myeloid leukemia
- Brain tumor
- Renal MALT lymphoma [18]
Microscopic Pathology
WM/LPL is a form of an indolent (slowly growing) non-hodgkin lymphoma. LPL is called so because the lymphoma cells have the characteristics of both lymphocytes and plasma cells. After a detailed clinicopathological assessment and review of the published literature, the following diagnostic criteria was proposed for WM:[19]
- IgM monoclonal gammopathy of any concentration.
- Bone marrow infiltration by small lymphocytes, plasmacytoid cells and plasma cells in following patterns:[20]
- Diffuse.
- Interstitial.
- Nodular.
- Paratrabecular.
- Following lymphoid organs are involved in WM:
- Bone marrow.
- Lymph nodes.
- Spleen.
- The bone marrow contains variable numbers of pleomorphic lymphoid cells.
- Dutcher bodies may be seen as intracytoplasmic inclusions positive for periodic acid Schiff.
- Mast cell hyperplasia is common and may stimulate tumor cell proliferation and monoclonal IgM secretion.
- Gene expression profiling has indicated that lymphoid cells of WM more closely resemble those of chronic lymphocytic leukemia than those of myeloma.[21]
Immunohistochemistry
Malignant cells in Waldenström macroglobulinemia have following immunophenotypic characteristics:[3]
- Express pan B-cell antigens surface with following immunophenotype:[22][23][19]
- Variable expression of:
- Following aren't expressed:
- IgM positive (mostly).
- IgG positive (few).
- IgA (rare).
- IgD negative (lack).
References
- ↑ Royer RH, Koshiol J, Giambarresi TR, Vasquez LG, Pfeiffer RM, McMaster ML (2010). "Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation". Blood. 115 (22): 4464–71. doi:10.1182/blood-2009-10-247973. PMC 2881498. PMID 20308603.
- ↑ Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C; et al. (2006). "Characterization of familial Waldenstrom's macroglobulinemia". Ann Oncol. 17 (3): 488–94. doi:10.1093/annonc/mdj111. PMID 16357024.
- ↑ 3.0 3.1 3.2 Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM (2011). "Oncogenically active MYD88 mutations in human lymphoma". Nature. 470 (7332): 115–9. doi:10.1038/nature09671. PMID 21179087.
- ↑ Treon, Steven P.; Xu, Lian; Yang, Guang; Zhou, Yangsheng; Liu, Xia; Cao, Yang; Sheehy, Patricia; Manning, Robert J.; Patterson, Christopher J.; Tripsas, Christina; Arcaini, Luca; Pinkus, Geraldine S.; Rodig, Scott J.; Sohani, Aliyah R.; Harris, Nancy Lee; Laramie, Jason M.; Skifter, Donald A.; Lincoln, Stephen E.; Hunter, Zachary R. (2012). "MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia". New England Journal of Medicine. 367 (9): 826–833. doi:10.1056/NEJMoa1200710. ISSN 0028-4793.
- ↑ Varettoni M, Arcaini L, Zibellini S, Boveri E, Rattotti S, Riboni R; et al. (2013). "Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms". Blood. 121 (13): 2522–8. doi:10.1182/blood-2012-09-457101. PMID 23355535.
- ↑ Shi M, Spurgeon S, Press R, Olson S, Fan G (2015). "MYD88 mutation analysis of a rare composite chronic lymphocyte leukemia and lymphoplasmacytic lymphoma by flow cytometry cell sorting". Ann Hematol. 94 (11): 1941–4. doi:10.1007/s00277-015-2460-6. PMID 26231802.
- ↑ Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ; et al. (2013). "A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia". Blood. 122 (7): 1222–32. doi:10.1182/blood-2012-12-475111. PMID 23836557.
- ↑ Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH; et al. (2011). "Oncogenically active MYD88 mutations in human lymphoma". Nature. 470 (7332): 115–9. doi:10.1038/nature09671. PMC 5024568. PMID 21179087.
- ↑ Mori N, Ohwashi M, Yoshinaga K, Mitsuhashi K, Tanaka N, Teramura M; et al. (2013). "L265P mutation of the MYD88 gene is frequent in Waldenström's macroglobulinemia and its absence in myeloma". PLoS One. 8 (11): e80088. doi:10.1371/journal.pone.0080088. PMC 3818242. PMID 24224040.
- ↑ Abeykoon JP, Paludo J, King RL, Ansell SM, Gertz MA, LaPlant BR; et al. (2018). "MYD88 mutation status does not impact overall survival in Waldenström macroglobulinemia". Am J Hematol. 93 (2): 187–194. doi:10.1002/ajh.24955. PMID 29080258.
- ↑ 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, Aliyah R. Sohani, Nancy Lee Harris, Jason M. Laramie, Donald A. Skifter, Stephen E. Lincoln & Zachary R. Hunter (2012). "MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia". The New England journal of medicine. 367 (9): 826–833. doi:10.1056/NEJMoa1200710. PMID 22931316. Unknown parameter
|month=ignored (help) - ↑ Zachary R. Hunter, Lian Xu, Guang Yang, Yangsheng Zhou, Xia Liu, Yang Cao, Robert J. Manning, Christina Tripsas, Christopher J. Patterson, Patricia Sheehy & Steven P. Treon (2014). "The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis". Blood. 123 (11): 1637–1646. doi:10.1182/blood-2013-09-525808. PMID 24366360. Unknown parameter
|month=ignored (help) - ↑ Treon, S. P.; Hunter, Z. R.; Aggarwal, A.; Ewen, E. P.; Masota, S.; Lee, C.; Santos, D. Ditzel; Hatjiharissi, E.; Xu, L.; Leleu, X.; Tournilhac, O.; Patterson, C. J.; Manning, R.; Branagan, A. R.; Morton, C. C. (2006). "Characterization of familial Waldenström's macroglobulinemia". Annals of Oncology. 17 (3): 488–494. doi:10.1093/annonc/mdj111. ISSN 1569-8041.
- ↑ 14.0 14.1 Yun S, Johnson AC, Okolo ON, Arnold SJ, McBride A, Zhang L; et al. (2017). "Waldenström Macroglobulinemia: Review of Pathogenesis and Management". Clin Lymphoma Myeloma Leuk. 17 (5): 252–262. doi:10.1016/j.clml.2017.02.028. PMC 5413391. PMID 28366781.
- ↑ Roelandt F. J. Schop, W. Michael Kuehl, Scott A. Van Wier, Gregory J. Ahmann, Tammy Price-Troska, Richard J. Bailey, Syed M. Jalal, Ying Qi, Robert A. Kyle, Philip R. Greipp & Rafael Fonseca (2002). "Waldenstrom macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions". Blood. 100 (8): 2996–3001. doi:10.1182/blood.V100.8.2996. PMID 12351413. Unknown parameter
|month=ignored (help) - ↑ Waldenström macroglobulinemia. International Waldenström Macroglobulinemia foundation (2015)http://www.iwmf.com/sites/default/files/docs/WM_Review_Ghobrial_Jan2014.pdf Accessed on November 12, 2015
- ↑ Morra E, Varettoni M, Tedeschi A, Arcaini L, Ricci F, Pascutto C, Rattotti S, Vismara E, Paris L, Cazzola M (2013). "Associated cancers in Waldenström macroglobulinemia: clues for common genetic predisposition". Clin Lymphoma Myeloma Leuk. 13 (6): 700–3. doi:10.1016/j.clml.2013.05.008. PMID 24070824.
- ↑ Chi PJ, Pei SN, Huang TL, Huang SC, Ng HY, Lee CT (2014). "Renal MALT lymphoma associated with Waldenström macroglobulinemia". J. Formos. Med. Assoc. 113 (4): 255–7. doi:10.1016/j.jfma.2011.02.007. PMID 24685302.
- ↑ 19.0 19.1 Owen RG (2003). "Developing diagnostic criteria in Waldenstrom's macroglobulinemia". Semin Oncol. 30 (2): 196–200. doi:10.1053/sonc.2003.50069. PMID 12720135.
- ↑ Owen RG, Barrans SL, Richards SJ, O'Connor SJ, Child JA, Parapia LA; et al. (2001). "Waldenström macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors". Am J Clin Pathol. 116 (3): 420–8. doi:10.1309/4LCN-JMPG-5U71-UWQB. PMID 11554171.
- ↑ Chng WJ, Schop RF, Price-Troska T, Ghobrial I, Kay N, Jelinek DF; et al. (2006). "Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma". Blood. 108 (8): 2755–63. doi:10.1182/blood-2006-02-005488. PMC 1895596. PMID 16804116.
- ↑ Dimopoulos MA, Gertz MA, Kastritis E, Garcia-Sanz R, Kimby EK, Leblond V; et al. (2009). "Update on treatment recommendations from the Fourth International Workshop on Waldenstrom's Macroglobulinemia". J Clin Oncol. 27 (1): 120–6. doi:10.1200/JCO.2008.17.7865. PMID 19047284.
- ↑ Vijay A, Gertz MA (2007). "Waldenström macroglobulinemia". Blood. 109 (12): 5096–103. doi:10.1182/blood-2006-11-055012. PMID 17303694.