Waldenström's macroglobulinemia pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
Waldenström macroglobulinemia is an uncontrolled clonal proliferation of terminally differentiated [[B lymphocyte]]s, which are normally involved in [[humoral immunity]]. Genes involved in the pathogenesis of Waldenström macroglobulinemia include ''MYD88-L265P, and CXCR4'' | Waldenström macroglobulinemia is an uncontrolled clonal proliferation of terminally differentiated [[B lymphocyte]]s, which are normally involved in [[humoral immunity]]. Genes involved in the pathogenesis of Waldenström macroglobulinemia include ''MYD88-L265P, and CXCR4''. | ||
==Pathophysiology== | ==Pathophysiology== | ||
*Waldenström macroglobulinemia arises from terminally differentiated B lymphocytes, which are normally involved in humoral immunity. | *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: | * It is understood that Waldenström macroglobulinemia is mediated by 2 major factors: | ||
*#The secretion of IgM paraprotein | *#The secretion of [[IgM]] [[paraprotein]] | ||
*#*Causes symptoms of hyperviscosity syndrome | *#*Causes symptoms of [[hyperviscosity syndrome]] | ||
*#The infiltration of tissues with neoplastic lymphoplasmacytic cells | *#The infiltration of tissues with [[neoplastic]] lymphoplasmacytic cells | ||
*#*Mainly the bone marrow, spleen,and lymph nodes | *#*Mainly the [[bone marrow]], [[spleen]],and [[Lymph node|lymph nodes]] | ||
*#*Sometimes the liver, | *#*Sometimes the [[liver]], [[gastrointestinal tract]], [[Lung|lungs]], [[kidneys]], [[skin]], [[eyes]], and [[central nervous system]] | ||
==Genetics== | ==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.<ref name="pmid20308603">{{cite journal| author=Royer RH, Koshiol J, Giambarresi TR, Vasquez LG, Pfeiffer RM, McMaster ML| title=Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation. | journal=Blood | year= 2010 | volume= 115 | issue= 22 | pages= 4464-71 | pmid=20308603 | doi=10.1182/blood-2009-10-247973 | pmc=2881498 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20308603 }} </ref><ref name="pmid16357024">{{cite journal| author=Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C et al.| title=Characterization of familial Waldenstrom's macroglobulinemia. | journal=Ann Oncol | year= 2006 | volume= 17 | issue= 3 | pages= 488-94 | pmid=16357024 | doi=10.1093/annonc/mdj111 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357024 }} </ref> | *The exact pathogenesis of Waldenström macroglobulinemia is not completely understood; however, its [[Heredity|familial pattern]] of involvement supports the role played by [[Genetics|genetic factors]] in the pathogenesis of this disease.<ref name="pmid20308603">{{cite journal| author=Royer RH, Koshiol J, Giambarresi TR, Vasquez LG, Pfeiffer RM, McMaster ML| title=Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation. | journal=Blood | year= 2010 | volume= 115 | issue= 22 | pages= 4464-71 | pmid=20308603 | doi=10.1182/blood-2009-10-247973 | pmc=2881498 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20308603 }} </ref><ref name="pmid16357024">{{cite journal| author=Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C et al.| title=Characterization of familial Waldenstrom's macroglobulinemia. | journal=Ann Oncol | year= 2006 | volume= 17 | issue= 3 | pages= 488-94 | pmid=16357024 | doi=10.1093/annonc/mdj111 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357024 }} </ref> | ||
*Development of Waldenström macroglobulinemia is the result of multiple genetic mutations.<ref name="UTDR">{{cite journal |vauthors=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 |title=Oncogenically active MYD88 mutations in human lymphoma |journal=Nature |volume=470 |issue=7332 |pages=115–9 |year=2011 |pmid=21179087 |doi=10.1038/nature09671 |url=}}</ref> | *Development of Waldenström macroglobulinemia is the result of multiple [[genetic mutations]].<ref name="UTDR">{{cite journal |vauthors=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 |title=Oncogenically active MYD88 mutations in human lymphoma |journal=Nature |volume=470 |issue=7332 |pages=115–9 |year=2011 |pmid=21179087 |doi=10.1038/nature09671 |url=}}</ref> | ||
*Somatic mutations as well as chromosomal abnormalities play a part in the pathogenesis of this disease: | *Somatic mutations as well as [[Chromosome abnormality|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.<ref>{{Cite journal | **A mutation of the [[MYD88|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.<ref>{{Cite journal | ||
| author = [[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]] | | author = [[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]] | ||
| title = MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia | | title = MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia | ||
| Line 32: | Line 32: | ||
| pmid = 22931316 | | pmid = 22931316 | ||
}}</ref> | }}</ref> | ||
*** | ***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]].<ref /><ref /> | ||
***[[Monoclonal gammopathy of undetermined significance]] patients found to have | ***[[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]].<ref /> | ||
**Less commonly, nonsense or frameshift mutations in the CXR4 gene have also been reported in patients with Waldenström macroglobulinemia.<ref>{{Cite journal | **Less commonly, [[Nonsense mutation|nonsense]] or [[Frameshift mutation|frameshift mutations]] in the CXR4 gene have also been reported in patients with Waldenström macroglobulinemia.<ref>{{Cite journal | ||
| author = [[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]] | | author = [[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]] | ||
| title = 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 | | title = 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 | ||
| Line 46: | Line 46: | ||
| pmid = 24366360 | | pmid = 24366360 | ||
}}</ref> | }}</ref> | ||
***Patients with | ***Patients with Waldenström's macroglobulinemia with co-existing mutation of MYD88 & CXCR4 are more likely to have [[hyperviscosity syndrome]] and [[bone marrow]] involvement.<ref name="UTDR" /> | ||
**Many cytogenetic abnormalities were reported in Waldenström macroglobulinemia patients including a deletion of the long arm of chromosome 6 (most common) and chromosome 20, trisomy 4 and 5, and monosomy 8.<ref>{{Cite journal | **Many cytogenetic abnormalities were reported in Waldenström macroglobulinemia patients including a [[Deletion (genetics)|deletion]] of the long arm of [[Chromosome 6 (human)|chromosome 6]] (most common) and [[Chromosome 20 (human)|chromosome 20]], [[trisomy]] 4 and 5, and [[monosomy]] 8.<ref>{{Cite journal | ||
| author = [[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]] | | author = [[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]] | ||
| title = Waldenstrom macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions | | title = Waldenstrom macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions | ||
| Line 65: | Line 65: | ||
==Associated Conditions== | ==Associated Conditions== | ||
Several studies showed an increased incidence of following second cancers in patients with | Several studies showed an increased incidence of following second cancers in patients with Waldenström macroglobulinemia:<ref name="Acs">{{cite journal |vauthors=Morra E, Varettoni M, Tedeschi A, Arcaini L, Ricci F, Pascutto C, Rattotti S, Vismara E, Paris L, Cazzola M |title=Associated cancers in Waldenström macroglobulinemia: clues for common genetic predisposition |journal=Clin Lymphoma Myeloma Leuk |volume=13 |issue=6 |pages=700–3 |year=2013 |pmid=24070824 |doi=10.1016/j.clml.2013.05.008 |url=}}</ref> | ||
*[[Diffuse large B-cell lymphoma]] | *[[Diffuse large B-cell lymphoma]] | ||
*[[Myelodysplastic syndrome]]/[[Acute myeloid leukemia]] | *[[Myelodysplastic syndrome]]/[[Acute myeloid leukemia]] | ||
| Line 85: | Line 85: | ||
===Immunohistochemistry=== | ===Immunohistochemistry=== | ||
Malignant cells in | Malignant cells in Waldenström macroglobulinemia:<ref name="UTDR" /> | ||
*Express pan B-cell antigens (CD19, CD20, CD22, CD79A), and CD5 | *Express pan B-cell antigens (CD19, CD20, CD22, CD79A), and CD5 | ||
*Variable expression of CD11c, CD43, CD25 | *Variable expression of CD11c, CD43, CD25 | ||
Revision as of 17:33, 31 October 2018
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Waldenström's macroglobulinemia Microchapters |
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Differentiating Waldenström's macroglobulinemia from other Diseases |
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Diagnosis |
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Waldenström's macroglobulinemia pathophysiology On the Web |
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American Roentgen Ray Society Images of Waldenström's macroglobulinemia pathophysiology |
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Directions to Hospitals Treating Waldenström's macroglobulinemia |
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Risk calculators and risk factors for Waldenström's macroglobulinemia pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2] Mirdula Sharma, MBBS [3]
Overview
Waldenström macroglobulinemia is an uncontrolled clonal proliferation of terminally differentiated B lymphocytes, 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]
- 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, nonsense or frameshift mutations in the CXR4 gene have also been reported in patients with Waldenström macroglobulinemia.[5]
- Patients with Waldenström's macroglobulinemia with co-existing mutation of MYD88 & CXCR4 are more likely to have hyperviscosity syndrome and bone marrow involvement.[3]
- Many cytogenetic abnormalities were reported in Waldenström macroglobulinemia patients including a deletion of the long arm of chromosome 6 (most common) and chromosome 20, trisomy 4 and 5, and monosomy 8.[6]
- 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]
Epigenetics
- Three most common epigenetic causes are DNA methylation, histone acetylation, and non-coding RNAs such as miRNAs.[7]
- Upregulation 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:[8]
- Diffuse large B-cell lymphoma
- Myelodysplastic syndrome/Acute myeloid leukemia
- Brain tumor
- Renal MALT lymphoma [9]
Microscopic Pathology
Following are the images of microscopic histology of waldenström's macroglobulinemia:
-
Rouleaux formation, plasmacytoid cells, and lymphoid cells in the PBF
-
Uni-binucleated plasmacytoid cells in the PBF
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Plasmacytoid cells in the bone marrow aspirates
-
Tetranucleated plasmacytoid/plasma cell and lymphoid cell in the bone marrow aspirates
Immunohistochemistry
Malignant cells in Waldenström macroglobulinemia:[3]
- Express pan B-cell antigens (CD19, CD20, CD22, CD79A), and CD5
- Variable expression of CD11c, CD43, CD25
- Most express IgM surface immunoglobulin, while fewer express IgG or IgA and lack IgD
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.
- ↑ 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) - ↑ 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.