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  | pmid = 20940415
  | pmid = 20940415
}}</ref>
}}</ref>
*  
*These secondary genetic alterations and dysregulated signaling pathways are as follows:
*  
**Deregulation of cell cycle:<ref>{{Cite journal
| author = [[Pedro Jares]], [[Dolors Colomer]] & [[Elias Campo]]
| title = Molecular pathogenesis of mantle cell lymphoma
| journal = [[The Journal of clinical investigation]]
| volume = 122
| issue = 10
| pages = 3416–3423
| year = 2012
| month = October
| doi = 10.1172/JCI61272
| pmid = 23023712
}}</ref>
**#INK4a/CDK4/RB1 pathway.
**#ARF/MDM2/p53 pathway.
**Deregulation of DNA damage repair:<ref>{{Cite journal
| author = [[Silvia Bea]], [[Rafael Valdes-Mas]], [[Alba Navarro]], [[Itziar Salaverria]], [[David Martin-Garcia]], [[Pedro Jares]], [[Eva Gine]], [[Magda Pinyol]], [[Cristina Royo]], [[Ferran Nadeu]], [[Laura Conde]], [[Manel Juan]], [[Guillem Clot]], [[Pedro Vizan]], [[Luciano Di Croce]], [[Diana A. Puente]], [[Monica Lopez-Guerra]], [[Alexandra Moros]], [[Gael Roue]], [[Marta Aymerich]], [[Neus Villamor]], [[Lluis Colomo]], [[Antonio Martinez]], [[Alexandra Valera]], [[Jose I. Martin-Subero]], [[Virginia Amador]], [[Luis Hernandez]], [[Maria Rozman]], [[Anna Enjuanes]], [[Pilar Forcada]], [[Ana Muntanola]], [[Elena M. Hartmann]], [[Maria J. Calasanz]], [[Andreas Rosenwald]], [[German Ott]], [[Jesus M. Hernandez-Rivas]], [[Wolfram Klapper]], [[Reiner Siebert]], [[Adrian Wiestner]], [[Wyndham H. Wilson]], [[Dolors Colomer]], [[Armando Lopez-Guillermo]], [[Carlos Lopez-Otin]], [[Xose S. Puente]] & [[Elias Campo]]
| title = Landscape of somatic mutations and clonal evolution in mantle cell lymphoma
| journal = [[Proceedings of the National Academy of Sciences of the United States of America]]
| volume = 110
| issue = 45
| pages = 18250–18255
| year = 2013
| month = November
| doi = 10.1073/pnas.1314608110
| pmid = 24145436
}}</ref>
**#Mutation in ATM gene.
**#Mutation in p53 gene.
**Deregulation of apoptosis:
**#BCL2 amplifications.
<ref>{{Cite journal
| author = [[J. M. Adams]] & [[S. Cory]]
| title = The Bcl-2 apoptotic switch in cancer development and therapy
| journal = [[Oncogene]]
| volume = 26
| issue = 9
| pages = 1324–1337
| year = 2007
| month = February
| doi = 10.1038/sj.onc.1210220
| pmid = 17322918
}}</ref>   
**#BCL2L11 deletions.
**#FBXO10 deficiency.<ref>{{Cite journal
| author = [[Y. Li]], [[M. N. Bouchlaka]], [[J. Wolff]], [[K. M. Grindle]], [[L. Lu]], [[S. Qian]], [[X. Zhong]], [[N. Pflum]], [[P. Jobin]], [[B. S. Kahl]], [[J. C. Eickhoff]], [[S. M. Wuerzberger-Davis]], [[S. Miyamoto]], [[C. J. Thomas]], [[D. T. Yang]], [[C. M. Capitini]] & [[L. Rui]]
| title = FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma
| journal = [[Oncogene]]
| volume = 35
| issue = 48
| pages = 6223–6234
| year = 2016
| month = December
| doi = 10.1038/onc.2016.155
| pmid = 27157620
}}</ref>
**#MCL1 overexpression.<ref>{{Cite journal
| author = [[Joseph D. Khoury]], [[L. Jeffrey Medeiros]], [[George Z. Rassidakis]], [[Timothy J. McDonnell]], [[Lynne V. Abruzzo]] & [[Raymond Lai]]
| title = Expression of Mcl-1 in mantle cell lymphoma is associated with high-grade morphology, a high proliferative state, and p53 overexpression
| journal = [[The Journal of pathology]]
| volume = 199
| issue = 1
| pages = 90–97
| year = 2003
| month = January
| doi = 10.1002/path.1254
| pmid = 12474231
}}</ref>
**Deregulation of chromatin modifiers:<ref>{{Cite journal
| author = [[Jenny Zhang]], [[Dereje Jima]], [[Andrea B. Moffitt]], [[Qingquan Liu]], [[Magdalena Czader]], [[Eric D. Hsi]], [[Yuri Fedoriw]], [[Cherie H. Dunphy]], [[Kristy L. Richards]], [[Javed I. Gill]], [[Zhen Sun]], [[Cassandra Love]], [[Paula Scotland]], [[Eric Lock]], [[Shawn Levy]], [[David S. Hsu]], [[David Dunson]] & [[Sandeep S. Dave]]
| title = The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells
| journal = [[Blood]]
| volume = 123
| issue = 19
| pages = 2988–2996
| year = 2014
| month = May
| doi = 10.1182/blood-2013-07-517177
| pmid = 24682267
}}</ref>
**#WHSC1 mutations.
**#MLL2 mutations.
**#MEF2B mutations.
**Constitutive activation of oncogenic pathways:<ref>{{Cite journal
| author = [[Lan V. Pham]], [[Archito T. Tamayo]], [[Linda C. Yoshimura]], [[Piao Lo]] & [[Richard J. Ford]]
| title = Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis
| journal = [[Journal of immunology (Baltimore, Md. : 1950)]]
| volume = 171
| issue = 1
| pages = 88–95
| year = 2003
| month = July
| pmid = 12816986
}}</ref><ref>{{Cite journal
| author = [[Edgar Gil Rizzatti]], [[Roberto Passetto Falcao]], [[Rodrigo Alexandre Panepucci]], [[Rodrigo Proto-Siqueira]], [[Wilma Terezinha Anselmo-Lima]], [[Oswaldo Keith Okamoto]] & [[Marco Antonio Zago]]
| title = Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFbeta signalling pathways
| journal = [[British journal of haematology]]
| volume = 130
| issue = 4
| pages = 516–526
| year = 2005
| month = August
| doi = 10.1111/j.1365-2141.2005.05630.x
| pmid = 16098065
}}</ref><ref>{{Cite journal
| author = [[Robert Kridel]], [[Barbara Meissner]], [[Sanja Rogic]], [[Merrill Boyle]], [[Adele Telenius]], [[Bruce Woolcock]], [[Jay Gunawardana]], [[Christopher Jenkins]], [[Chris Cochrane]], [[Susana Ben-Neriah]], [[King Tan]], [[Ryan D. Morin]], [[Stephen Opat]], [[Laurie H. Sehn]], [[Joseph M. Connors]], [[Marco A. Marra]], [[Andrew P. Weng]], [[Christian Steidl]] & [[Randy D. Gascoyne]]
| title = Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma
| journal = [[Blood]]
| volume = 119
| issue = 9
| pages = 1963–1971
| year = 2012
| month = March
| doi = 10.1182/blood-2011-11-391474
| pmid = 22210878
}}</ref><ref>{{Cite journal
| author = [[Jamie N. Anastas]] & [[Randall T. Moon]]
| title = WNT signalling pathways as therapeutic targets in cancer
| journal = [[Nature reviews. Cancer]]
| volume = 13
| issue = 1
| pages = 11–26
| year = 2013
| month = January
| doi = 10.1038/nrc3419
| pmid = 23258168
}}</ref>
**#Classical NF-kB pathway.
**#Alternate NF-kB pathway.
**#PI3K/AKT/mTOR pathway.
**#NOTCH pathway.
**#JAK/STAT3 pathway.
**#WNT pathway.
*SOX11, a SOX family transcription factor, has recently been identified as an important molecular feature of MCL regardless of cyclin D1 status.<ref>{{Cite journal
| author = [[Ana Mozos]], [[Cristina Royo]], [[Elena Hartmann]], [[Daphne De Jong]], [[Cristina Baro]], [[Alexandra Valera]], [[Kai Fu]], [[Dennis D. Weisenburger]], [[Jan Delabie]], [[Shih-Sung Chuang]], [[Elaine S. Jaffe]], [[Carmen Ruiz-Marcellan]], [[Sandeep Dave]], [[Lisa Rimsza]], [[Rita Braziel]], [[Randy D. Gascoyne]], [[Francisco Sole]], [[Armando Lopez-Guillermo]], [[Dolors Colomer]], [[Louis M. Staudt]], [[Andreas Rosenwald]], [[German Ott]], [[Pedro Jares]] & [[Elias Campo]]
| title = SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype
| journal = [[Haematologica]]
| volume = 94
| issue = 11
| pages = 1555–1562
| year = 2009
| month = November
| doi = 10.3324/haematol.2009.010264
| pmid = 19880778
}}</ref>
   


==Genetics==
==Genetics==

Revision as of 20:55, 13 November 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2] Sowminya Arikapudi, M.B,B.S. [3]

Overview

Pathophysiology

Pathogenesis

  • The translocation t(11;14)(q13;q32) is considered the precipitating oncogenic event that induces cell cycle deregulation due to overexpression of cyclin D1.
  • This translocation juxtaposes the CCDN1 gene encoding cyclin D1 to the immunoglobulin heavy chain (IgH) leading to its overexpression. However, less commonly, mutations in CCDN2 and CCDN3 have also been identified in cases of mantle cell lymphoma lacking the t(11;14) translocation.[1]
  • In addition to the pathogonomic translocation, MCL progression is controlled by secondary genetic abberations and dysregulated signaling pathways involved in DNA damage response, proliferation, and apoptosis.[2]
  • These secondary genetic alterations and dysregulated signaling pathways are as follows:
    • Deregulation of cell cycle:[3]
      1. INK4a/CDK4/RB1 pathway.
      2. ARF/MDM2/p53 pathway.
    • Deregulation of DNA damage repair:[4]
      1. Mutation in ATM gene.
      2. Mutation in p53 gene.
    • Deregulation of apoptosis:
      1. BCL2 amplifications.

[5]

      1. BCL2L11 deletions.
      2. FBXO10 deficiency.[6]
      3. MCL1 overexpression.[7]
    • Deregulation of chromatin modifiers:[8]
      1. WHSC1 mutations.
      2. MLL2 mutations.
      3. MEF2B mutations.
    • Constitutive activation of oncogenic pathways:[9][10][11][12]
      1. Classical NF-kB pathway.
      2. Alternate NF-kB pathway.
      3. PI3K/AKT/mTOR pathway.
      4. NOTCH pathway.
      5. JAK/STAT3 pathway.
      6. WNT pathway.
  • SOX11, a SOX family transcription factor, has recently been identified as an important molecular feature of MCL regardless of cyclin D1 status.[13]


Genetics

Genes involved in the pathogenesis of mantle cell lymphoma include:

  • CCDN1 (primarily)
  • CCDN2 (less frequently)
  • CCDN3 (less frequently)

Gross Pathology

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

References

  1. ↑ Itziar Salaverria, Cristina Royo, Alejandra Carvajal-Cuenca, Guillem Clot, Alba Navarro, Alejandra Valera, Joo Y. Song, Renata Woroniecka, Grzegorz Rymkiewicz, Wolfram Klapper, Elena M. Hartmann, Pierre Sujobert, Iwona Wlodarska, Judith A. Ferry, Philippe Gaulard, German Ott, Andreas Rosenwald, Armando Lopez-Guillermo, Leticia Quintanilla-Martinez, Nancy L. Harris, Elaine S. Jaffe, Reiner Siebert, Elias Campo & Silvia Bea (2013). "CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma". Blood. 121 (8): 1394–1402. doi:10.1182/blood-2012-08-452284. PMID 23255553. Unknown parameter |month= ignored (help)
  2. ↑ Patricia Perez-Galan, Martin Dreyling & Adrian Wiestner (2011). "Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era". Blood. 117 (1): 26–38. doi:10.1182/blood-2010-04-189977. PMID 20940415. Unknown parameter |month= ignored (help)
  3. ↑ Pedro Jares, Dolors Colomer & Elias Campo (2012). "Molecular pathogenesis of mantle cell lymphoma". The Journal of clinical investigation. 122 (10): 3416–3423. doi:10.1172/JCI61272. PMID 23023712. Unknown parameter |month= ignored (help)
  4. ↑ Silvia Bea, Rafael Valdes-Mas, Alba Navarro, Itziar Salaverria, David Martin-Garcia, Pedro Jares, Eva Gine, Magda Pinyol, Cristina Royo, Ferran Nadeu, Laura Conde, Manel Juan, Guillem Clot, Pedro Vizan, Luciano Di Croce, Diana A. Puente, Monica Lopez-Guerra, Alexandra Moros, Gael Roue, Marta Aymerich, Neus Villamor, Lluis Colomo, Antonio Martinez, Alexandra Valera, Jose I. Martin-Subero, Virginia Amador, Luis Hernandez, Maria Rozman, Anna Enjuanes, Pilar Forcada, Ana Muntanola, Elena M. Hartmann, Maria J. Calasanz, Andreas Rosenwald, German Ott, Jesus M. Hernandez-Rivas, Wolfram Klapper, Reiner Siebert, Adrian Wiestner, Wyndham H. Wilson, Dolors Colomer, Armando Lopez-Guillermo, Carlos Lopez-Otin, Xose S. Puente & Elias Campo (2013). "Landscape of somatic mutations and clonal evolution in mantle cell lymphoma". Proceedings of the National Academy of Sciences of the United States of America. 110 (45): 18250–18255. doi:10.1073/pnas.1314608110. PMID 24145436. Unknown parameter |month= ignored (help)
  5. ↑ J. M. Adams & S. Cory (2007). "The Bcl-2 apoptotic switch in cancer development and therapy". Oncogene. 26 (9): 1324–1337. doi:10.1038/sj.onc.1210220. PMID 17322918. Unknown parameter |month= ignored (help)
  6. ↑ Y. Li, M. N. Bouchlaka, J. Wolff, K. M. Grindle, L. Lu, S. Qian, X. Zhong, N. Pflum, P. Jobin, B. S. Kahl, J. C. Eickhoff, S. M. Wuerzberger-Davis, S. Miyamoto, C. J. Thomas, D. T. Yang, C. M. Capitini & L. Rui (2016). "FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma". Oncogene. 35 (48): 6223–6234. doi:10.1038/onc.2016.155. PMID 27157620. Unknown parameter |month= ignored (help)
  7. ↑ Joseph D. Khoury, L. Jeffrey Medeiros, George Z. Rassidakis, Timothy J. McDonnell, Lynne V. Abruzzo & Raymond Lai (2003). "Expression of Mcl-1 in mantle cell lymphoma is associated with high-grade morphology, a high proliferative state, and p53 overexpression". The Journal of pathology. 199 (1): 90–97. doi:10.1002/path.1254. PMID 12474231. Unknown parameter |month= ignored (help)
  8. ↑ Jenny Zhang, Dereje Jima, Andrea B. Moffitt, Qingquan Liu, Magdalena Czader, Eric D. Hsi, Yuri Fedoriw, Cherie H. Dunphy, Kristy L. Richards, Javed I. Gill, Zhen Sun, Cassandra Love, Paula Scotland, Eric Lock, Shawn Levy, David S. Hsu, David Dunson & Sandeep S. Dave (2014). "The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells". Blood. 123 (19): 2988–2996. doi:10.1182/blood-2013-07-517177. PMID 24682267. Unknown parameter |month= ignored (help)
  9. ↑ Lan V. Pham, Archito T. Tamayo, Linda C. Yoshimura, Piao Lo & Richard J. Ford (2003). "Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis". Journal of immunology (Baltimore, Md. : 1950). 171 (1): 88–95. PMID 12816986. Unknown parameter |month= ignored (help)
  10. ↑ Edgar Gil Rizzatti, Roberto Passetto Falcao, Rodrigo Alexandre Panepucci, Rodrigo Proto-Siqueira, Wilma Terezinha Anselmo-Lima, Oswaldo Keith Okamoto & Marco Antonio Zago (2005). "Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFbeta signalling pathways". British journal of haematology. 130 (4): 516–526. doi:10.1111/j.1365-2141.2005.05630.x. PMID 16098065. Unknown parameter |month= ignored (help)
  11. ↑ Robert Kridel, Barbara Meissner, Sanja Rogic, Merrill Boyle, Adele Telenius, Bruce Woolcock, Jay Gunawardana, Christopher Jenkins, Chris Cochrane, Susana Ben-Neriah, King Tan, Ryan D. Morin, Stephen Opat, Laurie H. Sehn, Joseph M. Connors, Marco A. Marra, Andrew P. Weng, Christian Steidl & Randy D. Gascoyne (2012). "Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma". Blood. 119 (9): 1963–1971. doi:10.1182/blood-2011-11-391474. PMID 22210878. Unknown parameter |month= ignored (help)
  12. ↑ Jamie N. Anastas & Randall T. Moon (2013). "WNT signalling pathways as therapeutic targets in cancer". Nature reviews. Cancer. 13 (1): 11–26. doi:10.1038/nrc3419. PMID 23258168. Unknown parameter |month= ignored (help)
  13. ↑ Ana Mozos, Cristina Royo, Elena Hartmann, Daphne De Jong, Cristina Baro, Alexandra Valera, Kai Fu, Dennis D. Weisenburger, Jan Delabie, Shih-Sung Chuang, Elaine S. Jaffe, Carmen Ruiz-Marcellan, Sandeep Dave, Lisa Rimsza, Rita Braziel, Randy D. Gascoyne, Francisco Sole, Armando Lopez-Guillermo, Dolors Colomer, Louis M. Staudt, Andreas Rosenwald, German Ott, Pedro Jares & Elias Campo (2009). "SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype". Haematologica. 94 (11): 1555–1562. doi:10.3324/haematol.2009.010264. PMID 19880778. Unknown parameter |month= ignored (help)

Template:WH Template:WS

Overview

Development of mantle cell lymphoma is the result of (non-inherited) genetic mutations in somatic cells. Mantle cell lymphoma cells generally over-express cyclin D1 due to a t(11:14)[1] chromosomal translocation in the DNA. Cells affected by mantle cell lymphoma proliferate in a nodular or diffuse pattern with two main cytologic variants: typical or blastic.

Microscopic pathology

Cells affected by mantle cell lymphoma proliferate in a nodular or diffuse pattern with two main cytologic variants: typical or blastic.

  • Typical cases are small to intermediate sized cells with irregular nuclei.
  • Blastic (aka blastoid) variants have intermediate to large sized cells with finely dispersed chromatin and are more aggressive in nature.

The tumor cells accumulate in the lymphoid system, including lymph nodes and the spleen, with non-useful cells eventually rendering the system dysfunctional. Mantle cell lymphoma may also replace normal cells in the bone marrow, which impairs normal blood cell production.

  • Intermediate magnification micrograph of mantle cell lymphoma of the terminal ileum. Endoscopic biopsy. H&E stain. Histomorphologic features: Monomorphic small lymphoid cells less than twice the size of a resting lymphocyte. Abundant mitoses. Sclerosed blood vessels. Scattered epithelioid histiocytes.

    Intermediate magnification micrograph of mantle cell lymphoma of the terminal ileum. Endoscopic biopsy. H&E stain. Histomorphologic features: Monomorphic small lymphoid cells less than twice the size of a resting lymphocyte. Abundant mitoses. Sclerosed blood vessels. Scattered epithelioid histiocytes.

  • Mantle cell lymphoma. Notice the irregular nuclear contours of the medium-sized lymphoma cells and the presence of a pink histiocyte. By immunohistochemistry the lymphoma cells expressed CD20, CD5 and Cyclin D1 (high power view, H&E).

    Mantle cell lymphoma. Notice the irregular nuclear contours of the medium-sized lymphoma cells and the presence of a pink histiocyte. By immunohistochemistry the lymphoma cells expressed CD20, CD5 and Cyclin D1 (high power view, H&E).

  • Lymph node with mantle cell lymphoma (low power view, H&E).

    Lymph node with mantle cell lymphoma (low power view, H&E).

  • Micrograph of terminal ileum with mantle cell lymphoma (bottom of image). H&E stain.

    Micrograph of terminal ileum with mantle cell lymphoma (bottom of image). H&E stain.

  • Micrograph of terminal ileum with mantle cell lymphoma (bottom of image - brown colour). Cyclin D1 immunostain.

    Micrograph of terminal ileum with mantle cell lymphoma (bottom of image - brown colour). Cyclin D1 immunostain.

References

Template:Hematology

Template:WH Template:WS

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