Desmoid tumor pathophysiology: Difference between revisions

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*Desmoid tumors are:
*Desmoid tumors are:
**Benign tumors
**Benign tumors
**Extremely aggressiveness locally
**Aggressive local infiltration
**Have high rate of local recurrence
**High local recurrence rate
**Don't metastasize
**Don't metastasize
*Their exact aetiology remains uncertain, although they are frequently associated with previous trauma or surgical incision. On the molecular level, desmoids are characterised by mutations in the [[β-catenin gene]], CTNNB1, or the adenomatous polyposis coli gene, APC.<ref name="radio">Desmoid tumor. Dr Tim Luijkx and Radswiki et al. Radiopedia 2015 http://radiopaedia.org/articles/aggressive-fibromatosis. Accessed on January 20, 2015</ref>
*Their exact aetiology remains uncertain, although they are frequently associated with previous trauma or surgical incision. On the molecular level, desmoids are characterised by mutations in the [[β-catenin gene]], CTNNB1, or the adenomatous polyposis coli gene, APC.<ref name="radio">Desmoid tumor. Dr Tim Luijkx and Radswiki et al. Radiopedia 2015 http://radiopaedia.org/articles/aggressive-fibromatosis. Accessed on January 20, 2015</ref>

Revision as of 16:02, 28 February 2019

Desmoid tumor Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Desmoid tumor from other Diseases

Epidemiology and Demographics

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

CT

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Faizan Sheraz, M.D. [3]

Overview

Desmoid tumor may occur as part of Gardner syndrome. A minority of desmoid tumors are associated with Turcot syndrome, Familial adenomatous polyposis, and estrogen therapy.

Pathophysiology

  • Desmoid tumors are:
    • Benign tumors
    • Aggressive local infiltration
    • High local recurrence rate
    • Don't metastasize
  • Their exact aetiology remains uncertain, although they are frequently associated with previous trauma or surgical incision. On the molecular level, desmoids are characterised by mutations in the β-catenin gene, CTNNB1, or the adenomatous polyposis coli gene, APC.[1]
  • The exact etiology of desmoid tumors is unknown. However, the following etiologies seem to play a role in development of desmoid tumors:[2][3][4][5][6]

Genetics

  • The key factor in pathogenesis of desmoids at genetic level is beta-catenin stabilization implicated by mutations in two mediators of Wnt-APC-beta-catenin pathway.[7]

Mutations in adults

  • Wnt/beta-catenin signaling pathway
    • Mutational analysis shows that Wnts play an important role in controlling diverse developmental processes such as patterning of the body axis, central nervous system and limbs, and the regulation of inductive events during organogenesis.[8]
    • Sporadic tumors occur due to somatic mutations in Beta-catenin/APC coding genes
    • Activating mutations in APC gene/Beta-catenin gene (CTNNB1) lead to dysregulation of beta-catenin (a cytosolic and nuclear protein which acts as a cellular adhesion molecule) levels in cell leading to its accumulation in nucleus which is associated with transcription activation of CYCD1 and MYC genes.[7][9]
    • This leads to promotion of proliferation and enhanced survival associated with development of desmoid tumor.[10][11][12][7][13][9][14][15][16][17][18][19][20]
    • Following is a summary of all the events that occur at molecular level secondary to activating mutations in APC gene/Beta-catenin gene (CTNNB1)/Wnt signaling pathway, eventually leading to development of desmoid tumor.
 
 
 
Binding of an activating external/Wnt ligand to a receptor complex (a member of a seven-transmembrane-domain receptor of the frizzled family) and a LRP5/6 co-receptor(LDL-receptor-related protein family)[21][8]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Canonical Wnt (Wingless) signaling pathway activation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhibition of kinase activity of APC complex (which tightly binds and regulates Beta-catenin levels by its phosphorylation in proteasome at serine and threonine sites encoded in exon 3, leading to ubiquitin-mediated protein degradation)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Elevated Beta-catenin levels in cytoplasm (due to non-phosphorylation)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-catenin translocates to nucleus
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B-catenin together with TCF/LEF transcription factors, acts to activate transcription of genes such as CYCD1 and MYC
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Promotion of proliferation and enhanced survival
 
 
 
  • APC mutations
    • Function of normal APC protein is to prevent the accumulation of beta-catenin by mediating its phosphorylation and resultant degradation
    • Familial cases of desmoid are associated with germline mutations in the APC gene[22]
    • APC gene mutation on chromosome 5q is responsible for FAP
    • Generally, desmoid tumors occur more frequently when mutations are in the 3' end of the APC gene, specifically between codons 1445 and 1580
    • More than 300 mutations have been described leading to frame shifts or premature stop codons, resulting in a premature truncated APC gene product which causes loss of the beta-catenin regulatory domain[4][23][24][25][26][27][28][29][30][31][6][32]
    • This leads to accumulation of beta catenin which binds to, and activate the transcription factor tcf-4
    • Sex hormones seem to play a role in activation of these mutations and signaling pathways leading to desmoids[33]
  • Mutations in CTNNB1 (Beta-catenin gene) (64%) (sporadic desmoids) [11][34][35]
  • Sporadic tumors and trisomy 8 and 20[36][37][38][39][40]

Additional mutations in pediatric desmoids

  • In addition to CTNNB1 mutations, following mutations contribute to pediatric desmoids:[41]
    • AKT1 E17K mutation (31%)
    • BRAF V600E mutation (19%)
    • TP53 R273H mutation (9%)

Immunohistochemistry

  • Immunohistochemistry shows an elevated beta-catenin protein level in all tumors, regardless of the mutational status

Associated Diseases

Gross Pathology

  • Desmoid tumors arise from:
    • Connective tissue
    • Fasciae
    • Aponeuroses
  • Abdominal wall desmoid tumors arise from:
  • Musculoaponeurotic structures of the abdominal wall (especially the rectus and internal oblique muscles and their fascial coverings)
  • External oblique muscle and the transversalis muscle or fascia
  • Mostly measure 5 cm by 15 cm in diameter
  • Firm and gritty texture
  • Appears as glistening white and coarsely trabeculated, resembling scar tissue on cut surface
  • No distinct capsule
  • Ill defined margins
  • Well circumscribed on imaging

Location

Frequent locations in the abdomen are:

Microscopic Pathology

Histologically, desmoid tumors consist of:[42]

  • Elongated fibroblasts and myofibroblasts
  • Myofibroblasts are characterized by elongated, tapered cytoplasm; elongated, vesicular, typical-appearing nuclei; and multiple small nucleoli
  • Cells are linearly arranged
  • Cells are surrounded and separated from each other by collagen
  • These tumors show a tendency to evolve over time

Stages of evolution of desmoid tumors

Vandevenne et al described three stages of evolution of desmoid tumors as follows:

Stages of evolution of desmoid tumors
Stage Histological features
First stage
  • More cellular lesions
  • Fewer areas of hyalinized collagen
Second stage
  • Increased amount of collagen deposition in central and peripheral tumor areas
Third stage
  • Increased fibrous composition
  • Decreased cellularity
  • Decreased water content

Reference

  1. ↑ Desmoid tumor. Dr Tim Luijkx and Radswiki et al. Radiopedia 2015 http://radiopaedia.org/articles/aggressive-fibromatosis. Accessed on January 20, 2015
  2. ↑ De Wever I, Dal Cin P, Fletcher CD, Mandahl N, Mertens F, Mitelman F; et al. (2000). "Cytogenetic, clinical, and morphologic correlations in 78 cases of fibromatosis: a report from the CHAMP Study Group. CHromosomes And Morphology". Mod Pathol. 13 (10): 1080–5. doi:10.1038/modpathol.3880200. PMID 11048801.
  3. ↑ Middleton SB, Frayling IM, Phillips RK (2000). "Desmoids in familial adenomatous polyposis are monoclonal proliferations". Br J Cancer. 82 (4): 827–32. doi:10.1054/bjoc.1999.1007. PMC 2374411. PMID 10732754.
  4. ↑ 4.0 4.1 Li C, Bapat B, Alman BA (1998). "Adenomatous polyposis coli gene mutation alters proliferation through its beta-catenin-regulatory function in aggressive fibromatosis (desmoid tumor)". Am J Pathol. 153 (3): 709–14. PMC 1853030. PMID 9736021.
  5. ↑ Escobar C, Munker R, Thomas JO, Li BD, Burton GV (2012). "Update on desmoid tumors". Ann Oncol. 23 (3): 562–9. doi:10.1093/annonc/mdr386. PMID 21859899.
  6. ↑ 6.0 6.1 Giarola M, Wells D, Mondini P, Pilotti S, Sala P, Azzarelli A; et al. (1998). "Mutations of adenomatous polyposis coli (APC) gene are uncommon in sporadic desmoid tumours". Br J Cancer. 78 (5): 582–7. PMC 2063069. PMID 9744495.
  7. ↑ 7.0 7.1 7.2 Tejpar S, Nollet F, Li C, Wunder JS, Michils G, dal Cin P; et al. (1999). "Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor)". Oncogene. 18 (47): 6615–20. doi:10.1038/sj.onc.1203041. PMID 10597266.
  8. ↑ 8.0 8.1 Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC (2000). "An LDL-receptor-related protein mediates Wnt signalling in mice". Nature. 407 (6803): 535–8. doi:10.1038/35035124. PMID 11029008.
  9. ↑ 9.0 9.1 Cheon SS, Cheah AY, Turley S, Nadesan P, Poon R, Clevers H; et al. (2002). "beta-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds". Proc Natl Acad Sci U S A. 99 (10): 6973–8. doi:10.1073/pnas.102657399. PMC 124513. PMID 11983872.
  10. ↑ Barker N (2008). "The canonical Wnt/beta-catenin signalling pathway". Methods Mol Biol. 468: 5–15. doi:10.1007/978-1-59745-249-6_1. PMID 19099242.
  11. ↑ 11.0 11.1 Lazar AJ, Hajibashi S, Lev D (2009). "Desmoid tumor: from surgical extirpation to molecular dissection". Curr Opin Oncol. 21 (4): 352–9. doi:10.1097/CCO.0b013e32832c9502. PMID 19436199.
  12. ↑ Aitken SJ, Presneau N, Kalimuthu S, Dileo P, Berisha F, Tirabosco R; et al. (2015). "Next-generation sequencing is highly sensitive for the detection of beta-catenin mutations in desmoid-type fibromatoses". Virchows Arch. 467 (2): 203–10. doi:10.1007/s00428-015-1765-0. PMID 25838078.
  13. ↑ Heinrich MC, McArthur GA, Demetri GD, Joensuu H, Bono P, Herrmann R; et al. (2006). "Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor)". J Clin Oncol. 24 (7): 1195–203. doi:10.1200/JCO.2005.04.0717. PMID 16505440.
  14. ↑ Abraham SC, Reynolds C, Lee JH, Montgomery EA, Baisden BL, Krasinskas AM; et al. (2002). "Fibromatosis of the breast and mutations involving the APC/beta-catenin pathway". Hum Pathol. 33 (1): 39–46. PMID 11823972.
  15. ↑ Signoroni S, Frattini M, Negri T, Pastore E, Tamborini E, Casieri P; et al. (2007). "Cyclooxygenase-2 and platelet-derived growth factor receptors as potential targets in treating aggressive fibromatosis". Clin Cancer Res. 13 (17): 5034–40. doi:10.1158/1078-0432.CCR-07-0336. PMID 17785554.
  16. ↑ Cheon S, Poon R, Yu C, Khoury M, Shenker R, Fish J; et al. (2005). "Prolonged beta-catenin stabilization and tcf-dependent transcriptional activation in hyperplastic cutaneous wounds". Lab Invest. 85 (3): 416–25. doi:10.1038/labinvest.3700237. PMID 15654359.
  17. ↑ Merchant NB, Lewis JJ, Woodruff JM, Leung DH, Brennan MF (1999). "Extremity and trunk desmoid tumors: a multifactorial analysis of outcome". Cancer. 86 (10): 2045–52. PMID 10570430.
  18. ↑ Kim HS, Kim J, Nam KH, Kim WH (2016). "Clinical significance of midkine expression in sporadic desmoid tumors". Oncol Lett. 11 (3): 1677–1684. doi:10.3892/ol.2016.4129. PMC 4774436. PMID 26998061.
  19. ↑ Kotiligam D, Lazar AJ, Pollock RE, Lev D (2008). "Desmoid tumor: a disease opportune for molecular insights". Histol Histopathol. 23 (1): 117–26. doi:10.14670/HH-23.117. PMID 17952864.
  20. ↑ Crago AM, Chmielecki J, Rosenberg M, O'Connor R, Byrne C, Wilder FG; et al. (2015). "Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid-type fibromatosis by whole-exome sequencing and genomic analysis". Genes Chromosomes Cancer. 54 (10): 606–15. doi:10.1002/gcc.22272. PMC 4548882. PMID 26171757.
  21. ↑ Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP; et al. (1996). "A new member of the frizzled family from Drosophila functions as a Wingless receptor". Nature. 382 (6588): 225–30. doi:10.1038/382225a0. PMID 8717036.
  22. ↑ Alman BA, Li C, Pajerski ME, Diaz-Cano S, Wolfe HJ (1997). "Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors)". Am J Pathol. 151 (2): 329–34. PMC 1857985. PMID 9250146.
  23. ↑ Bertario L, Russo A, Sala P, Eboli M, Giarola M, D'amico F; et al. (2001). "Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis". Int J Cancer. 95 (2): 102–7. PMID 11241320.
  24. ↑ Schiessling S, Kihm M, Ganschow P, Kadmon G, Büchler MW, Kadmon M (2013). "Desmoid tumour biology in patients with familial adenomatous polyposis coli". Br J Surg. 100 (5): 694–703. doi:10.1002/bjs.9053. PMID 23334997.
  25. ↑ Nieuwenhuis MH, Vasen HF (2007). "Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature". Crit Rev Oncol Hematol. 61 (2): 153–61. doi:10.1016/j.critrevonc.2006.07.004. PMID 17064931.
  26. ↑ Sinha A, Tekkis PP, Gibbons DC, Phillips RK, Clark SK (2011). "Risk factors predicting desmoid occurrence in patients with familial adenomatous polyposis: a meta-analysis". Colorectal Dis. 13 (11): 1222–9. doi:10.1111/j.1463-1318.2010.02345.x. PMID 20528895.
  27. ↑ Caspari R, Olschwang S, Friedl W, Mandl M, Boisson C, Böker T; et al. (1995). "Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444". Hum Mol Genet. 4 (3): 337–40. PMID 7795585.
  28. ↑ Bertario L, Russo A, Sala P, Varesco L, Giarola M, Mondini P; et al. (2003). "Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis". J Clin Oncol. 21 (9): 1698–707. doi:10.1200/JCO.2003.09.118. PMID 12721244.
  29. ↑ Friedl W, Caspari R, Sengteller M, Uhlhaas S, Lamberti C, Jungck M; et al. (2001). "Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families". Gut. 48 (4): 515–21. PMC 1728231. PMID 11247896.
  30. ↑ Wallis YL, Morton DG, McKeown CM, Macdonald F (1999). "Molecular analysis of the APC gene in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition". J Med Genet. 36 (1): 14–20. PMC 1762945. PMID 9950360.
  31. ↑ Church J, Xhaja X, LaGuardia L, O'Malley M, Burke C, Kalady M (2015). "Desmoids and genotype in familial adenomatous polyposis". Dis Colon Rectum. 58 (4): 444–8. doi:10.1097/DCR.0000000000000316. PMID 25751801.
  32. ↑ Halling KC, Lazzaro CR, Honchel R, Bufill JA, Powell SM, Arndt CA; et al. (1999). "Hereditary desmoid disease in a family with a germline Alu I repeat mutation of the APC gene". Hum Hered. 49 (2): 97–102. doi:10.1159/000022852. PMID 10077730.
  33. ↑ Hong H, Nadesan P, Poon R, Alman BA (2011). "Testosterone regulates cell proliferation in aggressive fibromatosis (desmoid tumour)". Br J Cancer. 104 (9): 1452–8. doi:10.1038/bjc.2011.107. PMC 3101926. PMID 21468052.
  34. ↑ Lazar AJ, Tuvin D, Hajibashi S, Habeeb S, Bolshakov S, Mayordomo-Aranda E; et al. (2008). "Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors". Am J Pathol. 173 (5): 1518–27. doi:10.2353/ajpath.2008.080475. PMC 2570141. PMID 18832571.
  35. ↑ Mullen JT, DeLaney TF, Rosenberg AE, Le L, Iafrate AJ, Kobayashi W; et al. (2013). "β-Catenin mutation status and outcomes in sporadic desmoid tumors". Oncologist. 18 (9): 1043–9. doi:10.1634/theoncologist.2012-0449. PMC 3780636. PMID 23960186.
  36. ↑ Fletcher JA, Naeem R, Xiao S, Corson JM (1995). "Chromosome aberrations in desmoid tumors. Trisomy 8 may be a predictor of recurrence". Cancer Genet Cytogenet. 79 (2): 139–43. PMID 7889507.
  37. ↑ Kouho H, Aoki T, Hisaoka M, Hashimoto H (1997). "Clinicopathological and interphase cytogenetic analysis of desmoid tumours". Histopathology. 31 (4): 336–41. PMID 9363449.
  38. ↑ Bridge JA, Swarts SJ, Buresh C, Nelson M, Degenhardt JM, Spanier S; et al. (1999). "Trisomies 8 and 20 characterize a subgroup of benign fibrous lesions arising in both soft tissue and bone". Am J Pathol. 154 (3): 729–33. doi:10.1016/S0002-9440(10)65319-9. PMC 1866419. PMID 10079250.
  39. ↑ Qi H, Dal Cin P, Hernández JM, Garcia JL, Sciot R, Fletcher C; et al. (1996). "Trisomies 8 and 20 in desmoid tumors". Cancer Genet Cytogenet. 92 (2): 147–9. PMID 8976373.
  40. ↑ Mertens F, Willén H, Rydholm A, Brosjö O, Carlén B, Mitelman F; et al. (1995). "Trisomy 20 is a primary chromosome aberration in desmoid tumors". Int J Cancer. 63 (4): 527–9. PMID 7591262.
  41. ↑ Meazza C, Belfiore A, Busico A, Settanni G, Paielli N, Cesana L; et al. (2016). "AKT1 and BRAF mutations in pediatric aggressive fibromatosis". Cancer Med. 5 (6): 1204–13. doi:10.1002/cam4.669. PMC 4924379. PMID 27062580.
  42. ↑ Economou, Athanasios; Pitta, Xanthi; Andreadis, Efstathios; Papapavlou, Leonidas; Chrissidis, Thomas (2011). "Desmoid tumor of the abdominal wall: a case report". Journal of Medical Case Reports. 5 (1): 326. doi:10.1186/1752-1947-5-326. ISSN 1752-1947.

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