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gastrointestinal stromal tumor
Monday 29 May 2006
digestive GIST
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Definition: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract.
GIST is typically characterized by immunohistochemical expression of c-kit. The interstitial cell of Cajal also expresses c-kit and CD34. Therefore, GIST is considered to show differentiation along the lines of interstitial cell of Cajal (the smooth muscle pacemaker interstitial cell of Cajal, or Cajal cells ).
They are defined as tumors whose behavior is driven by mutations in the KIT gene (85%), PDGFRA gene (10%), or BRAF kinase (rare).
95% of GISTs stain positively for KIT (CD117). Most (66%) occur in the stomach and gastric GISTs have a lower malignant potential than tumors found elsewhere in the GI tract.
Digital cases
JRC:3180 : Stomach GIST.
JRC:12565 : Stomach GIST (Leiomyoblastoma).
Images
gastrointestinal stromal tumor / GIST
epithelioid gastrointestinal stromal tumor / epithelioid GIST
In the earlier literature, GIST was classified as a smooth muscle tumor variously termed leiomyoma, epithelioid leiomyoma, leiomyoblastoma, leiomyosarcoma, epithelioid leiomyosarcoma, or malignant leiomyoblastoma.
GIST of the digestive tract is now considered to be the distinctive entity, distinguished from leiomyoma, leiomyosarcoma, schwannoma, and other mesenchymal tumors.
Molecular types
KIT-associated GIST
PDGFR-associated GIST
SDH-associated GIST
RAS-associated GIST
quadruple wild type GIST
Morphological types
epithelioid gastrointestinal stromal tumor / epithelioid GIST
Localization
stomach : gastric GIST
duodenum : duodenal GIST
intestinal GIST
colonic GIST
MicroGISTs
Although Gastrointestinal stromal tumors (GISTs) affect about 0.0014% of the population, GISTs smaller than 1 cm (microGISTs) are detectable in about 20% to 30% of elderly individuals. This suggests that microGISTs likely represent premalignant precursors that evolve only in a minute fraction of cases toward overt GISTs. (20861712)
Small GISTs share with overt GIST KIT/PDGFRA mutation. Nevertheless, microGISTs display an overall lower frequency of mutations, particularly canonical KIT mutations, and also carry rare and novel mutations. (20861712)
These molecular features, together with the peculiar pathologic characteristics, suggest that the proliferation of these lesions is likely sustained by weakly pathogenic molecular events, supporting the epidemiologic evidence that microGISTs are self-limiting lesions. (20861712)
Etiology
sporadic GISTs
- gain-of-function mutations of c-kit receptor tyrosine kinase (KIT) gene
- KIT-mutated GIST (KIT-associated GIST)
- gain-of-function mutations of PDGFR-alpha gene coding for platelet-derived growth factor receptor (PDGFRA) alpha (12949711)
- PDGFRA-mutated GIST (PDGFRA-associated GIST)
NF-associated GISTs
- NF germline mutations
- no KIT or PDGFRA mutations (16096406)
Variants
KIT+ gastrointestinal stromal tumor
KIT- gastrointestinal stromal tumor
pediatric gastrointestinal stromal tumor (pediatric GIST)
NF1-associated gastrointestinal stromal tumor
Predisposition
neurofibromatosis type 1 (NF1) (16096406)
Carney triad (15712189)
Differential diagnosis (11215292)
digestive sarcomas
- digestive leiomyosarcoma
- digestive fibrosarcoma
Prognosis
local recurrence
metastasis
Molecular biology
KIT or PDGFRA mutations (90%)
- KIT activating mutations (70%)
- PDGFRA activating mutations (20%)
KIT overexpression (95%)
rare KIT amplification (15869870)
wild-type KIT/PDGFRA GIST
- About 10-15% of gastrointestinal stromal tumors (GISTs) carry wild-type sequences in all hot spots of KIT and platelet-derived growth factor receptor alpha (PDGFRA) (wt-GISTs).
- These tumors are currently defined by having no mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of the PDGFRA gene.
- 1-2% of GISTs being classified as ’wild type’ so far might, in fact, carry KIT mutations in exon 8.
- This mutational subtype was shown to be activating and imatinib sensitive in vitro.
- Screening for KIT exon 8 mutations should become a routine in the diagnostic work-up of GIST and that patients with an exon 8 mutation and a significant risk for tumor progression should be treated with imatinib.
Cytogenetics
ploidy anomalies
- hypo- to near-diploid
- near-triploid
- hypotetraploid
loss of chromosome 14
loss of both chromosomes 14 and 22
loss of 9p21 (54%) (p16INK4a and p14ARF gene loss) (15929122)
loss of 1p
loss of 15
loss of 3p
loss of 10q
anomalies of chromosome 13q (19430298)
- loss of 13q
- Recent studies suggest that loss of 13q could be correlated with GIST progression.
- Chromosome 13 instability of GISTs may play a role in tumor progression. Loss of 13q, especially loss of Rb, RFP2, KCNRG, and KLF5 genes are frequent events in high-risk GISTs.
- Loss of 13q may be associated with tumor progression.
loss of 19
loss of 22q: 22q13, (15580284)
CGH (14730211, 9406576, 16982739, 17330260)
CGH losses
- 1p loss (17330260)
- 10q loss
- 13q loss
- 14q loss (71%)
- 14q11.2-q32.33 loss (16982739)
- 14q11.2 loss (17330260)
- 14q32.33 loss (17330260)
CGH gains
LOH study
allelic losses (loss of heterozygosity)
- 9p21 LOH (15181453)
- 14q LOH (47%-65%) (11123422, 10942800)
- 22q LOH (50%-75%) (15580284, 11123422, 10942800)
gene overpexpression and amplification (15864317)
Videos
Gleevec
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See also
STI-571 (imatinib mesylate, Gleevec)
anti-tyrosine kinase drug
Open References
A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del). Huss S, Künstlinger H, Wardelmann E, Kleine MA, Binot E, Merkelbach-Bruse S, Rüdiger T, Mittler J, Hartmann W, Büttner R, Schildhaus HU. Mod Pathol. 2013 Jul;26(7):1004-12. doi : 10.1038/modpathol.2013.47 PMID: 23599150
References
Aberrations of chromosome 13q in gastrointestinal stromal tumors: analysis of 91 cases by fluorescence in situ hybridization (FISH). Zhou W, Zeng X, Liu T. Diagn Mol Pathol. 2009 Jun;18(2):72-80. PMID: 19430298
Molecular and clinicopathologic characterization of gastrointestinal stromal tumors (GISTs) of small size. Rossi S, Gasparotto D, Toffolatti L, Pastrello C, Gallina G, Marzotto A, Sartor C, Barbareschi M, Cantaloni C, Messerini L, Bearzi I, Arrigoni G, Mazzoleni G, Fletcher JA, Casali PG, Talamini R, Maestra R, Dei Tos AP. Am J Surg Pathol. 2010 Oct;34(10):1480-91. PMID: 20861712
Liu H, Li W, Zhu S. Clinical images. Extragastrointestinal stromal tumor of lesser omentum mimicking a liver tumor. Am J Surg. 2009 Jan;197(1):e7-8. Epub 2008 Aug 29.
Assamaki R, Sarlomo-Rikala M, Lopez-Guerrero JA, Lasota J, Andersson LC, Llombart-Bosch A, Miettinen M, Knuutila S. Array comparative genomic hybridization analysis of chromosomal imbalances and their target genes in gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2007 Jun;46(6):564-76. PMID: 17330260
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Verweij J., van Oosterom A., Blay J.Y., Judson I., Rodenhuis S., van der Graaf W. , et al. Imatinib mesylate (STI-571 Glivec®, Gleevec®) is an active agent for gastrointestinal stromal tumors, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study Eur. J. Cancer 2003 ; 39 : 2006-2011.
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