gastrointestinal stromal tumor
Monday 29 May 2006
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.
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.
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)
- 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 germline mutations
- no KIT or PDGFRA mutations (16096406)
Differential diagnosis (11215292)
- digestive leiomyosarcoma
- digestive fibrosarcoma
- hypo- to near-diploid
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)
- 1p loss (17330260)
- 10q loss
- 13q loss
- 14q loss (71%)
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)
KIT or PDGFRA mutations (90%)
- KIT activating mutations (70%)
- PDGFRA activating mutations (20%)
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.
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STI-571 (imatinib mesylate, Gleevec)
anti-tyrosine kinase drug
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
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
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