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gastrointestinal stromal tumor

Monday 29 May 2006

digestive GIST


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).


- 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


- stomach : gastric GIST
- duodenum : duodenal GIST
- intestinal GIST
- colonic GIST


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)


- 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)

- NF-associated GISTs

  • NF germline mutations
  • no KIT or PDGFRA mutations (16096406)


- KIT+ gastrointestinal stromal tumor
- KIT- gastrointestinal stromal tumor
- pediatric gastrointestinal stromal tumor (pediatric GIST)
- NF1-associated gastrointestinal stromal tumor


- neurofibromatosis type 1 (NF1) (16096406)
- Carney triad (15712189)

Differential diagnosis (11215292)

- digestive sarcomas

  • digestive leiomyosarcoma
  • digestive fibrosarcoma


- 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.


-  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

- CGH gains

LOH study

- allelic losses (loss of heterozygosity)

- gene overpexpression and amplification (15864317)


- Gleevec

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See also

- digestive tumors

- 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


- 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

- Badalamenti G, Rodolico V, Fulfaro F, et al. Gastrointestinal stromal tumors (GISTs): focus on histopathological diagnosis and biomolecular features. Ann Oncol 2007;6:136–40.

- Hirota M, Shimada S, Yamamoto K, et al. Pancreatectomy using the no-touch isolation technique followed by extensive intraoperative peritoneal lavage to prevent cancer cell dissemination: a pilot study. JOP 2005; 6:143–51.

- 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.

- Demetri G.D., von Mehren M., Blanke C.D., van den Abbeele A.D., Eisenberg B., Roberts P.J. , et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors N. Engl. J. Med. 2002 ; 347 : 472-480

- Reith JD, Goldblum JR, Lyles RH, Weiss SW. Extragastrointestinal (Soft Tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol 2000;13:577–85.

- Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-offunction mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577-80.

- Yamamoto H, Oda Y, Kawaguchi K, Nakamura N, Takahira T, Tamiya S, Saito T, Oshiro Y, Ohta M, Yao T, Tsuneyoshi M. c-kit and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue). Am J Surg Pathol 2004; 28:479-488.

- Kim JH, Boo YJ, Jung CW, Park SS, KimSJ, Mok YJ, et al. Multiple malignant
extragastrointestinal stromal tumors of the greater omentum and results of
immunohistochemistry and mutation analysis: A case report. World J Gastroenterol 2007;13:3392-5.

- Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006;23:70–83.

- Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal tumors: recent advances in understanding of their biology. Hum Pathol 1999; 30: 1213-20. Ann Chir Gynecol 1998;87:278–81.

- Miettinen M, Majidi M, Lasota J. Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review. Eur J Cancer 2002; 38:39–51.

- Miettinen M, Monihan JM, Sariomo RM, Kovavitch AJ, Carr NJ, Emory TS, et al.
Gastrointestinal Stromal Tumors/Smooth muscle Tumors (GISTs) Primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases. Am J Surg Pathol 1999; 23:1109–18.

- Tervahartiala P., Halavaara J. Radiology of GIST Ann. Chir. Gynaecol. 1998 ; 87 : 291-292

- Mazur MT, Clark HB. Gastric stromal tumours: Reappraisal of histogenesis. Am J Surg Pathol 1983; 7:507-19