Gastrointestinal stromal tumors: Overview of pathologic features, molecular biology, and therapy with imatinib mesylate

J. S. Koh, Jonathan Trent, L. Chen, A. El-Naggar, K. Hunt, R. Pollock, Wei Zhang

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors develop at any site but are most commonly reported in the stomach. They originate from the neoplastic transformation of the intestinal pacemaker cell, the interstitial cell of Cajal. GISTs strongly express the receptor tyrosine kinase KIT and have mutations in the KIT gene, most frequently in exon 11 encoding the intracellular juxtamembranous region. Expression of KIT is seen in almost all GISTs, regardless of the site of origin, histologic appearance, or biologic behavior, and is therefore regarded as one of the key diagnostic markers. Distinction from smooth muscle tumors, such as leiomyosarcomas, and other mesenchymal tumors is very important because of prognostic differences and therapeutic strategies. Predicting the biologic behavior of GISTs is often difficult by conventional pathologic examination; tumor size and mitotic rate are the most important prognostic indicators. The prognostic significance of KIT mutations is controversial and thus far has not been clearly linked with biologic behavior. KIT mutations are associated with tumor development, and cytogenetic aberrations are associated with tumor progression. The pathogenesis of GISTs involves a gain-of-function mutation in the KIT proto-oncogene, leading to ligand-independent constitutive activation of the KIT receptor. KIT-wild-type GISTs have shown mutually exclusive platelet-derived growth factor receptor (PDGFR) mutation and activation. The use of imatinib mesylate (also known as Gleevec or STI-571) has greatly increased the therapeutic efficacy for this otherwise chemotherapy-resistant tumor. GISTs with very low levels of KIT expression may respond to imatinib mesylate therapy if the receptors are activated by specific mechanisms. KIT-activating mutations fall into two groups: the regulatory type and the enzymatic site type. The regulatory type of mutation is conserved at the imatinib binding site, whereas the enzymatic site mutation has a structurally changed drug-binding site, resulting in drug resistance. Resistance to the drug is the major cause of treatment failure in cancer therapy, emphasizing the need for researchers to understand KIT signaling pathways so as to identify new therapeutic targets. This review summarizes the pathologic features of GISTs, recent advances in understanding their molecular and biologic features, and therapy with imatinib mesylate.

Original languageEnglish
Pages (from-to)565-574
Number of pages10
JournalHistology and Histopathology
Volume19
Issue number2
StatePublished - Apr 1 2004
Externally publishedYes

Fingerprint

Gastrointestinal Stromal Tumors
Molecular Biology
Mutation
Neoplasms
Therapeutics
Drug Resistance
Binding Sites
Interstitial Cells of Cajal
Smooth Muscle Tumor
Platelet-Derived Growth Factor Receptors
Biological Therapy
Proto-Oncogenes
Leiomyosarcoma
Imatinib Mesylate
Receptor Protein-Tyrosine Kinases
Treatment Failure
Chromosome Aberrations
Gastrointestinal Tract
Exons
Stomach

Keywords

  • GIST
  • Imatinib mesylate
  • KIT

ASJC Scopus subject areas

  • Anatomy
  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

Cite this

Koh, J. S., Trent, J., Chen, L., El-Naggar, A., Hunt, K., Pollock, R., & Zhang, W. (2004). Gastrointestinal stromal tumors: Overview of pathologic features, molecular biology, and therapy with imatinib mesylate. Histology and Histopathology, 19(2), 565-574.

Gastrointestinal stromal tumors : Overview of pathologic features, molecular biology, and therapy with imatinib mesylate. / Koh, J. S.; Trent, Jonathan; Chen, L.; El-Naggar, A.; Hunt, K.; Pollock, R.; Zhang, Wei.

In: Histology and Histopathology, Vol. 19, No. 2, 01.04.2004, p. 565-574.

Research output: Contribution to journalArticle

Koh, JS, Trent, J, Chen, L, El-Naggar, A, Hunt, K, Pollock, R & Zhang, W 2004, 'Gastrointestinal stromal tumors: Overview of pathologic features, molecular biology, and therapy with imatinib mesylate', Histology and Histopathology, vol. 19, no. 2, pp. 565-574.
Koh, J. S. ; Trent, Jonathan ; Chen, L. ; El-Naggar, A. ; Hunt, K. ; Pollock, R. ; Zhang, Wei. / Gastrointestinal stromal tumors : Overview of pathologic features, molecular biology, and therapy with imatinib mesylate. In: Histology and Histopathology. 2004 ; Vol. 19, No. 2. pp. 565-574.
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