Gastrointestinal stromal tumor - an evolving concept

Abstract

Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. The discovery that these tumors, formerly thought of smooth muscle origin, are indeed better characterized by specific activating mutation in genes coding for the receptor tyrosine kinases (RTKs) CKIT and PDGFRA and that these mutations are strongly predictive for the response to targeted therapy with RTK inhibitors has made GISTs the typical example of the integration of basic molecular knowledge in the daily clinical activity. The information on the mutational status of these tumors is essential to predict (and subsequently to plan) the therapy. As resistant cases are frequently wild type, other possible oncogenic events, defining other "entities," have been discovered (e.g., succinil dehydrogenase mutation/dysregulation, insuline growth factor expression, and mutations in the RAS-RAF-MAPK pathway). The classification of disease must nowadays rely on the integration of the clinico-morphological characteristics with the molecular data.

Keywords: CKIT; gastrointestinal stromal tumors; gastrointestinal tract; receptor tyrosine kinase; targeted therapy.

Figure 1

Histology, immunohistochemistry, and molecular genetics of GISTs. (A,B) Histology. (A) Spindle cell tumor, with paranuclear vacuoles (so-called “leiomyoblastoma”). HE 40×. (B) Epitheloid tumor. Large, clear cytoplasm with central nucleus. HE 40×. (C) Spindle cells diffusely positive for CKIT (CD117). IHC 10×. (D) Epitheloid cells strongly and diffusely positive for DOG1, with evident membrane enhancement. IHC 40×. (E) Sanger sequencing with a duplication of GCC TAT in positions 502–503 (p.A502-Y503 dup). Mutation associated with sensitivity to imatinib. (F). Sanger sequencing with a substitution (A–C) in position 842, (p.D842V), imatinib resistant.

Figure 2

Structure of RTK III, with localization of the activating mutations in KIT and PDGFRA. EC, extracellular; JM, juxtamembrane; TK, tyrosine kinase.

Figure 3

Possible therapeutic targets (red) and targeted drugs in GISTs.

Figure 4

Evolution of the concept of GISTs since 70 years. EM, electron microscopy; IHC, immunohistochemistry; ICC, interstitial cells of Cajal; MB, molecular biology; SDH, succinil dehydrogenase; IGFR, insuline growth factor receptor; NGS, next generation sequencing.