GISTs belong to a peculiar cell lineage normally giving rise to interstitial cells of Cajal of the gastrointestinal tract, while other tumors such as leiomiosarcomas derive from different cell lineages. GISTs are characterized by a risk of recurrence based on the mitotic-index and the size of the neoplasm, with the tendency to spread to liver and peritoneum.
GIST cell morphology can be spindle-shaped (that is the most frequent type), epithelioid or mixed.
Most GISTs (75-80%) harbour mutations in the transmembrane receptor KIT, with tyrosine kinase activity. The majority of mutations (70%) occur in the juxtamembrane domain (exon 11) and consist in deletions, frame insertions and/or missense mutations.
Other mutations occur at lower frequencies in external domains (20%) of KIT (exon 8 and 9) and in kinase domain I and II (10%) (exon 13 and 17, respectively). Among the 20-25% of GISTs without KIT mutations, about 8% harbour mutations in a KIT-like tyrosine kinase receptor, Platelet-Derived Growth Factor Receptor Alpha (PDGFr alfa). These mutations occur in exons 12, 14 or 18. On the whole, 85-90% of GISTs have mutations in KIT or PDGFr alfa.
The interaction of KIT ligand (Stem Cell Factor, SCF) with KIT or PDGFr alfa causes the activation of the tyrosine kinase domains and the phosphorylation of several molecules involved in promotion of cellular growth and survival.
Antibodies against c-kit (CD117) are widely employed in immunohistochemistry for identification and diagnosis of GISTs. C-kit antibody, used together with CD34, S-100, desmin and smooth muscle actin, allows to distinguish between GISTs and other tumors (neural or muscular tumors).
The most frequent KIT mutation occurs in the juxtamembrane domain (exon 11) and it is responsible for the constitutive kinase activation. Mutations in the kinasic domain, which are the most frequent in PDGFr alfa (exon 18), modify the activation loop that controls the conformation of ATP-binding site.
By means of this and other mechanisms, KIT or PDGFr alfa mutations maintain a proliferative boost in GIST cells.
Mutations of KIT are related with high grade of activation and phosphorylation, but GISTs that lack identifiable mutations (5-10%) often display KIT activation. This evidence underlines the key role of this molecule in the pathogenesis of GIST.
The treatment of patients with advanced GIST has been revolutionized by the introduction of imatinib in clinical practice. Recent clinical trials have shown that the presence and type of KIT or PDGFr alfa mutations correlate with response to imatinib. For example, GIST patients harbouring c-kit mutations in exons 9 or 11 respond to imatinib in 45% and 85% of cases, respectively. On the contrary, patients with the most common mutation of PDGFr alfa (D842V) have poor response to imatinib (primary resistance) while patients harbouring other mutations of PDGFr alfa have variable response rates. Patients without detectable mutations of KIT or PDGFr alfa have very poor response to imatinib.
Molecular analysis is useful to identify imatinib-resistant patients that may take benefits from sunitinib, a second generation tyrosine kinase inhibitor approved for patients unresponsive to imatinib. Clinical trials have recently demonstrated that mutational screening not only predicts imatinib resistance, but also helps the choice of the correct dose. In particular, the length of disease stabilization is significantly longer in patients with exon 9 c-kit mutations when they are treated at a higher dose (800 mg/day instead of 400 mg/day) while it is ineffective in patients harbouring other KIT or PDGFr alfa mutations.