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Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal (GI) tract. Before the current definition of GIST evolved, GISTs were classified as benign or malignant smooth muscle tumours including true smooth muscle tumours (leiomyomas, leiomyoblastomas, leiomyosarcomas) and neuronal tumours (schwannomas)^1,8.

In the past 10 years, a new definition of GIST has been widely accepted that includes distinct morphology, location, and immunohistochemical staining criteria^1,9,10. GISTs are mesenchymal neoplasms, with spindle cell or epithelioid morphology. GISTs are located primarily in the GI tract, omentum, and mesentery. The defining molecular marker of GIST is the KIT tyrosine kinase receptor (also known as c-Kit).

Epidemiology of GIST

Historically, gastrointestinal stromal tumours (GIST) was misdiagnosed or went undiagnosed¹. Since the clarification of the definition of GIST, more tumours are being diagnosed, and cases are being more clearly diagnosed. This is evident in the increase in GIST diagnoses with a concurrent decrease in diagnoses of "GIST-like" tumours¹¹.

GIST is now recognised as having a much higher incidence than previously thought. Under the current, widely accepted definition of GIST as a distinct molecular and pathologic entity, the incidence of GIST is in the range of 10-20 cases per million persons per year^2,6,9-11. The prevalence of GIST in a population-based study was estimated to be 129 cases per million persons¹⁰. GIST tumours occur at a median age of 60 years and are slightly more predominant in men than women⁶.

Cellular Origins of GIST

Interstitial cells of Cajal (ICCs), which are intercalated between the autonomic nerves and muscle walls of the gut, are believed to function as "pacemaker" cells for GI tract motility. ICCs have been shown to express the KIT proto-oncogene receptor (KIT, CD117) on their surface. This receptor, a transmembrane tyrosine kinase, binds the stem-cell factor and is believed to be essential for development of normal haematopoiesis, proliferation, and migration of primordial germ cells during embryogenesis, as well as for pacemaker functions in ICCs¹². Similarly, GISTs express the tyrosine kinase receptor KIT in most cases, unlike GI leiomyomas and leiomyosarcomas, which do not express KIT receptors¹². The ultrastructure of ICCs is also consistent with GIST cells¹³, both of which have abundant mitochondria, intermediate filaments, microtubules, and cytoplasmic interdigitating projections^12,13. The shared histologic morphology and immunohistochemical reactivity of ICCs and GISTs suggest that GIST is derived from ICCs or their stem-cell precursors¹².

In the majority of GISTs, the ICCs, which mediate peristalsis in the upper intestine, undergo uncontrolled growth. Growing tumours stimulate angiogenesis or formation of new blood vessels via production of cytokines, such as vascular endothelial growth factor (VEGF). Cells located within the growing blood vessels then secrete other cytokines, including platelet-derived growth factors (PDGFs). These bind to associated PDGF receptors on pericytes, resulting in increased vascular and endothelial cell stability.

KIT: A Defining Marker for GIST

The presence of the KIT protein (also known as CD117 cell surface antigen), in conjunction with specific histological criteria, defines GIST. KIT is a cell membrane receptor tyrosine kinase that binds the growth factor called stem-cell factor (SCF). SCF is also known as mast-cell growth factor, Steel factor (SLF), and KIT ligand (KL).

Approximately 95% of GISTs stain positive for KIT (CD117) in immunohistochemical tests¹⁵. About one third of the remaining GISTs are found to have abnormal platelet-derived growth factor receptor alpha (PDGFRα)¹⁶. These 2 proteins are responsible at the molecular level for GIST tumorigenesis. Glivec specifically targets most activating mutations in KIT and PDGFRα seen in patients with GIST ⁶.

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