U.S. Residents
About Gastrointestinal Stromal Tumours
(GIST) and the KIT Protein Marker
Gastrointestinal Stromal Tumour Definition
Epidemiology of Gastrointestinal Stromal Tumours (GIST)
Cellular Origins of Gastrointestinal Stromal Tumours (GIST)
The KIT Protein: A Defining Marker for Gastrointestinal Stromal Tumours
Gastrointestinal Stromal Tumour Definition
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 Gastrointestinal Stromal Tumours has been widely accepted that includes distinct morphology, location, and immunohistochemical staining criteria1,9,10. GISTs are mesenchymal neoplasms, with spindle cell or epithelioid morphology. Gastrointestinal Stromal Tumours are located primarily in the Gastrointestinal tract, omentum, and mesentery. The defining molecular marker of GIST is the KIT protein tyrosine kinase receptor (also known as c-Kit protein or simply, c-KIT).
Epidemiology of Gastrointestinal Stromal Tumours (GIST)
Historically, gastrointestinal stromal tumours (GIST) was misdiagnosed or went undiagnosed1. Since the clarification of the definition of Gastrointestinal Stromal Tumours, 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 Gastrointestinal Stromal Tumours as a distinct molecular and pathologic entity, the incidence of GIST is in the range of 10-20 cases per million persons per year2,6,9-11. The prevalence of Gastrointestinal Stromal Tumours 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 Gastrointestinal Stromal Tumours (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 gastrointestinal 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 kit protein tyrosine kinase receptor in most cases, unlike gastrointestinal 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 projections12,13. The shared histologic morphology and immunohistochemical reactivity of ICCs and GISTs suggest that GIST is derived from ICCs or their stem-cell precursors12.
Cellular Origins of Gastrointestinal Stromal Tumours
Image reproduced with permission from Thomsen L, et al. Nature Med. 1998;4:848-851.14
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.
The KIT Protein: A Defining Marker for Gastrointestinal Stromal Tumours
The presence of the KIT protein (also known as CD117 cell surface antigen), in conjunction with specific histological criteria, defines GIST. The KIT Protein 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 tumourigenesis. Glivec specifically targets most activating mutations in KIT and PDGFRα seen in patients with GIST 6.
Figure 1. Spectrum of staining for KIT (CD117) in GIST
Images courtesy of Pancras C.W. Hogendoorn, MD, PhD.