OVERVIEW
• Gastrointestinal stromal tumor (GISTs) are the most common mesenchymal tumor of the GI tract and originate from the intestinal pacemaker cells, the interstitial cells of Cajal. It is distinguished from other mesenchymal tumors (e.g. leiomyoma, schwannoma) through immunohistochemistry identifying markers of GIST, which are equally expressed in interstitial cells of Cajal: CD117 (KIT) – gene product of stem cell factor receptor proto-oncogene c-kit; CD34 – hematopoietic progenitor cell antigen; PDGF receptor alpha (PDGFRA) – alternative and mutually exclusive oncogenic mechanisms to c-kit pathway.
EPIDEMIOLOGY
• GISTs constitute 0.1–3% of all GI neoplasms. The estimated annual incidence is 10–15 new cases per million people or approximately 3,000 to 5,000 new cases in the US yearly. Although GISTs may occur at all ages, the peak incidence is in the sixth decade of life, with a slight male predominance.
• More than half of GISTs start in the stomach 50-60%. Other locations include the small intestine 25–30% (ileum>jejunum>duodenal), colon/rectum/rectovaginal septum 2–10%, esophagus 9%. Less common locations include retroperitoneal, pancreas, etc.
• Up to 50% of GISTs are metastatic or multifocal at the time of presentation.
PATHOLOGY
• The malignant potential of GISTs is difficult to assess even after pathologic review.
• Favorable prognostic factors include: gastric location, < 5 cm in diameter, mitotic index 5 mitoses per 10 HPFs, absence of necrosis, low proliferating cell nuclear antigen, Ki-67 analogue index < 10%, confined tumor, lack of metastasis to other sites.
• Unfavorable prognostic factors include: esophageal/colonic/rectal location, > 10 cm in diameter, mitotic index 10 mitoses per 10 HPFs, presence of coagulative necrosis, invasion of adjacent organs, evidence of peritoneal seeding or distant metastases.
CLINICAL PRESENTATION
• GISTs can either be asymptomatic, found incidentally at the time of GI evaluation by either endoscopic or contrast studies, at operation, or may cause life-threatening symptoms.
• Symptoms are site specific and include: dysphagia for tumors of the esophagus, nausea and vomiting caused by gastric outlet obstruction for gastric tumors, obstructive jaundice for periampullary tumors, and bowel obstruction usually caused by intussusceptions for tumors of the small bowel and colon. In up to 20% of patients, an asymptomatic abdominal mass is the presenting complaint.
DIAGNOSIS
• As part of the analysis, blood tests and CT scanning are often undertaken.
• A biopsy sample will be investigated under the microscope. The histopathologist identifies the characteristics of GISTs (spindle cells in 70-80%, epitheloid aspect in 20-30%). Smaller tumors can usually be found to the muscularis propria layer of the intestinal wall. Large ones grow, mainly outward, from the bowel wall until the point where they outstrip their blood supply and necrose (die) on the inside, forming a cavity that may eventually come to communicate with the bowel lumen.
• When GIST is suspected—as opposed to other causes for similar tumors—the pathologist can use immunohistochemistry (specific antibodies that stain the molecule CD117 (also known as c-kit) —see below). 95% of all GISTs are CD117-positive (other possible markers include CD34, DOG-1, desmin, vimentin and others). Other cells that show CD117 positivity are mast cells.
• If the CD117 stain is negative and suspicion remains that the tumor is a GIST, the newer antibody DOG-1 (Discovered On GIST-1) can be used. Also sequencing of Kit and PDGFRA can be used to prove the diagnosis.
• Barium fluoroscopic examinations (upper GI series and small bowel series) and CT are commonly used to evaluate the patient with upper abdominal pain. Both are adequate to make the diagnosis of GIST, although small tumors may be missed, especially in cases of a suboptimal examination.
• Small GISTs appear as intramural masses. When large (> 5 cm), they most commonly grow outward from the bowel. Internal calcifications may be present. As the tumor outstrips its blood supply, it can necrose internally, creating a central fluid-filled cavity that can eventually ulcerate into the lumen of the bowel or stomach.
• The tumor can directly invade adjacent structures in the abdomen. The most common site of spread is to the liver. Spread to the peritoneum may be seen. In distinction to gastric adenocarcinoma or gastric/small bowel lymphoma, malignant adenopathy (swollen lymph nodes) is uncommon (<10%).
NON-SURGICAL TREATMENT
• Medical therapy
o Recurrent and locally advanced or metastatic tumors are increasingly treated with imatinib (Gleevec) in palliative, adjuvant, or neoadjuvant setting. Tumor response imatinib correlates with expression of CD117 (c-kit). Disease control is achieved in 70–85% of patients with unresectable or metastatic disease and is associated with prolonged progression-free survival and overall survival (median 36 months); 90% disease-free survival in adjuvant setting after curative resection of GIST.
o Another medical treatment involves sunitinib for imatinib-resistant GISTs.
• Radiation therapy
o Presently there is no defined role for radiation therapy.
SURGICAL TREATMENT
• GISTs are highly resistant to conventional chemotherapy. Treatment is primarily surgical resection of localized GIST with 1 cm margin.
• The operative approach is en-bloc resection of tumor-involved organ with inclusion of intact pseudocapsule. Radical lymphadenectomy is not routinely indicated as lymph node involvement less than 10%. Even in the presence of metastases, the primary tumor should be resected if possible for palliation of symptoms and to prevent development of complications such as obstruction, etc. Independent risk factors that predict recurrence include male gender, presence of deletion or insertion c-kit exon 11 mutations, high mitotic rate, and mixed cytomorphology.
