GISTs demonstrate a fairly equal distribution between men and women; however, some literature suggest that there is a slight male predominance [9]. Although GIST has been reported in patients of all ages, including children, most people affected by the disease are between 40 and 80 years old at the time of diagnosis, with a median age of 60 years. Most GISTs are sporadic. Nonetheless, there are several case reports of familial germline mutations in the KIT or PDGFRα proto-oncogenes [10,11].

Approximately 60% of GISTs occur in the stomach, whereas 30% of cases are found in the small intestine, 5% in the rectum, and 5% in the esophagus (Fig. 1) [9]. Rarely, they can also develop in the omentum, mesentery, pancreas, or other retroperitoneal organs [12].

Fig. 1 (A) A large exophytic gastric GIST. (B) GIST emanating from the anti-mesenteric border of jejunum.

Most (70%) patients diagnosed with GIST have vague symptoms, such as abdominal pain, GI bleeding from a mucosal erosion, or an abdominal mass [13]. Ten percent of the cases are detected only at the time of autopsy. Intestinal obstruction from GISTs is rare, because GISTs behave like other sarcomas and usually displace rather than invade adjacent structures. Occasionally, however, they may serve as lead points for intussusception. Patients with esophageal or duodenal GIST may rarely present with dysphagia or jaundice, respectively.

Because of the infrequency of GIST, the disease is rarely suspected before the time of surgery. A high index of suspicion is required to make the diagnosis. The best radiologic study to characterize a mass suspicious for GIST, as well as to evaluate the extent of the disease, is a contrast-enhanced computed tomography (CT) of the abdomen and pelvis. Metastases to the lungs or other extra-abdominal locations are usually observed only in advanced cases. On a CT scan, GISTs typically appear as hyperdense, enhancing masses, closely associated with the stomach or small intestine (Fig. 2). The liver and peritoneal surface are the most common sites of metastatic disease. Lymph node metastases are rare, except in the pediatric population [14]. Children are also more likely to present with multifocal disease and lack a KIT or PDGFRα mutation. GISTs may appear heterogeneous because of central necrosis or intratumoral hemorrhage. Magnetic resonance imaging (MRI) may be useful in rectal GIST. Positron emission tomography (PET) is not specific enough for the diagnosis of GIST, but can be used to monitor the clinical response to imatinib treatment, although it is rarely needed. On endoscopy, GIST appears as a submucosal mass, since it originates from the bowel wall and not the mucosa. This can be confirmed via endoscopic ultrasound. Often, however, endoscopic evaluation is unnecessary.

Fig. 2 (A) CT scan showing a small gastric GIST arising from the posterior wall of the stomach (arrow). (B) A large GIST arising from the mesocolon of the right colon (arrows).

Recent studies have shown that endoscopic fine-needle aspiration (FNA) for the diagnosis of GIST has a sensitivity as high as 80% [15]; however, preoperative tissue diagnosis is usually not required unless the diagnosis is in doubt. A biopsy is recommended for metastatic disease or if neoadjuvant imatinib is under consideration.

In GIST, a gain-of-function mutation in KIT (85%) leads to constitutive activation of KIT and its tyrosine kinase function. Several mutations have been described, the most common being KIT exon 11 (70%) and exon 9 (10%) [4,6]. As mentioned previously, 3% to 5% of GISTs harbor a mutation in the PDGFRα proto-oncogene, whereas 10% to 15% of tumors carry wild-type alleles of KIT and PDGFRα, yet overexpress KIT. GISTs may also be positive for CD34 (60%–70%), smooth-muscle actin (SMA; 30%–40%), S-100 protein (5%), and, rarely, desmin [16]. Unlike other GI malignancies, the behavior of GIST is difficult to predict based on histopathology alone. Although the best indicator of malignancy is the confirmation of metastatic disease, 3 characteristics have been shown to predict how GISTs will behave: size, mitotic rate, and tumor location [17]. In general, GISTs of 10 cm or larger are more likely to recur. Mitotic index is the dominant predictor of recurrence, as tumors with at least 5 mitoses per 50 high-powered fields (HPFs) are 15 times more likely to recur than those with fewer than 5 mitoses per 50 HPFs. Also, GISTs originating in the small intestine exhibit a more aggressive behavior than those of similar size and mitotic index originating in the stomach. Importantly, neither small size nor low mitotic rate excludes the potential for malignant behavior. Patients with either a KIT exon 9 mutation or KIT exon 11 deletion involving amino acid W557 and/or K558 experience a higher rate of recurrence, whereas point mutations and insertions of KIT exon 11 confer a more favorable prognosis.

Recently, we developed a GIST prognostic nomogram based on tumor size (cm), location of disease (stomach, small intestine, colon, rectum, or other), and mitotic index (<5 or ≥5 mitoses per 50 HPFs) from 127 patients treated at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1983 and 2002 [18]. It predicts recurrence-free survival at 2 and 5 years after complete surgical resection of localized primary GIST (Fig. 3). We validated the nomogram using a series of patients from the Mayo Clinic and another series from the Spanish National Registry, and showed better predictive accuracy than those of 2 commonly used staging systems developed at the National Institutes of Health GIST workshop and the Armed Forces Institute of Pathology–Miettinen staging system [19]. Including the presence or type of KIT or PDGFRα mutation did not improve the discriminatory ability, although this may be because of limited sample sizes.

Fig. 3 Nomogram to estimate 2-year and 5-year recurrence-free survival after surgical resection of primary GIST in the absence of tyrosine kinase inhibitor therapy.

(From Gold JS, Gonen M, Gutierrez A, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol 2009;10:1045; with permission.)

Successful treatment of GIST requires assessment of the extent and progression of disease, and integration of surgery and molecular-targeted therapy. Thus, a multidisciplinary team that includes radiologists, medical oncologists, pathologists, and surgeons is paramount for the effective care of these patients.