Contrast-enhanced computed tomography (CT) of the abdomen and pelvis is useful to evaluate the primary tumor as well as to assess the extent of the disease and whether metastatic disease is present. The liver and peritoneal surface are the most common sites of the metastatic disease. On CT scan, GISTs typically appear as hyperdense, enhancing masses, closely associated with the stomach. Magnetic resonance imaging or contrast-enhanced ultrasound may be alternatives. Hypermetabolic uptake in fluorodeoxyglucose-positron emission tomography (PET) is highly sensitive, but not specific enough for the diagnosis of GIST. PET can be used to monitor the clinical response of tumor to treatment.

Endoscopy may be useful in the diagnosis of gastric GIST. On endoscopy, GIST appears as a submucosal mass, since it originated from the bowel wall and not the mucosa. This can be confirmed via endoscopic ultrasound (EUS). EUS can also be used to guide fine needle aspiration (FNA) for pathologic confirmation. Recent studies have shown that endoscopic FNA for the diagnosis of GIST has a sensitivity as high as 80% [8]. However, biopsies by either percutaneous or endoscopic techniques theoretically can precipitate tumor rupture and lead to tumor dissemination or hemorrhage. Preoperative tissue diagnosis is usually not necessary for primary localized tumors unless diagnosis is in doubt. Biopsy may be useful when another diagnosis, such as lymphoma, that would not benefit from surgical resection is entertained. Biopsy is also recommended for metastatic disease or in cases where the mass is marginally resectable and neoadjuvant imatinib is under consideration.

Pathologically, the diagnosis of GIST relies on morphology and immunohistochemistry. GISTs are monotonous tumors that can be divided into 3 principal subtypes depending on the microscopic morphology. The majority of GISTs (approximately 70% of cases) are spindle cell type, and about 20% of cases are composed of epithelioid cells, which are commonly seen in pediatric GISTs. The remaining 10% of GISTs have a mixed spindle and epithelioid cell morphology [2].

Immunohistochemical characteristics of GIST have proven very helpful in diagnosis. KIT (CD117) expression is a specific and sensitive marker for GIST, and approximately 95% of GISTs are immunoreactive for KIT. Most GISTs show a strong and diffuse cytoplasmic staining for KIT, although there is a variability in the level of KIT expression. KIT overexpression is usually related to mutations in the KIT gene, although PDGFRA mutations and other unknown mechanism also appear to result in KIT overexpression without KIT gene mutation. Although KIT-positivity is a major defining feature for GIST, KIT-positivity alone may not be sufficient for diagnosis because there are non-GISTs that are positive for KIT. GIST can be confidently diagnosed if the morphology and immunophenotype are concordant; however, tumors with any unusual features should be sent to a referral institution with special expertise. In addition to KIT (CD117), 60%-70% of GISTs express CD34, but several other mesenchymal neoplasms, which enter into the differential diagnosis of GISTs, stain with CD34. 30%-40% of GISTs express smooth muscle actin and nuclear and cytoplasmic positivity for S100 protein occurs in 5%-10%, while a small minority of GISTs (2%) express desmin [9,10].

Traditional microscopy and immunohistochemistry are usually sufficient to establish the diagnosis of GIST. However, in tumors where the diagnosis remains uncertain, real-time polymerase chain reaction testing for KIT or PDGFRA gene mutations may be useful. KIT gene mutations are detectable in 75%-80% of all GISTs. PDGFRA mutations represents a minority of the overall GISTs (5%-7%) and PDGRFA mutant GISTs are generally limited to the stomach, particularly with an epithelioid morphology, and clinically less aggressive [4,11]. The diagnosis of KIT-negative GIST (in the 5% range of all GISTs) depends on tissue morphology as well as genotyping the tumor for a KIT or PDGFRA mutation as some tumors negative for KIT by immunohistohemistry have been shown to have either mutation [12,13]. A subset of 7%-14% of GISTs is negative for detectable KIT and PDGFRA mutations. These are quite rare, but nearly all of them are represented in the stomach. GISTs associated with Carney’s triad (paraganglioma, pulmonary chondroma, and gastric GIST) also appear to lack kinase gene mutations.

Complete surgical resection is the mainstay of the treatment modality for GIST with no evidence of metastasis, and should be initial therapy if the tumor is technically resectable and associated with acceptable risk for morbidity. The objective of surgery is to remove all gross tumors and achieve negative microscopic margins (R0 resection). Wide margins have not been shown to be associated with better prognosis. En-bloc resection of the GIST and its pseudocapsule, if present, should be performed, and adjacent organs adhered to the tumor should also be completely resected en bloc. Care should be exercised to avoid excessive tumor manipulation, which can disrupt what may be a friable tumor and lead to bleeding and intraperitoneal dissemination. Avoidance of tumor rupture is imperative. Resection can usually be accomplished with only a wedge resection of the stomach, but it may require total or subtotal gastrectomy, depending on tumor location and size. Lymphadenectomy is not routinely necessary unless locoregional lymph nodes are enlarged, because regional lymph node involvement is rare in GIST.

All GISTs 2 cm or larger should be resected. Although a 2 cm cutoff is somewhat arbitrary, recent data suggest that it is reasonable [14]. However, the management of incidentally encountered GISTs smaller than 2 cm remains controversial. For a subset of patients with very small gastric GISTs (<2 cm) with no high-risk EUS features, endoscopic surveillance at 6- to 12-month intervals may be considered [16].

Successful use of laparoscopic techniques for the resection or small (<5 cm) primary GISTs has been reported in small series, reporting technical feasibility with favorable oncologic outcomes when performed by skilled surgeon [17-19]. Intraoperative endoscopy or laparoscopic ultrasound may be used to assist the laparoscopic procedure as needed. Advantages of laparoscopic resection also included minimal manipulation of the tumor as well as better cosmesis. However, long-term data for patients who have under gone laparoscopic resection for GIST are generally lacking.

Complete gross resection of the tumor is the most significant factor for outcome and can be accomplished in 85% of patients with primary localized disease [21-23]. Prognosis of low risk GIST after complete resection is excellent. However, high-risk GISTs have a high rate of recurrence [23]. Without any further treatment, at least 50% of patients develop tumor recurrence and 5-year survival rate is approximately 50% [1,19].

Since conventional adjuvant chemotherapy and radiation therapy has been proved ineffective in treating the majority of patients with malignant GIST, imatinib is being studied to determine whether it reduces recurrence. Adjuvant imatnib is provided in order to enhance the eradication of microscopic lesions after the complete gross resection, and proposed as an option for those patients with a substantial risk of recurrence. In a phase III trial by American College of Surgeons Oncology Group (ACOSOG, Z9001), 713 patients were randomized to imatinib 400 mg/day or placebo for 1 year after complete resection of primary GISTs (>3 cm) [24]. Imatinib demonstrated a significant increase in RFS as compared with a placebo, although no difference in overall survival (OS) between the two treatment arms was noted. Results from the recently completed randomized controlled Scandinavian Sarcoma Group XVIII (SSGXVIII/ AIO) trial suggested that adjuvant imatinib administered for 36 months improved RFS and OS, as compared to adjuvant imatinib administered for 12 months, for patients with a high estimated risk of recurrence of surgery [25]. Based on these results, it is recommended to use imatinib as an adjuvant treatment for at least 36 months for patients with high-risk GISTs (tumor greater than 5 cm in size with high mitotic rate>5 mitoses/50 HPF), but an optimal duration of adjuvant imatinib treatment has yet to be determined [26]. Estimation of risk of recurrence is important in selecting patients who would benefit from postoperative imatinib after complete resection. In addition to risk assessment, mutational analysis may guide the selection of those patients who are more likely to benefit from the treatment.

In the case of tumor rupture at the time of surgery, there has been spillage of tumor cells in the peritoneal cavity, so that occult peritoneal disease can be assumed. This puts the patients at a very high risk of peritoneal relapse [27]. Therefore, these patients should be considered for imatinib therapy either in adjuvant setting or in palliative setting. The optimal duration of treatment in these cases is unknown.

Neoadjuvant imatinib can be particularly attractive for patients with large or poorly localized primary tumors that would otherwise require extensive surgery or sacrifice of a large amount of normal tissue causing functional deficit. Neoadjuvant imatinib can be used to downstage the marginally resectable tumors. In these cases, a careful pretreatment and rapid treatment response assessment by CT and/or PET scan should be performed in multidisciplinary discussion. Duration of the neoadjuvant imatinib therapy may vary according to treatment response, and surgery should be performed after sufficient shrinkage of the tumors (typically between 4 and 6 months, up to 12 months) [17]. For patients who have undergone complete resection after neoadjuvant imatinib, continuation of imatinib following resection is warranted

Most recurrence occurs within 2 years after surgery, and the most common sites for disease recurrence are liver and peritoneum. Although there is no evidence that earlier detection of recurrent GIST improve survival, the consensus statements advocate the intense surveillance during this period. For high and intermediate risk, CT scans of the abdomen and pelvis are recommended every 3 to 4 months for 3 years, then every 6 months until 5 years, and yearly thereafter. For patients with low or very low risk disease, CT scans are recommended every 6 months for 5 years after surgery [17,28].

The majority of the patients undergoing complete resection of primary GIST would develop tumor recurrence, and the median time to recurrence after surgery ranges from 18 to 25 months [1,17,22,29,30] The most commonly involved site of recurrence is liver, and peritoneal dissemination follows next. Metastases to extra-abdominal sites such as lung or bone sometimes occur with disease progression [1,29]. Local recurrence limited to gastric wall of gastric GISTs is infrequent.

Because of the lack of any alternative therapies, surgical resection was considered for patients with recurrence after primary resection and for those with metastatic GIST in the pre-imatinib era. Patients with limited hepatic metastasis or isolated peritoneal recurrence were sometimes treated with surgical resection. The results of the surgical management for these patients have been variable depending on the factors such as tumor size, risk profile, completeness of tumor resection and the disease-free interval after initial surgery [30]. However, outcome was usually very poor: the median survival of such patients only ranged from 6 months to 19 months [1, 30-32]. The literatures in the era before the introduction of imatinib clearly demonstrate that surgery alone is not sufficient to provide long-term survival for GIST patients.

Imatinib is now the first line treatment in patients who develop recurrent metastatic disease. Imatinib therapy has significantly improved the prognosis of patients with metastatic GIST. Imatinib is reported to achieve partial tumor response or stable disease in approximately 80% in advanced GISTs [33,34]. Remarkably, the median survival has improved to nearly 5 years [35]. The majority of patients with metastatic GIST achieve a response within 6 months of imatinib therapy with a median time to response of approximately 3 months [33,34]. However, positive responses after imatinib therapy alone in metastatic GIST are not maintained indefinitely, and the median interval to disease progression is less than 2 years [34]. Thus, a multimodal approach utilizing surgical resection in conjunction with imatinib therapy to treat recurrent and metastasis GIST in multidisciplinary team is highly desirable.

It is well recognized that the clones of resistant tumor cells develop continuously after initiation of imatinib therapy. The most common mechanism of the acquired resistance is additional point mutation in the KIT kinase domains [36,37]. The risk of disease progression on imatinib and developing imatinib resistance seems to be proportional to the amount of residual viable tumor. Therefore, once maximal response to imatinib occurs (generally after 2-6 months of therapy), metastatic disease can be evaluated by a multidisciplinary team for the chance of complete resection. Selected patients with metastatic GIST who have responsive disease or focal resistance to imatinib may benefit from elective surgical resection [38,39]. Imatinib therapy should be continued postoperatively, since treatment interruption is generally followed by rapid tumor regrowth in virtually all cases, even when lesions have been surgically excised [17,40].

However, surgery is generally not indicated in patients with generalized disease progression under imatinib treatment, unless to provide symptomatic relief [38,39]. In patients with overt diffuse progression, increasing the dose of imatinib or using other tyrosine kinase inhibitors, such as sumatinib, are more appropriate options [17].