Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor arising in the stomach, which is characterized by the protein-tyrosine kinase KIT (CD117) expression. Historically, surgical resection has been the mainstay of the curative treatment for localized primary tumors. However, more than an half of the patients with GISTs subsequently develop recurrence or metastasis. The discovery of the molecular pathogenesis of GIST led to the remarkable development of the molecular-targeted therapy with imatinib mesylate, a specific tyrosine kinase inhibitor, and the clinical management of GISTs has rapidly evolved during the last decade. As imatinib has demonstrated significant response in most metastatic GIST, it became the standard first line treatment in patients with metastatic or unresectable GISTs. Nonetheless, treating GIST with a single agent alone is proven to have many limitations because of development of imatinib resistance. Surgical resection still remains the only chance for a cure in GIST treatment. A key strategy for prolonging the survival of patients with GIST is to improve the outcome of surgery. Imatinib use in the GIST management may contribute to surgeons’ success in attaining this objective. It is clear that GIST is a complex disease, and a multidisciplinary approach with effective integration of surgery and targeted therapy is crucial to offer a better prognosis to the patients.
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor that typically arises from the alimentary tract. This tumor is thought to originate from the spindle cells present in the gut wall−the interstitial cells of Cajal.
Prior to 1980s, stromal tumors of the gastrointestinal tract were thought to be neoplasms of smooth muscle origin and were therefore designated as leomyomas, leiomyosarcomas or leiomyoblastoma. Subsequently, it is revealed that GISTs is a separate entity with distinct ultrastructural features and typical immunophenotype compared with smooth muscle tumors. For years, the only effective treatment available was surgery, but it is seldom curative for high-risk tumors. Postoperative recurrence and metastasis is as high as 40% to 90% of all cases of GISTs treated surgically [
The understanding of the pathobiology of GIST expanded significantly since the landmark work by Hirota et al. [
According to a population-based sample, the annual incidence of GIST was estimated at 10-20 cases million [
Approximately 60%-70% of the GISTs arise in the stomach, 20%-30% in the small intestine, 5% in the colon and in the rectum and less than 5% in the esophagus [
The majority (70%) of the patients diagnosed with GIST has non-specific symptoms, which are commonly related to mass effect or bleeding from a large-sized tumors, such as abdominal discomfort, gastrointestinal bleeding from a mucosal erosion, or an abdominal mass. GISTs can also rupture into the peritoneum causing peritonitis or life-threatening intraperitoneal hemorrhage. Asymptomatic small GISTs are often detected incidentally during surgery or endoscopy for other conditions, during rectal examination, or occasionally as incidental radiologic findings. 10% of the cases are detected only at the time of autopsy.
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% [
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 [
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
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
The best indicator of malignancy is the confirmation of metastatic disease. When there is no evidence of distant metastasis, the risk of relapse of operable disease is estimated on the bases of mitotic rate, tumor size, tumor location, surgical margins and whether tumor rupture occurred. Tumor size and mitotic count are considered by the 2002 consensus risk classification (
Based on long-term follow-up of more than 1,600 patients, Miettinen and Lasota [
Recently, a nomogram utilizing the same criteria has been developed by Gold et al. [
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. A proposed algorithm for treatment of primary and recurrent metastatic GIST is outlined (
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 [
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 [
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 [
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) [
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 [
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) [
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 [
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 [
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 [
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 [
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 [
However, surgery is generally not indicated in patients with generalized disease progression under imatinib treatment, unless to provide symptomatic relief [
As mentioned above, median time to tumor recurrence ranges from 18 to 25 months in patients who have undergone surgical resection. Although there is no evidence that earlier detection of recurrent GIST improves survival, imatinib therapy may suspend the tumor progression in most patients. Abdominal CT is an excellent imaging modality to monitor disease during the course of treatment and surveillance after surgery, and the National Comprehensive Cancer Network guidelines recommend CT scans should be obtained every 3 to 6 months for 3-5 years, then annually afterward [
In 2001, Joensuu et al. [
Surgical resection still remains the only chance for a cure in GIST treatment. A key strategy for prolonging the survival of patients with GIST is to improve the outcome of surgery, and imatinib use in the GIST management can aid attaining this objective successfully. It is clear that GIST is a complex disease. A multidisciplinary approach with close collaboration between the medical oncologist, the gastroenterologist, the radiologist, and the surgeon is essential to offer a better prognosis to the patients.
Furthermore, there are some points to be clarified. Notably, the ideal duration of adjuvant imatinib after surgery is still unclear. It is difficult of determine the exact place of surgery in metastatic or recurrent GIST patients. It is also unclear whether surgery makes any difference in outcomes in patients with metastatic GIST. Future and ongoing studies will further delineate the feasibility of multimodal treatment of this disease.
No potential conflict of interest relevant to this article was reported.
A nomogram to estimate 2 and 5 year recurrence-free survival after surgical resection of primary gastrointestinal stromal tumor in the absence of tyrosine kinase inhibitor therapy. HPF, highpower field; RFS, recurrence-free survival. Adopted from Gold et al. [
Algorithm for the treatment of gastrointestinal stromal tumor in imatinib era. RFA, radiofrequency ablation. a)If all gross disease or all imatinib-resistant disease is treatable. Adopted from Gold and DeMatteo [
Risk of aggressive behavior is dependents on size and mitotic degree in a GIST
Risk | Size (cm) | Mitotic count (/50 HPF) |
---|---|---|
Very low risk | <2 | <5 |
Low risk | 2-5 | <5 |
Intermediate risk | <5 | 6-10 |
5-10 | <5 | |
High risk | >5 | >5 |
>10 | Any mitotic rate | |
Any size | >10 |
GIST, gastrointestnal stromal tumor; HPF, high-power field. Adopted from Fletcher et al. [
Risk stratification of primary GIST by sites
Tumor parameter | Risk for progressive disease (%), based on site of origin | ||||
---|---|---|---|---|---|
|
| ||||
Mitotic index | Size (cm) | Stomach | Jejunum/ileum | Duodenum | Rectum |
≤5 per 50 HPF | ≤2 | None | None | None | None |
>2, ≤5 | Very low | Low | Low | Low | |
>5, ≤10 | Low | Moderate | - | ||
>10 | Moderate | High | High | High | |
>5 per 50 HPF | ≤2 | None | High | - | High |
>2, ≤5 | Moderate | High | High | High | |
>5, ≤10 | High | High | - | - | |
>10 | High | High | High | High |
Adopted from Miettinen and Lasota [
Insufficient data.