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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The stomach is considered the most common site of GIST, and the most common histopathological type of GISTs is spindle cell. Mutational analysis may help in defining the management of GIST. Multiple stratification modules are available for the estimation of GISTs’ prognosis. Surgery is considered the only curative option for GISTs. The discovery of KIT protein has allowed better identification of GISTs and has allowed creation of selective tyrosine kinase inhibitors which dramatically affected GIST management. Results of trials on neoadjuvant imatinib therapy are promising. Adjuvant imatinib therapy is recommended for 3 years and has proven to improve outcome in high-risk GISTs. New therapeutic agents are now available in case of imatinib resistance. Follow-up of patients with GISTs depends on the type of GIST.
General Surgery Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
*Address all correspondence to: tsaafan@gmail.com
1. Introduction
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract (GIT) [1, 2]. All GISTs are considered to have some degree of malignant potential [3]. The most common site of GISTs is the stomach (60%) [4]. Other common sites are jejunum and ileum (30%), duodenum (5%), rectum (2–3%), colon (1–2%), and esophagus (<1%) [4].
It has been estimated that GISTs comprise about 18% of all sarcomas and 80% of mesenchymal tumors found in the GIT [5]. GIST’s true incidence has been underestimated as they were usually misdiagnosed as leiomyomas, leiomyosarcomas, and leiomyoblastomas [6]. A study which used the Surveillance, Epidemiology and End Results (SEER) data from the National Cancer Institute, reported that the incidence of GIST has increased from 0.028 cases per 100,000 in 1992 to 0.688 cases per 100,000 in 2002, which is a 25-fold increase in incidence. This increase occurred after the availability of diagnostic criteria, especially after the year 2000 [7]. In 1992, 93% of mesenchymal tumors of GIT were identified as smooth muscle neoplasm and 6% as GISTs. In 1995, Miettinen et al. [8] discovered that 70% of GIST are positive for CD34, a myeloid progenitor cell antigen. Furthermore, CD34 were also found in Schwann cell tumors and some smooth muscle tumors [6]. In the late 1990s, Hirota et al. [9] discovered that GIST expresses KIT (CD117), a receptor tyrosine kinase encoded by the proto-oncogene c-kit. Subsequent studies showed that mutations in c-KIT are present in 85–100% of GIST cases, but not in leiomyomas or leiomyosarcomas. These findings made a breakthrough in identifications and management of GISTs. In the SEER data published by Perez et al. [7], 82% of mesenchymal tumors of GIST were classified as GIST and 17% were classified as smooth muscle neoplasms in 2002, which shows how GISTs were poorly identified and were under-diagnosed [7]. GISTs appear to be more common in African Americans, Asians, and Pacific Islanders than in Caucasian patients, and men appear to have a slightly increased incidence [7, 10]. GISTs tend to be infrequent before the age of 30 and are most common after the age of 60 [7]. The median age of diagnosis is between 58 and 65 years [7, 10, 11, 12, 13]. Two studies from Europe have shown that GIST incidence is about 1.1 cases/100,000/year [11, 14].
Though rare, GISTs can also affect the pediatric population. A study carried out by Miettinen et al. which included 1782 patients with gastric GIST, reported 44 cases under the age of 21 (2.6%) [15] with an age range from 5 to 21 and a median age of 14.5 years [15]. Prakash et al. [16] reported six cases of gastric GIST with a mean age of 12.8 and an age range from 10 to 18. Pediatric GISTs are commonly of epithelioid type, occur more in females, and have a higher incidence of multifocal presentation and lymph node metastasis. Pediatric GISTs also tend to lack a KIT or a platelet-derived growth factor receptor-α (PDGFRA) mutation [17, 18].
There are no known risk factors for GIST. Though most of GISTs are sporadic, the minority occur as part of hereditary syndrome.
Familial GIST syndrome: several family members with hereditary mutations in either the KIR or PDGFRA genes have been reported in the study [19, 20, 21, 22, 23, 24, 25, 26, 27, 28]. These families have a higher risk to develop multiple gastric and small bowel GISTs. Some patients may have skin hyperpigmentation, dysphagia, gastrointestinal autonomic nerve tumors, intestinal fibromatosis, and inflammatory fibroid polyps [19, 20, 21, 22, 23, 24, 25, 26, 27, 28].
Carney-Stratakis syndrome is an autosomal-dominant disease which is characterized by dyad of multifocal GISTs and paragangliomas [29]. Patients do not have KIT or PDGFRA mutations, but do have mutations of succinate dehydrogenase subunits (SDH) A, B, C, or D [30].
Carney’s triad: a very rare non-heritable syndrome characterized by gastric GIST, paraganglioma and pulmonary chondromas. These patients are characterized by mutations succinate dehydrogenase subunit (SDH) C [29] but lack mutations of KIT and PDGFRA.
Neurofibromatosis type 1: patients with NF1 are more predisposed for multifocal GISTs that mainly affect the small intestine [31].
GISTs are characterized by mutations in KIT and PDGFRA genes that encode tyrosine kinase receptor type III [32].
3.1. KIT-mutant GIST
Though 95% of GISTs are positive for KIT, only 60–85% have mutations in KIT. The most common mutations encountered are mutations of exon 11 (juxtamembrane domain) [4] which is found in about two-thirds of GISTs. Exon 9 (extracellular domain) is less common (9–20%) and is principally correlated with GIST of the small bowel and has a greater malignant potential [4, 33].
3.2. PDGFRA-mutant GIST
About 5–10% of GISTs have PDGFRA mutations which have a tendency for localized gastric GIST and epithelioid type [4]. The most common type of mutation is the PDGFRA exon 18 mutation D842V, which is associated with imatinib resistance and has a lower risk of recurrence than GIST with KIT mutations as well as a more benign course 9 [34].
3.3. Wild-type GIST
Approximately 12–15% of adult GIST and 90% of pediatric GIST do not have KIT and PDGFRA mutations [33]. Wild-type (WT) GISTs comprise GISTs that arise in NF1, Carney-Stratakis syndrome, and Carney triad [4]. WT GISTs may have other forms of mutations. BRAF V600E substitution has been described in 7–13% of WT GISTs [35, 36]. About 30% of WT GISTs are SDH deficient and occur solely in the stomach. They mainly affect children and young adults and have a variation in their nature from being indolent to progressive [4].
The three main histopathologic subtypes of GIST are spindle cell, epithelioid, and mixed types, with spindle cell type being the most common constituting about 70% of GISTs, while the other two subtypes, epithelioid and mixed, are less common, accounting for 20 and 10% of all GISTS, respectively [6]. Epithelioid GIST is commonly observed in the stomach and omentum [6]. About 95% of GIST will be immunohistochemical positive for CD117(c-KIT) [4]. Epithelioid type has a weaker KIT positivity than spindle cell type [37]. In addition, 70–90% are positive for CD34, 20–30% for actin, 8–10% for S-100, and 2–4% for desmin [38]. DOG1 marker, also known as ANO1, has more than 95% sensitivity for GIST and is expressed in more than 35% of GISTs negative for c-kit [39, 40].
About 60% of GISTs occur in the stomach, 30% in the jejunum and ileum, 5% in the duodenum, 2–3% in the rectum, 1–2% in the colon, and < 1% in the esophagus [4]. About 70% of GISTs are symptomatic, 20% are asymptomatic, and 10% are discovered at autopsy [41]. The main symptoms of GIST are GI bleeding, abdominal discomfort, and abdominal mass. GISTs are highly vascular tumors and may grow quickly and cause massive gastrointestinal or intraperitoneal hemorrhage [42]. Obstruction symptoms such as dysphagia, obstructive jaundice, and small bowel obstruction may also occur [42].
Extragastrointestinal GISTs occur in less than 10% of GISTs and mainly occur intra-abdominally and affect omentum and mesentery. Such tumors are considered more aggressive than gastric GIST and have a poorer prognosis similar to small bowel GISTs [43, 44].
About 50% of patients will present with metastatic disease with the most common site of metastasis being liver at about 65%. Other common metastatic sites are omentum and peritoneum. Extra-abdominal metastasis, lung bone, and lymph node metastasis are not common [13].
Various risk stratification models (Table 1) have been proposed that are based on site, size, mitotic index, and tumor rupture. Gastric GISTs are known to have better prognosis than non-gastric GIST [46].
Very low risk Low risk Intermediate risk High risk
Does not differentiate between malignant and benign tumors knowing the fact that even small-size tumors with a low mitotic count may metastasize Does not take GIST site into consideration
Very low risk Low risk Intermediate risk High risk
This classification considered a total area of 5 mm2 in 50 fields HPF characterized by the use of different optical components, while in practice, 50 HPF typically corresponds to a total area of 10 mm2 This classification is recommended by GEIS guidelines
Table 1.
Different stratification systems for GISTs.
Tumor rupture is known to be associated with a very high risk of GIST recurrence [47]. TNM staging is also available for GIST staging [48]. However, these stratification systems are not commonly used in clinical practice.
As an alternative to the risk classification systems that stratify patients into distinct groups, others have quantified the risk of disease recurrence after complete resection as a continuous variable through the use of a GIST nomogram that includes the disease site [49]. Different nomograms have been developed by others as well.
GIST nomograms [49, 50] have been used to assess the risk of disease recurrence after complete resection as a continuous variable instead of the risk stratification systems that stratify patients into separate groups. Recently, a new risk stratification system has been developed in which tumor size and mitotic counts were assessed as continuous, nonlinear variables, and prognostic contour maps were then generated based upon these data plus site and tumor rupture [51]. These prognostic contour maps resulting from nonlinear modeling are used for the assessment of individualized outcomes.
Deletion type of mutations affecting codons 557 and 558 in KIT gene is considered a risk factor for recurrence regardless of different classification systems [4].
Pfetin is a prognostic biomarker which is still under investigation with promising results. Lack of Pfetin expression seems to be associated with a higher GIST recurrence [52]. Orita et al. [52] had 45 GIST cases, of which 37 were in the stomach. All GIST patients had R0 resection. There were seven recurrences with five recurrences being gastric GIST recurrences. Thirteen GIST patients were Pfetin negative and 5/13 Pfetin negative GISTs had recurrences [52].
A computed tomography (CT) scan (Figure 1a and b) is considered the first imaging to be done to evaluate anatomic location, extension, and metastasis of GISTs. Oral and IV contrast should be given to delineate bowel margins. GISTs can display endophytic and exophytic growth, and large GISTs may appear heterogeneous due to focal areas of hemorrhage or necrosis [53]. Magnetic resonance imaging (MRI) is used to further evaluate liver metastasis or rectal GIST [54]. Fluorodeoxyglucose-positron emission tomography (FDG-PET) is highly sensitive but not specific for GIST, and it is mainly useful to monitor response to tyrosine kinase inhibitors [55, 56].
Figure 1.
An axial ( A) and coronal (B) CT image showing a well-defined mass lesion ( arrow) in the anterior gastric wall in the proximal stomach measuring 2.9x2.5x2.7.
Upper GI endoscopy may be useful for gastric GIST. Both GISTs and leiomyomas will appear as a submucosal mass with normal overlying mucosa and bulging into gastric lumen. Mucosal ulceration may occur. Endoscopic ultrasound (Figure 2) may not be useful, however, when combined with FNA sensitivity, and accuracy may reach 82 and 86%, respectively [57]. Routine biopsy is not needed routinely for local resectable gastric GISTs proved by imaging studies.
Figure 2.
Gastric EUS showing a well-defined hypoechoic gastric submucosal lesion (between the two arrows) from the fourth layer of the stomach wall suggestive of GIST.
Complete surgical resection is the recommendation of choice for localized GIST with a target of R0 resection with complete surgical removal of the tumor without disturbing the capsule [4]. Though surgery is considered the only curative option for GISTs, a multidisciplinary approach is needed for best medical and surgical management. Segmental resection of the stomach as wedge resection is accepted, and extensive resection is usually not needed. Lymphadenectomy is also not required as GISTs rarely metastasize to lymph nodes [4]. The discovery of KIT(CD117) (receptor tyrosine kinase) in GISTs has revolutionized GISTs management. Imatinib mesylate is a selective tyrosine kinase inhibitor that selectively inhibits KIT and had a significant impact on the prognosis of GISTs as will be discussed subsequently.
8.1. Management of primary resectable disease
8.1.1. Preoperative therapy for primary GISTs
There is still no consensus on the role of neoadjuvant imatinib therapy in resectable GISTs [4]. However, imatinib therapy might be considered for advanced or borderline resectable tumors. Multiple prospective and randomized trials have shown that neoadjuvant imatinib therapy (with a dose of 400 mg/day) in cases of advanced GIST will cause a reduction in tumor size and enable an R0 resection with an increased chance of organ preservation (Table 2). However, if KIT exon 9 mutation is detected and neoadjuvant therapy is planned, the dose may be increased to 800 mg per day as recommended by the European Society for Medical Oncology (ESMO) guidelines.
1. Advanced primary GIST of >5 cm (Group A, 30 p) 2. Recurrent or metastatic tumors of ≥2 cm (group B, 22 p)
Neoadjuvant 600 mg/day for 8–12 weeks of treatment with a median of 65 days then 600 mg/day adjuvant therapy for 2 years
1. Group A 4.9 y 2. Group B 5.5 y
RFS
1. The 2-y estimated overall survival was 93.3 and 90.9% in Group A and Group B, respectively, with a median follow-up of 3 y 2. The 5-y PFS and OS were 57% in group A, 30% in group B, and 77% in group A, 68% in group B, respectively
Primary GIST Metastatic GIST of ≥1 cm 3. 19 patients involved
Neoadjuvant 600 mg/day given at 3, 5, or 7 days; then adjuvant 600 mg/day for 2 years
32 m
Tumor cell apoptosis
All patients had a radiographic response with 1 week of imatinib therapy. In addition, the rate of tumor cell apoptosis had a positive correlation duration of imatinib therapy where the maximum tumor cell apoptosis was seen with 7 days neoadjuvant imatinib therapy
1. Primary GISTs in the stomach with tumor size of ≥10 cm with no metastasis 2. 53 patients enrolled
1. Neoadjuvant 400 mg/day for 6 months 2. Adjuvant 400 mg/day for at least 1 year
32 m
R0 resection rate
1. The R0 resection was achieved in 91% of patients (48/53) and at least half of the stomach was spared in 42/48 patients who had R0 resection. 2. After R0 resection, all patients received imatinib 400 mg/day for at least 1 year. The 2-year OS and PFS were 98 and 89%, respectively
Table 2.
Summary of studies assessing the role of neoadjuvant imatinib in treatment of GIST.
RFS, recurrence-free survival; OS, overall survival; y, years; m, months.
8.1.2. Surgery for primary GISTs
Surgical resection with negative margins is the recommended treatment for localized primary GISTs and is the only curative treatment for GIST [58, 59]. A published study that contained 200 GIST patients [13] with 46.5% of the cases being primary local GISTs and 39% of the cases gastric GIST, which was the most common type, reported that complete resection was achieved in 80 patients (86%) with primary disease, and those patients had a 54% of a 5-year survival rate with a median survival of 66 months, while patients with incompletely resected or unresectable disease had a median survival of 22 months. Complete resection of even a locally advanced disease is associated with improved survival [60].
Surgical resection is recommended for GISTs with a size of 2 cm or more [61]. However, there is still no consensus on the management of GIST less than 2 cm [62, 63]. Multiple studies have reported the occurrence of microscopic gastric GIST [64, 65, 66, 67]. Agaimy et al. [68] discovered microscopic GISTs in 22.5% of consecutive autopsies for adults of >50 years old with all lesions detected in cardia, fundus, and proximal body. Kawanowa et al. [67] reported 35% of microscopic GISTs in patients who had gastric resection for stomach cancer. Ninety percent of these microscopic GISTs were in the upper body.
GISTs have been reported as an incidental finding discovered by routine OGDs and in gastric specimens post sleeve gastrectomy [69, 70] and have caused a dilemma about whether routine preoperative gastroscopy should be done before each bariatric procedure to avoid missing such incidental tumors [70]. Sepe et al. [71] had developed an algorithmic approach for gastric GIST which was adopted by The National Comprehensive Cancer Network (NCCN). They proposed that GISTs with no high-risk EUS features (irregular border, cystic spaces, ulceration, echogenic foci, and heterogeneity) can be followed up by EUS. NCCN adopted this approach and suggested that EUS surveillance every 6–12 months may be done for GISTs of <2 cm with no high-risk features [72].
Endoscopic resection of gastric small submucosal tumors is a promising technique with a favorable outcome. Andalib et al. [73] described endoscopic resection of 12 cases with gastric GISTs arising from muscularis propria with an average size of 2.4 cm and no complications of bleeding or perforation. However, 50% of cases had positive microscopic margins but there is no evidence that a positive microscopic margin after macroscopic resection requires re-excision [74], and with an average follow-up of 12 months, none of the patients had recurrence. Zhou et al. [75] described endoscopic resection of 26 cases of gastric submucosal tumors, out of which 16 were gastric GISTs. The mean tumor size was 2.8 cm and all of the tumors were resected completely without interruption of capsule. None of the patients had severe complications as bleeding perforation or abdominal abscess [75]. No recurrence was found with a mean follow-up of 8 months. Nevertheless, tumor spillage and perforation after endoscopic resection had been described [76], and the technique needs to be validated by prospective multicenter trials and cannot be routinely recommended.
As mentioned before, surgery is the main and only curative option for primary localized resectable GISTs [77]. The primary technical goal of surgery is complete macroscopic resection with an intact pseudocapsule and a negative microscopic margin (R0 resection) [77]. Routine lymphadenectomy is not needed as adult GISTs rarely metastasize to lymph nodes [78]. Pediatric GISTs, however, have a higher incidence of lymph node metastasis [78] and lymphadenectomy may be needed for this population [79, 80].
Wedge resection with negative margins is the usual treatment for gastric GISTs [81] unless the tumor is found invading the surrounding tissues where en bloc resection of involved surrounding organs may be appropriate [81]. Patients with low-grade tumors may have a 5-year survival up to 80%. It is still important to avoid tumor rupture and spillage, as this is associated with an increased risk of recurrence and low survival rates [47, 60]. The role of laparoscopy in gastric GISTs is developing with promising outcomes. Two meta-analysis studies have concluded that, when compared to open, laparoscopy seems to result in shorter hospital stays with no difference in operative time, adverse events, estimated blood loss, margin positivity, or overall survival (OS) and recurrence rates [82, 83]. Current NCCN guidelines [84] recommend that a laparoscopic wedge resection for gastric GISTs of 5 cm or less is appropriate and tumor resection may be done using a laparoscopic or a laparoscopic-assisted technique with hand port for GISTs more than 5 cm.
8.1.3. Adjuvant therapy for primary GISTs
Unlike neoadjuvant imatinib therapy, the role of adjuvant imatinib therapy is better established. Recurrence rates of 50% have been reported in localized GISTs that have been completely resected [4]. Multiple randomized trials have proven the efficacy of adjuvant imatinib.
The first randomized phase II trial done on the role of adjuvant imatinib was The American College of Surgeons Oncology Group (ACOSOG) trial Z9000 [85] which assessed the role of adjuvant imatinib dose of 400 mg/day for 1 year for patients with a high-risk GIST. High risk was defined in this study as a tumor diameter of >10 cm, intraperitoneal tumor rupture, or up to four peritoneal implants. The study involved 106 patients with GISTs, 50% of the cases were gastric GISTs. After a median follow-up of 7.7 years, the 1-, 3-, and 5-year overall survivals (OS) were 99, 97, and 83%, respectively, which is much better than historical controls (35%) [85]. The 1-, 3-, and 5-year RFS rates were 96, 60, and 40%, respectively. Recurrence free survival (RFS) was lower with a larger tumor size, KIT exon 9 mutation, a high mitotic rate, and older age. They concluded that adjuvant imatinib for 1 year prolongs RFS and OS, but the optimal duration of adjuvant imatinib was still to be decided.
Three phase III trials have assessed the efficacy of adjuvant imatinib, ACOSOG Z9001 [86], SSG XVIII trials [87], and EORTC 62024 [88]. Only ACOSOG Z9001and EORTC 62024 had no treatment control arm. The American College of Surgeons Oncology Group (ACOSOG) trial Z9001 [86] is the first randomized phase III, double-blinded, placebo-controlled, multicenter trial done regarding the role of adjuvant imatinib therapy. A total of 359 patients were randomized to receive imatinib 400 mg/day for 1 year, and 354 patients were randomized to receive placebo for 1 year following surgical resection of the tumor. The trial reported that imatinib therapy significantly prolonged RFS when compared to placebo (98 versus 83%) in all risk categories (based upon size, mitotic rate, and location in the GI tract) [86]. Overall survival was similar at 1 year with 99.2 versus 99.7%, and imatinib therapy was tolerated with low side effects. The trial planned a minimum follow-up of 3 years for the patients but it was stopped early with a shorter median follow-up of 19.7 months. The lack of difference in overall survival in this trial may be explained by a short duration follow-up, a limited number of relapses, and a high degree of efficacy of imatinib in relapsed disease [89]. As a result of this study, The U.S. Food and Drug Administration approved adjuvant imatinib in the adjuvant setting by the U.S. Food and Drug Administration for GISTs of ≥3 cm, without guidance as to the optimal duration of treatment or which patients are most likely to benefit. The long-term results of this study were published with a median follow-up of 74 months with no difference in the 5-year RFS and OS.
Another phase III prospective, randomized, open-label trial was done by The Scandinavian Sarcoma Group (SSG) XVIII [87]. This trial compared 36 versus 12 months therapy of adjuvant imatinib (400 mg daily) in 400 patients with a high-risk-resected GIST with a median follow-up of 54 months. A high-risk GIST was defined as a tumor size of >10 cm, a mitotic count of >10/50 high-power fields (HPF), a tumor size of >5 cm with a mitotic rate of >5/HPF, or a tumor rupture. About 50% of the patients had gastric GIST in this study. The study reported prolonged 5-year RFS and OS rates for patients assigned for 36 months imatinib adjuvant therapy compared with patients assigned for the 12-month group, 65.6 versus 47.9% and 92% versus 81.7%, respectively. The results of this trial resulted in NCCN guidelines recommending adjuvant imatinib for at least 3 years for patients with intermediate or high risk of GIST recurrence [90]. In a latter follow-up report for the Scandinavian trial with a median follow-up of 90 months, patients assigned to a 3-year group had a persistent favorable outcome with significantly greater RFS (71 versus 52% and overall survival (92 versus 85%) [91].
The EORTC 62024 trial [88] is a phase III open-label randomized trial which assessed the efficacy of adjuvant imatinib for 2 years in localized surgically resected high- or intermediate-risk GISTs [88]. After surgical resection, 908 patients were randomized to either receive 2 years of imatinib 400 mg/day or observation alone. After a median follow-up of 4.7 years, RFS at 3 years was 84% in imatinib group versus 66% in control group and 69 versus 63% at 5 years (P < 0.001). No difference was detected in a 5-year OS. The 5-year imatinib failure-free survival (IFFS, the time to death or starting a TKI other than imatinib) was 87% in imatinib group and 84% in control group (P = 0.23). Among patients with a high-risk GIST (528 patients), there was a trend favoring adjuvant imatinib (P = 0.087).
As a result of the findings of the previous trials, both NCCN and ESMO guidelines as well as consensus of the scientific community recommend 3 years of adjuvant treatment with imatinib in high-risk patients [4]. By contrast, adjuvant therapy is not needed in low-risk patients, and there are no sufficient data to support adjuvant imatinib therapy in intermediate-risk patients [4]. Whether doses higher than 400 mg/day should be used is still questionable. Moreover, whether the imatinib dose should be continued more than 3 years is not known. A single-arm phase II 5-year adjuvant imatinib trial, PERSIST5, has completed its accrual, and still survival data reports are pending. Whether patients who had R1 resection for their GISTs should receive adjuvant imatinib is also not clear as there are no data to support adjuvant imatinib therapy in such cases. Re-excision may be appropriate in these situations.
8.2. Management of metastatic and recurrent GIST
GISTs mostly recur in the first 5 years after surgical resection, while less recurrence is observed after 10 years [92]. A study, with pooled analysis from 10 series and included 1625 patients, reported that 5-year, 10-year, and 15-year RFS were 70.5, 62.9, and 59.9%, respectively [92]. It was observed that the larger the size of the tumor, the higher the risk of recurrence. Compared with tumors of <1.1 cm in size, tumors with sizes of 1.1–2, 2.1–5, 5.1–10.0, 10.1–15.0, and > 15 cm were associated with a hazard ratio (HR) of 2.19, 4.45, 21.56, and 27.98, respectively. There was also a positive correlation between tumor mitosis rates and risk of recurrence. Compared with tumors with a very low mitosis count (<2/50 HPF), tumors with a low count (2–5/50 HPF), a moderate count (6–10/50 HPF), and a high count (>10/50 HPF) were associated with HR of 3.78, 11.1, and 22.09, respectively. Gastric GISTs had better RFS than other types of GISTs. Tumor rupture was associated with a worse prognosis. About two-third and half of patients with recurrence had liver metastasis and peritoneal disease, respectively [93].
Patients with advanced (primary unresectable or metastatic GIST) are treated initially with imatinib rather than surgery.
A phase III randomized trail (EU-AUS trial) [94] included 946 patients randomized to either receive imatinib once or twice daily. At a median follow-up of 760 days, the trial reported that 56% of 473 patients receiving imatinib 400 mg/day had progressed while 50% (235) of 473 patients assigned to imatinib 400 twice/day had progressed. OS was 69 and 74%, respectively. There was no significant difference in response rates between the two groups. The study concluded that, although a daily dose of 400 mg of imatinib is enough, a dose of 400 mg twice daily significantly prolongs PFS.
In a phase II open-label multicentric randomized trial, B2222 study, which included 147 patients with advanced GIST, 73 patients received imatinib 400 mg/day and 74 patients received imatinib 600 mg/day. The study reported equal response rates, median progression-free survival, and median overall survival among both groups with a median survival of 57 months for all patients. No advantage was seen with using a higher dose of imatinib (600 mg/day) in this study. This study was followed by another phase III open-label multicentric randomized trial, S0033 study [95], which compared imatinib dose 400 mg/day to imatinib dose 400/mg twice daily. The study included 746 patients with advanced GIST with a median follow-up of 4.5 years. Similar findings were found with no statistically significant difference in response rates, PFS, or OS between either doses of imatinib. However, after progression on imatinib dose of 400 mg/day, 33% of the patients who were crossed over to receive a higher imatinib dose 400 mg twice daily achieved either an objective response or a stable disease [95].
Further analysis of data from EU-AUS and S0033 trials reported that tumor genotype has a significant prognostic impact on PFS and OS, with tumors with mutation of KIT exon 9 having a worse prognosis when compared to tumors with mutation of KIT exon 11 [96, 97].
A subsequent meta-analysis combining S0033 and EU-AUS trials [98] reported a minor albeit significant PFS advantage for a higher imatinib dose of 400 mg twice daily for patients with advanced GIST. The PFS benefit was only evident in patients with KIT exon 9 mutations treated with a high-dose imatinib without difference in OS between the two groups, while patients with KIT exon 11 had a more favorable prognosis. Thus, genotype is required for the treatment of advanced or metastatic GISTs.
The findings of the results of the previous studies [94, 95, 98] designated imatinib dosage of 400 mg/day to be the standard treatment for patients with advanced GISTs, and patients with advanced GISTs with KIT exon 9 mutations to be started on the higher imatinib dose (400 mg twice daily), keeping in mind that the toxicity of imatinib is dose-dependent [99]. Imatinib treatment should be life long as interruption of treatment has a higher rate of disease progression as proven by the phase III randomized trial [100, 101, 102]. Indications of surgery in advanced GISTs are still debatable. Multiple retrospective studies have shown that debulking surgery may be beneficial in patients with a stable disease without generalized progression as surgery may improve the prognosis. However, patients should be treated with imatinib first before attempting surgery [103, 104, 105, 106, 107, 108].
8.3. Alternatives of imatinib in case of resistance or progression of disease with imatinib therapy
Most patients with advanced GISTs will show improvement with imatinib therapy, although a subgroup of patients will fail to show a response. Resistance to imatinib may be primary or secondary. Primary resistance is defined as continuous growth or growth within 6 months of therapy, and occurs in 15–20% of patients with advanced GIST [109] and occurs frequently in patients with wild-type (WT) GIST or KIT exon 9 mutations or D842V mutation in PDGFRA exon 18 [110]. Unfortunately, most patients develop secondary resistance, which is defined as patients who received treatment with imatinib for longer than 6 months and had an initial response and then developed progressive disease. Secondary KIT mutations occur frequently in KIT exons 13, 14, and 17 and a D842V mutation in PDGFRA exon 18 [111, 112, 113].
If a patient develops resistance, escalating imatinib dosage to 800 mg daily or shifting to a second-line therapy like sunitinib may be recommended.
Sunitinib is considered a second-line therapy for patients with advanced GIST refractory to imatinib therapy. Outcomes of a randomized phase III trial versus placebo reported a prolongation of the time to progression from 1.5 to 6.3 months in patients with GIST who progressed on imatinib treatment [114]. It is approved by the EMA and the FDA for the treatment of patients with GIST resistant to imatinib therapy and for patients who are not tolerant to imatinib therapy.
In case of progression on imatinib and sunitinib, regorafenib is considered a third-line therapy [4]. It was recently approved by EMA and FDA for the treatment of patients with unresectable or metastatic GISTs who are resistant or intolerant to imatinib and sunitinib, and it was tested in a phase III randomized trial which included patients with advanced GIST who progressed after imatinib and sunitinib failed. The study reported that regorafenib, when compared to placebo, has significant improvement in PFS [115]. Inadequate data are available for the efficacy of other tyrosine kinase inhibitors (e.g., sorafenib, pazopanib, and ponatinib) for imatinib and sunitinib refractory GISTs [4].
There are no studies assessing the efficacy of different follow-up modules. Nevertheless, follow-up strategies were created based on the fact that most recurrences occur within the first 5 years after surgery.
A follow-up schedule frequency is based on the risk of aggressiveness and recurrence of GISTs [4]. CT is favored over other imagings, such as MRI and FDG-PET scan, because it is more readily obtainable, although other modalities can be used in case CT is inconclusive.
9.1. Follow-up for localized resectable GISTs
Very low-risk patients with surgically removed tumor do not require a follow-up. Low-risk patients require an annual CT. Intermediate- and high-risk patients require CT every 4 months for the first 1–2 years, every 6 months for 3–5 years, and then CT every year thereafter [4].
9.2. Follow-up for unresectable/metastatic GISTs
Follow-up should be done at the start of every 3 months and can be delayed to every 6 months if there is response to the treatment.
Surgery is the only curative option for GISTs. The discovery of KIT protein had allowed the development of tyrosine kinase inhibitors which considerably affected the diagnosis and management of GISTs. A multidisciplinary approach is required for optimal management. Neoadjuvant imatinib therapy has produced favorable results so far; however, more studies are needed to define the optimal dose and duration of imatinib therapy. Adjuvant imatinib therapy for 3 years improves outcome in patients with high risk. Mutational analysis has an important role in the management of GISTs. New therapeutic agents have been developed for patients with imatinib resistance.
Conflict of interest
The author declares that there is no conflict of interest.
References
1.Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): Early results of RTOG 0132/ACRIN 6665. Journal of Surgical Oncology. 2009;99(1):42-47. [PubMed: 18942073]
2.McAuliffe JC, Hunt KK, Lazar AJ, et al. A randomized, phase II study of preoperative plus postoperative imatinib in GIST: Evidence of rapid radiographic response and temporal induction of tumor cell apoptosis. Annals of Surgical Oncology. 2009;16(4):910-919 [PubMed: 18953611]
3.Miettinen M, Killian JK, Wang ZF, et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. The American Journal of Surgical Pathology. 2013;37(2):234-240 [PubMed:23282968]
4.Poveda A, García Del Muro X, López-Guerrero JA, Cubedo R, Martínez V, Romero I, Serrano C, Valverde C, Martín-Broto J. GEIS (Grupo Español de Investigación en Sarcomas/Spanish Group for Sarcoma Research). GEIS guidelines for gastrointestinal sarcomas (GIST). Cancer Treatment Reviews. 2017 Apr;55:107-119. DOI: 10.1016/j.ctrv.2016.11.011. Epub 2017 Mar 2. Review. PubMed PMID: 28351781
5.Ducimetiere F, Lurkin A, Ranchere-Vince D, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294
6.Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Human Pathology. 2002;33(5):459, 465. [PubMed: 12094370]
7.Perez EA, Livingstone AS, Franceschi D, et al. Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors. Journal of the American College of Surgeons. 2006;202(4):623-629. [PubMed: 16571433]
8.Miettinen M, Virolainen M, Maarit SR. Gastrointestinal stromal tumors—value of CD34 antigen in their identification and separation from true leiomyomas and schwannomas. The American Journal of Surgical Pathology. 1995;19(2):207-216. [PubMed: 7530409]
9.Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-580. [PubMed: 9438854]
10.Ma GL, Murphy JD, Martinez ME, Sicklick JK. Epidemiology of gastrointestinal stromal tumors in the era of histology codes: Results of a population-based study. Cancer Epidemiology, Biomarkers and Prevention. 2015;24:298
11.Ducimetiere F, Lurkin A, Ranchere-Vince D, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294
12.Tran T, Davila JA, El-Serag HB. The epidemiology of malignant gastrointestinal stromal tumors: An analysis of 1,458 cases from 1992 to 2000. The American Journal of Gastroenterology. 2005;100(1):162-168. [PubMed: 15654796]
13.DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Annals of Surgery. 2000;231(1):51-58
14.Cassier PA, Ducimetière F, Lurkin A, et al. A prospective epidemiological study of new incident GISTs during two consecutive years in Rhône Alpes region: Incidence and molecular distribution of GIST in a European region. British Journal of Cancer. 2010;103:165
15.Miettinen M, Lasota J, Sobin LH. Gastrointestinal stromal tumors of the stomach in children and young adults: A clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. The American Journal of Surgical Pathology. 2005;29(10):1373-1381. [PubMed: 16160481]
16.Prakash S, Sarran L, Socci N, et al. Gastrointestinal stromal tumors in children and young adults: A clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. Journal of Pediatric Hematology/Oncology. 2005;27(4):179-187. [PubMed: 15838387]
17.Kaemmer DA, Otto J, Lassay L, et al. The GIST of literature on pediatric GIST: Review of clinical presentation. Journal of Pediatric Hematology/Oncology. 2009;31(2):108-112
18.Agaram NP, Laquaglia MP, Ustun B, et al. Molecular characterization of pediatric gastrointestinal stromal tumors. Clinical Cancer Research. 2008;14(10):3204-3215
19.Maeyama H, Hidaka E, Ota H, et al. Familial gastrointestinal stromal tumor with hyperpigmentation: Association with a germline mutation of the c-kit gene. Gastroenterology. 2001;120:210
20.Nishida T, Hirota S, Taniguchi M, et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nature Genetics. 1998;19:323
21.Tarn C, Merkel E, Canutescu AA, Shen W, Skorobogatko Y, Heslin MJ, Eisenberg B, Birbe R, Patchefsky A, Dunbrack R, Arnoletti JP, von Mehren M, Godwin AK. Analysis of KIT mutations in sporadic and familial gastrointestinal stromal tumors: therapeutic implications through protein modeling. Clinical Cancer Research. 2005 May 15;11(10):3668-3677
22.Hirota S, Okazaki T, Kitamura Y, et al. Cause of familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germline mutation of the c-kit gene. The American Journal of Surgical Pathology. 2000;24:326
23.Beghini A, Tibiletti MG, Roversi G, et al. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer. 2001;92:657
24.Hirota S, Nishida T, Isozaki K, et al. Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene. Gastroenterology. 2002;122:1493
25.Chompret A, Kannengiesser C, Barrois M, et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology. 2004;126:318
26.de Raedt T, Cools J, Debiec-Rychter M, et al. Intestinal neurofibromatosis is a subtypeof familial GIST and results from a dominant activating mutation in PDGFRA. Gastroenterology. 2006;131:1907
27.Pasini B, Matyakhina L, Bei T, et al. Multiple gastrointestinal stromal and other tumors caused by platelet-derived growth factor receptor alpha gene mutations: A case associated with a germline V561D defect. The Journal of Clinical Endocrinology and Metabolism. 2007;92:3728
28.Ricci R, Martini M, Cenci T, et al. PDGFRA-mutant syndrome. Modern Pathology. 2015;28:954
29.Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney–Stratakis syndrome): Molecular genetics and clinical implications. Journal of Internal Medicine. 2009;266(1):43-52. [PubMed: 19522824]
30.Miettinen M, Killian JK, Wang ZF, et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. The American Journal of Surgical Pathology. 2013;37(2):234-240. [PubMed: 23282968]
31.Andersson J, Sihto H, Meis-Kindblom JM, et al. NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics. The American Journal of Surgical Pathology. 2005;29(9):1170-1176. [PubMed: 16096406]
33.Martin-Broto J, Rubio L, Alemany R, Lopez-Guerrero JA. Clinical implications of KIT and PDGFRA genotyping in GIST. Clinical and Translational Oncology: Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2010;12:670-676. [PubMed PMID: 20947481]
34.Lasota J, Dansonka-Mieszkowska A, Sobin LH, et al. A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential. Laboratory Investigation. 2004;84(7):874-883. [PubMed: 15146165]
35.Hostein I, Faur N, Primois C, et al. BRAF mutation status in gastrointestinal stromal tumors. American Journal of Clinical Pathology. 2010;133(1):141-148. [PubMed: 20023270]
36.Agaram NP, Wong GC, Guo T, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes, Chromosomes and Cancer. 2008;47(10):853-859. [PubMed: 18615679]
37.Bamboat ZM, Dematteo RP. Updates on the management of gastrointestinal stromal tumors. Surgical Oncology Clinics of North America. 2012;21(2):301-316. [PubMed: 22365521]
38.Miettinen M, Lasota J. Gastrointestinal stromal tumors–definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Archiv-An International Journal of Pathology. 2001;438:1-12. [PubMed PMID: 11213830]
39.Novelli M, Rossi S, Rodriguez-Justo M, et al. DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours. Histopathology. 2010;57(2):259-270. [PubMed: 20716168]
40.Liegl B, Hornick JL, Corless CL, Fletcher CD. Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. The American Journal of Surgical Pathology. 2009 Mar;33(3):437-446. DOI: 10.1097/PAS.0b013e318186b158. [PubMed PMID: 19011564]
41.Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era–a population-based study in western Sweden. Cancer. 2005;103(4):821-829. [PubMed: 15648083]
42.Chaudhry UI, DeMatteo RP. Management of resectable gastrointestinal stromal tumor. Hematology/Oncology Clinics of North America. 2009;23(1):79-96. [PubMed: 19248972]
43.Reith JD, Goldblum JR, Lyles RH, et al. Extragastrointestinal (soft tissue) stromal tumors: An analysis of 48 cases with emphasis on histologic predictors of outcome. Modern Pathology. 2000;13(5):577-585. [PubMed: 10824931]
44.DeMatteo RP, Maki RG, Agulnik M, et al. Gastrointestinal Stromal Tumor. In: Amin MB, editor, AJCC Cancer Staging Manual, 8th, AJCC, Chicago 2017. p. 523. no abstract available
45.Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Human Pathology. 2008;39(10):1411-1419. [PubMed: 18774375]
46.Miettinen M, Lasota J. Gastrointestinal stromal tumors: Review on morphology, molecular pathology, prognosis, and differential diagnosis. Archives of Pathology and Laboratory Medicine. 2006;130(10):1466-1478. [PubMed PMID: 17090188]
47.Takahashi T, Nakajima K, Nishitani A, Souma Y, Hirota S, Sawa Y, Nishida T. An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors. International Journal of Clinical Oncology. 2007;12:369-374
48.DeMatteo RP, Maki RG, Agulnik M, et al. Gastrointestinal Stromal Tumor. In: Amin MB, editor. AJCC Cancer Staging Manual, 8th, AJCC, Chicago 2017. p. 523
49.Gold JS, Gönen M, Gutiérrez 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. The Lancet Oncology. 2009;10:1045
50.Bischof DA, Kim Y, Behman R, et al. A nomogram to predict disease-free survival after surgical resection of GIST. Journal of Gastrointestinal Surgery. 2014;18:2123
51.Joensuu H, Vehtari A, Riihimäki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: An analysis of pooled population-based cohorts. The Lancet Oncology. 2012;13:265
52.Orita H, Ito T, Kushida T, et al. Pfetin as a risk factor of recurrence in gastrointestinal stromal tumors. BioMed Research International. 2014;2014:651935. DOI: 10.1155/2014/651935
53.Kim HC, Lee JM, Choi SH, et al. Imaging of gastrointestinal stromal tumors. Journal of Computer Assisted Tomography. 2004;28(5):596-604. [PubMed: 15480031]
54.Jiang ZX, Zhang SJ, Peng WJ, et al. Rectal gastrointestinal stromal tumors: Imaging features with clinical and pathological correlation. World Journal of Gastroenterology. 2013;19(20):3108-3116. [PubMed: 23716991]
55.Gold JS, Dematteo RP. Combined surgical and molecular therapy: The gastrointestinal stromal tumor model. Annals of Surgery. 2006;244(2):176-184. [PubMed: 16858179]
56.Van den Abbeele AD. The lessons of GIST–PET and PET/CT: A new paradigm for imaging. The Oncologist. 2008;13(suppl 2):8-13
57.Watson RR, Binmoeller KF, Hamerski CM, et al. Yield and performance characteristics of endoscopic ultrasound-guided fine needle aspiration for diagnosing upper GI tract stromal tumors. Digestive Diseases and Sciences. 2011;56(6):1757-1762. [PubMed: 21360279]
58.Wang D, Zhang Q, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: Long-term follow-up results of radiation therapy oncology group 0132. Annals of Surgical Oncology. 2012;19(4):1074-1080
59.Kurokawa Y, Yang HK, Cho H, Ryu MH, Masuzawa T, Park SR, Matsumoto S, Lee HJ, Honda H, Kwon OK, Ishikawa T, Lee KH, Nabeshima K, Kong SH, Shimokawa T, Yook JH, Doki Y, Im SA, Hirota S, Hahn S, Nishida T, Kang YK. Phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumours of the stomach. British Journal of Cancer. 2017 Jun 27;117(1):25-32. DOI: 10.1038/bjc.2017.144 Epub 2017 May 23. PubMed PMID: 28535156; PubMed Central PMCID: PMC5520207
60.Ng EH, Pollock RE, Munsell MF, et al. Prognostic factors influencing survival in gastrointestinal leiomyosarcomas. Implications for surgical management and staging. Annals of Surgery. 1992;215(1):68-77. [PubMed: 1731651]
61.NCCN 2010 guidelines. NCCN Task Force report: Management of patients with gastrointestinal stromal tumor (GisT)—update of the NCCN clinical practice guidelines. Journal of the National Comprehensive Cancer Network. 2007;5(suppl. 2):1-29
62.Casali PG, Jost L, Reichardt P, et al. Gastrointestinal stromal tumours: ESMO clinical recommendations for diagnosis, treatment and follow-up. Annals of Oncology. 2009;20(Suppl 4):64
63.Blackstein ME, Blay JY, Corless C, et al. Gastrointestinal stromal tumours: Consensus statement on diagnosis and treatment. Canadian Journal of Gastroenterology. 2006;20:157
64.Abraham SC, Krasinskas AM, Hofstetter WL, Swisher SG, Wu TT. Seedling mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric junction. The American Journal of Surgical Pathology. 2007;31:1629-1635
65.Agaimy A et al. Microscopic gastrointestinal stromal tumors in esophageal and intestinal surgical resection specimens: A clinicopathologic, immunohistochemical, and molecular study of 19 lesions. The American Journal of Surgical Pathology. 2008;32:867-873
66.Agaimy A et al. Minute gastric sclerosing stromal tumors (GisT tumorlets) are common in adults and frequently show c-KiT mutations. The American Journal of Surgical Pathology. 2007;31:113-120
67.Kawanowa K et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Human Pathology. 2006;37:1527-1535
68.Agaimy A, Wunsch PH, Dirnhofer S, et al. Microscopic gastrointestinal stromal tumors in esophageal and intestinal surgical resection specimens: A clinicopathologic, immunohistochemical, and molecular study of 19 lesions. The American Journal of Surgical Pathology. 2008;32(6):867-873. [PubMed: 18408593]
69.Saafan T, Bashah M, El Ansari W, Karam M. Erratum to: Histopathological changes in laparoscopic sleeve Gastrectomy specimens: Prevalence, risk factors, and value of routine Histopathologic examination. Obesity Surgery. 2017 Oct;27(10):2778. DOI: 10.1007/s11695-017-2819-y. [PubMed PMID: 28752381]
70.Salama A, Saafan T, El Ansari W, Karam M, Bashah M. Erratum to: Is routine preoperative esophagogastroduodenoscopy screening necessary prior to laparoscopic sleeve Gastrectomy? Review of 1555 cases and comparison with current literature. Obesity Surgery. 2017 Nov;27(11):3068. DOI: 10.1007/s11695-017-2837-9. [PubMed PMID: 28748357]
71.Sepe PS, Brugge WR. A guide for the diagnosis and management of gastrointestinal stromal cell tumors. Nature Reviews. Gastroenterology and Hepatology. 2009 Jun;6(6):363-371. DOI: 10.1038/nrgastro.2009.43 Epub 2009 Apr 14. Review. PubMed PMID: 19365407
72.Demetri GD, von Mehren M, Antonescu CR, et al. Journal of the National Comprehensive Cancer Network. 2010;8(suppl 2):S1, S42-S41, S44 [PubMed: 20457867]
73.Andalib I, Yeoun D, Reddy R, Xie S, Iqbal S. Endoscopic resection of gastric gastrointestinal stromal tumors originating from the muscularis propria layer in North America: Methods and feasibility data. Surgical Endoscopy. 2017 Sep 15. DOI: 10.1007/s00464-017-5862-9. [Epub ahead of print] PubMed PMID: 28916847
74.Demetri GD, Benjamin RS, Blanke CD, Blay JY, et al. NCCN Task Force report: Management of patients with gastrointestinal stromal tumor (GIST)—update of the NCCN clinical practice guidelines. Journal of the National Comprehensive Cancer Network. 2007;5(Suppl 2):S1-S29 quiz S30
75.Zhou PH, Yao LQ, Qin XY, Cai MY, Xu MD, Zhong YS, Chen WF, Zhang YQ, Qin WZ, Hu JW, Liu JZ. Endoscopic full-thickness resection without laparoscopic assistance for gastric submucosal tumors originated from the muscularis propria. Surgical Endoscopy. 2011 Sep;25(9):2926-2931. DOI: 10.1007/s00464-011-1644-y. Epub 2011 Mar 18. PubMed PMID: 21424195
76.Davila RE, Faigel DO. GI stromal tumors. Gastrointestinal Endoscopy. 2003;58:80-88
77.Raut CP, Ashley SW. How I do it: Surgical management of gastrointestinal stromal tumors. Journal of Gastrointestinal Surgery. 2008 Sep;12(9):1592-1599. DOI: 10.1007/s11605-008-0501-3. Epub 2008 Mar 4. Review. PubMed PMID: 18317848
78.Prakash S, Sarran L, Socci N, et al. Gastrointestinal stromal tumors in children and young adults: A clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. Journal of Pediatric Hematology/Oncology. 2005;27:179-187
79.Kaemmer DA, Otto J, Lassay L, et al. The gist of literature on pediatric GIST: Review of clinical presentation. Journal of Pediatric Hematology/Oncology. 2009;31(2):108-112. [PubMed: 19194193]
80.Agaram NP, Laquaglia MP, Ustun B, et al. Molecular characterization of pediatric gastrointestinal stromal tumors. Clinical Cancer Research. 2008;14(10):3204-3215. [PubMed: 18483389]
81.Kitagawa Y, Dempsey DT. Stomach. In: Brunicardi F, Andersen DK, Billiar TR, Dunn DL, Hunter JG, Matthews JB, Pollock RE, editors. Schwartz’s Principles of Surgery, 10eNew. York, NY: McGraw-Hill; 2015. Available from: http://accesssurgery.mhmedical.com/content.aspx?bookid=980§ionid=59610868. Accessed December 06, 2017
82.Pelletier JS, Gill RS, Gazala S, Karmali S. A systematic review and meta-analysis of open vs. laparoscopic resection of gastric gastrointestinal stromal tumors. Journal of Clinical Medicine Research. 2015 May;7(5):289-296. DOI: 10.14740/jocmr1547w Epub 2015 Mar 1. Review. PubMed PMID: 25780475; PubMed Central PMCID: PMC4356087
83.Koh YX, Chok AY, Zheng HL, Tan CS, Chow PK, Wong WK, Goh BK. A systematic review and meta-analysis comparing laparoscopic versus open gastric resections for gastrointestinal stromal tumors of the stomach. Annals of Surgical Oncology. 2013 Oct;20(11):3549-3560. DOI: 10.1245/s10434-013-3051-1 Epub 2013 Jun 21. Review. PubMed PMID: 23793362
84.Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: Update on the management of patients with gastrointestinal stromal tumors. Journal of the National Comprehensive Cancer Network. 2010;8(suppl 2):S1, S42-S41, S44
85.DeMatteo RP, Ballman KV, Antonescu CR, et al. Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance) Intergroup Phase 2 Trial. Annals of Surgery. 2013;258(3):422-429. [PubMed: 23860199]
86.Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: A randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9669):1097-1104. [PubMed: 19303137]
87.Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: A randomized trial. JAMA. 2012;307(12):1265-1272. [PubMed: 22453568]
88.Casali PG, Cesne AL, Velasco AP, et al. Imatinib failure-free survival (IFS) in patients with localized gastrointestinal stromal tumors (GIST) treated with adjuvant imatinib (IM): The EORTC/AGITG/FSG/GEIS/ISG randomized controlled phase III trial. Journal of Clinical Oncology. 2013;31(suppl):abstract 10500
89.Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, Corless CL, Fletcher CD, Roberts PJ, Heinz D, Wehre E, Nikolova Z, Joensuu H. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. Journal of Clinical Oncology. 2008 Feb 1;26(4):620-625. DOI: 10.1200/JCO.2007.13.4403. [PubMed PMID: 18235121]
90.Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: Update on the management of patients with gastrointestinal stromal tumors. Journal of the National Comprehensive Cancer Network. 2010;8(suppl 2):S1, S42-S41, S44. [PubMed: 20457867]
91.Joensuu H, Eriksson M, Sundby Hall K, et al. Adjuvant Imatinib for high-risk GI stromal tumor: Analysis of a randomized trial. Journal of Clinical Oncology. 2016;34:244
92.Joensuu H, Vehtari A, Riihimaki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: An analysis of pooled population-based cohorts. The Lancet Oncology. 2012;13(3):265-274
93.Bamboat ZM, Dematteo RP. Updates on the management of gastrointestinal stromal tumors. Surgical Oncology Clinics of North America. 2012;21(2):301-316. [PubMed: 22365521]
94.Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet. 2004;364(9440):1127-1134. [PubMed: 15451219]
95.Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. Journal of Clinical Oncology. 2008;26(4):626-632. [PubMed: 18235122]
96.Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. Journal of Clinical Oncology. 2008;26(33):5360-5367. [PubMed: 18955451]
97.Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. European Journal of Cancer. 2006;42(8):1093-1103. [PubMed: 16624552]
98.Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: A meta-analysis of 1,640 patients. Journal of Clinical Oncology. 2010;28(7):1247-1253. [PubMed: 20124181]
99.Van Glabbeke M, Verweij J, Casali PG, et al. Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: A study of the European Organisation for Research and Treatment of Cancer, the Italian sarcoma group, and the Australasian gastro-intestinal trials group (EORTC-ISG-AGITG). European Journal of Cancer. 2006;42:2277-2285
100.Blay JY, Le Cesne A, Ray-Coquard I, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. Journal of Clinical Oncology. 2007;25(9):1107-1113. [PubMed: 17369574]
101.Le Cesne A, Ray-Coquard I, Bui BN, et al. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: An open-label multicentre randomised phase 3 trial. The Lancet Oncology. 2010;11(10):942-949 [PubMed: 20864406]
102.Ray-Coquard IL, Bin Bui N, Adenis A, et al. Risk of relapse with imatinib (IM) discontinuation at 5 years in advanced GIST patients: Results of the prospective BFR14 randomized phase III study comparing interruption versus continuation of IM at 5 years of treatment: A French Sarcoma Group Study. Journal of Clinical Oncology. 2010;28(suppl):15s, abstract 10032
103.Bonvalot S, Eldweny H, Pechoux CL, et al. Impact of surgery on advanced gastrointestinal stromal tumors (GIST) in the imatinib era. Annals of Surgical Oncology. 2006;13(12):1596-1603. [PubMed: 16957966]
104.Raut CP, Posner M, Desai J, et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. Journal of Clinical Oncology. 2006;24(15):2325-2331. [PubMed: 16710031]
105.Rutkowski P, Nowecki Z, Nyckowski P, et al. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. Journal of Surgical Oncology. 2006;93(4):304-311. [PubMed:16496358]
106.Andtbacka RH, Ng CS, Scaife CL, et al. Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Annals of Surgical Oncology. 2007;14(1):14-24. [PubMed: 17072676]
107.Gronchi A, Fiore M, Miselli F, et al. Surgery of residual disease following molecular-targeted therapy with imatinib mesylate in advanced/metastatic GIST. Annals of Surgery. 2007;245(3):341-346. [PubMed: 17435538]
108.DeMatteo RP, Maki RG, Singer S, et al. Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor. Annals of Surgery. 2007;245(3):347-352. [PubMed: 17435539]
109.Antonescu CR, DeMatteo RP. CCR 20th anniversary commentary: A genetic mechanism of Imatinib resistance in gastrointestinal stromal tumor-where are we a decade later? Clinical Cancer Research. 2015 Aug 1;21(15):3363-3365. DOI: 10.1158/1078-0432.CCR-14-3120. [PubMed PMID: 26240289; PubMed Central PMCID: PMC4526110]
110.Benjamin RS, Debiec-Rychter M, Le Cesne A, et al. Gastrointestinal stromal tumors II: Medical oncology and tumor response assessment. Seminars in Oncology. 2009;36(4):302-311. [PubMed: 19664491]
111.Debiec-Rychter M, Cools J, Dumez H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 2005;128(2):270-279. [PubMed: 15685537]
112.Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. Journal of Clinical Oncology. 2006;24(29):4764-4774. [PubMed: 16954519]
113.Wardelmann E, Thomas N, Merkelbach-Bruse S, et al. Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations. The Lancet Oncology. 2005;6(4):249-251. [PubMed: 15811621]
114.Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet. 2006;368(9544):1329-1338. [PubMed: 17046465]
115.Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302. [PubMed: 23177515]
116.Wang D, Zhang Q, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: Long-term follow-up results of Radiation Therapy Oncology Group 0132. Annals of Surgical Oncology. 2012;19(4):1074-1080. [PubMed: 22203182]
117.McAuliffe JC, Hunt KK, Lazar AJ, et al. A randomized, phase II study of preoperative plus postoperative imatinib in GIST: Evidence of rapid radiographic response and temporal induction of tumor cell apoptosis. Annals of Surgical Oncology. 2009;16(4):910-919. [PubMed: 18953611]
118.Hohenberger P, Langer CM, Wendtner CM, et al. Neoadjuvant treatment of locally advanced GIST: Results of APOLLON, a prospective, open label phase II study in KIT- or PDGFRA-positive tumors. Journal of Clinical Oncology. 2012;30(suppl):abstract 10031
Written By
Tamer Saafan
Submitted: 04 November 2017Reviewed: 17 April 2018Published: 05 November 2018
Open access peer-reviewed chapter
