Overview of Advancement and Management of Gastrointestinal Stromal Tumors
Mahim Koshariya1*, Bhoomika Agarwal1, Rahul Rathod1
1Department of Surgery, Gandhi Medical College and Hamidia Hospital Bhopal, Madhya Pradesh, India
*Correspondence to: Mahim Koshariya, MS, Professor, Department of Surgery, Gandhi Medical College and Hamidia Hospital Bhopal, Sultania Road, Madhya Pradesh 462001, India; Email: mahimk2000@yahoo.co.uk
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of gastrointestinal tract with different expressions of CD117 (transmembrane KIT receptor tyrosine kinase) from other related tumors, which provides insights into the disease management of GIST. Tyrosine kinase inhibitors reduce the incidence of tumor recurrence and make the tumor resectable. Despite the malignant potential of GISTs, gastric GIST shows a better prognosis versus GISTs at other locations. Contrast-enhanced computed tomography (CECT) is considered the radiological diagnosis of choice because biopsy increases the risk of bleeding and tumor spreading. In addition to surgical resection which remains the mainstay of GIST treatment, active surveillance is also available for gastric tumor with a size <2cm. Currently, given the clinical consensus of an increased response of the tumor to chemotherapy after resection of the advanced lesion, patients with metastasis are also indicated for cytoreductive surgery. Various minimally invasive techniques including endoscopic (endoscopic band ligation, endoscopic muscularis dissection, endoscopic submucosal dissection, endoscopic submucosal tunnelling, endoscopic full-thickness resection), laparoscopic and combined techniques (laparoscopic endoscopic cooperative surgery, combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique) have been developed for surgical resection of tumors. Due to the high recurrence rate even during treatment, patients receive a physical examination and CECT follow-up every 3-5 months for 5 years followed by annual visits.
Keywords: GIST, Imatinib, Tyrosine Kinase Inhibitors, resection
1 INTRODUCTION
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal (GI) tract with a high risk of malignancy. Before the 1990s, GISTs were commonly misinterpreted and classified as leiomyomas, leiomyosarcomas, leiomyoblastomas, schwannomas, and GI autonomic nerve tumors[1]. Recent research has found expressions of CD117 antigen (transmembrane KIT receptor tyrosine kinase) in GISTs, which is undetectable in other GI tract spindle cell tumors[2]. The identification of oncogenic mutations in the genes c-KIT and platelet derived growth factor alpha (PDGFRA) genes encoding receptor tyrosine kinase, revolutionized the concept in GIST diagnosis and its therapeutic management. This has enabled the use of tyrosine kinase inhibitors (TKIs) such as imatinib, which has transformed a disease with minimal therapeutic options other than surgery into a disease with multimodal therapy, prolonged survival, and possible cure. This review aims to give a broad overview of the histogenesis, molecular pathogenicity, clinical appearance, diagnostics, and surgical and non-surgical management of GIST.
2 EPIDEMIOLOGY
GISTs account for 0.1% to 3% of all cancers in GI tract. Its prevalence has shown a trend of increase in the last decade due to better categorization of tumors or a genuine increase in occurrence. Data on Indian GIST patients are scarce, where the prevalence of small bowel GISTs have shown an increase, resulting in small bowel as the most prevalent site of GIST in India (40.7%) versus gastric GISTs (25.4%) worldwide[3].
GIST is most diagnosed in elderly patients around the age of 60, with a male preponderance. The majority of GIST cases are sporadic; however, familial GISTs with germline KIT and PDGFRA mutations have also been reported[4]. Exons 9, 11, 13, and 17 of the KIT gene while exon 12 and 18 of the PDGFRA gene are frequently mutated[5]. GISTs are also responsible to form Von Recklinghausen Neurofibromatosis type 1 partially and Carney's triad, both of which are characterised by the absence of KIT mutations.
3 PATHOGENESIS
Interstitial cells of Cajal (Intestinal pacemaker cells) are considered the source of GI stromal tumors with CD34 positive on immunohistochemistry. KIT (CD117) is an immunohistochemical marker of GIST, which is generally observed in 95% of cases[6]. The c-KIT proto-oncogene codes for the transmembrane receptor tyrosine kinase KIT, which is involved in haematopoiesis, gametogenesis, and intestinal pacemaker cell development and maintenance. By binding its cytokine ligand, steel factor or stem cell factor, the KIT receptor is activated, which leads to the activation of an intracellular signalling pathway and further regulates essential cellular processes such as proliferation, differentiation, and anti-apoptotic signalling. Gain of functional mutations in the c-KIT gene causes the receptor to be activated even without ligand, resulting in overgrowth of cancer or other benign lumps.
In GIST pathogenesis, KIT and PDGFRA mutations are mutually exclusive events; however, there are little difference in the activation of downward signalling.
There are no KIT or PDGFRA mutations in wild type GISTs, but there are other mutations observed such as B-type raf proto-oncogene (BRAF) V600E exon 15 and insulin-like growth factor-1 receptor overexpression[7].
4 CLINICAL PRESENTATION
Extra GI GISTs account for around 5% of GISTs and may develop in the retroperitoneum, omentum, mesentry, gall bladder, appendix, and urinary bladder[8]. They are most commonly found in the stomach (50-70%), small intestine (25-35%), colon and rectum (5-10%), and oesophagus (5%)[9]. Most GIST patients are symptomatic (69%), few are detected by chance (21%), and 10% are diagnosed after autopsy[10]. Most patients complain of nonspecific abdominal aches, followed by bleeding in the form of melena and hematemesis.
Bleeding is attributable to the erosion of tumors in the GI tract. Due to its high vascularity, erosion of GI tract tumors can also lead to life threatening haemorrhage or even intraperitoneal bleeding in the event of tumor rupture. Other symptoms include abdominal distension, nausea, and vomiting. Depending on the location of the mass, larger tumors may block the lumen of the GI tract due to endogenous growth or compress the GI tract due to exogenous growth, resulting in dysphagia, obstructive jaundice, or constipation[11].
Around 15-47% of patients with GIST present with metastatic disease[12]. Distant metastases are mostly observed in the peritoneum, omentum, and liver but not in lymph node metastases.
5 DIAGNOSIS
The diagnosis of GIST requires a thorough medical history review and physical examination, followed by radiological and tissue diagnosis if feasible. The radiological approach of choice for characterizing an abdominal tumor suspected or confirmed for GIST is contrast-enhanced CT (oral+IV contrast) of the abdomen and pelvis[13]. Typical appearance of GIST on contrast enhanced computerized tomography (CECT) is a soft, well-circumscribed mass within the wall of hollow viscera (subepithelial) and may be heterogenous due to necrosis or haemorrhage within the mass. Abdominal CECT is also used for treatment response assessment (Choi Criteria) and surveillance. Magnetic resonance imaging outperformed CT for peri-rectal GIST and metastasis.
18F-Fluoro-2-deoxy-D-glucose positron emission tomography combined with CT provides high sensitivity for the detection of tumors with high glucose metabolism. Tyrosine kinase receptor increases glucose transport protein signalling, which accounts for the detection of even small ill-defined tumors/metastases on PET-CT. It may also be utilized to distinguish between benign and malignant lesions, as well as to evaluate TKI treatment response, since metabolic alterations occur prior to anatomical changes[11]. However, it has not yet supplanted abdominal CECT as the preferred imaging modality.
GIST presents endoscopically on endoscopic ultrasound (EUS) as a submucosal lesion, with or without ulceration, present in the upper and lower GI tract. Irregular extraluminal borders, heterogenous echogenicity and cystic spaces within the lesion are suggestive of high grade tumor[14]. EUS can be used to determine the depth of GIST invasion and acquire tissue samples for biopsy. EUS-guided biopsy forceps are of limited use due to the subepithelial location of the tumor, and therefore EUS-guided fine-needle aspiration (FNA) if desired is preferred over biopsy[15].
Colonoscopy is often used to detect masses suspected of being GIST in the colon, rectum and anus.
Although a pre-operative biopsy is not always necessary, it should be performed if required for the differential diagnosis of a inoperable tumor.
6 HISTOPATHOLOGY
Histologically, GIST is divided into Spindle cell appearance (70%), epithelioid (20%), and mixed type cell morphology (10%).
Immunohistochemistry is introduced to differentiate GIST from other mesenchymal tumors. IHC staining to detect the CD117 (tyrosine kinase KIT receptor) level is the most important diagnostic test for GIST (tyrosine kinase KIT receptor). It is estimated 88% of GISTs are positive for CD117 and DOG-1. DOG1 is a receptor-activated chloride channel, which is calcium dependant. DOG1 is expressed in GIST and therefore can be used to diagnose KIT-negative tumors. Previous research revealed that DOG-1 has better sensitivity and specificity as compared to CD117[16].
For c-KIT negative GIST, few cases are found to have mutations in BRAF V600E gene, overexpression of insulin-like growth factor, neurotrophic tyrosine kinase receptor type 3, or fibroblast growth factor receptor 1.
7 STAGING
The tumor node metastasis staging, which is routinely utilised in cancer, has significant limitations in GIST staging and is not advised in this condition.
8 PROGNOSTIC FACTORS AND RISK STRATIFICATION
All GISTs have malignant potential. Gastric GISTs have a better prognosis than tumors at other locations. The three most important prognostic factors are tumor size, mitotic index (per 50 high power field) and tumor location, with mitotic index having the most weightage[17]. A prior study found that tumors with a size of >10cm or >5cm with mitotic count >5/50hpf was associated with a poor prognosis[5]. Another important risk factor is tumor rupture. Moreover, mutations, such as deletion in exon 11 are associated with worse prognosis as compared to other point mutations.
Ki67 reflects the ability of the tumor to proliferate and metastasize, and a high value indicates poor prognosis. For GISTs, as seen in studies, Ki67>5% signifies an increased risk of recurrence and metastasis (P<0.001)[5]. To the best of our knowledge, several classification systems have been developed to predict the risk of recurrence and metastasis. In the earliest classification systems given by National Institute of Health (NIH), patients were classified into very low, low, intermediate and high-risk groups depending on size of the tumor and mitotic index. Another system was proposed by Armed Forces Institute of Pathology that also considers the location of the tumor. Joensuu and colleagues developed the updated NIH classification in 2008, which found that tumour rupture during surgery resulted in poor prognosis[16].
Completeness of surgical resection has also been considered a prognostic factor; however ideal margin of resection is still unknown. These risk assessment systems facilitate the administration of neoadjuvant and adjuvant therapies.
9 TREATMENT
GISTs require a multidisciplinary approach to treatment which requires the cooperation of specialists from various fields such as histopathologists, radiologists, surgeons, and oncologists, as well as nuclear medicine specialists. A wide variety of treatment options are available for the treatment of GISTs, and patient selection of various treatments is a critical and challenging decision. The mainstay of treatment still is a complete surgical excision.
9.1 Active Surveillance
Debates exist in the management of GISTs less than 2cm in diameter. Despite their malignant potentials, most of these tumors remains insidious and are found on autopsies. Low-risk gastric submucosal tumours without evidence of malignancy on esophagodudenoscopy (EGD) (ulceration, irregular margins, or fast growth) might be treated by continuous monitoring only[18]. However, common consensus suggests that surgery should be performed for a confirmed GIST, and active surveillance is considered if patient refuses surgery.
For active surveillance, National Comprehensive Cancer Network (NCCN) guidelines suggest endoscopy with EGD +/- EUS every 6-12 months. Malignant findings on EUS warrant surgery or further workup including CECT, EUS, or EUS-FNA.
9.2 Surgery
Surgery may be the only treatment option that offers a cure for patients with primary, resectable and localised GISTs. The major objective of surgery is to remove the tumor with negative margins both macroscopically and microscopically (R0). The procedure is frequently a wedge resection or segmental resection of the affected area of the stomach or small intestine. In the event of locally advanced tumors, involvement of adjacent organs requires total resection of part or all of the involved organ. If the surgery will lead to substantial functional complications, such as total gastrectomy or abdomino-perineal rectum resection, neoadjuvant treatment is encouraged to shrink the tumour before surgery. Lymph node excision is not necessary unless enlarged as lymph node metastasis is very rare. However, the surgery needs to be performed with extreme caution, because of the extreme fragility of the tumor and the risk of life-threatening hemorrhage and tumor spreading after rupture. Therefore, tumors should be managed with “no-touch” technique.
Cytoreductive surgery for advanced metastatic disease has become an accepted practice for disseminated solid tumors.
Despite the lack of prospective trials, it has been suggested that laparoscopic surgery is indicated for tumors of <5cm in size or located in favourable anatomic locations, given a low recurrence rate, shorter hospital stay and low mortality. To eliminate spilling or spreading of tumors, the specimen is collected from the abdomen in a plastic bag[11]. For laparoscopic resection, modified lithotomy or split leg position may be considered for benefit of better visualisation of the tumor.
For gastric tumors, exophytic tumors towards greater curvature or anterior stomach, can easily be visualised and resected. An intraluminal tumor can be identified using intraop endoscopy or laparoscopic ultrasound. Posterior gastric tumors require mobilisation of stomach. A partial gastrectomy is adequate for the management of most tumors, and open surgery is preferred for gastroesophageal junction tumors. Tumors involving jejunum and ileum are easily resected under laparoscopy; however, tumors located in 2nd part of duodenum may require pancreatico-duodenectomy. GISTs located in 3rd and 4th part of duodenum, can be resected followed by either direct anastomosis to jejunum or Roux-en-Y anastomosis to jejunum.
Neo-adjuvant chemotherapy is encouraged for patient with rectal GISTs to allow abdomino-perineal resection and permanent colostomy in the patient.
9.3 Role of Endoscopy
During Endoscopy, GISTs can be divided into 4 types according to the location of the tumor.
Type 1-protruding into the lumen, attached to muscularis propria via a narrow connection;
Type 2-protruding into the lumen, wider connection to muscularis propria;
Type 3-in the middle of the gastric wall;
Type 4-exophytic (protruding through serosa).
Types 1 and 2 are mostly indicated for endoscopic enucleation, while types 3 and 4 require more sophisticated endoscopic and laparoscopic combined procedures[19]. Endoscopic excision of GIST, which is usually linked to muscularis propria, has a risk of a positive deep margin that may lead to perforation.
Among endoscopic techniques, endoscopic band ligation can be considered for tumors of <=12mm or located superficial to muscularis propria. This involves aspiration of the tumor using a transparent cap followed by band ligation. For tumors <2cm, and 2-5cm, located in the superficial layer, endoscopic submucosal dissection can be considered. Following the labelling of tumour borders, a solution (a combination of normal saline, epinephrine, and indigo carmine dye) is injected into the submucosal layer, which isolates the tumour from the rest of the layers and allows for better enbloc excision. Endoscopic muscularis dissection is a new technique that is available for tumors attached to muscularis propria. Endoscopic submucosal tunnelling is based on the principle of peroral endoscopic submucosal tumor resection (POET). A solution is injected into the submucosal layer and a tunnel is formed 5cm above the tumor followed by dissection of the tumor from muscularis layer. Nevertheless, the operation is not suitable for tumors located at fundus, greater curvature or tumors >4cm in size. In endoscopic full-thickness resection, complete thickness of the esophageal wall from where tumor is located is removed via circumferential incision, creating a perforation which is then sealed with an endoscopic clip and endo loop ligature. Creation of this pseudo perforation exponentially increases the risk of spreading of the tumor. To avoid this spreading, non-endoscopic wall-inversion surgery that uses both endoscopy and laparoscopy to push the tumor into the esophageal lumen, and suturing is done laparoscopically. Nonetheless, it is only suitable for tumors with a size of <3cm. Combination of laparoscopic and endoscopic approaches to neoplasia without exposure techniques is being developed for larger tumours. Another combined surgical procedure for GISTs is laparoscopic endoscopic cooperative surgery.
10 FOLLOW-UPS AFTER SURGERY
Follow-up after surgical resection of GISTs typically includes a medical history and physical examination every 3 to 6 months for 5 years and by yearly intervals, as well as serial CT scans every 3 to 6 months for 3 to 5 years and then yearly intervals. Disease recurrence is closely monitored.
11 SYSTEMIC THERAPY
Until about 2003, GIST was considered to have a poor prognosis due to a high incidence of recurrence even after complete resection of tumors, and conventional chemotherapy is ineffective. In early 2000s, after the discovery of the pathologic role of KIT mutations in GIST, targeted chemotherapy agents significantly improved the treatment outcome of the disease. One such agent is imatinib mesylate (tyrosine kinase inhibitor), which was used in the treatment of chronic myelogenous leukaemia with bcr-abl mutation and was trialed upon for GIST. It is an effective, well tolerated, orally available compound that has completely revolutionized the treatment of GIST.
11.1 Neoadjuvant Chemotherapy
Initially, chemotherapy was given only in patients with metastatic disease that were not suitable for surgery. In contrast, imatinib has proven its efficacy as a neoadjuvant and adjuvant chemotherapy agent. It downsizes the locally advanced GISTs, thereby significantly improving adjacent organ preservation and decreasing morbidity[20]. It also decreases the risk of tumor rupture and spillage in the abdominal cavity and demonstrates great potential as a neoadjuvant agent in primary tumors located at difficult locations such as gastro-esophageal junction, duodenum, and rectum. This may convert the need for open laparotomy for tumor resection to laparoscopical resection[21].
Mutation studies are recommended before start of neoadjuvant therapy to predict the treatment response, and a CT scan should be performed after 1st month of therapy to determine the treatment response[22]. The usual follow-up schedule is to perform abdominal CECT every 3 months. The response evaluation criteria in solid tumors is used to estimate the response from abdominal CECT but fails to deliver satisfactory outcomes. In contrast, the Choi Criteria contributes to the determination of early treatment response by incorporating assessment of tumor density and size[23]. Neoadjuvant trials of GIST have demonstrated that maximum radiographic response to imatinib generally requires 3-6 months of treatment[24], and current NCCN guidelines recommend a starting dose of 400mg for imatinib daily. There is no defined timing for surgery, which should be recommended after the tumor has shrunk to the point suitable for complete resection, or when a plateau response is achieved. If surgical resection is scheduled, imatinib can be discontinued shortly before surgery and resumed once GI function is restored.
11.2 Adjuvant Chemotherapy
Incidence of recurrence even after complete resection of the tumor is as high as 90% in the first 2 years after surgery, out of which 50% of the patients die of the recurrent disease. Role of adjuvant therapy with imatinib following surgery has been explored in several clinical trials. In localised disease, adjuvant therapy is recommended for intermediate and high-risk groups. In a randomised study of high-risk patients, 3 years of adjuvant imatinib treatment was linked with increased relapse-free and overall survival compared to 1 year after therapy[25]. Overall survival benefit is seen in patients receiving therapy for at least 3 years, and shorter duration of imatinib therapy delays recurrence but disease trajectory remains unchanged. Extended adjuvant therapy in high risk patients appears appropriate in the absence of disease progression or adverse effects[26]. The usual dose of imatinib is 400-600mg daily, and a higher dose is recommended for GISTs with exon 9 mutation given the low treatment response of GISTs.
Adjuvant therapy is discouraged for NF-1-related GISTs that are unresponsive to imatinib in the advanced setting. Experts are divided as to whether KIT/PDGFRA wild-type SDH-negative GISTs should be treated with adjuvant treatment.
12 METASTATIC DISEASES
GIST metastasis is commonly seen in the liver, mesentery, and omentum, and less frequently in the lungs, subcutaneous tissue, and lymph nodes.
Imatinib is the primary treatment modality for metastatic/recurrent disease, approved by Food and Drug Administration in 2002. This was approved after the results of a multicentric trial that tested 2 doses of imatinib (400 and 600mg) for treatment of advanced GIST in which patients achieved partial response in a median duration of 3 months[27]. Serious side effects are rarely observed in majority cases. Common side effects included periorbital edema, nausea, diarrhea, fatigue, rash, myalgia, headache.
Therefore, the starting recommended dose of imatinib is 400mg once daily with the highest safe dose being 800mg once daily, usually recommended for patients with exon 9 mutation on KIT. In patients who progress on imatinib 400mg daily, dose escalation is considered; however, toxicity also increases with the increasing dose. Research has proved that a high dose of imatinib is of no clinical advantages except for few particular mutations, which demonstrates the advantage of gene sequencing before therapy[28].
As in resectable tumors, duration of imatinib therapy is debatable, but the accepted standard is indefinite. Some studies have shown that disease recurs within a short period of time after cessation of treatment, with a high risk of disease progression, as in a randomized trial in France[29].
If the disease starts progressing after the use of imatinib, sunitinib, 2nd line drug approved for the treatment, is adopted. Sunitinib targets KIT, PDGFRA, vascular endothelial growth factor, and RET proto-oncogene and is effective in resistant cases. Sunitinib was initially given on a four-week-on, two-week-off schedule, with a beginning dosage of 50mg daily. Continuous regimen is now considered more effective with a dose of 37.5mg daily[30].
12.1 Cytoreductive Surgery
While imatinib remains the standard of care for patients with metastatic/recurrent disease, cytoreductive surgery has gained popularity in patients with resectable tumors. Few reasons behind cytoreductive surgery gaining inertia are partial response to imatinib, including progression of the disease on imatinib. Once the disease becomes resistant to imatinib, disease progression may be localised or systemic. Cytoreductive surgery considered beneficial for patients with non-progressive or locally progressive disease, and patients who remain responsive to TKI have the greatest advantages in terms of resectability of the tumor. The primary goal of surgery in such patients is macroscopic resection of the disease R0 or R1 which improves the response to TKI in some cases. If complete resection is unavailable, progressing lesions can be removed.
If a patient is not indicated for surgery, radiofrequency ablation can be considered. Treatment with imatinib should also be continued indefinitely after surgery to avoid recurrence/progression.
13 RECENT ADVANCES
As research into GIST management continues, novel drugs are emerging, particularly for treatment of GISTs resistant to imatinib. Alternate pathways of treatment are also being explored.
In addition to imatinib, sunitinib, and regorafenib, sorafenib targets multiple kinases including KIT and PDGFRA[31]. It is currently used in hepatocellular carcinoma and renal cell carcinoma. Nilotinib is another 2nd generation TKI that targets KIT, PDGFRA and BCR-ABL. KIT with exon 9 mutation should be avoided. It has shown variable results in terms of efficacy and action in various clinical trials for GIST. Pazopanib functioned in the PLAETTE trial in non-GIST soft tissue sarcoma and is a multi-targeted angiogenesis inhibitor that has achieved excellent quality of life results in metastatic renal cell carcinoma. Low response to Pazopanib in conjunction with limited evidence warrants selective use. Another highly selective TKI with inhibitory effect of KIT and WT-GIST, Mastinib, has been found to have a similar profile as imatinib and also has fewer side effects as compared to Sunitinib.
BLU-285, crenolanib and dabrafenib in patients with resistant mutations to PDGFRA D842V and BRAF-mutated GIST also provided therapeutic benefits. ETV1 and mitogen activated protein kinase inhibitor also showed significant gains. Imatinib and binimetinib disrupted ETV1 protein, resulting in the suppression of GIST cell growth.
Repretinib[32], also a KIT and PDGFRA kinases inhibitor, is a potent agent for advanced GIST. Common side effects were alopecia, myalgia, nausea, fatigue, palmar-plantar erythrodysesthesia and diarrhoea. Avapritinib, a potent, highly selective oral inhibitor of PDGFRα mutant kinases was well tolerated in patients with advanced GIST[32]. Selective TKIs PLX3397, PLX9486 and AZD3229 are next generation TKIs that target specific secondary KIT mutations.
Dasatinib, multi TKI and Ipilimumab, anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) antibody, in combination was found to be safe but not synergistic. Nivolumab was also administered with or without ipilimumab for advanced GIST where higher clinical benefits were observed in the single arm as compared to the combination arm.
Mammalian/mechanistic target of Rapamycin (mTOR) inhibitors such as sirolimus to TKI can be used for patients with advanced cancer when imatinib refractory disease is present without available standard options[32]. Crenolanib, a selective inhibitor of PDGFRα and FMS such as tyrosine kinase 3 with nanomolar activity against PDGFRα D842V mutant GIST is also being investigated.
For chemotherapy, imatinib remains the drug of choice which forms the part of neo-adjuvant and adjuvant regimens. As resistance to imatinib is inevitable, other TKI drugs such as sunitinb and regorafinib have been introduced for the management of GISTs resistant to imatinib. In addition to TKI, PDGFRA inhibitors, anti-CTLA4 antibodies, and mTOR inhibitors are on trial for management the advanced GISTs resistant to imatinib.
14 CONCLUSION
GISTs are rare but the most common mesenchymal tumors with a high potential for malignant transformation. With a better understanding of the pathogenesis, GISTs almost universally express the CD117 antigen, which contributes to distinguishing them from other GI mesenchymal tumors. The identification of the oncogenic mutations of c-KIT and PDGFRA as well as other rare mutations facilitate further development of targeted therapies. Though surgery remains the primary treatment for patients with GISTs, imatinib plays an important role as the primary drug for adjuvant and neoadjuvant treatment for both resectable and metastatic GISTs. Since imatinib resistance is almost inevitable due to development of secondary mutations, along with other previously approved drugs such as Sunitinib, Nilotinib, other drugs such as pazopanib and dasatinib that target multiple KIT and PDGFRA kinases have been developed. Other alternate routes of targeting GISTs, such as anti-CTLA4 antibodies, mTOR inhibitors are also in trials. Cytoreductive surgery is considered safe and beneficial for advanced and metastatic GISTs. Due to high risk of surgery, minimally invasive techniques for resection of GIST are being developed with laparoscopy and endoscopy as well as combined procedures. With all these new drugs and surgical techniques, the clinical management of GISTs is developing towards or personalised treatment of GISTs patients. However, more research and a multidisciplinary approach are needed to further improve prognosis while identifying more rare mutations, secondary mutations, and responses to developed drugs.
Acknowledgements
Not applicable.
Conflicts of Interest
There was no conflict of interest.
Author Contribution
All authors contributed to the manuscript and approved the final version.
Abbreviation List
BRAF, B-type raf proto-oncogene
CTLA4, Cytotoxic T lymphocyte associated protein 4
CECT, Contrast enhanced computed tomography
EGD, Esophagodudenoscopy
EUS, Endoscopic ultrasound
FNA, Fine needle aspiration
GIST, Gastrointestinal stromal tumor
GI, Gastrointestinal
mTOR, Mammalian/mechanistic target of Rapamycin
NIH, National Institute of Health
NCCN, National Comprehensive Cancer Network
PDGFRA, Platelet derived growth factor alpha
TKI, Tyrosine kinase inhibitors
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