Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tissue-derived tumors of the gastrointestinal tract, distinct from sarcomas of myogenic or neurogenic origin of the gastrointestinal tract. the concept of GIST was first introduced by Mazur et al. in 1983, and its molecular features were discovered 10 years ago by Hirota et al. GIST is currently defined as histologically enriched with spindle cells, epithelioid cells, occasional or pleomorphic cells in a fascicular, diffuse arrangement, immunophenotypically expressing KIT protein (CD117), nestin, and proteins of unknown function (discovered on GIST l, DOG1, genetically present with frequent c-kit genes and platelet Cajal cells can also express CD34 when CD117 is present. Cajal cells can also express CD34, and CD34 positivity has diagnostic value when CD117 is not expressed. It has been reported that protein kinase C-theta (PKC-e) is also highly specific for GIST, even when c-kit and PDGFRa mutations are negative. 1. Pathogenesis and biological behavior Mutations in GIST include mutations in the proto-oncogene c-kit and PDGFR-α gene. Most GISTs occur from c-kit gene mutations. c-kit mutations mainly occur in exon ll (exonll) in the proximal membrane region, followed by exon 9 (exon 9) in the outer membrane region, and exons 13, 14, and 17 (exon13, 14, 17) in the tyrosine region can also be mutated. GIST with exon 11 mutations can be located in the small intestine or in the stomach, and the pathological morphology is predominantly of the spindle cell and mixed cell types. Exon 9 mutations account for approximately 30% to 21% of GISTs, and exon 9 mutations are mainly located in the small intestine. In general, there is only 1 locus of c-kit mutation in a given tumor, and the presence of 2 or more different mutated loci at the same time is extremely rare. c-kit mutations are also present in GISTs smaller than lcm that are found incidentally, and there is debate about the early oncogenic role of the mutation in the progression of these GISTs. The prognostic role of c-kit mutations is unclear because of conflicting results. From recent data, typical mutations are observed in approximately 8% to 50% of large tumor GISTs, with a mutation frequency of approximately 35%, much higher than previously reported. Nearly 35% of c-kit mutation-negative GISTs have activating mutations in the PDGFR-α motif, which may be another cause of GIST development, especially playing an important role in tumor formation in c-kit mutation-negative tumors. mutations in PDGFR-α are functionally acquired or non-functional, and mutations can occur not only in tumor tissue but also in normal tissue. -α mutations are mainly located in exons 12 and 18, which are mutually exclusive with c-kit mutations. c-kit mutations are absent in GIST with PDGFR-α mutations. PDGFR-α mutations mostly occur in the stomach, and the pathological morphology is mostly epithelial and mixed cells, which are less malignant. GISTs without mutations in both c-kit and PDGFR-α genes account for about 10-15% of GISTs, or “wild-type” GISTs, whose mechanism of occurrence is unknown. It has been suggested that in these GISTs, tyrosine kinases are activated despite the absence of c-kit mutations. In the early days of the GIST concept, many papers considered GISTs to be benign or malignant. However, as it was found in the clinic that GISTs considered benign could also recur or metastasize, the benign-malignant classification was discarded by most scholars. Currently, GIST is considered to have no absolute benignity and is a tumor with potentially malignant behavior. Its biological behavior is difficult to predict, and the most valuable reference indicators are the size, nuclear division index and anatomical location of the tumor. Since the grading criteria proposed by Fletcher have been widely used in clinical practice, tumor size and nuclear division number have become the most recognized indicators to determine the malignancy of GIST. In recent years, it has been found that tumor site is also an independent predictor of recurrence after primary GIST resection, and the malignancy of GISTs at different sites with the same tumor size and nuclear fission number is not completely consistent (the highest recurrence rate after small bowel GIST). New grading criteria incorporating the site of GIST occurrence were then proposed and gradually accepted by clinicians. It was found that different mutation sites were also associated with malignancy of GIST, with higher recurrence rates after surgery for GIST with c-kit exon 9 and 11 mutations, and intermediate recurrence rates for wild type. The apoptosis-regulating genes IGF and IGFR are hot spots in oncology research in recent years, and Bracconi et al. reported that high-risk GIST with insulin-like growth factor 1 and 2 (lnsu-lin-like growth factor l/2, IGFI and IGF2) expression had a higher recurrence rate after surgery. Wang Lin et al. reported significant differences in the positive rates of IGF1 and IGF2 between the benign, low-grade malignant and malignant groups, suggesting that high IGF expression suggests increased malignant potential. In general, among many possible influencing factors, nuclear division count is the best indicator to predict the risk of tumor malignancy, and combined with tumor size and location will be more accurate in predicting the malignancy of GIST. As new molecular markers will continue to be discovered and improved, the biological behavior of GIST will be further understood. 2. Diagnosis The diagnosis of GIST is usually obtained during preoperative biopsy or emergency surgery. When histological samples are not available, especially for small submucosal tumors that cannot be obtained during endoscopic biopsy, transabdominal surgical biopsy should eventually be considered. The conventional wisdom has been that GIST is mostly discouraged from biopsy due to the possibility of tumor breakdown and spread caused by biopsy. However, with the advent of the effective targeted drug Imatinib, percutaneous puncture biopsy and intraoperative frozen section biopsy are feasible when the tumor is estimated to be unresectable. The 2007 edition of the NCCN guidelines suggests that treatment with imatinib after biopsy can be considered as long as it is done to avoid functional impairment caused by surgical procedures. Although opposition still exists, more and more surgeons have slowly begun to accept and apply preoperative biopsy. 3. Treatment 3.1. Surgical treatment Due to the extremely poor effect of conventional chemotherapy and radiotherapy (less than 5%), surgical resection is the only curative method for GIST. The first surgery must be complete resection of the tumor, and non-contact surgical resection must be performed intraoperatively following the principle of tumor-free operation, as well as preventing tumor rupture and obtaining negative margins (R0 resection). Since lymph node metastasis is rare in GIST, and many retrospective studies suggest that lymph node dissection does not improve survival and reduce recurrence rates, and there have been no reports of jumping lymph node metastasis in GIST, surgery for GIST does not advocate routine extended resection or regional lymph node dissection. Whether patients with positive cut margins (R1 resection) should undergo reoperation or imatinib adjuvant therapy has also been debated. The use of minimally invasive surgery (including intra-laparoscopic resection and combined laparoscopic and endoscopic resection techniques) is still controversial. Domestic and foreign scholars have made attempts in this area, and according to the literature, the average operative time and average hospital stay of laparoscopic surgery are significantly shorter than those of open surgery, and the long-term follow-up recurrence rate is basically the same as that of traditional open surgery. However, in order to avoid the high risk of tumor rupture, peritoneal dissemination, and postoperative peritoneal metastasis, the European Society of Medical Oncology of Falcon 2005 suggested that laparoscopic resection should be considered only when the tumor is ≤2 cm in diameter. Therefore, the clinical work should decide the surgical method according to the actual situation of the patient. The debate of en-bloc resection lies in the safety margin, i.e. how many centimeters away from the tumor is appropriate, because there are still issues of surgical comorbidity, postoperative function and patient tolerance to be considered, and the scope of surgery should be appropriate, so the choice is different for different sites. If the tumor invades or infiltrates the adjacent organs, in order to remove the tumor completely, it is not advisable to separate the tumor reluctantly but only to make a combined organ resection. If there is already abdominal dissemination, multi-organ resection is not very meaningful. Some scholars believe that as long as the resection is clean, the postoperative local recurrence rate of combined visceral resection and local resection is similar, and the overall survival rate of multivisceral resection is also reduced. However, some people propose resection of the greater omentum or peritoneal dissection for complete surgery. 3.2. Targeted therapy With imatinib (lmatinib) and sunitinib (Sunitinib) becoming the standard first- and second-line therapeutic agents for GIST, respectively, GIST has become a paradigm of targeted therapy for solid tumors. Because imatinib is highly effective in advanced GIST, several phase III trials have now been conducted for adjuvant treatment with imatinib after resection of the primary GIST. Other than imatinib and sunitinib, the NCCN guidelines do not recommend other agents for GIST treatment. Before the advent of imatinib, the prognosis of GIST was poor, with a median OS of only 9 to 18 months at the discretion of most studies, and the chance of cure was almost nil even with complete resection of the lesion. The adoption of imatinib has fantastically changed the natural history of recurrence and metastasis in GIST resistant to radiotherapy and chemotherapy. Imatinib has become the new standard of care for advanced/progressive GIST. Based on the results of North American S0033 and European EORTC62005, the NCCN guidelines recommend an initial dose of 400 mg/d for advanced/progressive GIST, and treatment with imatinib should be continued until disease progression or intolerability, even in patients who achieve CR. It is worth noting that although patients with c-kit exon 11 mutations are more sensitive to imatinib, there is no significant benefit from dose adjustment in this group of patients, whereas patients with c-kit exon 9 mutations can benefit significantly from imatinib dose increases. However, there is controversy as to whether imatinib dose adjustment or direct switch to sunitinib is preferred. With the detection of c-kit, PDGFRA and other mutation types, drug therapy for progressive GIST will be more targeted to minimize the proportion of primary drug resistance. Several studies have shown that the effect of surgical treatment is positive for patients with progressive GIST after neoadjuvant therapy with TKI agents. nCCN guidelines also emphasize the application of imatinib for neoadjuvant therapy and the possibility of surgical treatment for some patients. It is currently considered that all patients without extensive progression after neoadjuvant therapy should be aggressively treated with surgery. Even those with local progression (secondary drug resistance) should have aggressive surgery. The optimal timing of surgery after neoadjuvant therapy has also been debated. Since secondary resistance usually occurs about 2 years after imatinib treatment, surgery should usually be performed within 2 years of imatinib treatment. Most scholars recommend that surgery should be considered only after 6-12 months of disease stabilization or remission after imatinib treatment, i.e. after the appearance of maximal effect, but it is difficult to judge the point of maximal effect in clinical practice, and most surgeons emphasize early resection when they can, so as to avoid poor surgical effect after drug resistance, or even loss of surgical opportunity due to drug resistance outbreak. Patients with progressive GIST can also try to take targeted drugs while performing local treatment such as intervention and radiofrequency. The author treated a patient who had mild shrinkage of the lesion and stabilized it for another 4 months after treatment with Imatinib 600 mg/d plus interventional embolization. In case of liver metastasis, complete resection of the primary and metastatic foci is the first principle, and local treatment such as radiofrequency and hepatic artery embolization is considered in combination with unresectable foci on a case-by-case basis. Although approximately 85% of primary GIST loyalists can undergo radical surgical resection, the recurrence rate is higher than 50% within 2 years after surgery, and the 5-year survival rate is around 50%. How to reduce the recurrence rate after radical resection has been a difficult and hot topic in the field of GIST treatment. Although it is inconclusive whether imatinib is routinely applied as adjuvant therapy after GIST, it should be used as adjuvant therapy in patients with high risk of recurrence. Three large international phase III trials led by ACOSOG, EORTC and SSG/AIO are underway. The Z9001 trial by ACOSOG in the United States showed a 1-year survival rate of 97% in the dosing group compared to 83% in the control group. In the subgroup analysis, the difference was significant in the medium- and high-risk group with tumor diameter >6 cm, and the application of imatinib for postoperative adjuvant therapy benefited patients more significantly in RFS (96% vs. 67%-86%), so postoperative adjuvant therapy has become a consensus. The same results were obtained with adjuvant imatinib in 16 units in China organized by Zhan Wenhua et al. The historical control data reported abroad also suggest the importance of adjuvant therapy, so it is correct to apply adjuvant therapy to postoperative high-risk patients. Despite the remarkable, these results are still preliminary and it is not fully accepted whether adjuvant therapy with imatinib becomes the current standard choice. The optimal duration of imatinib adjuvant therapy is still unknown, and the SSG/AIO trial with randomized 1- and 3-year treatment may help to shed light on the duration issue. 62024 trial with 2-year duration of treatment will provide important information on this issue. Since there are better prognostic factors than size and nuclear split count that have a greater impact on postoperative recurrence, further studies of adjuvant therapy are critical to how patients are selected. For example, large tumors of the stomach (including those >lO cm in diameter) with low nuclear fractionation (≤5/50 HPF) are now also considered to have a low risk of recurrence (≤10%) and may not require adjuvant therapy, whereas duodenal tumors and small bowel tumors with tumor diameter >5 cm or nuclear fractionation >5/50 HPF, diameter <5 cm but high nuclear fractionation phase may be recommended for adjuvant therapy with imatinib. This requires further meta-analysis. CT and PET/PET-CT are mostly used to evaluate the efficacy of imatinib. CT is generally preferred, but the onset of imatinib is mostly 3 to 6 months, with a median time of about 4 months, and the median time for CT to detect tumor shrinkage also takes 3 to 4 months, while PET is able to detect tumor response to imatinib within hours or days, which is often consistent with the remission of clinical symptoms, so it is considered that PET/PET-CT is considered more preferable before and after 2 to 4 weeks of treatment to assess the efficacy. Currently, CT evaluation is mostly performed before and about 1 month after targeted therapy in clinical practice, and individualized imaging data of patients are established for subsequent comparison, and thereafter every 3 months as an examination cycle, which should be reviewed promptly when symptoms or signs worsen. When 2 consecutive CT results do not suggest further improvement, it is suggested that Imatinib treatment has reached its maximum effect, and this is a more appropriate time for surgery. At present, the Choi criteria have basically replaced the RE-CIST (response evalu-ation criteria in solid tumors) criteria, which were mainly evaluated by the change of tumor diameter measured by CT, but did not reflect the efficacy of TKI well; while the Choi criteria integrated the tumor diameter and tumor density ( CT value) to determine the efficacy of TKI, which can better correspond to the results of PET and predict the disease progression and survival. Resistance to imatinib in both advanced and postoperative GISTs exists in most patients, although initial treatment is effective. primary and secondary resistance to imatinib in GISTs exists. Primary resistance is rare, i.e., tumor growth occurs within the first 6 months of treatment, and is 10%-15%. primary resistance to imatinib may be related to the mechanism of GIST development. the B2222 trial also showed that patients with mutations in wild-type GIST, c-kit exon 9 and PDGFRa exon 18 (D842V) are prone to primary resistance. Secondary mutations leading to primary resistance are relatively rare, and about 10% of primary resistance is due to new mutations on top of the original c-kit or PDGFR-a mutations. Some scholars believe that there may be a KIT activation pathway that does not require kinase involvement. Secondary resistance occurs after 6 months of treatment, and approximately 50% of GIST patients initially sensitive to imatinib develop secondary resistance after 2 years of drug administration. The main reason for its occurrence is acquired secondary c-kit or PDGFR-a gene mutations. The secondary mutations are mostly located near the ATP binding site encoded from c-kit or near the KIT kinase activation loop. These secondary mutations alter the KIT construct and hide the imatinib binding site, thereby causing drug resistance to occur. Secondary mutations mainly occur in GIST with exon 11 mutations, while GIST with exon 9 mutations are relatively rare. The study showed that 73% of GISTs resistant to imatinib developed new mutations, and the new mutations were mainly missense mutations in the tyrosine kinase region, with the main mutation sites located in c-kit exons 13, 14, 17 or 18. Bauer et al. suggested that abnormal activation of KIT is another important cause of secondary resistance to imatinib. burger et al. found that long-term oral administration of imatinib can increase the expression of ABC transporter protein by Tam et al. found that there is amplification of insulin-like growth factor 1 receptor (IGF-1R) in imatinib GISTs and that treatment targeting IGF-1R has the potential to provide a significant benefit to GISTs, especially those resistant to imatinib. imatinib-insensitive GISTs. Other mechanisms such as plasma glycoprotein acids and increased expression of multidrug resistance genes may be associated with imatinib resistance. Several drugs that may be effective in imatinib-resistant GIST (Sunitinib, Nilotinib, etc.) are currently under investigation or in clinical trials. New generation TKI agents are characterized by multi-target action and usually possess some anti-neoangiogenic ability. Sunitinib significantly prolongs progression-free survival and improves overall remission rates in patients with GIST who have failed or are intolerant to imatinib therapy. However, sunitinib has more side effects than imatinib, which may lead to hypertension, impairment of cardiac function and thyroid function and other adverse effects that do not occur with imatinib, but is still generally well tolerated by patients. in January 2006, the US FDA approved sunitinib as a second-line drug for the treatment of imatinib-resistant progressive GIST, and sunitinib was officially launched in China in June 2008. In addition, the application of protein kinase inhibitor PKC-412 and marine biological extract ET-743 in progressive GIST is also under further study. 4.Gene testing At present, whether from diagnosis to treatment to evaluation of prognosis, the importance of detecting the type of gene mutation in GIST patients is increasingly emphasized. It is especially important to perform genetic testing, especially when immunohistochemical results cannot be established, or in cases with clear CD117 negativity, or to diagnose familial GIST, and to evaluate GIST in pediatric patients. The choice of clinical tyrosine kinase inhibitors, treatment response and prognosis vary depending on the tombstone locus where the mutation occurs. For example, the detection of c-kit exon 9 and 11 mutation status is currently the most important predictor of imatinib resistance. Imatinib was found to have significantly higher objective remission rates and PFS in patients with c-kit exon II mutations than in patients with wild-type and exon 9 mutations in clinical practice, and the NCCN also recommends that patients with exon 9 be treated with imatinib 800 mg/d at the start. Since the efficacy of imatinib for wild-type GIST is lower than that of both exon 11 and exon 9 mutants, this group of patients should be surgically resected early. Even in CD117(+) GIST, those with c-kit exon 11 mutations are generally sensitive to imatinib, while those with exon 9 Ala502_Tyr503 mutations and PDGFR-α exon 18 Asp842Val mutations are not sensitive to imatinib. In conclusion, genetic testing brings us more and more information and should be performed in all GIST patients. Genetic testing is even more essential for patients with CD117-negative, clinical high-risk and malignant, recurrent metastatic GIST. However, the prevalence of genetic testing is too low in China due to the conditions, which affects the treatment specification and case statistics of GIST patients. In addition to the aforementioned CD117, nestin, protein of unknown function (DOGD and protein kinase C (PKC-e), there are reports summarizing p53, p27, Ki-67, Bax of the Bcl-2 protein family, high mobility group protein.1 (HMGB-1), matrix metalloproteinase 2 (MMP2), cyclooxygenase. 2 (COX-2), heat shock protein (Hsp)90, carbonic anhydrase related protein (CA-RP), anti-human telomerase reverse transcriptase antibody and transcription factor E2F1 may be associated with the prognosis of GIST.