Gastrointestinal Stromal Tumor (GIST), is the rare type of tumor but also the most common tumor of mesenchymal origin of the GI tract. The earliest knowledge of this disease dates back to the middle of the last century, but the real in-depth study started in 1998. Following this, the successful treatment of this disease with small molecule targeted drugs was discovered by chance, which further promoted the large-scale development and testing of such drugs. As a result, the research and treatment of this disease is updated at an extremely fast pace, with the NCCN guidelines updated at least twice a year, and the number of research papers published on this disease has been increasing year by year in the last decade.
The incidence of GIST in Western countries does not differ significantly geographically, while the incidence of GIST in China is not high, but the large population base also makes GIST patients in China not few. It should be said that the research and attention to GIST in China is basically in line with international standards. For this relatively new tumor concept, it is significant to update the knowledge and standardize the treatment. Therefore, in late 2007, consensus opinions on pathology, medicine and surgery of GIST were published in the Chinese Journal of Pathology and the Chinese Journal of Oncology, and the consensus is revised regularly by the experts who wrote it. The publication of the domestic consensus is conducive to improving clinicians’ understanding of the disease and thus standardizing the diagnosis and treatment of the disease.
Clinical features.
The incidence of GIST is not high, about 1.4/100,000 people in western countries and the prevalence is about 12.9/100,000 people, and it is estimated that there are about 30,000 cases in China.GIST has an insidious onset and patients’ symptoms are often non-specific. Gastrointestinal bleeding is more common, and some present with abdominal discomfort or abdominal masses. Asymptomatic or incidental findings are not uncommon and can account for about 20% of patients. The disease can occur in any part of the gastrointestinal tract, but most commonly in the stomach (~50%) and small intestine (~25%). Recurrence and metastasis of the disease are often confined to the abdominal cavity and manifest as hepatic metastases and/or disseminated metastases to the abdominal cavity. Even in very advanced patients, extra-abdominal metastases, such as pulmonary and bone metastases, rarely occur, and likewise, lymph node metastases are very rare.
Diagnosis of GIST.
Conventional diagnostic methods for GIST are also applicable to GIST. but only pathological diagnosis is the only means to confirm the diagnosis of GIST. However, because GIST originates in the mesenchymal tissue of the luminal wall of the gastrointestinal tract below the mucosa (rather than in the mucosal epithelium), preoperative acquisition of biopsy pathology to confirm the diagnosis sometimes appears difficult. Especially for GIST in the small intestine, preoperative biopsy is not necessary as a routine because of the brittle texture and abundant blood supply, which can easily lead to tumor bleeding and dissemination during biopsy.
For those who need clear pathological diagnosis for neoadjuvant treatment, ultrasonic endoscopic aspiration biopsy can be chosen, which can minimize the risk of implantation and metastasis, with high confirmation rate, and is superior to biopsy by percutaneous puncture. In fact, in some patients with gastric GIST, due to the combination of mucosal ulcers, normal gastroscopic forceps biopsy can also successfully obtain tumor tissue and confirm the diagnosis; in addition, rectal low level mesenchymal tumor can be obtained through anal mass aspiration for pathology. Our own experience proves that for patients who cannot be biopsied by the above methods, it is actually quite safe to select a suitable site for ultrasound-guided percutaneous puncture, and the risk of bleeding and needle tract implantation is very low.
Since there is no definite standard for the classification of benign and malignant GIST, the only internationally accepted classification is the risk of malignancy (risk), and the importance of nuclear division count as one of the two major factors in the risk classification is obvious. A standardized and detailed pathological diagnosis report can provide clinicians with the most information about the benign and malignant tendencies of tumors and help to select and develop treatment plans. The current pathology report of GIST should include at least the tumor size, site and nuclear division images, and the nuclear division images should be selected from the local area where the most concentrated nuclear divisions of tumor cells occur, and the total number of nuclear divisions in 50 high magnification views of them should be accumulated. Since Fletcher proposed the malignancy risk grading for GIST in 2002, it has remained the most widely accepted and easy to use and remember grading criteria, because tumor size and nuclear division number are still the most recognized indicators of GIST malignancy. However, with the retrospective analysis of bulk cases in the United States, it was found that the malignancy of GIST at different sites with the same tumor size and nuclear division number was not completely consistent, therefore, a new grading scale incorporating the site of GIST occurrence was proposed and gradually accepted by clinicians with the following grading scale (Table 1):
The new grading scale was based on a retrospective study of a large number of cases, and it was seen that, in addition to tumor size and nuclear division, tumor site was an independent predictor of recurrence after primary GIST resection (the highest rate of recurrence after small bowel GIST) [6]. In addition, GIST with clear infiltrative growth and the occurrence of recurrent metastases are completely malignant and do not require risk grading. In addition, an increasing number of pathology departments have established molecular pathology centers, and molecular pathology (tumor cell KIT and PDGFRA gene mutation testing) should be performed if available. Even if your hospital is not equipped to perform the tests, there are specialized testing centers in Beijing, Shanghai and Guangzhou, respectively, and these centers have performed a large number of samples with reliable results. Mutation testing is necessary for GIST, especially for GIST with a high risk of malignancy. This is because genetic testing can further clarify the diagnosis in patients who are CD117 negative in immunohistochemical testing; it can predict the therapeutic effect of targeted drugs, and mutation testing for targeted drug-resistant progressive lesions can better provide a basis for the selection of the next treatment option.
Surgical treatment of GIST.
1, limited GIST.
Surgery is still the main treatment for primary, limited GIST. Minimally invasive surgery is performed for GISTs up to 5 cm in diameter.
Imatinib (IM, Gleevec) neoadjuvant therapy should be considered in the following cases of primary, limited GIST: 1. Difficulty in complete resection and difficulty in obtaining negative margins; 2. GIST that may require combined organ resection; 3. GIST with high surgical risk and high rate of postoperative complications, and 4. GIST resection with sacrifice of organ function. For example, GIST of the descending duodenum and GIST of the lower rectum, where radical treatment may require pancreaticoduodenectomy or Mile, have high surgical risk and also result in a lower postoperative quality of life for the patient because organ function cannot be preserved. At this time, neoadjuvant treatment with IM can be given first when pathological confirmation is obtained. The neoadjuvant treatment of IM has been shown to benefit most patients by reducing the extent of surgical resection and lowering the risk of surgery from the case reports of GIST neoadjuvant treatment, while multicenter clinical trials are underway abroad. As for the tumor changes during neoadjuvant therapy, the maximum therapeutic effect of IM is generally achieved in 4-6 months for effective patients, after which the tumor basically stops shrinking. However, individual patient response to IM varies widely, and the duration of neoadjuvant therapy cannot be generalized. Surgery should be performed when complete resection of the tumor is expected without affecting organ function; if the timing of surgical intervention is delayed, patients may experience IM resistance and tumor progression between CT evaluations and lose the opportunity for radical treatment. It should also be noted that a few patients show IM drug resistance at the beginning, so neoadjuvant therapy may be ineffective and timely surgical intervention is fundamental. The drug should be stopped for 3-7 days before surgery, otherwise, the edema of the gastrointestinal wall may increase the incidence of postoperative fistula.
2. Postoperative treatment of GIST.
Patients with primary GIST have a surgical resection rate of about 85%, an overall postoperative recurrence rate of >50%, and an overall 5-year survival rate of about 50%. The median postoperative recurrence time for high-risk GIST patients is 2 years after surgery. Therefore, adjuvant therapy is important for GIST. Based on the North American large sample multicenter phase III clinical trial (ACOSOG Z9001), GIST >3 cm in diameter had a lower recurrence rate at 1 year postoperatively with adjuvant therapy compared to the placebo group, and in a subgroup analysis, the greatest difference in postoperative recurrence-free survival was found between the IM and placebo groups in high-risk GIST patients with tumor diameters >6 cm (96% in the IM group and 67%-86% in the placebo group ). Accordingly, the US FDA also approved the indication of IM adjuvant for the adjuvant treatment of GIST. Our consensus is that IM adjuvant therapy should be given to patients with intermediate to high risk GIST. The duration of adjuvant therapy should be at least 1 year, and the duration of adjuvant therapy should be extended for high-risk patients.
3. Treatment of recurrent and metastatic GIST.
Surgical re-excision of recurrent and/or metastatic GIST does not improve its survival rate. And IM, as a new tyrosine kinase inhibitor (TKI), has revolutionized the treatment of progressive GIST and become a model of targeted therapy for solid tumors. The relatively high selection of its targets of action has led to precise effects and low side effects. Currently, the longest follow-up phase II clinical trial (B2222) showed that 147 patients with metastatic advanced GIST had an objective effective rate of 68.1%, a disease control rate of 83.7%, and a median survival of 58 months from the time of enrollment in 2002 to the present. Moreover, the survival benefit was similar in patients who achieved partial remission (PR) and stable disease (SD), suggesting that IM should be adhered to as long as the tumor can be controlled. with the use of more and more patients using IM, its good effect and safety for the treatment of progressive GIST has been widely accepted as the first-line treatment for progressive GIST. Many cases and experiences of applying IM for GIST have been accumulated at home and abroad, about 65%-70% can reach PR, 15%-20% SD, and a few (5% or less) can reach CR, with an overall benefit rate close to 90%. Foreign clinical trials still recommend 400 mg/day as the initial treatment dose, and also, treatment should not be interrupted in case of treatment benefit, otherwise the tumor will grow rapidly. However, genetic monitoring of patients in the trials and re-evaluation of efficacy revealed that patients with exon 9 (exon 9) mutations in the KIT gene started with 800 mg/day had better progression-free survival than the low-dose group, while no such difference was seen for other mutation types. Therefore, the US NCCN guidelines recommend starting patients with exon 9 mutations at 800 mg/day. The side effects of IM are usually mild and easily managed symptomatically, and the intake can be reduced in patients with moderate toxicity, and only severe cases require discontinuation. Patients with progressive GIST should take IM continuously until tumor progression.
4. Treatment of GIST disease progression (PD) under targeted therapy.
While IM certainly has outstanding efficacy, a minority of patients show drug resistance at the beginning, and many patients who start treatment with benefit gradually develop drug resistance as they take IM for a longer period of time, with a median time of about 2 years after taking IM. Studies of surgical intervention in patients who develop drug-resistant progression have gradually increased in recent years, and relevant clinical trials are already underway abroad. Preliminary reports suggest that surgical treatment to remove progressive lesions or to pursue R0 resection in cases with limited progression may prolong patients’ postoperative progression-free survival, while surgical treatment in patients with generalized drug resistance and full progression of lesions is not effective. However, the modality, timing, and efficacy of surgical intervention for progressive GIST remain to be known from clinical trials with larger samples. Currently, for tumor resistance progression in IM therapy, the treatment dose of IM should be increased or switched to sunitinib malate (Sunitinib, SU, Sutent), and surgical intervention to remove limited progression of the tumor lesions may also be carefully considered for appropriate patients.
Sunitinib (SU), a TKI that has been marketed in China, is an inhibitor of multiple tyrosine kinases and acts simultaneously on the vascular endothelial growth factor receptor. A randomized, double-blind, placebo-controlled clinical trial of SU in patients with GIST who had failed or were intolerant to previous IM therapy showed that SU significantly prolonged progression-free survival and improved overall remission rates (PR) in treated patients. However, SU has more side effects than IM, including the potential for hypertension, cardiac impairment and other adverse effects not seen with IM, but is still generally well tolerated by patients. There are currently two dosing regimens to choose from for SU, 37.5 mg/day uninterrupted continuous dosing or 50 mg/day with 4 weeks of oral rest for 2 weeks (4/2 regimen). In our experience, the national population seems to tolerate the low-dose SU better, with fewer and less severe side effects, and preliminary results from foreign clinical trials also show that the duration of benefit (PFS) is better in the low-dose continuous dosing group than in the 4/2 regimen. SU is now a second-line treatment for GIST, giving new hope to GIST patients. More new TKI-based drugs are in clinical trials or development, and the treatment of progressive GIST is bound to evolve in the future.
In summary, the NCCN and domestic consensus opinions provide good guidance on the diagnosis and treatment of GIST from three aspects: pathology, medicine, and surgery, respectively. However, as a relatively new tumor type, many issues remain to be studied; early detection, early diagnosis, and early surgical treatment can truly improve the treatment outcome of GIST. It is believed that with the further understanding of GIST and the gradual formation of treatment norms, the prognosis of GIST patients will be further improved.