Gastrointestinal Stromal Tumors: Abstract: Gastrointestinal stromal tumors (GISTs) are a group of tumors that independently originate from mesenchymal stem cells in the gastrointestinal tract. With the continuous development and improvement of clinicopathological techniques in the last decade, GISTs have gained widespread attention as an independent clinical pathology, and the progress of their diagnosis and treatment is now reviewed. A review is presented.1 In the early 1980s, mesenchymal tumors of the gastrointestinal tract were considered to be a tumor of smooth muscle origin. GISTs (gastrointestinal stromal tumors) are a group of tumors that originate independently from the mesenchymal stem cells of the gastrointestinal tract. In the past decade, with the continuous development and improvement of clinicopathological techniques, GISTs have gained widespread attention as an independent clinical pathology, and the progress of their diagnosis and treatment is now reviewed. 1. Tissue origin In the early 1980s, mesenchymal tumors of the gastrointestinal tract were considered to be a tumor of smooth muscle origin (morphologically can be cloacal or epithelial-like, benign, junctional and malignant), and very few of them were tumors of neurogenic origin (nerve sheath tumors or neurofibromas), so these tumors were often classified as smooth muscle tumors (or sarcomas) and neurofibromas (or sarcomas). With the application of electron microscopy and immunohistochemistry, many studies have found that the ultrastructure of such tumors of the gastrointestinal tract is not as rich in smooth muscle cells and Schwann cells as other smooth muscle tumors (e.g., uterine smooth muscle tumors) and that their immunophenotype lacks myogenic and neurogenic expression [1]. In 1983 Mazur and Clark [2] named these tumors as gastrointestinal mesenchymal tumors. With the development of molecular and ultrastructural techniques, many scholars at home and abroad believe that GISTs originate from the interstitial cells of Cajal (ICC) in the intestinal wall, and recently there is evidence that such cells are also found in the omentum, which explains why GISTs can arise outside the intestinal wall [1]. 2, clinical manifestations GISTs account for 2.2% of gastrointestinal malignancies, with an annual incidence of about 2/100,000 and an incidence of about 20-30,000 cases in China and 3,000-6,000 new cases in the United States each year, with an average of 5,000 cases and a median age of 60 years for patients and less than 10% for those <40 years old [3, 4]. The majority of GISTs originate in the stomach, accounting for approximately 50% to 60% of the total, with the small intestine in second place, accounting for approximately 25% to 30%, followed by the rectum (5%), esophagus (2%), and other abdominal organs (5%, such as the appendix, gallbladder, pancreas, and omentum). GISTs occurring in the external omentum, mesentery or retroperitoneum of the gastrointestinal tract are also known as extra-gastrointestinal stromal tumor (EGIST), and this type is predominantly malignant [1, 5, 6]. The common complaints of GISTs are gastrointestinal bleeding, abdominal masses, abnormal pain and gastrointestinal obstruction symptoms. According to the bulk of clinical cases reported (1765 cases), 54.4% of patients first presented with anemia, vomiting blood or black stool caused by GI bleeding, 16.8% presented with epigastric pain and discomfort, 1.7% had symptoms of acute abdomen, and only few patients could be detected with GISTs during general physical examination [1, 4]. Metastases from GISTs are predominantly abdominal implants and liver metastases, but can also occur simultaneously, followed by lung and bone. The prognosis of metastatic GISTs is poor, with a median survival time of <1 year. In contrast, it has been shown that the prognosis of GISTs with liver metastases is relatively better than that of metastases to other organs (lung and bone). In addition, malignant GISTs have fewer lymph node metastases, unlike gastrointestinal cancers, which have more lymph node metastases [5-7]. 3. Diagnosis GISTs have insidious onset and no specificity in clinical manifestations and imaging examinations, so early diagnosis is difficult, but detailed and standardized imaging examinations can provide a valuable basis for preoperative diagnosis and postoperative follow-up. Barium meal imaging of the digestive tract, CT, MRI and PET are currently the main imaging methods [7]. With the development of diagnostic techniques in recent years, immunohistochemistry and electron microscopy have also become indispensable tools for the diagnosis of GISTs. Barium meal imaging can show the change of mucosal surface and lumen of GISTs: gastric mesenchymal tumors mainly show the flattening or disappearance of local mucosal folds without obvious narrowing of the gastric lumen; mesenchymal tumors in the small intestine all have different degrees of limited disappearance and destruction of intestinal mucosa, involving only one side of the intestinal wall and developing along the long axis of the intestinal lumen, resulting in lateral narrowing of the intestinal lumen, and this change has certain diagnostic significance [8], but GISTs extra-luminal However, when GISTs grow in nodular masses, barium meal imaging is more difficult to detect. CT and MRI scans can show the anatomical relationship of the tumor and play a very important role in determining the surgical approach. In the evaluation of metastases, especially in the occurrence of liver metastases, the positive rate is over 90% [7, 9].CT scan results can also be used to assess the effectiveness of treatment: on CT, we usually consider the presence of reduced volume, density and cystic changes in the lesion as an indication of effective treatment, which is clinically seen in 92% of patients who are effective on imatinib treatment; the presence of solid nodules on the outer wall of the cystic lesion, or The appearance of solid nodules on the outer wall of the cystic lesion, or an increase in density in the area of the cystic lesion, is considered to be an early sign of local recurrence or the development of drug resistance, and these changes often precede the increase in the volume of the lesion [1, 10]. However, it is more difficult to differentiate enlarged lymph nodes from peritoneal metastases on CT plain scan, and it has been suggested that enlargement of a single abdominal lymph node is relatively rare, and that GISTs are significantly enhanced on CT enhancement, whereas enlarged lymph nodes are not significantly enhanced [4]. PET is often used to define the extent of primary tumor development, to understand the presence or absence of micro-metastases and to assess and guide drug therapy due to its higher resolution [1, 4, 11]. Ultrasound endoscopy (EUS) has also been recently recommended by an increasing number of scholars for the diagnosis of GISTs. EUS is mostly performed at layer 4 (myelomeningocele) to understand the characteristics of tumor location, morphology, size and intratumoral morphology, and according to the literature, EUS examination can detect tumors <2 cm in diameter [9]. In addition, we can perform fine needle aspiration cytology (FNAC) and endoscopic excision of the mucosal layer or submucosal layer (ESMR) under the guidance of EUS for their differential diagnosis [3, 4, 12, 13], but some scholars do not advocate this operation for patients with well-defined malignant GISTs [1]. The positive rate of imaging examination has not been reported in a large number of cases in the domestic and international literature, but most scholars believe that endoscopy and CT examination are the most basic preoperative examinations, while the final diagnosis depends on pathological examination of postoperative specimens and immunohistochemical testing [9]. ICC, the cell of origin of GISTs, is the only cell in the gastrointestinal tract that expresses CD117 and CD34, and immunohistochemistry of GISTs shows overexpression of CD117 and CD34 [5, 14].CD117 is a tyrosine kinase transmembrane receptor protein, and because of its nearly 95% positive expression, it is now a specific marker for confirming the diagnosis of GISTs, and when combined with BCL- 2, CD34, SMA, S-100 and desmin can differentiate between GISTs, gastrointestinal smooth muscle tumors and neurogenic tumors, and other immunomarkers such as vimentin can also help to determine the differentiation and differential diagnosis of GISTs [1, 15-17]. However, the final diagnosis of GISTs still requires pathological histological examination. Pauwels et al [18] concluded that after imatinib treatment (>1 year) in patients with GISTs, it may lead to a shift in tumor morphology and immunohistochemical characteristics that produce results similar to the characteristics of other gastrointestinal tumors, which poses a diagnostic and differential diagnosis challenge. The current benign and malignant properties of GIST can be classified into 3 categories. Indicators of malignancy: (1) histologically confirmed metastasis (liver, omentum, mesentery, etc.); (2) infiltration into adjacent organs; (3) nuclear schistosome phase >10/50 HPF; (4) tumor infiltration into the mucosal lamina propria and muscular layer; indicators of potential malignancy: (1) gastric tumor >5.5 cm, intestinal tumor >4 cm; (2) nuclear schistosome phase, gastric tumor ＞(2) nuclear schizophrenic phase, gastric tumor >5/50 HPF, intestinal tumor >1/50 HPF; (3) central necrosis of tumor; (4) obvious nuclear heterogeneity; (5) abundant tumor cells with active growth; (6) epithelial-like cells in nested or glandular vesicle; (7) high aneuploid DNA content; (8) increased expression of PCNA and Ki-67; those who do not have the above indicators are benign. Studies have confirmed that 10%-30% of GISTs are malignant at diagnosis, and 70%-90% are potentially malignant [9]. In addition, Heinrich et al [1] believed that there is a strong link between the status of kinase mutations and the effect of imatinib treatment in patients with GISTs, and proposed a molecular-based classification of GISTs: i.e., Sporadic, Familial, Pediatric, and NF-1-related; Yokoi et al [19] also proposed combining tumor presence or absence of hemorrhage or necrosis, tumor size (<5 cm vs ≥5 cm) and Ki-67 marker index (<3% vs ≥3%) to classify benign and malignant GISTs histologically, and these classifications are helpful in the assessment of prognosis [3,4]. There is no consensus among domestic and foreign scholars on the clinicopathological staging of GISTs [9]. 4, Treatment Surgical resection is the main treatment for patients with GISTs [1,20], while radiotherapy and chemotherapy are less effective. According to statistics, approximately 83% of patients can undergo clinically curative resection, but 50% of patients will recur and metastasize [21]. 15% to 50% of patients have metastases at the time of consultation, and treatment should be mainly local, including peritoneal perfusion chemotherapy or hepatic artery embolization chemotherapy (TACE). Since patients with GISTs rarely have lymph node metastases, intraoperative lymph node dissection can be omitted [4]. the growth characteristics of GISTs are overhanging and non-invasive, so an enlarged resection of the lesion is not beneficial. When lumpectomy was widely used in clinical practice, Nickl et al [12] suggested the application of laparoscopic techniques to GISTs as a diagnostic and therapeutic tool. The pathophysiological mechanism of GISTs is due to the dysfunction of the Kit signaling system triggering disordered cell proliferation and inhibition of apoptosis, and the molecular target drug against the c-Kit gene, STI-571 (imatinib mesylate, imatinib mesylate The advent of STI-571 (imatinib mesylate, trade name Gleevec), a molecular target for the c-Kit gene, has led to a marked improvement in the treatment and prognosis of GISTs. Imatinib is a protein tyrosine kinase inhibitor, a strong inhibitor of platelet-derived growth factor receptor (PDGF-R) and stem cell factor (SCF) receptor c-Kit, and is highly selective, unlike broad-spectrum antimitotic agents, and does not inhibit the proliferation of normal cells [22]. The successful treatment of GISTs with distant metastases using imatinib was reported in 2001 [14]. It is now generally accepted by scholars at home and abroad that the daily application of imatinib 400-800 mg is the most effective and safe, and can be well tolerated. The median survival among patients who respond well to this drug is about 20-24 months, while even more than 36 months has been reported in large research centers [1, 3]. Surgical resection is the only known way to treat patients with GISTs more completely, but the postoperative outcome is largely determined by the presence or absence of residual micro-metastases. In contrast, the application of imatinib, which is being extensively studied as a neoadjuvant treatment option, can be used not only for postoperative prophylaxis in primary GISTs that are completely resected during surgery, but also to allow successful resection of certain unresectable primary lesions and metastases [6, 11, 23]. Patients with stable disease after effective imatinib should continue to take the drug until the disease progresses [4]. However, it is indisputable that imatinib can only control but not completely cure GISTs [1], so it has been suggested that after 6 to 12 months of treatment with the maximum dose of imatinib, if there are still imaging-detectable lesions, resection or tumor reduction should be used [20, 24]. Kit mutations occur in almost all patients with GISTs, but KIT gene mutations are not a prerequisite for imatinib treatment, and for those patients who do not have KIT mutations (CD117 negative), which account for 6% of GISTs, some authors believe that imatinib still has a potential role [25-28] and can act and enhance its antitumor effects [29], but this view is controversial [1, 11]. In some patients who develop liver metastases that lead to hepatic impairment, treatment with imatinib is still considered safe [22]. And in patients with recurrent and metastatic GISTs, an appropriately prolonged cycle of imatinib therapy is also considered effective and safe [30]. However, with the widespread use of imatinib in the treatment of GISTs, clinical resistance to it has emerged, especially in patients who have responded well to imatinib treatment. Some studies have shown that the emergence of drug resistance is due to the development of secondary Kit mutations in these patients, which further indicates that imatinib is only a drug that inhibits cell growth and does not completely kill tumor cells [1, 11]. In the presence of imatinib resistance, increasing the drug dose can sometimes slow down the tumor recurrence, and if it is ineffective, then we have to re-evaluate the patient for the possibility of another surgery or treat the tumor using radiofrequency ablation, for example. Alternatively, we can apply the latest studies of converting enzyme inhibitors (e.g., SU11248) to inhibit secondary mutations, which are currently in clinical trials [1, 4, 6]. Blair et al [31] found partial GISTs ras p21, a marker that not only helps to differentiate between GISTs, smooth muscle tumors and smooth muscle sarcomas, inhibitors of ras may also become the 2nd imatinib in the near future. Early imatinib alone can be used for the treatment of CML, and the combination with chemotherapeutic drugs can enhance the anti-leukemic effect, and whether this experience can be extended to combine chemotherapeutic drugs, arsenic trioxide and tumor angiogenesis inhibitors with imatinib for the treatment of GISTs remains to be studied. 5, prognosis Referring to the assessment methods commonly used at home and abroad, the following aspects can be summarized: (1) age: patients are generally middle-aged and elderly, the prognosis of younger people is poor; (2) gender: male is a potential malignant indicator of GISTs [15]; (3) site: the 10-year survival rate of gastric malignant GISTs is 74%, while the 10-year survival rate of small intestine malignant GISTs is only 17% The prognosis is better in the stomach than in the small intestine [1, 12]; (4) tumor size and nuclear fission phase: large tumors (>5cm), nuclear fission phase (>5mitoses/50HPF), the prognosis is poor [3, 12]; (5) malignancy: 50% of low-grade malignant GISTs recur, 60% metastases; 83% of highly malignant GISTs recur, all metastases occur; ( (6) Immunohistochemistry: GISTs with positive expression of waveform proteins only are often malignant and have poor prognosis; GISTs with high expression of proliferation markers PCNA and Ki267 have poor prognosis; (7) Molecular biology: GISTs with c2kit gene mutation have poorer prognosis than GISTs without mutation; P16 deletion is a common molecular abnormality in patients with GISTs, and P16(-) GISTs patients have a poorer prognosis. In addition to this, there are reports on the prognostic impact of p53 on patients [4, 32]. However, it has also been debated whether the prognosis of patients with GISTs is related to the degree of Kit mutation, the degree of nuclear division and the size of the tumor [17, 28, 33]. Koay et al [33] concluded that PCR-SSCP (PCR and single strand conformation polymorphism) is a relatively rapid, sensitive, and affordable route for c-Kit mutation analysis, which can effectively assess the effect of tyrosine inhibitor therapy and thus patient prognosis. However, it has been difficult to develop a meaningful prognostic assessment criteria for patients undergoing surgical resection of GISTs, mainly because of (1) the degree of conflicting pathological diagnoses, missed diagnoses, and misdiagnoses before and after the introduction of KIT immunohistochemistry, (2) the existence of both gastric and non-gastric patients undergoing surgery for GISTs, (3) the existence of patients undergoing primary and local recurrent surgery, and (4) single-center statistics. surgical patients are performed over too long a time span [1]. 6. outlook In the past few years, the development of diagnosis and treatment of GISTs can be said to have been revolutionized, but there are still many questions to be studied in depth, and future studies should explore the mechanisms underlying the different effects of GISTs on imatinib: determining the optimal dosing regimen (optimal dose, timing and how to combine it with surgery, etc.) and neoadjuvant treatment options; determining the clinicopathological staging. To clarify the mechanisms of drug resistance and design new drugs to prevent and overcome imatinib