Gastrointestinal Stromal Tumors (GISTs) are a group of tumors that originate in the mesenchymal tissue of the gastrointestinal tract and account for the majority of GI mesenchymal tumors. As a relatively new concept, mesenchymal tumors should cover what was previously called “gastrointestinal smooth muscle tumors” or “gastrointestinal smooth muscle sarcomas”. However, the concept of gastrointestinal smooth muscle tumors or sarcomas as tumors of mesenchymal origin has not been excluded, except that in the current clinicopathologic diagnosis, these tumors account for only a small proportion of tumors of mesenchymal origin in the gastrointestinal tract. Therefore, we must now change the concept of gastrointestinal mesenchymal-derived tumors from the concept of predominantly smooth muscle tumors to the concept of predominantly gastrointestinal mesenchymal tumors.
(I) Research history and nomenclature
Mesenchymal-derived tumors of the gastrointestinal tract account for only a minority of gastrointestinal tract tumors, but are diverse and morphologically complex. In the past, due to the limitation of pathological techniques, many spindle cell tumors of the gastrointestinal tract mixed with smooth muscle fibers or nerve bundles were often diagnosed as smooth muscle-derived tumors or neurogenic tumors. Nowadays, most of them are considered to be c-kit positive or CD34 positive mesenchymal tumors resembling Interstitial Cells of Cajal (ICC), the current definition of gastrointestinal mesenchymal tumors, while smooth muscle-derived or neurogenic tumors account for only a very small percentage.
In 1960, Matin et al. first reported 6 cases of cytoplasm-rich round or polygonal cell tumors of the gastric wall, named gastric epithelioid smooth muscle tumors; in 1962, Stout reported 69 cases of mesenchymal tumors of the stomach, called “odd-type smooth muscle tumors” or “smooth muscle In 1962, Stout reported 69 cases of mesenchymal tumors of the stomach, which were called “odd-type smooth muscle tumors” or “smooth muscleoblastoma”; in 1969, they were called epithelioid smooth muscleoblastoma in the WHO tumor classification, but they were not given sufficient attention, although there were doubts because no evidence of smooth muscle was found under electron microscopy. GIST was defined to include all gastrointestinal spindle cell tumors of unknown biological behavior and origin. In 1998, Kindblon et al. showed that GIST is similar to Cajal cells surrounding the interosseous plexus of the gastrointestinal tract, with positive expression of c-kit gene, CD117, and CD34. ICC are gastrointestinal pacemaker cells, so it is also called gastrointestinal pacemaker cell tumor (GIST). （ICC is a gastrointestinal pacemaker cell, so it is also called Gastrointestinal Pacemaker Cell Tumor (GIPACT). However, GIST can occur outside the gastrointestinal tract, such as the greater omentum and mesentery, and GIST tumor cells do not have ICC function. Therefore, it is now thought that GIST may not originate from ICC but from a precursor cell (mesenchymal stem cell) homologous to ICC, which may also explain the focal myogenic marker expression in some tumor cells. Therefore, most authors currently disagree with the use of GIPACT nomenclature instead of GIST nomenclature. The GIST nomenclature is more appropriate at this stage.
(B) Pathological features
1. Gross morphology
The tumor varies in size from 0.2 cm to 44 cm, originating from the intrinsic muscular layer of the gastrointestinal tract wall, and can grow intraluminal, extraluminal, or both intraluminal and extraluminal. Therefore, according to the location of the tumor body, it can be classified as intraluminal, intramural, dumbbell, extraluminal and intra-abdominal gastrointestinal tract. Most of the tumors are swollen, with clear borders, hard and friable; the cut surface is flesh-like, gray-red, and secondary changes such as hemorrhage, necrosis and cystic change may be present in the center. The number of tumors may be multiple.
2. Histological characteristics
GISTs are mainly composed of spindle cells and epithelioid cells, both of which can appear in different tumors at the same time, but with a wide range of morphological changes. Based on the number of both types of cells, they can be divided into spindle cell type, epithelioid cell type and mixed spindle and epithelioid cell type. The arrangement of tumor cells is also diverse, with bundle and sheet-like arrangements predominating. The morphology of the stomach and small intestine was highly variable, while the morphology of the rectum was less variable, mostly of spindle cell type, with many crossed bundle arrangements. The tumor cells are unequally differentiated and may appear as vacuolated cells and ring-like cells at the nuclear end.
3. Immunohistochemical characteristics
Immunohistochemical studies of GISTs have shown that CD117 (c-kit) and CD34 are important markers. 80-100% of GISTs have diffuse CD117 expression, while smooth muscle cells and nerve fibers do not express CD117. 60-80% of GISTs have diffuse positive CD34 expression in tumor cells, and benign GISTs have higher CD34 expression. CD34 expression is specific and valuable in differentiating GISTs from smooth muscle tumors or tumors of neurogenic origin, and CD117 is often positively expressed when CD34 is positively expressed. In addition, GISTs can also have expression of myogenic or neurogenic markers, such as 2-SMA, desim, and S-100. However, the positivity rate is low and mostly focal positive.
(iii) Clinical manifestations
GISTs are the most common mesenchymal-derived tumors of the gastrointestinal tract, accounting for 1 to 3% of malignant tumors of the gastrointestinal tract, with an estimated annual incidence of about 1 to 2/10,000, mostly in middle-aged and elderly patients, rare in patients under 40 years of age, and no significant difference in incidence between men and women. Most GISTs occur in the stomach (50-70%) and small intestine (20-30%), colorectal about 10-20%, esophagus 0-6%, mesenteric, omental and retroperitoneal rare.
The symptoms of GISTs depend on the size and location of the tumor and are usually nonspecific. Bleeding from the gastrointestinal tract is the most common symptom. In the esophagus, symptoms of dysphagia are often common as well. Some patients are seen for bowel perforation, which can increase the risk of abdominal implantation and local recurrence.
Approximately 11-47% of patients with GISTs have metastases at the time of their first visit. Metastases are mainly in the liver and abdominal cavity, while lymph node and extra-abdominal metastases are rare even in more advanced patients. Metastases can occur even 30 years after resection of the primary tumor. Small bowel GISTs have the highest rate of malignancy and lymph node metastasis, while esophageal GISTs are less malignant. Therefore, strictly speaking, GISTs are not benign or at least a class of malignant tumors including potentially malignant.
CT, ultrasound endoscopy, and gastrointestinal imaging can assist in the determination of the size, local infiltration, metastasis, and location of GISTs.
(iv) Diagnosis and differential diagnosis
Preliminary diagnosis can be made based on the clinical manifestations of the patient’s GI bleeding or from time to time, combined with the findings of non-mucosal occurrence of tumors by endoscopy such as gastroscopy and enteroscopy, and tumors occurring in the wall of the GI tract as shown by CT or endoscopic ultrasound. Gastrointestinal imaging can help diagnose the exact location and approximate extent of the tumor in the gastrointestinal tract. However, clinical diagnosis is not sufficient to confirm the diagnosis of GISTs, which ultimately requires pathological sections and immunohistochemistry results. The typical immunohistochemical phenotype of GISTs is positive for CD117 and CD34. Nearly 30% of cases are positive for SMA, and a small percentage of cases are positive for S-100 and Desmin interstitial protein. However, a few cases (<5%) were CD117 negative, and some CD117-positive non-GISTs tumors were present. Therefore, the immunohistochemical diagnosis of GISTs is not absolute and needs to be combined with clinical and general pathological findings, and sometimes other tumors need to be excluded by immunohistochemistry.
GISTs often need to be differentiated from the following tumors, which often have clinical manifestations similar to those of GISTs.
1. Gastrointestinal smooth muscle tumors/sarcomas Most GISTs have diffuse positive expression of CD117 and CD34 and no or focal SMA expression, while smooth muscle tumors/sarcomas have negative CD117 and CD34 expression and diffuse positive SMA expression.
2, Gastrointestinal nerve sheath tumors S-100 expression was found in only a few cases of GISTs, whereas gastrointestinal nerve sheath tumors had diffuse positive expression of S-100 and negative expression of CD117 and CD34.
3, Gastrointestinal autonomic neuroma CD117, CD34, S-100, SMA and Desmin were negatively expressed, and neurosecretory granules were visible on electron microscopy.
In addition to clinical factors such as local infiltration, metastasis and recurrence, tumor site is also a consideration in determining the malignancy of GISTs, which is generally said to be less malignant in the stomach, esophagus and rectum, and more malignant in the small intestine and colon. The size of the tumor and the number of nuclear divisions are also one of the criteria to determine the malignancy of GISTs. (See the table below)
Table Determination of malignancy of GISTs
Malignant degree Tumor size (maximum diameter, cm) Nuclear division number/50HPF
Low grade △
Stomach ≤5 ≤5
Small intestine ≤2 ≤2
Moderate △
Stomach 5～10 ≤5
Small intestine 2～5 ≤5
High △△
Stomach >10 >5
Small intestine >5 >5
Note: △ Both tumor size and nuclear division number must be met.
△△ Tumor size and nuclear division number can be met by one of them
(V) Treatment
The traditional treatment of GISTs is mainly surgery. Although great progress has been made recently in the pathology and basic research of GISTs, and new chemotherapeutic drugs have also been researched, surgery is still the best treatment method to achieve clinical cure.
1. Surgical treatment and principles
Due to the potential malignancy of GISTs, clinical suspicion of GISTs should be performed according to the principles of malignant tumor surgery. Since GISTs are often brittle, rich in blood supply, and metastasize through blood and peritoneum, special attention should be paid to avoid tumor rupture and extrusion during surgery, and the supply and return vessels should be ligated first for intestinal GISTs. Intraoperative biopsies should not be taken in suspicious cases unless the tumor is not curable.
GISTs are generally not suitable for tumor removal. GISTs of the stomach with a diameter of <3 cm can be locally resected or wedge resection with the cutting edge at least 3 cm from the tumor; 3-5 cm should be wedge resection or major gastrectomy with the cutting edge at least 5 cm from the tumor; those with a diameter of >5 cm should be operated according to the scope of D2 clearance for gastric cancer. For rectal GISTs, especially lower GISTs, surgical management is sometimes very difficult, because it is difficult to determine their malignancy before surgery. The choice between anus preservation and enlargement should be made on the premise of full preoperative consultation with the patient. For those with local infiltration or distal metastasis, combined organ resection should be performed under the premise of radical treatment.
2. Chemotherapy
Traditional chemotherapy GISTs as smooth muscle sarcoma treatment, the common scheme is Adriamycin + cisplatin (AD scheme), clinical remission rate <10%, the efficacy is not good.
3. Targeted therapy
Imatinib: Imatinib, an inhibitor of c-kit kinase activity, has been used in clinical practice for the first time in 2000, mainly for patients who cannot undergo radical surgery, and has also been reported for high-risk GISTs. The application method is 400-800 mg/day for 12-24 months. According to the phase II clinical study, PR reached 63% and SD reached 20%; the phase III clinical study still lacks long-term follow-up reports, but PFS at 6 months was reported to be over 70%. Imatinib for neoadjuvant chemotherapy in GISTs has also been reported to be successful in small samples.
Sunitinib (Sutent ): Results of a new study reported at the 2005 ASCO Annual Meeting confirmed that sunitinib, a new tyrosine kinase inhibitor, significantly prolonged survival in patients with gastrointestinal mesenchymal tumors (GISTs) who were not responding to imatinib (Gleevec) therapy. Although gastrointestinal mesenchymal tumors are relatively rare, this study provides a new investigational agent for the treatment of imatinib-resistant patients with other solid tumors.
Although imatinib inhibits multiple tyrosine kinase receptor pathways, its treatment-induced kinase receptor mutations often lead to the development of drug resistance. Sunitinib inhibits multiple tyrosine kinase pathways such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor alpha (PDGFR-α). Showing better activity in early studies, Dr. Demetri and his colleagues investigated its effect in GIST patients who were no longer treated with imatinib. They conducted a double-blind, phase III randomized controlled clinical study comparing sunitinib with placebo in patients whose disease progressed after imatinib treatment or who had difficulty tolerating its severe adverse effects, enrolling 312 patients, 208 in the treatment group and 104 in the control group. The treatment regimen consisted of 50 mg/d orally for four weeks with a two-week stoppage and a six-week course. Patients were unblinded immediately if disease progression was detected, and in the case of patients in the placebo group, they were treated with the treatment regimen. Results of the interim study found that the mean time to tumor progression was 1.5 months in the control group and 6.3 months in the treatment group, a statistically significant difference. The investigators used CT and PET examinations to evaluate the patients’ response to treatment. CT showed no significant change in the size of the primary lesion, but PET scans revealed a significant reduction in metastases.
Currently, the U.S. FDA has approved sunitinib for gastrointestinal mesenchymal tumors that have progressed or are resistant to Gleevec. Common side effects of sunitinib include: diarrhea, skin discoloration, inflammation of the mouth, weakness, and taste changes.
Sorafenib: Gelderblom of Leiden University Medical Center in the Netherlands presented a study at the 2009 ASCO Gastrointestinal Oncology Symposium on the use of sorafenib in fourth-line treatment of gastrointestinal mesenchymal tumors (GIST) after treatment failure with imatinib, sunitinib, and erlotinib. The study showed that sorafenib still showed significant clinical efficacy in patients who had undergone multiple lines of treatment.
(vi) Prognosis
The overall 5-year survival rate of GISTs is 35%, with a 5-year survival rate of 50-65% for complete tumor resection and <12 months for those who cannot be resected. Tumor location, size, nuclear division number and age are all related to prognosis. Esophageal gists have the best prognosis, while small bowel gists have the worst prognosis. < p="">