Gastrointestinal mesenchymal tumors arise from Cajal mesenchymal (Cajal) stromal cells or common precursor cells, both of which express type III tyrosine kinase receptors. Mutations in the tyrosine kinase receptor c-KIT (CD117) or related tyrosine kinase receptors lead to uncontrolled cell growth and mesenchymal tumor formation. Gastrointestinal mesenchymal tumors are non-epithelial, mesenchymal cell tumors. It is the most common soft tissue malignancy of the abdomen.
Incidence and pathologic staging
In the United States, the annual incidence of gastrointestinal mesenchymal tumors is estimated to be between 3 and 7 per million. In Europe, Korea and Hong Kong, higher rates of 15-20 per million have been reported. Because incidence data are extracted from large data from tumor registries, where benign tumors are not recorded, it is often assumed that the true incidence of gastrointestinal mesenchymal tumors may be higher.
New cases of diagnosed gastrointestinal mesenchymal tumors have increased exponentially since 1998. This is due to the discovery of its reliable biomarkers c-KIT and platelet-derived growth factor receptor alpha polypeptide. Retrospective surveillance, epidemiology and end results (SEER) data reveal a progressive increase in the proportion of mesenchymal cell tumors classified as gastrointestinal mesenchymal tumors.
Gastrointestinal mesenchymal tumors were most commonly found in the stomach (50% to 60%), followed by the small intestine (30% to 35%), colon and rectum (5%), esophagus (<1%< span="">), and a small proportion outside the GI tract (mesenteric, greater omentum, and retroperitoneum; <5%< span="">). The mean age at diagnosis was 63 years. Less than 1% of patients were under 20 years of age. Familial symptoms such as Carney’s triad, familial gastrointestinal mesenchymal tumor symptoms, or gastrointestinal mesenchymal tumor-associated neurofibromatosis types are usually found within 20 years of age.
Although mesenchymal cell tumors are rare, there is an increasing number of types of mesenchymal cell tumors with well-defined molecular characteristics. They are usually classified as gastrointestinal mesenchymal tumors, smooth muscle tumors (benign smooth muscle tumors or malignant smooth muscle sarcomas), and nerve sheath tumors. The classification of mesenchymal cell tumors involves the gastrointestinal tract and surrounding soft tissues and now also includes gastrointestinal mesenchymal tumors, inflammatory fibrous polyps, sclerofibromas, synovial sarcomas, inflammatory myofibroblastomas, and clear cell sarcomas. However, gastrointestinal mesenchymal tumors remain the most common mesenchymal cell tumors affecting the GI tract. Gastrointestinal mesenchymal tumors are c-KIT and PDGFRA-associated mesenchymal cell tumors.
Clinical presentation, diagnosis and imaging of gastrointestinal mesenchymal tumors
In many patients, the early presentation of gastrointestinal mesenchymal tumors can be nonspecific, such as vague abdominal discomfort and bloating.
Up to 25% of patients have incidental findings on imaging studies, such as renal colic or injury. Symptoms are related to the size of the tumor. Because gastrointestinal mesenchymal tumors occur in the submucosa and do not show local infiltration, they can grow larger than tumors in the mucosal layer before causing bleeding or obstructive symptoms. The average diameter reported in the literature is 10-13 cm, and gastrointestinal mesenchymal tumors larger than 5 cm are more likely to be symptomatic.
The most common symptoms of GI mesenchymal tumors are gastrointestinal bleeding, abdominal pain, or ulcer-like symptoms. The degree of GI bleeding can range from anemia due to occult chronic bleeding to life-threatening black stools or vomiting of blood. Sometimes gastrointestinal mesenchymal tumors can also present as palpable masses, intestinal obstruction or, in a few cases, acute abdominal hemorrhage due to free rupture of a large tumor in the abdominal cavity.
1.About size and symptoms
Recently, there have been reports of a group of small gastrointestinal mesenchymal tumors. These tumors, defined as those less than 1 cm in diameter, were first reported in Japan and were found incidentally in up to 35% of middle-aged and elderly autopsies. These microscopic tumors have the same KIT or PDGFRA mutations as clinically detected gastrointestinal mesenchymal tumors. Because of their higher incidence, microscopic mesenchymal tumors are thought to be precursor lesions to gastrointestinal mesenchymal tumors. However, it is still unknown whether molecular alterations or second strikes lead to larger, more malignant tumors. The criteria for whether microscopic gastrointestinal mesenchymal tumors require imaging follow-up or prophylactic resection are still to be determined.
2.Tumor site
Tumor anatomical site is also associated with tumor pathology and prognostic changes. Esophageal and gastric mesenchymal tumors are usually smaller in size and have a smaller average mitotic count when detected compared to small bowel mesenchymal tumors. They also typically have better overall survival rates. However, small bowel mesenchymal tumors may respond better to imatinib.
Most gastrointestinal mesenchymal tumors are found in the abdominal cavity. Previous studies have demonstrated that 50% of patients already have metastases at the time of detection. The liver is the most common site of metastasis, but rarely invades regional lymph nodes or extra-abdominal organs. Pathologic lymph node involvement in resected specimens is usually considered to be an implant metastasis rather than true lymph node dissemination. The overall risk of recurrence in patients with primary gastrointestinal mesenchymal tumors who undergo resection is approximately 30%. There was no difference in recurrence-free survival between R0 and R1 resections. The median time to recurrence was 12-16 months. 80% of recurrences occurred within two years after surgery. However, intraoperative tumor rupture or intra-abdominal hemorrhage significantly reduced the tumor-free survival time.
3. Diagnostic imaging results
The main form of diagnosis is usually CT, but MRI can also be used. Gastrointestinal mesenchymal tumors grow endogenously in the submucosa, making them more difficult to distinguish size and extent on imaging compared to other epithelial tumors. As mentioned previously, gastrointestinal mesenchymal tumors can be viewed on high-resolution stage III CT as heterogeneous masses with a rich blood supply and irregularities that often occur in the stomach or small intestine. As with other foregut tumors, three-stage CT (oral and venous imaging, arterial and venous stages) provides a better understanding of the nature and extent of the vascularity of these tumors. Since most metastases are intra-abdominal, abdominal CT scans are sufficient to capture most metastatic lesions. Due to submucosal growth, direct visual upper gastrointestinal endoscopy is challenging and does not allow accurate localization of the biopsy specimen.
After imaging, preoperative biopsy is largely unnecessary if mesenchymal cell tumors are highly suspected and resectable. However, in cases of apparent metastasis or at the margins of surgical resection, tissue biopsy is critical to localize specific mutations and systemic molecular therapy. In many medical centers, ultrasound endoscopic biopsy is performed more often than percutaneous CT-guided biopsy. For tissue biopsy, laparoscopy may also be considered. The obtained tissue can be used for immunohistochemistry and mitotic count analysis. Fine needle aspiration can also be used for cytology and histology. Follow-up immunohistochemical staining can be performed with KIT, PDGFRA, CDKN2A, PI3K and DOG1 markers.
4. Imaging for efficacy assessment
The two most common imaging studies used to assess the staging and efficacy of gastrointestinal mesenchymal tumors are contrast-enhanced CT and positron emission tomography (PET), which can be used for initial evaluation and trend analysis of disease progression. Standardized uptake values (SUV) and maximum SUV allow PET scans to quantify trends in tumor metabolism over time and to compare two different sites of the same tumor simultaneously. The response of gastrointestinal mesenchymal tumors to imatinib can be seen on PET scans as early as 1 week after treatment.
Since the metabolic response precedes the anatomical response. Specifically, PET scans can detect a response to systemic molecular therapy several months before conventional three-stage CT abdominal and pelvic scans. Previous studies have shown metabolic reductions of more than 25% in metastatic gastrointestinal mesenchymal tumors treated with imatinib. PET scans can complement the ambiguity of CT scans.
For example, liver metastases that appear isointense on CT scans and are missed in disease assessment can be seen on PET scans. While the role of PET in this regard remains prospective, it can also be helpful in providing information related to tumor function. Another situation in which PET scans may be helpful is in the assessment of early response in neoadjuvant chemotherapy (as evidenced by reduced metabolic activity), which may be converted to surgery rather than continuing systemic molecular therapy.
Tyrosine kinase receptor mutations and gastrointestinal mesenchymal tumor pathogenesis Gastrointestinal mesenchymal tumor pathogenesis is dominated by two mutations: the KIT gene (and its associated overexpression of the tyrosine kinase KIT receptor) and the PDGFRA gene. Between 80-85% of patients with gastrointestinal mesenchymal tumors exhibit positive KIT or PDGFRA mutations. The latter is a transmembrane tyrosine kinase receptor that is thought to transduce multiple downstream signaling pathways including PI3K/AKT/mTOR and MAPK/STAT3 ultimately leading to cell proliferation, angiogenesis and anti-apoptosis. All these pathways are thought to play a key role in the development of gastrointestinal mesenchymal tumors. Notably, mutations in KIT and PDGFRA are independent of each other and patients do not become positive for both.
The cell morphology of gastrointestinal mesenchymal tumors includes a predominantly spindle-shaped (70%) and epithelial appearance (20%). KIT-positive gastrointestinal mesenchymal tumors usually exhibit a spindle-shaped cell morphology, whereas KIT-negative gastrointestinal mesenchymal tumors with PDGFRA mutations can be epithelial or mixed. Familial gastrointestinal mesenchymal tumors are most commonly characterized by c-KIT exon 11 mutations.
Gene microarray analysis has yielded additional gastrointestinal mesenchymal tumor markers, most notably the DOG1, FLJ10261 gene, which is widely expressed in all mutant types of gastrointestinal mesenchymal tumors. In immunocytochemistry, DOG1 was associated with the expression of the calcium gating protein anoctinin-1. It is positive in 97% of gastrointestinal mesenchymal tumors and, together with c-KIT, has a sensitivity of 100% in detecting gastrointestinal mesenchymal tumors.
The significance and clinical applications of DOG1 mutations include: DOG1 antibodies are more sensitive than KIT antibodies, especially in detecting gastric mesenchymal tumors and PDGFRA mutated mesenchymal tumors. dOG1 immunoreactivity is not seen in other mesenchymal cell tumors, making it highly specific for gastrointestinal mesenchymal tumors. These data have led many medical centers to use DOG1 as a key biomarker for the diagnosis of gastrointestinal mesenchymal tumors. The immune response of DOG1 in other sarcomas should be determined before its widespread use as a diagnostic.
Treatment of gastrointestinal mesenchymal tumors
1. Surgical resection of limited lesions
Prior to the discovery of c-KIT and PDGFRA mutations, surgical resection was the only possible cure for gastrointestinal mesenchymal tumors. Less than half of the patients underwent resection of the primary site only because of the presence of metastases. In a retrospective analysis of 200 surgically resected cases, DeMatteo et al. showed that 46% of patients had only primary lesions, 47% had metastases, and 7% presented with local recurrence. Only 33% of patients underwent R0 resection. When the primary tumor is resected, tumor size is a prognostic factor. In addition, for patients without metastasis who had R0 resection of the primary site, the local recurrence rate was 35%, and 44% had recurrence to the liver, resulting in an overall 5-year survival rate of only 54%.
2. In the past, laparoscopic surgery for gastric mesenchymal tumors was performed only by wedge resection.
This technique is safe and feasible from an oncological point of view. More advanced laparoscopic techniques are being developed all the time. A recent study compared 78 patients undergoing laparoscopic gastric wedge resection, major gastrectomy and combined laparoscopic endoscopic surgery (LECS). In the combined bimicroscopic procedure, the endoscope was used to peel the tumor mucosa from the gastric lumen. In this study, all procedures were performed with adequate tumor resection, and laparoscopic wedge resection was safe and effective for gastric mesenchymal tumors smaller than 5 cm.
3. Tyrosine kinase inhibitors for the treatment of gastrointestinal mesenchymal tumors
Prior to the introduction of imatinib, gastrointestinal mesenchymal tumors were thought to be drug-resistant because non-targeted conventional chemotherapeutic agents were ineffective, and this changed in 1999 when KIT expression was first reported in gastrointestinal mesenchymal tumors. Shortly thereafter, Novartis introduced imatinib mesylate for the treatment of chronic myelogenous leukemia. Imatinib inhibits Bcr-Abl kinase in the pathogenesis of chronic myeloid leukemia. The similarity between KIT and Bcr-Abl signaling led to a phase 1 clinical trial of imatinib in patients with advanced gastrointestinal mesenchymal stromal tumors, which yielded results.
4. Imatinib for the treatment of metastatic gastrointestinal mesenchymal tumors
Imatinib has been shown to be effective in metastatic gastrointestinal mesenchymal tumors in small phase 1 phase 2 clinical trials and in at least two multicenter prospective randomized controlled phase 3 trials. It is important to note that imatinib is an inhibitor of the cytochrome P450 system. Therefore, imatinib can interact with many drugs, including warfarin. In addition, some drugs may affect the metabolism of imatinib, which may lead to reduced clinical effects. Such drugs include phenytoin sodium, rifampin, and goldenseal.
Summary of treatment points
1, Patients with gastrointestinal mesenchymal tumors with negative tumor gross margins (regardless of R0/R1) have the best chance of long-term survival.
2. The complication rate of laparoscopic resection and combined laparoscopic-endoscopic surgery is comparable to that of open surgery.
3, metastatic gastrointestinal mesenchymal tumor.
a. First-line therapy is imatinib 400 or 800 mg per day;
b. Patients with positive KIT exon 9 mutations may be treated with imatinib at a starting dose of 800 mg per day; c. Interruption of dosing will result in reduced survival and imatinib should be continued until disease progression or surgical resection.
4. Adjuvant chemotherapy for gastrointestinal mesenchymal tumors
a. Imatinib after R0 or R1 resection in patients with gastrointestinal mesenchymal tumors improves survival time. b. Mutation analysis shows that patients with exon 11 deletion have the best prognosis.
5, gastrointestinal mesenchymal tumor drug resistance
a. Second-line therapy: sunitinib, a multitargeted tyrosine kinase inhibitor, has the best prognosis in wild-type gastrointestinal mesenchymal tumors and in patients with KIT exon 9 mutations;
b. Third-line therapy: Regifinil 160 mg daily for patients with tumor progression on second-line therapies such as sunitinib.
6. Neoadjuvant therapy for gastrointestinal mesenchymal tumors with potential for resection
Preoperative imatinib for 8-10 weeks increases the likelihood of surgical resection and long-term survival.
Molecular identification of gastrointestinal mesenchymal tumors has significantly improved the accuracy of diagnosis. Although surgery is currently the only potentially curative treatment, the continued use of imatinib and sunitinib has significantly reduced mortality and prolonged survival over the past decade.
Complete resection of metastatic foci has also improved the likelihood of long-term survival. Mutation phenotype identification continues to improve the prognosis of patients with gastrointestinal mesenchymal tumors. In parallel, more intensive large prospective randomized trials are underway to identify better individualized treatments for this disease.