Gastrointestinal stromal tumors (GIST) are quite rare, accounting for about 1% of all gastrointestinal malignancies. However, they are the most common mesenchymal tumors of the gastrointestinal tract and constitute 10-15% of all sarcomas. Their incidence is currently estimated at about 15 cases per 1 million inhabitants per year. They were first described as a distinct entity in 1998 and are now treated surgically-oncologically within a multimodal treatment concept due to advances in systemic therapy with tyrosine kinase inhibitors. The basis of curative treatment for patients with GIST is complete tumor resection, as only this can achieve a cure.
GIST are defined as mesenchymal, spindle cell-like, or epithelioid cell tumors with immunohistochemical evidence of CD117 expression. As a special form, there are extra-gastrointestinal CD117 stromal tumors in the omentum, mesentery, and retroperitoneum.
The tendency for malignant transformation of GIST depends on tumor size and the number of mitoses and allows the following classification of malignancy risk (tumor size in cm, number of mitoses in n/50 HPF = "high-power-field", microscopic field):
very low risk: < 2 cm, < 5/50 HPF
low risk: 2-5 cm, < 5/50 HPF or < 5 cm, 6-10/50 HPF
intermediate risk: 5-10 cm, < 5/50 HPF or > 5 cm, > 5/50 HPF
high risk: > 10 cm, any number of mitoses or any size, > 10/50 HPF
In addition to tumor size and number of mitoses, the location of a GIST is also of prognostic significance. With the same tumor size and number of mitoses, a GIST of the stomach has a better prognosis regarding recurrence-free survival than a GIST of the small intestine after an R0 resection. Colorectal GIST have the worst prognosis. Classification is preferably based on the Miettinen classification, which calculates the risk of recurrence in percentage.
General Principles of Surgical GIST Therapy
Regardless of tumor size, malignancy risk, and organ manifestation, complete resection (R0) is the primary goal of surgical therapy, achieving 5-year survival rates between 48 and 65%. For small tumors (< 1 cm) that are incidentally discovered, some authors recommend a conservative approach. Prognosis for survival decreases with tumor sizes over 10 cm, despite R0 resection.
Compared to other solid tumors of the gastrointestinal tract, GIST have some peculiarities that must be considered to achieve surgical-oncological radicality:
1. GIST develop not in the area of the mucosa but in the muscularis propria.
This means that they can evade detection by endoscopically obtained mucosal biopsies, and also, for small, early GIST, an endoscopic mucosal resection cannot lead to an R0 resection. This can only be ensured by resection including the muscularis. Resection in the esophagus must extend into the peri-esophageal fat tissue, in the stomach into the free abdominal cavity, and in the rectum into the mesorectum.
2. GIST very rarely lead to lymphatic metastasis.
Unlike solid malignancies of the gastrointestinal tract, GIST do not tend to lymphatic metastasis. Only in far advanced metastatic stages can lymph node metastases occasionally be observed, then as distant metastases, e.g., in the axilla. Lymph node dissection is therefore unnecessary to achieve an R0 resection, and a safety margin of 2 cm is considered sufficient.
3. The indication for resection arises from a tumor size of 2 cm and in smaller GIST with detectable tendency to increase in size.
The surgical approach to GIST is based on tumor size, location, and, if known, the assessment of malignancy risk and thus does not fundamentally correspond to the resection principles of a solid carcinoma of the same organ. According to the recommendations of the NCCN (National Comprehensive Cancer Network of the USA) and the ESMO (European Society for Medical Oncology), the indication for resection arises from a tumor size over 2 cm, but also in the case of a detectable increase in size. A tumor size of 2 cm correlates with an increase in malignancy risk, which is no longer considered very low from 2 cm.
Primary GIST of the Stomach
The most common location of gastrointestinal stromal tumors is the stomach. Symptoms such as upper GI bleeding, dyspepsia, and upper abdominal discomfort occur in about 65-70% of cases, with upper GI bleeding being the most common symptom at 54%. In 17% of cases, a GIST tumor is incidentally discovered during diagnostic measures or other procedures.
The extent of resection primarily depends on tumor size and the recommended safety margin of 2 cm. Resection techniques primarily include local excisions or enucleations and wedge resections, rarely partial or total gastrectomies, and multivisceral procedures for large and metastatic tumors. The most commonly performed procedure is wedge resection, which can be considered adequate therapy for a GIST of the stomach as long as tumor-free resection margins are achieved and intraoperative tumor rupture can be prevented. Locally limited resection procedures for GIST of the stomach are possible because, regardless of tumor size, lymph node dissection can usually be omitted.
Laparoscopic Resection Procedures for GIST of the Stomach
Laparoscopic procedures are considered, for example, when a GIST is located on the greater curvature side and a tangential gastric wall resection can be performed. The criteria for oncological resection include not only a sufficient safety margin of 2 cm but also preservation of the tumor's pseudocapsule, no direct grasping of the tumor surface, and retrieval using a retrieval bag.
Adjuvant Therapy with Imatinib
Over 90% of all GIST are characterized by overexpression of the KIT receptor CD117, which is due to activating mutations in the C-KIT gene. While in normal cells activation of the KIT receptor occurs only after binding of a stem cell factor, the mutations lead to stem cell factor-independent activation, resulting in the malignant growth behavior of GIST.
Imatinib is a phenylaminopyrimidine derivative that can block the ATP-binding site of specific tyrosine kinases such as KIT and PDGFRA. This, in turn, blocks the signaling pathways through which the malignant growth behavior of GIST is mediated.
Patients with a high and possibly also with an intermediate recurrence risk according to Miettinen should therefore receive adjuvant therapy with Imatinib for 3 years after potentially curative surgery.
Procedure for Locally Advanced or Metastatic GIST
For a locally advanced GIST, pre-treatment with a tyrosine kinase inhibitor such as Imatinib is advisable. Neoadjuvant therapy not only facilitates an R0 resection by significantly reducing tumor size, but also leads to regression of neoangiogenesis zones, allowing extensive multivisceral resections such as gastrectomy with splenectomy, pancreas, and diaphragm resection in large gastric GIST to be avoided.
After starting neoadjuvant therapy with Imatinib in a primarily unresectable or metastatic GIST, most patients can be expected to respond within 6 months of starting therapy. The local conditions should therefore be reassessed after 6 months to determine whether resection of the residual tumor can be performed in an initially inoperable GIST. In metastatic GIST, resection of the residual tumor may be considered only after 12 months of neoadjuvant treatment.
If distant metastases are already present (liver, peritoneum) or if a local recurrence has occurred under therapy with Imatinib, the indication for resection must be made individually. It must be weighed whether further pharmacological measures can achieve disease control or whether resection of a liver metastasis or peritoneal spread is possible with acceptable risk.
Systemic antiproliferative treatment should definitely be continued even after successful resection of a metastatic residual tumor or a focally progressive metastasis. If it is discontinued, new metastases or tumor recurrence must be expected.