Gastrointestinal stromal tumors (GISTs) are the most common sarcomas of the digestive tract. They require multidisciplinary collaboration in oncology involving the specialties of surgeons, pathologists, molecular biologists, radiologists, oncologists, and gastroenterologists.1 Sporadic or familial genetic mutations in the KIT, PDGFRA, HRAS, NRAS, BRAF, NF1, or the SDH genes result in GIST development. The National Comprehensive Cancer Network (NCCN), the European Society for Medical Oncology (ESMO), and many other countries have devised clinical practical guidelines for the diagnosis, treatment, and follow-up priorities with GIST patients. These guidelines are updated annually or biannually based on current research on best evidence-based practices and expert consensus to improve patient outcomes and reduce healthcare costs.2
The NCCN guidelines for GISTs recommend evaluation of GIST by a multidisciplinary team with experience in sarcoma diagnosis and treatment. Abdominal/pelvic CT scan with contrast, with or without MRI, and chest imaging are recommended to rule out metastasis of GIST. Small gastric GISTs (less than 2 cm) may be assessed using endoscopic ultrasound-guided (EUS) fine-needle aspiration.3,4 For gastric GISTs larger than 2 cm, endoscopy with or without ultrasound may be utilized on a case-dependent basis.3
KIT and PDGFRA mutation genotyping are highly recommended especially when medical therapies are a considered intervention.3 Mutational analysis is considered standard practice for diagnostic assessment with possible exclusion of non-rectal GISTs that are less than 2 cm in size.4 Genotyping may guide decision-making on medication selection and dosage based on projected responsiveness of GIST to imatinib and other tyrosine kinase inhibitor (TKI) interventions.3
GISTs usually test positive in immunohistochemical assays for the expression of c-kit protein (CD117) in KIT-positive GISTs and the DOG1 protein in about 40% of KIT-negative GISTs.2 In wild-type GISTs which lack KIT or PDGFRA mutations, mutation testing of the succinate dehydrogenase (SDH) gene is indicated. Loss-of-function mutations within the SDH gene subunits (SDHB, SDHC, and SDHD) are associated with the autosomal dominant familial syndrome, Carney-Stratakis Syndrome. Next-generation sequencing should be performed to search for alternative driver mutations such as the BRAF, NF1, NTRK, and FGFR fusions as this sequencing may identify tumors that will respond to targeted drug therapy.3
Tumor Classification Systems
The World Health Organization (WHO) updated its classification system for sarcomas including more molecular and cytogenetic data into the classifications. According to WHO, GISTs are classified into three subtypes: benign, uncertain malignant potential, and malignant.
The French Federation of Cancer Centers Sarcoma Group (FNCLCC) and the National Cancer Institute (NCI) developed the most used tumor grading systems for sarcomas. FNCLCC bases grading on tumor differentiation, necrosis, and mitotic activity. NCI bases tumor grading on histology, location, and tumor necrosis. The FNCLCC predicts metastasis development and mortality slightly better than NCI in comparison studies.
The American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) separates GIST grading from other sarcomas using a two-grade system based on mitotic rate.
- Low risk is considered having a mitotic rate of less than or equal to 5 mitoses per 5 mm2, or per 50 high-power field (HPF)
- High risk is considered having a mitotic rate of greater than 5 mitoses per 5 mm2, or per 50 HPF
For GIST staging, the NCCN and ESMO guidelines follow the AJCC/UICC’s tumor-node-metastasis (TNM) classification, dividing into four distinct stages with subdivisions.3
|IA||T1 or T2||N0||M0||Low|
|IV||Any T||N1||M0||Any grade|
|Any T||Any N||M1||Any grade|
T1 indicates tumor size less than or equal to 2 cm. T2 indicates tumor size between 2 and 5 cm. T3 indicates that tumor size is greater than 5 cm but less than 10 cm. T4 indicates tumor size greater than 10 cm. N0 indicates no regional lymph nodes have metastasis. N1 indicates regional lymph nodes have metastasis. M0 indicates no distant metastasis. M1 indicates distant metastasis.5
NCCN recommends surgical resection for small gastric GISTs less than 2 cm with no high-risk features. High risk features include irregular borders, ulceration, heterogeneity, cystic spaces, and echogenic foci. GISTs less than 2 cm should be monitored using endoscopic ultrasound-guided fine-needle aspiration (EUS) to consider the need for surgical resection. If the GISTs are classified as low-risk, they may be periodically monitored using EUS or other imaging methods. GISTs larger than 2 cm should be evaluated using endoscopy with or without ultrasound to consider the need for resection. Surgical resection is recommended for known GISTs that are larger than 2 cm but which have a minimal risk of morbidity with resection.3,4 For GISTs that are resectable but have increased likelihood of morbidity, NCCN recommends use of neoadjuvant therapy using imatinib or avapritinib for imatinib-resistant GISTs resulting from PDGFRA exon 18 mutations, especially the D842V mutation. If the drug therapy is successful in reducing morbidity risk by decreasing tumor size, the surgeon can consider the feasibility of surgical resection. After complete resection of GISTs, oncologists should prescribe adjuvant imatinib for patients whose GISTs have an intermediate or high likelihood of recurrence. Patients who received neoadjuvant imatinib should continue using imatinib following surgical resection. Follow-ups after resection for abdominal and pelvic CT scans should continue every 3 to 6 months for 5 years. If the disease has not progressed over that period, follow-ups may switch to annually.3
ESMO guidelines stipulate endoscopic ultrasound-guided (EUS) assessment for patients with small esophagogastric or duodenal GISTs less than 2 cm. These individuals should have an EUS annually to monitor progression. If the GIST grows or the patient becomes symptomatic, surgical resection is the treatment of choice. The standard treatment for localized GISTs is complete surgical resection without removal of clinically negative lymph nodes.4 For small rectal GISTs, ESMO recommends excision regardless of size. Any GIST larger than 2 cm requires biopsy. For large GIST resection, ESMO recommends open surgery versus laparoscopic approach.3,4
NCCN recommends TKI therapy for cases of advanced disease, including recurrent, metastatic, or unresectable GISTs. The first line of TKI therapy is imatinib which may be used as a neoadjuvant treatment prior to resection. If resection is still not possible following this treatment, the imatinib therapy should continue. If patients develop imatinib-resistant GISTs through secondary mutations or have a form of GIST that is already imatinib-resistant, NCCN recommends therapy with the second-line TKI, sunitinib. If the patient’s GIST progresses after taking imatinib and sunitinib, drug therapy should switch to regorafenib, and when regorafenib no longer is effective, ripretinib is recommended.3 If clinical benefit (stable disease or responsiveness to drug therapy) is apparent, oncologists should continue lifelong palliative TKI therapy to improve quality of life and provide optimal patient care.
Grupo Espanol de Investigacion en Sarcomas (GEIS) guidelines following failed responses to imatinib, sunitinib, and regorafenib include possible use of fourth-line TKIs: sorafenib, pazopanib, and ponatinib, which target secondary KIT mutations.1
GEIS and ESMO recommend avoidance of adjuvant therapy in patients with neurofibromatosis type 1 and SDH expression-negative GISTs.1,4 PDGFRA D842V-mutated GISTS should not be treated with adjuvant imatinib.1,2,3,4 GEIS suggests that adjuvant therapy consideration for patients with wild-type GIST is on a case-by-case basis. For low-risk patients with microscopic margins after surgical resection, there is a lack of evidence supporting the efficacy of adjuvant therapy; therefore, the surgeon should consider surgical re-excision for these patients.1 ESMO suggests consideration of imatinib therapy for patients at high-risk of peritoneal relapse due to tumor rupture during surgical resection.4
According to ESMO, no research publications indicate optimal routine follow-up procedures for patients surgically treated with localized disease. Relapses often occur in the liver, peritoneum, bone, and other sites of metastasis. Risk assessment using mitotic index, tumor size, and tumor location may aid in selecting routine follow-up scheduling. High-risk patients generally relapse in 1 to 3 years following completion of adjuvant therapy. Low-risk patients may relapse later, but this is more unlikely.4
Routine follow-ups for GIST patients differ among institutions. Many institutions schedule high-risk patients for follow-ups with a routine abdominal/pelvic CT scan or MRI every 3-6 months for 3 years during adjuvant therapy to monitor disease progression and treatment efficacy. More frequent follow-ups may be necessary to manage drug side effects.
On completion of adjuvant therapy, follow-ups are scheduled every 3 months for a 2-year duration to monitor disease recurrence/progression. If the disease remains stable or does not recur, follow-ups are scheduled every 6 months for 5 years, then annually for another 5 years.4
For low-risk GISTs, CT scans or MRIs are suggested every 6 to 12 months for 5 years. For very low-risk GISTs, follow-ups may not be required, but the risk of disease progression is not zero. To minimize exposure for x-ray radiation, abdominal MRIs are an alternative imaging option.4
- Poveda A, Muro XG del, López-Guerrero JA, et al. GEIS guidelines for gastrointestinal sarcomas (GIST). Cancer Treatment Reviews. 2017; 55:107-119. doi:10.1016/j.ctrv.2016.11.011
- Nishida T, Blay J-Y, Hirota S, Kitagawa Y, Kang Y-K. The standard diagnosis, treatment, and follow-up of gastrointestinal stromal tumors based on guidelines. Gastric Cancer. 2016; 19(1):3-14. doi:10.1007/s10120-015-0526-8
- Choti, MA. Gastrointestinal stromal tumors (GISTs): guidelines. Medscape. Accessed June 29, 2021.
- Casali PG, Abecassis N, Bauer S, et al. Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2018; 29:iv68-iv78. doi:10.1093/annonc/mdy095
- Choti, MA. Gastrointestinal stromal tumors (GISTs): staging. Medscape. Accessed June 29, 2021.
Article reviewed by Debjyoti Talukdar, MD on July 1, 2021.