Gastrointestinal stromal tumours

What is a gastrointestinal stromal tumour?

Gastrointestinal stromal tumours (GISTs) are malignant mesenchymal tumours with a variable clinical behaviour, marked by differentiation towards the interstitial cells of Cajal. GISTs belong to the family of soft tissue sarcomas but are treated separately due to their peculiar histogenesis, clinical behaviour and specific therapy.¹

How common are gastrointestinal stromal tumours? (Epidemiology)²

• Gastrointestinal stromal tumours are the most common mesenchymal malignancy (sarcoma) of the gastrointestinal tract. However, they only comprise 1–2% of all GI malignancies. Most tumours affect the stomach and small intestine.

• The incidence of GIST is 10–15 cases per million worldwide. Small incidental lesions are commonly identified during abdominal surgery, radiological or endoscopic studies, and at autopsy.

• GISTs usually affect male Caucasians between the ages of 60 and 74 years.

• Advanced-stage disease is reportedly present in 47% of cases, usually with metastases to the liver and peritoneum.

• The median age of presentation is 60–65 years, but with a wide range. Occurrence in children is very rare.

Pathogenesis

GISTs originate from pluripotential mesenchymal cells committed to become interstitial cells of Cajal (ICC), which are the pacemaker cells situated between the circular and longitudinal layers of the muscularis propria along the GI tract. Most GISTs arise within the muscularis propria and appear as submucosal or mural masses in endoscopy or imaging.²

• There are oncogenic kinase mutations in most GISTs. 75-80% of GISTs have mutations of the KIT receptor tyrosine kinase.³

• 10% have mutations in tyrosine kinase platelet-derived growth factor receptor alpha (PDGFRA).⁴

• The different kinase mutations produce different clinical features and also have an impact on which part of the gastrointestinal tract the tumour affects, as well as how aggressive the tumour is.

Clinical features²

Symptomatic tumours present with a mass-like effect, leading to early satiety or obstruction, or symptoms associated with ulceration/tumour rupture, such as pain, bleeding, anaemia, and perforation.

All GISTs have the potential to become malignant. Aggressive GISTs tend to metastasise to the liver and/or throughout the abdomen. They rarely metastasise to the lymph nodes. Spread outside the abdominal cavity is unusual but, when it occurs, is usually to the lungs and bone.

They may also present as an incidental finding during investigation for other diseases.

Differential diagnosis

GISTs should be differentiated from other gastrointestinal non-epithelial neoplasms such as leiomyomas, leiomyosarcomas and schwannomas by immunohistochemical staining.

Investigations^{1 2}

Diagnosis relies on a combination of clinical, imaging, histopathology, immunohistochemistry, and molecular studies.

Endoscopic ultrasound assessment is the standard approach for patients with oesophagogastric or duodenal nodules less than 2 cm.

Mutational analysis inclusion in the diagnostic work-up of all GISTs should be considered standard practice, with the possible exclusion of less than 2 cm non-rectal GISTs.

Computed tomography (CT) is the gold standard for evaluating abdominal masses, since it provides information about the size, location, and presence or absence of regional and distant spread. The use of oral and intravenous contrast improves the evaluation of the tumour margins.

Associated diseases

• People with neurofibromatosis type I have an increased risk of developing GISTs.

• There is a familial gastrointestinal tumour syndrome.

• GIST can also form part of Carney's triad tumour syndrome (the association of gastric stromal tumours, paraganglioma and pulmonary chondroma occurring mostly in girls and young women).

Gastrointestinal stromal tumour treatment and management¹

Localised tumours

Biopsy/excision is the standard approach to tumours 2 cm or more in size. If a diagnosis of GIST is made on biopsy, resection is performed unless one major morbidity is expected. If a biopsy is not feasible, active surveillance is a valid alternative.

Subsequent management depends on the risk of recurrence according to the prediction of tumour behaviour.

Imatinib is a selective kinase inhibitor which binds to activated c-KIT receptors and blocks the cell signalling pathway, preventing uncontrolled cell proliferation. It is administered orally. Imatinib is recommended by NICE as an option as adjuvant treatment for up to 3 years for adults who are at high risk of relapse after surgery for KIT (CD117)-positive gastrointestinal stromal tumours.⁵

Advanced disease

Some metastatic GISTs may be technically resectable.

Imatinib treatment at 400 mg/day is recommended as first-line management of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic gastro-intestinal stromal tumours.⁶

Imatinib at 600 or 800 mg/day is not recommended by NICE for people with unresectable and/or metastatic gastrointestinal stromal tumours whose disease has progressed after treatment with 400 mg/day imatinib.⁷

Sunitinib is a tyrosine kinase inhibitor. It inhibits vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, which reduces tumour cell proliferation and tumour blood vessel development. Sunitinib is recommended by NICE as a treatment option for people with unresectable and/or metastatic malignant gastrointestinal stromal tumours if imatinib treatment has failed because of resistance or intolerance.⁸

Regorafenib is an oral multi-kinase inhibitor which targets angiogenic, stromal and oncogenic receptor tyrosine kinase. Regorafenib is recommended by NICE as an option for treating unresectable or metastatic gastrointestinal stromal tumours in adults whose disease has progressed on, or who are intolerant to, prior treatment with imatinib and sunitinib, only if their Eastern Cooperative Oncology Group (ECOG) performance status is 0 to 1.⁹

Ripretinib is a kinase inhibitor. Ripretinib is not recommended by NICE for treating advanced gastrointestinal stromal tumour (GIST) in adults after 3 or more kinase inhibitors, including imatinib. However, this does not affect treatment with ripretinib that was started in the NHS before this guidance was published (May 2023), who may continue until they and their NHS clinician consider it appropriate to stop.¹⁰

Prognosis²

One large review found a 5-year survival to be 74%, and the 5-year cause-specific survival 82%. The 5-year cause-specific survival by treatment included surgery at 86%, chemotherapy/targeted therapy with or without surgery at 77%, and radiation at 75%.

Tumour size greater than 5 cm, poorly and undifferentiated grade, age over 60 years, and distant metastases at presentation were associated with worse overall survival.