Gastrointestinal Stromal Tumour

Gastrointestinal stromal tumours (GISTs) are soft tissue sarcomas. They are the most common mesenchymal neoplasm of the gastrointestinal tract.¹ They are very difficult to treat, being resistant to conventional chemotherapy.

• GISTs are rare. They represent 0.1-3% of all gastrointestinal cancers.²
• There are approximately 900 new cases per year in the UK.³
• They can occur in either sex and at any age but 75% are diagnosed in > 50 year olds.⁴

There are oncogenic kinase mutations in most GISTs. 75-80% of GISTs have mutations of the KIT receptor tyrosine kinase.^5,6,7,8 8% have mutations in tyrosine kinase platelet derived growth factor receptor alpha (PDGFRA).

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.

• GISTs can occur anywhere in the gastrointestinal tract.
• 50% are found in the stomach, 25% in the small bowel and 10% in the colon and rectum.
• They can also develop in the mesentery, omentum, retroperitoneum and pelvis.

Presenting symptoms

• Non-specific symptoms such as early satiety, bloating, fatigue (because of anaemia).
• Fever, weight loss and night sweats.
• Gastrointestinal bleeding (most common presenting symptom).
• Symptoms of abdominal mass and bowel obstruction.
• They may also present as an incidental finding during investigation for other diseases.

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

• GISTs are often discovered incidentally by computerised tomography (CT) or endoscopy.¹
• Endoscopic ultrasound helps to accurately locate the lesions on the wall of the gastrointestinal tract.
• For large tumours, CT of chest, abdomen and pelvis is recommended to assess primary tumour extension and to stage for metastases.⁹
• PET is helpful in identifying small metastases.
• MRI may help provide greater anatomical detail in the anorectal region and help surgery planning.^1,9
• Biopsy is only recommended for lesions of indeterminate type or unresectable and/or metastatic tumours.⁹ If a GIST is highly suspected in a resectable tumour, biopsy should not be performed before resection because of the risk of tumour spread.
• Pathological review of all cases should be made by a pathologist experienced in this tumour type. Specific immunohistochemical staining is used to support the diagnosis.^9,9

• 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 the Carney triad tumour syndrome (the association of gastric stromal tumours, paraganglioma and pulmonary chondroma occurring mostly in girls and young women).¹⁰

• Localised tumours: Complete surgical resection is the principle treatment. Careful handling is needed so as to avoid tumour rupture and intra-abdominal dissemination. Laparoscopic surgery may be used for small tumours. A follow-up CT should be performed at 3 months.⁹ Subsequent management depends on the risk of recurrence according to the prediction of tumour behaviour. The Association of Upper Gastrointestinal Surgeons algorithm of overall care should be followed (see below).
• Advanced disease: Some metastatic GISTs may be technically resectable. Otherwise, in unresectable and metastatic disease that is KIT-positive, imatinib, a tyrosine kinase inhibitor, should be used.¹¹ Side effects include anaemia, neutropenia, oedema, fatigue, nausea, diarrhoea, skin rashes and liver toxicity.⁹ If patients do respond to this drug, they should remain on it indefinitely, unless drug tolerance becomes an issue or there is radiological and symptomatic progression.^1,9 (Imatinib interruption results in rapid progression in most patients with advanced GIST.¹²) CT is used to detect recurrence and is recommended at 3 monthly intervals in patients treated with imatinib for unresectable/metastatic disease.⁹ Patients should be closely followed up and surgical resection should be performed if the tumour becomes resectable.⁹

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 occurs is usually to the lungs and bone.

It is recommend that the National Institutes of Health workshop assessment criteria should be used to predict tumour behaviour and assess prognosis.⁹ All tumours have the potential to become malignant. These assessment criteria help to define the risk of aggressive behaviour based on tumour size and mitotic count. The criteria are stated in the Association of Upper Gastrointestinal Surgeons Guidelines (see reference below) and determine subsequent follow-up and management.

• Imatinib controls disease in 70-85% of patients with advanced GIST with an estimated median overall survival time > 36 months in all large clinical studies.^5,13
• However, imatinib resistance can develop over time and most patients are not cured. Resistant lesions can sometimes be picked up on imaging as a new nodule within a larger, pre-existing tumour mass and may be suitable for resection. Sunitinib, another kinase inhibitor has also been approved in the US for the treatment of advanced GIST in patients who fail imatinib therapy.
• Tumour size is an independent prognostic factor in survival. Tumours > 10cm have a 5 year survival rate of approximately 20%.⁴
• Overall, more than 80% of patients die of recurrent disease.¹⁴

The use of adjuvant imatinib for minimum residual disease in the management of patients with completely resected GIST is currently being trialled. Research is also under way looking at imatinib use to downsize disease before surgery. Other alternative agents to treat imatinib resistant tumours are also being studied.¹

Patients should be considered for inclusion in clinical trials of adjuvant therapy.⁹