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Gastrointestinal stromal tumours (GISTs) are soft tissue sarcomas. They are the most common mesenchymal neoplasm of the gastrointestinal tract. Traditionally, they have been very difficult to treat due to resistance to conventional chemotherapy.
- GISTs are rare. They represent 0.1-3% of all gastrointestinal cancers.
- However GISTs are the most common primary mesenchymal tumours of the gastrointestinal tract.
- The estimated incidence of GISTs is around 15 per million of population per annum.
- There are approximately 900 new cases per year in the UK.
- The median age of presentation is 60–65 years, but with a wide range. Occurrence in children is very rare.
- There are oncogenic kinase mutations in most GISTs.
- 75-80% of GISTs have mutations of the KIT receptor tyrosine kinase. 10% 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.
- Nonspecific symptoms such as early satiety, bloating, fatigue (because of anaemia).
- Fever, weight loss and night sweats.
- Gastrointestinal bleeding (the 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) scan or endoscopy.
- Endoscopic ultrasound helps to locate the lesions on the wall of the gastrointestinal tract accurately.
- For large tumours, CT scanning of the chest, abdomen and pelvis is recommended to assess primary tumour extension and to stage for metastases.
- Positron emission tomography (PET) imaging is helpful in identifying small metastases.
- Magnetic resonance imaging (MRI) can may help to provide greater anatomical detail in the anorectal region and help surgery planning.
- Biopsy is only recommended for lesions of indeterminate type or unresectable and/or metastatic tumours. 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.
- 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).
Spread and the prediction of tumour behaviour
- All GISTs have the potential to become malignant.
- The National Institutes of Health workshop assessment criteria have been drawn up to predict tumour behaviour and assess prognosis. 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 (AUGIS) Guidelines for the management of GISTs and may be used to determine subsequent follow-up and management.
- 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.
- Other work to produce staging systems for GISTs is ongoing with the aim of using these to provide prognostic information.
- Complete surgical resection is the principal treatment. Careful handling is needed so as to avoid tumour rupture and intra-abdominal dissemination. Open, trans-sacral or endoscopic surgery are treatment options. Laparoscopic surgery may also be used for some tumours.[11, 12]
- Subsequent management depends on the risk of recurrence according to the prediction of tumour behaviour.
- Adjuvant imatinib (a tyrosine kinase inhibitor):
- Prolongs recurrence-free survival after resection of localised primary GISTs.[13, 14, 15]
- The availability of imatinib followed by other tyrosine kinase inhibitors has dramatically improved the outcome of GISTs.
- Side-effects include anaemia, neutropenia, oedema, fatigue, nausea, diarrhoea, skin rashes and liver toxicity.
- A follow-up CT scan should be performed at three months after surgery.
- AUGIS has produced an algorithm of overall care which may be followed.
- Some metastatic GISTs may be technically resectable.
- In unresectable and metastatic disease that is KIT-positive, the National Institute for Health and Care Excellence (NICE) recommends that imatinib should be used.
- 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.[19, 20]
- If patients respond to imatinib, they should remain on it unless or until the tumour becomes unresponsive (as imatinib interruption results in rapid progression in most patients with advanced GIST). Unresponsiveness is indicated by radiological and/or symptomatic progression.NICE does not recommend increasing the dose of imatinib at this stage.
- CT scanning is used to detect recurrence and is recommended at three-monthly intervals in patients treated with imatinib for unresectable/metastatic disease. Patients should be closely followed up and surgical resection should be performed if the tumour becomes resectable.
- Sunitinib, another kinase inhibitor, has also been approved by NICE as a treatment option for people with unresectable and/or metastatic malignant GIST if:
- Imatinib treatment has failed because of resistance or tolerance; and
- The drug cost of sunitinib (excluding any related costs) for the first treatment cycle will be met by the manufacturer.
- Other alternative agents to treat imatinib-resistant tumours are also being studied.
Further reading and references
; European Society for Medical Oncology (2012)
; Gastrointestinal stromal tumour. Lancet. 2007 May 19369(9574):1731-41.
; Gastrointestinal stromal tumors: from a surgical to a molecular approach. Int J Cancer. 2003 Nov 1107(2):171-6.
; Recent advances in the treatment of gastrointestinal stromal tumors. Ther Adv Med Oncol. 2014 May6(3):115-127.
Kindblom LG, "Gastrointestinal Stromal Tumors Diagnosis, Epidemiology and Prognosis" in "Gastrointestinal Stromal Tumors: Current management and Future Challenges". Chair: Blanke CD. ASCO 2003
; European Society for Medical Oncology (2012)
; Deletion of Trp-557 and Lys-558 in the juxtamembrane domain of the c-kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors. Int J Cancer. 2003 Oct 10106(6):887-95.
; Recent advances and novel agents for gastrointestinal stromal tumor (GIST). J Hematol Oncol. 2012 May 85:21. doi: 10.1186/1756-8722-5-21.
; An evaluation of 2537 gastrointestinal stromal tumors for a proposed clinical Arch Surg. 2009 Jul144(7):670-8.
; Surgical management of gastrointestinal stromal tumours. Br J Surg. 2009 Jun96(6):567-78.
; Laparoscopic management and longterm outcomes of gastrointestinal stromal tumors. J Am Coll Surg. 2009 Jan208(1):80-6. Epub 2008 Oct 31.
; Development and validation of a prognostic nomogram for recurrence-free survival Lancet Oncol. 2009 Nov10(11):1045-52. Epub 2009 Sep 28.
; Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal Lancet. 2009 Mar 28373(9669):1097-104. Epub 2009 Mar 18.
; Imatinib as adjuvant therapy for gastrointestinal stromal tumours - A systematic Int J Cancer. 2010 Dec 2.
; Management of gastrointestinal stromal tumor: the imatinib era and beyond. Indian J Cancer. 2013 Jan-Mar50(1):31-40. doi: 10.4103/0019-509X.112289.
; NICE Technology Appraisal Guideline (November 2010)
; NICE Technology Appraisal (2004)
; Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 121(23):4342-9.
; Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004 Sep 25-Oct 1364(9440):1127-34.
; Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007 Mar 2025(9):1107-13.
; NICE Technology Appraisal Guidance (September 2009)
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