Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas. They are the most common mesenchymal neoplasm of the gastrointestinal tract.¹ Traditionally, they have been very difficult to treat due to resistance to conventional chemotherapy.

Epidemiology

• Gastrointestinal stromal tumours (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

Pathogenesis

• There are oncogenic kinase mutations in most gastrointestinal stromal tumours (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.

Clinical features

• Gastrointestinal stromal tumours (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

• 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.

Differential diagnosis

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

Investigations

• Gastrointestinal stromal tumours (GISTs) are often discovered incidentally by computerised tomography (CT) scan or endoscopy.¹
• 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.⁹
• Positron emission tomography (PET) imaging is helpful in identifying small metastases.
• MRI can may help to 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

Associated diseases

• People with neurofibromatosis type I have an increased risk of developing gastrointestinal stromal tumours (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).¹⁰

Spread and the prediction of tumour behaviour

• All gastrointestinal stromal tumours (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.⁹ 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 for the management of GISTs (see reference below) and may be used to determine subsequent follow-up and management.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 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.¹¹

Management

Localised tumours

• Complete surgical resection is the principle 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.^12,13
• 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 gastrointestinal stromal tumours (GISTs).^14,15,16 Side-effects include anaemia, neutropenia, oedema, fatigue, nausea, diarrhoea, skin rashes and liver toxicity.^9,17
• Research is also underway looking at imatinib use to downsize disease before surgery.
• A follow-up CT scan should be performed at 3 months after surgery.⁹
• The Association of Upper Gastrointestinal Surgeons has produced an algorithm of overall care which may be followed.⁹

Advanced disease

• Some metastatic GISTs may be technically resectable.
• In unresectable and metastatic disease that is KIT-positive, the National Institute for Health and Clinical Excellence (NICE) recommends that imatinib should be used.¹⁸
• 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.^5,19
• 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).²⁰ Unresponsiveness is indicated by radiological and/or symptomatic progression,^1,9 and NICE does not recommend increasing the dose of imatinib at this stage.¹⁷
• CT scanning 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
• 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.²¹
• Other alternative agents to treat imatinib-resistant tumours are also being studied.¹

Document references

1. Rubin BP, Heinrich MC, Corless CL; Gastrointestinal stromal tumour. Lancet. 2007 May 19;369(9574):1731-41. [abstract]
2. Rossi CR, Mocellin S, Mencarelli R, et al; Gastrointestinal stromal tumors: from a surgical to a molecular approach. Int J Cancer. 2003 Nov 1;107(2):171-6. [abstract]
3. Kindblom LG, "Gastrointestinal Stromal Tumors Diagnosis, Epidemiology and Prognosis" in "Gastrointestinal Stromal Tumors: Current management and Future Challenges". Chair: Blanke CD. ASCO 2003
4. DeMatteo RP, Lewis JJ, Leung D, et al; Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000 Jan;231(1):51-8. [abstract]
5. Heinrich MC, Corless CL, Demetri GD, et al; Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-9. [abstract]
6. Hirota S, Isozaki K, Moriyama Y, et al; Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998 Jan 23;279(5350):577-80. [abstract]
7. Rubin BP, Singer S, Tsao C, et al; KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 2001 Nov 15;61(22):8118-21. [abstract]
8. Wardelmann E, Losen I, Hans V, et al; 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 10;106(6):887-95. [abstract]
9. Guidelines for the management of gastrointestinal stromal tumours (GISTS), Association of Upper Gastrointestinal Surgeons for Great Britain and Ireland (2005)
10. Carney JA; Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc. 1999 Jun;74(6):543-52. [abstract]
11. Woodall CE 3rd, Brock GN, Fan J, et al; An evaluation of 2537 gastrointestinal stromal tumors for a proposed clinical Arch Surg. 2009 Jul;144(7):670-8. [abstract]
12. Gervaz P, Huber O, Morel P; Surgical management of gastrointestinal stromal tumours. Br J Surg. 2009 Jun;96(6):567-78. [abstract]
13. Tabrizian P, Nguyen SQ, Divino CM; Laparoscopic management and longterm outcomes of gastrointestinal stromal tumors. J Am Coll Surg. 2009 Jan;208(1):80-6. Epub 2008 Oct 31. [abstract]
14. Gold JS, Gonen M, Gutierrez A, et al; Development and validation of a prognostic nomogram for recurrence-free survival Lancet Oncol. 2009 Nov;10(11):1045-52. Epub 2009 Sep 28. [abstract]
15. Dematteo RP, Ballman KV, Antonescu CR, et al; Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal Lancet. 2009 Mar 28;373(9669):1097-104. Epub 2009 Mar 18. [abstract]
16. Essat M, Cooper K; Imatinib as adjuvant therapy for gastrointestinal stromal tumours - A systematic Int J Cancer. 2010 Dec 2. [abstract]
17. Gastrointestinal stromal tumours (unresectable/metastatic) - imatinib, NICE Technology Appraisal Guideline (November 2010); Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours. Part review of NICE technology appraisal guidance 86
18. Gastro-intestinal stromal tumours (GIST) - imatinib, NICE Technology Appraisal (2004)
19. Verweij J, Casali PG, Zalcberg J, et al; Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34. [abstract]
20. Blay JY, Le Cesne A, Ray-Coquard I, et al; 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 20;25(9):1107-13. [abstract]
21. Sunitinib for the treatment of gastrointestinal stromal tumours, NICE Technology Appraisal Guidance (September 2009)

Acknowledgements