Gastrointestinal stromal tumour

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Gastrointestinal stromal tumours (GIST) are neoplasms of mesenchymal origin. It can be found anywhere in the GI tract, but most commonly stomach. GISTs have variable biological behaviour, but should be treated as potentially malignant. They were previously thought to be of smooth muscle origin, but GISTs have distinct biological and histological characteristics and it is likely that many tumours classified as leiomyoma or leiomyosarcoma were in fact GISTs. There is an overlap between some GISTs and gastrointestinal autonomic nerve tumour.

The precursor cells are believed to be interstitial cells of Cajal, a type of cell found within the gastrointestinal myenteric plexuses which have a pacemaker function within the gut. The distribution of GISTs mimic the concentration of ICCs within the gut. Similarly, like the interstitial cells of Cajal that they are believed to be derive from, GISTs are characteristically (95% of cases) positive for c-kit (CD117), a signalling protein with tyrosine kinase activity.[1] GIST is unusual in that it is a tumour where only one or two aberrantly activated molecules are responsible for driving proliferation.

In a minority of cases, over-activation of the same pathway is a result of mutations in platelet-derived growth factor receptor alpha (PDGFRA).[2][3]

Contents

Histology

Histology includes immunohistochemistry for Kit (CD117) expression. They are also usually CD34 positive. An alternative marker, DOG1, has been described in 2008.[4][5]

The Royal College of Pathologists recommend the following immunohistochemical panel in their dataset:

Prognosis

The earliest prognostication was based on a NIH consensus agreed in 2001 and published in 2002.[6] This was primarily based on size and mitotic count.

Other features that have been taken into account by Joensuu[7] and Miettinen et al.[8][9][10] are:

  • site
  • size (lower risk in stomach ≤10cm; intestinal ≤5cm)
  • proliferation index/mitotic activity (lower risk if ≤ 5 mitoses in 50 high power fields)
  • cell morphology (spindle versus epitheloid)

Analysis of individual mutations suggests that the precise mutation in either c-kit of PDGFA can affect behaviour and response to imitinab.[11][12] For instance, GISTs with a mutation in exon 9 may benefit from a higher (400mg b.d.) dose of imitinab.

Treatment

If operable, local excision with satisfactory margins.

Chemotherapy may be used as an adjuvant to surgery or to treat inoperable tumours. Most cases respond well to imatinib, an oral medication that specifically inhibits tyrosine kinase activity. The specific mutation determines the response, with the best response noted in point mutations in exon 11. Response can be assessed with CT or PET. GISTs are unusual in that tumour size is not a reliable guide for tumour response as the tumour can stay the same size or even enlarge despite effective treatment. Radiological changes in the density of tumour, as measured by Hounsfield units, may be a better guide.[13][14]

Secondary resistance is common, developing after a median of 2 years, but imatinib can show sustained benefit in some cases of metastatic disease for some years. Sunitinib can be used as second line or in cases of primary resistance.[15]

References

  1. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science (New York, N.Y.). 1998 Jan 23; 279(5350):577-80.
  2. Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y, Kitamura Y. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 2003 Sep; 125(3):660-7.
  3. Lasota J, Stachura J, Miettinen M. GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology. Laboratory investigation; a journal of technical methods and pathology. 2006 Jan; 86(1):94-100.(Link to article – subscription may be required.)
  4. Espinosa I, Lee CH, Kim MK, Rouse BT, Subramanian S, Montgomery K, Varma S, Corless CL, Heinrich MC, Smith KS, Wang Z, Rubin B, Nielsen TO, Seitz RS, Ross DT, West RB, Cleary ML, van de Rijn M. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. The American journal of surgical pathology. 2008 Feb; 32(2):210-8.(Link to article – subscription may be required.)
  5. Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. The American journal of surgical pathology. 2009 Sep; 33(9):1401-8.(Link to article – subscription may be required.)
  6. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Human pathology. 2002 May; 33(5):459-65.
  7. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Human pathology. 2008 Oct; 39(10):1411-9.(Link to article – subscription may be required.)
  8. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. The American journal of surgical pathology. 2005 Jan; 29(1):52-68.
  9. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Archives of pathology & laboratory medicine. 2006 Oct; 130(10):1466-78.
  10. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Seminars in diagnostic pathology. 2006 May; 23(2):70-83.
  11. Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD, Ryan CW, von Mehren M, Blanke CD, Rankin C, Benjamin RS, Bramwell VH, Demetri GD, Bertagnolli MM, Fletcher JA. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008 Nov 20; 26(33):5360-7.(Link to article – subscription may be required.)
  12. Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010 Mar 1; 28(7):1247-53.(Link to article – subscription may be required.)
  13. Choi H. Response evaluation of gastrointestinal stromal tumors. The oncologist. 2008; 13 Suppl 2:4-7.(Link to article – subscription may be required.)
  14. Desai J. Response assessment in gastrointestinal stromal tumor. International journal of cancer. Journal international du cancer. 2010 Oct 18.(Epub ahead of print) (Link to article – subscription may be required.)
  15. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14; 368(9544):1329-38.(Link to article – subscription may be required.)
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