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Title: Gastrointestinal Stromal Tumour: An update. Author: Kamal Kumar Mahawar Specialist Registrar, Department of Surgery Wansbeck General Hospital Ashington NE63 9JJ Northumberland, United Kingdom Institution: Department of Surgery, Wansbeck General Hospital, Ashington, UK. Author for Correspondence: Mr. Kamal Kumar Mahawar Specialist Registrar, Department of Surgery Wansbeck General Hospital, Woodhorn Lane Ashington NE63 9JJ, United Kingdom. Tel No: Tel 01670 521212 bleep 026 Email: [email protected] Conflict of Interest: None Word Count: 1243 1 Background: There are few areas of medicine, which have seen as rapid advancements in last few years as Gastrointestinal Stromal Tumour (GIST). Most rapid advancements have taken place in the study of immunohistochemistry and genetic make up of the tumours. The advent of Imatinib mesylate has changed the outlook of patients with advanced disease. But at the same time resistance to Imatinib has become a problem and newer therapies are being tried. 2 Review: GISTs are the most common mesencymal tumours of the gastrointestinal tract, which probably arise from interstitial cells of Cajal, the regulators of gut peristalsis [1-2]. It mostly affects older adults [3]. Stomach (60-70%) and the small bowel (25-35%) are the predominant location but it can virtually affect any part of gastrointestinal tract [3-5]. Bleeding and abdominal pain are the commonest presentation [6]. Other presentations are perforation or obstruction [7] of the gastrointestinal tract, palpable mass or weight loss. Rarely they can present as irritable bowel syndrome [8], or acute appendicitis [9]. Intussusception too has been reported [10]. Synchronous gastrointestinal tract adenocarcinomas and stromal tumours have also been reported [11-12]. Some have observed a familial version of GIST [13]. CT scan is a reliable tool for both identification of tumour [14] and for preoperative assessment of its extent, local invasion, and metastasis [15]. In a recent review [16] of CT and MRI findings in 31 patients with GISTs, it was found that primary tumours were typically exophytic (79%), larger than 5 cm (84%), and inhomogenously enhancing (84%). Metastases were most commonly to mesentery (26%) or liver (32%). Lung metastases, bowel obstruction, vascular invasion, and significant lymphadenopathy were not seen in any patient. A recent study (Epub ahead of print) showed that with consistent clinical and radiologic findings, the combined use of cytomorphology and immunohistochemistry on FNA and/or core biopsy can provides a reliable pathological diagnosis of GIST [17]. 3 These tumours express a variety of antigens on immunohistochemical staining. They may be positive for Vimentin (98%), c-Kit protein (CD117) (90%), CD34 (70%), SMA (Smooth Muscle Actin) (20-30%), S100 (10%), and Desmin (8%)[3, 18-19]. Though CD117 expression is considered very characteristic of GISTs, it is by no means restricted to them and there are a number of other tumours that can express the marker [6, 20]. At the same time, there is a very well defined, albeit small, group of patients whose tumour shows the characteristic GIST morphology [15], but is negative for c-kit (CD117). Genetically these are two different subsets of patients; one with c-kit gene mutation and the other with intact c-kit gene. In the latter subgroup PDGFR– alpha (Platelet Derived Growth Factor Receptor –alpha) gene mutations are responsible for abnormal kinase function (6). Immunostaining with PDGFR-alpha can be used to distinguish between KIT-negative GISTs and other gastrointestinal mesenchymal lesions [22]. Recently a new marker called DOG 1, which is expressed in 97.8% of GISTs, has been described [23]. It is expressed irrespective of the type of mutation. Even though the KIT protein can be expressed by a variety of tumours, Sihto et al [24] showed that KIT and PDGFRA gene mutations were only seen in GISTs and not with any other tumour. Others [25] have observed aberration of the cell cycle regulators to be frequent finding and believe it may be a contributing factor in the pathogenesis of GISTs. Tumours with mitotic activity exceeding 5 per 50 high power fields or those larger than 5 cm are more likely to behave in a malignant fashion and have a higher chance of intraabdominal recurrence and liver metastases whereas those smaller than 2 cm and with mitotic activity less than 5 per 50 high power fields are likely to be benign (3). A 4 major review published in 2002 [19] concluded that approximately 55% of tumours behaved in a malignant fashion and at the time of operative treatment 20% patients had liver and/or peritoneal metastases. A recent study concluded that DNA aneuploidy and c-Kit mutations could be considered as prognostic factors in GISTs [26]. The study observed that the c-Kit mutation positive GISTs were larger in size than the c-Kit negative GISTs. The aneuploid tumours were associated with large size, high mitotic counts, high-risk groups, high cellularity and severe nuclear atypia. There was also a tendency for c-Kit mutations to be more frequent in aneuploid GISTs. Andersson et al have recently reported that KIT exon 11 deletion to be an independent adverse prognostic factor in patients with GIST [27]. Others [28] have found HIF-1 alpha (Hypoxiainducible factor-1alpha) expression in GIST to correlate with high-grade aggressive tumours. In this study, high expression of HIF-1alpha was significantly correlated with tumour recurrence and distant metastasis. Malignant GISTs are more likely to be associated with a positive E2F1 and p53 phenotype and a negative p16 and p27(KIP1) phenotype [25]. Surgery remains the mainstay of treatment and the complete tumour resection with negative tumour margins should be the aim of surgical treatment [29-32]. The outcome depends on the grading of tumour (mitotic activity), tumour size and completeness of surgical resection [19, 31-32]. In their retrospective analysis of 69 patients, Pierie et al [32] showed that the 5- year survival was 42 % in patients with complete resection as opposed to 9% after incomplete resection. Regional lymphadenectomy has been considered unnecessary and long-term follow up is required [19]. Laparoscopic surgery 5 has been shown to be safe and effective in surgical resection of gastric GISTs and laparoscopic wedge resection of gastric tumours may even be the preferred modality of treatment [33-34]. Conventional chemotherapy and radiotherapy have been shown to be of no benefit [35]. Metastasis resection is considered an experimental procedure [30]. Imatinib mesylate (Glivec ®) or STI 571, KIT selective tyrosine kinase inhibitor, has clinical use in unresectable and metastatic tumours [36-37] and is under investigation as a neoadjuvant and adjuvant therapy [30, 35, 38]. It is a competitive inhibitor of various tyrosine kinases including BCR-ABL, KIT, and the platelet derived growth factor receptors [36]. It achieves a partial response or stable disease in about 80% of patients with metastatic GIST [39]. Heinrich et al [40] showed that patients of GIST with exon 11 KIT mutation had a partial response rate of 83.5% with imatinib whereas tumours containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had partial response rates of 47.8% (P<0.0001). Imatinib has been reported to be hepatotoxic mandating regular monitoring of liver function tests during treatment [41]. Some patients also develop an acquired resistance to imatinib during chronic therapy and nearly half (46%) of these patients have a secondary mutation [39, 42]. Resistance to Imatinib has prompted research for newer therapies. In a recent study [43], targeting KIT expression and antiapoptotic proteins with flavopiridol was suggested as a means to disrupt GIST cell dependence on KIT signalling and collectively render these cells sensitive to apoptosis. In another study [44] SU11248, an orally active small-molecule tyrosine kinase inhibitor, was found to be a useful therapeutic agent to treat gastrointestinal stromal tumors harbouring the imatinib-resistant KIT-V654A or KIT- 6 T670I mutations, but it had no effect on the activity of the PDGFRA-D842V mutant. Surgical debulking after systemic treatment with kinase inhibitors can be used as an option in patients with stable disease or with limited progression [45]. In this study debulking procedures were not found to be useful in patients with generalized progression on kinase inhibitors. Others have shown good results with hepatectomy in combination with imatinib for resistant cases with respectable liver disease [46]. 7 References: 1. Kindblom LG, Remoti HE, Aldenberg F, Meis-Kindblom JM. Gastointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumours show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998; 152: 1259-1269. 2. 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Eur J Gastroenterol Hepatol 2006; 18(7): 785-787. 42. Bertucci F, Goncalves A, Monges G, Madroszyk A, Guiramand J, Moutardier V, Noguchi T, Dubreuil P, Sobol H. Acquired resistance to imatinib and secondary KIT exon 13 mutation in gastrointestinal stromal tumour. Oncol Rep. 2006; 16(1): 97-101. 43. Sambol EB, Ambrosini G, Geha RC, Kennealey PT, Decarolis P, O'connor R, Wu YV, Motwani M, Chen JH, Schwartz GK, Singer S. Flavopiridol targets c-KIT transcription and induces apoptosis in gastrointestinal stromal tumor cells. Cancer Res 2006; 66(11): 5858-66. 44. Prenen H, Cools J, Mentens N, Folens C, Sciot R, Schoffski P, Van Oosterom A, Marynen P, Debiec-Rychter M. Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res 2006; 12(8): 2622-7. 45. Raut CP, Posner M, Desai J, Morgan JA, George S, Zahrieh D, Fletcher CD, Demetri GD, Bertagnolli MM. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 2006; 24(15): 2325-31. 46. Sakakura C, Hagiwara A, Soga K, Miyagawa K, Nakashima S, Yoshikawa T, Kin S, Nakase Y, Yamaoka N, Sagara Y, Yamagishi H. Long-term survival of a case with multiple liver metastases from duodenal gastrointestinal stromal tumor drastically 14 reduced by the treatment with imatinib and hepatectomy. World J Gastroenterol 2006; 12(17): 2793-7. 15 Abbreviations: GIST: Gastrointestinal Stromal Tumour CT: Computed Tomography SMA: Smooth Muscle Actin PDGFR– alpha: Platelet Derived Growth Factor Receptor –alpha HIF-1 alpha: Hypoxia-inducible factor-1 alpha 16