Download Title: Intussusception of small bowel GIST presenting as an

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.
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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].
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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
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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
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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-
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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
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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