28 Casali PG et al, Tumor response to Imatinib mesylate in advanced GIST.Proc Am Soc Oncol.2004; 23:821.Abstract 9028 29 DeMatteo et al, and the American College of Surgeons Oncology Group ACOSOG Intergroup Adjuvant GIST Study Team. Adjuvant Imatinib mesylate increases recurrence free survival in patients with completely resected localized primary gastrointestinalstromaltumors: North American Intergroup phase III trial ACOSOG Z9001 .Proc Am Soc Clin Oncol 2007; 25(18s) Abstract 10079.
Approximately 85% to 90% of all cases of gastrointestinalstromaltumors (GIST) are associated with gain-of-func- tion mutations in the gene KIT [1-4]. A further 5% to 10% of cases of GIST are associated with activating mutations in the platelet-derived growth factor receptor alpha (PDGFRα) gene [1,4,5]. Activating Kit mutations in GIST occur principally in the extracellular domain, the jux- tamembrane domain (which regulates receptor dimeriza- tion), kinase domain I, and kinase domain II (or activation loop) . Imatinib, a small-molecule inhibitor of Kit and PDGFRα, represents an effective first-line ther- apy option for patients with advanced GIST . Imatinib is a potent inhibitor of wild-type Kit and juxtamembrane domain Kit mutants, while Kit activation loop mutants are resistant [1,7]. Secondary imatinib resistance is most
Gastrointestinalstromaltumors have been a diagnostic dilemma to the medical science in the past decades because of the clinical presentation and improper classification. These tumors generally arise in the gastrointestinal tract especially the stomach, however extraintestinal GISTs are not uncommon. The clinical presentation may vary from an indolent to aggressive course depending upon the tumor size, site of involvement, and mitotic figures. The advancements in histopathology, imaging techniques and molecular diagnostics allowed us to know the nature, mutations and biologic behavior of these tumors. Activating mutations of cKIT, PDGFRA or some other downstream key molecules endows the cells of Cajal with the capacity to grow as GIST. These mutant cells are amenable to newer therapeutic regimen, like imatinib mesylate that inhibits activation of the KIT and PDGFα proteins by binding to the adenosine triphosphate binding pocket required for receptor phosphorylation and activation. Apart from drug therapy, surgery is still the only potential curative treatment, if the tumor is amenable to it. Combinations of newer diagnostic techniques, surgical methods, and adjuvant or neoadjuvant therapies have opened doors to treat these cases in a far more efficient way.
Gastrointestinalstromaltumors though rare, are the commonest primary mesenchymal neoplasm of the ga- strointestinal tract. These tumors are heterogeneous with respect to patient demographics affected, clinical pres- entation, tumor size, mitotic count, histologic subtypes, and malignant potential. The recognition that GIST is a disease driven by an oncogenic kinase mechanism and the development of novel targeted tyrosine kinase inhi- bitors such as imatinib mesylate (Gleevec), has revolutionized the clinical understanding and management of GIST in the 21 st century. Accurate recognition of GIST by the expression of CD117 (c-kit) and/or DOG-1 now clearly defines this family of tumors. There is a growing body of evidence to suggest that additionally, complex epigenetic alterations occur during GIST tumorigenesis, which correlates with tumor aggressiveness. The de- coding of this molecular signature may help in predicting clinical behavior/susceptibility to standard treatment. Mediators of the epigenetic mechanisms and the recognition of other specific molecular abnormalities may serve as potential therapeutic targets in the future.
Abstract: Gastrointestinalstromaltumors (GISTs) are relatively common mesenchymal tumors. They originate from the wall of hollow viscera and may be found in any part of the digestive tract. The prognosis of patients with stromaltumors depends on various risk factors, including size, location, presence of mitotic figures, and tumor rupture. Emergency surgery is often required for stromaltumors with hemorrhage. The current literature suggests that stro- mal tumor hemorrhage indicates poor prognosis. Although the optimal treatment options for hemorrhagic GISTs are based on surgical experience, there remains controversy with regard to optimum postoperative management as well as the classification of malignant potential. This article reviews the biological characteristics, diagnostic features, prognostic factors, treatment, and postoperative management of GISTs with hemorrhage.
Although gastrointestinalstromaltumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract (GIT), overall they are rare neoplasms ranking a distant third in prevalence behind adenocarcinomas and lymphomas . They may also originate from the mesentery and the omentum. In the past, these tumors were a poorly defined pathological entity with uncertainty regarding the origin and terminology often being confused with leiomyomas and leiomyosarcomas. Kindblom in 1998 first hypothesized the origin of these tumors from pluripotential mesenchymal stem cells of the gastrointestinal tract which are programmed to differentiate into the interstitial cell of Cajal (ICC) . These tumors have microscopic features in common with the myenteric plexus subtype of ICC that are found in stomach and intestines, including frequent expression of CD34, embryonic smooth muscle myosin heavy chain, and the intermediate filament nestin. The observation that ICC cells can be immunohistochemically highlighted with an antibody to KIT (CD 117) led to the discovery that KIT is also strongly expressed in most GISTs [3,4]. These not only substantiated the hypothesis that GISTs arise from or share a common stem cell with the ICC, but it also provided a new, more sensitive and specific marker for its diagnosis. Gain-of-function mutations in exon 11 of the c-kit proto-oncogene are associated with most GISTs .
Abstract: Gastrointestinalstromaltumors (GISTs) are the most common sarcoma of the gastrointestinal tract, with transformation typically driven by activating mutations of c-KIT and less commonly platelet-derived growth factor receptor alpha (PDGFRA). Successful targeting of c-KIT and PDGFRA with imatinib, a tyrosine kinase inhibitor (TKI), has had a major impact in advanced GIST and as an adjuvant and neoadjuvant treatment. If treatment with imatinib fails, further lines of TKI therapy have a role, but disease response is usually only measured in months, so strategies to maximize the benefit from imatinib are paramount. Here, we provide an overview of the structure and signaling of c-KIT coupled with a review of the clinical trials of imatinib in GIST. In doing so, we make recommendations about the duration of imatinib therapy and suggest how best to utilize imatinib in order to improve patient outcomes in the future. Keywords: adjuvant, c-KIT, mutations, resistance, treatment, gastrointestinalstromaltumors, imatinib
Introduction: Colorectal gastrointestinalstromaltumors (GISTs) mesenchymal tumor is very un- common. GISTs effect mostly on the stomach and small intestine and rarely occur in the colon, rectum and esophagus, that originating from precursors of the interstitial cells that originate of Cajal. The symptoms of gastrointestinalstromal tumor depend on the site and size of the tumor, and may include abdominal pain, gastrointestinal bleeding or signs of obstruction; small tumors may, however, be asymptomatic. Some of the patients with gastrointestinalstromal tumor have bloody stools, obstruction and abdominal pain as the commonest manifestation. Immunocyto- chemical staining for CD117 is helpful in confirming the diagnosis. Case presentation: We report 3 new cases of GISTs: two occurred at the rectal and the other at descending Colon. Two cases are over 50 years of age and, and all cases the chief complain of bowel obstruction, abdominal pain in two cases, and one case with anemia and urine retention. All the patients were operated and were permormed pathology examinatiom. All case ware positive result for immunocytochemical stain- ing CD117. All cases we had presented had size more than 5 cm are considered as unfavorable prognostic factors to Fletcher criteria, all patients scheduled for chemotherapy with Glivec but just one patient continued to used Glivec. Post surgery follows up one patient post milles with urinary incontinence complaints found and that patients are trained to CIC (intermittent cathete- rization). Conclusion: Colorectal gastrointestinalstromaltumors are very rare and can present as mass abdomen. Resection and chemotherapy are the treatment of choice.
Ménétrier disease and gastrointestinalstromaltumors (GISTs) are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases (RTKs). In Ménétrier disease, overexpression of TGF-α, a ligand for the RTK EGFR, results in selective expansion of surface mucous cells in the body and fundus of the stomach. In GISTs, somatic mutations of the genes encoding the RTK KIT (or PDGFRA in a minority of cases) result in constitutive kinase activity and neoplastic transformation of gut pacemaker cells (interstitial cells of Cajal). On the basis of the involvement of these RTKs in the pathogenesis of these disorders, Ménétrier disease patients have been effectively treated with a blocking monoclonal antibody specific for EGFR and GIST patients with KIT and PDGFRA tyrosine kinase inhibitors.
Primary and secondary resistance to currently available licensed tyrosine kinase inhibitors poses a real clinical challenge in the management of advanced gastrointestinalstromaltumors. Within the frame of early phase clinical trials novel systemic treatments are currently being evaluated to target both the well explored and novel emerging downstream effectors of KIT and PDGFRA signaling. Alternative therapeutic approaches also include exploring novel inhibitors of the KIT/PDGFRA receptors, immune checkpoint and cyclin-dependent kinase inhibitors. The final clinical trial outcome data for these agents are highly anticipated. Integration of new diagnostic techniques into routine clinical practice can potentially guide tailored delivery of agents in the treatment of a highly polyclonal, heterogeneous disease such as heavily pretreated advanced gastrointestinalstromal tumor.
During the review process and after acceptance of this manuscript, data relevant with respect to SDH-deficient GISTs, one of the main topics of the present review, have been published: 1) Ben-Ami et al. (Ben-Ami E, Barysauskas CM, von Mehren M, Heinrich MC, Corless CL, Butrynski JE, et al. Long-term follow-up of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosin kinase inhibitor therapy. Ann Oncol. 2016; doi: 10.1093/ annonc/mdw228) reported that regorafenib induced objective responses and durable benefit in SDH-deficient GISTs; 2) Boikos et al. (Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S, et al. Molecular subtypes of KIT/PDGFRA wild-type gastrointestinalstromaltumors. A report from the National Institutes of Health GastrointestinalStromal Tumor Clinic. JAMA Oncol. 2016; doi: 10.1093/annonc/mdw228) propose genotype rather than presence or absence of chondromas as the discriminating factor between CT and CSS.
The interstitial cells of Cajal of the mysenteric plexus are considered the origin of GIST. It is expressing the cell- surface trans-membrane receptor KIT that has tyrosine kinase activity and is the protein product of the KIT proto- oncogene. There are frequent gain-of-function mutations of KIT in gastrointestinalstromaltumors. These mutations result in the constitutive activation of KIT signaling, which leads to uncontrolled cell proliferation and resistance to apoptosis. It has been reported that KIT activation occurs in almost all cases of gastrointestinalstromal tumor, regardless of the mutational status of KIT (1). unresectable or metastatic gastrointestinalstromal tumor is a fatal disease that resists conventional cytotoxic chemotherapy where the response rate to a cytotoxic drug as doxorubicin was less than 5%. The situation for radiotherapy was not too much different and its effectiveness has not been proved. The median duration of survival for patients with a metastatic gastrointestinalstromal tumor is approximately 20 months, and for patients with local recurrence it is 9 to 12 months. 2
Abstract: Background: Peritoneal and hepatic metastases are the main routes of spread of gastrointestinalstromaltumors (GIST). However, criteria to predict the site and pattern of recurrence in individual cases are still lacking. Pa- tients: We retrospectively analyzed 67 consecutive GISTs with complete gross descriptions to correlate macroscopic patterns with clinical course. Primary endpoint was the appearance of synchronous or metachronous peritoneal dis- ease. Tumors were classified into type I (luminal/intramural) and type II (extramural) based on the macroscopic/ histologic presence or absence of normal tissue between deeper tumor border and serosa, respectively. Results: Patients were 35 men and 32 women (mean age, 64 yrs) with gastric (n=32), small bowel (n=30) and large bowel (n=5) GISTs. Based on the above proposal, 22 tumors were classified as type I and 45 as type II. Type I tumors were predominantly gastric (18/22; P<0.001) and frequently had very low/low risk (14/22; P<0.001) whereas type II tu- mors were predominantly intestinal (31/45; P<0.001) and often of intermediate/high risk (36/45; P<0.001). Ten patients had synchronous peritoneal spread and 6/30 patients with a mean follow-up of 29 months developed meta- chronous peritoneal spread at a mean of 27 months. Tumor rupture was seen in 2 patients (3%). Thus, 16/40 pa- tients (40%) had synchronous or metachronous peritoneal progression. Taken by gross type, peritoneal progression was seen in 15/30 type II compared to 1/10 type I tumors (p=0.032). Conclusion: this study points to extramural growth as a predictor of peritoneal recurrence in GIST, probably as a consequence of tumor rupture or due to micro- scopic serosal penetration. This study aimed at alerting surgical pathologists to the importance of careful gross and microscopic assessment of resection specimen harboring GIST to allow for reliable prospective evaluation of serosal involvement as an adverse prognostic factor in GIST.
under 4 cm. Moreover, in a retrospective study of 207 pa- tients who underwent gastrectomy or esophagectomy for non-GIST neoplasms, 15 synchronous GISTs in the upper gastrointestinal tract of 11 (5.3 %) patients were found with an average size of 0.5 cm (0.1–4.0 cm) . After a median follow-up of 11 months (2–36 months), no patient experienced GIST recurrence. Synchronous GISTs that were incidentally found during the resection of other gastrointestinal neoplasms may not negatively affect long- term survival, although they often pose very low or low risk of malignant potential. Small GISTs (<2 cm) may be asymptomatic and nonmalignant when diagnosed but have a potential for malignant transformation. In the present study, there were five patients with intermediate/ high risk in the non-synchronous group, and they might more likely to experience tumor progression than that of patients with very low/low risk.
While clinical and radiographic findings may be suggestive, the definitive diagnosis of GIST relies on tissue diagnosis. Histologically, GIST can have a variable appear- ance, but has been classified in the past as frequently displaying features of smooth muscle tumors. A key observation in GIST diagnosis and therapy was the central role of mitogen receptor and GIST marker, c-Kit; gain-of-function of this receptor is crucial for tumor growth in most cases of GISTs. 6 Overexpression of c-Kit protein is detected
37.9 and 33.1%, respectively). There is solid evi- dence that compared with gastric tumors’, small intestinal tumors with similar size and mitotic activity have a markedly worse prognosis. Across the board GISTs localized outside of the stomach were larger, had a higher mitotic rate and had worse 5-year DFS (34.2 vs 58.1%) in comparison with gastric tumors. As mentioned above, comparison between tumors with KIT exon 9 and KIT exon 11 mutations (both, KIT del-inc557/558 and other KIT exon 11) of non- gastric origin did not show differences in tumor clinical behavior as assessed by survival analysis. Thus, the authors concluded that in extra-gastric sites, the worse prognosis of KIT exon 9 mutants is related to the tumor location itself rather than to an intrinsic aggressive biologic nature of this mutation. In further support for this hypothesis, six out of seven gastric KIT exon 9 mutants in the ConticaGIST series study were classified as nonhigh risk, with only one of these patients developing progressive disease (PD), following a relatively long DFS of 56 months  .
Standard treatment for localized GIST involves complete surgical excision. Lymph node dissection is not standard practise as tumor spread is typically hematogenous rather than through the lymphatic system. If complete surgical resec- tion with negative margins (R0 resection) is not achieved at first attempt and can be safely accomplished by repeat surgery, this option may be considered. In cases where R0 surgery cannot be achieved due to technical reasons or entails significant morbidities, then consideration may be given to a peri-operative course of imatinib with aims for cytoreduction. This approach was demonstrated to be safe and feasible in a Radiation Therapy Oncology Group (RTOG)-led prospective non-randomized phase II study. In this study 52 analyzable patients with KIT-positive GIST, 30 with locally advanced disease (defined as tumors 5 cm) and 22 with potentially operable recurrent metastatic disease (defined as tumors 2 cm) were enrolled and treated with imatinib 600 mg/day over a period of 8 to 12 weeks prior to definitive surgery. Patients were then treated with imatinib for 2 years as postoperative adjuvant treatment. 13 Results of
sensitivity analyses using different algorithms to identify recurrence. First, we shortened the time interval between initial surgical resection and detection of a recurrence from 90 to 60 days using the original surgical procedures to iden- tify recurrence. Second, keeping the days between the index date and identification of a recurrence fixed at 90 days, we added the following: 1) additional procedure/HCPCS codes for biopsy (32405), excision (11642, 22900, 49201), radiation (77413, 77300), chemotherapy (96408, 96410– 96412, 96549, Q0085), and other surgical procedures (88172, 88305, 43235, 43239); 2) a surgical procedure coupled with an ICD-9 cancer diagnosis (140–239 excluding benign tumors) on the same date; and 3) identification of inpatient hospitalization with an ICD-9 cancer diagnosis (140–239 excluding benign tumors).
Preoperative IM could promote safety of GIST surgical resection by facilitating tumor shrinkage and loss of vascularity [20, 21]. As revealed by the current study, al- though GIST is a kind of hypervascular tumor with a tendency to be fragile, no tumor rupture or blood trans- fusion occurred at operation among 19 operated pa- tients. Organ-preserving or less-mutilating surgery was also realized. Sphincter-sparing resection of tumors was adopted in 4 of 7 (57.1%) cases with excision margins pathologically negative, and 4 (100%) gastric GIST patients experienced partial gastrectomy, which was impossible before taking IM, judged by radiological find- ings or exploratory laparotomy. It has been reported by Demetri et al.  that IM plasma trough levels (C min ),
Between 1997 and 2007, fifty-four patients with GIST who underwent surgical resection in Uludag University of Faculty of Medicine were selected for this study. Seven of the patients had distant metastasis at the time of presentation. Ethical approval was obtained for the study. All specimens of the 54 patients showed posi- tive CD117 and/or CD34 immunostaining. According to the classification system proposed by Fletcher et al. (Table 1), 29 (53.7%) patients belonged to the high-risk group. Forty-two (77.8%) patients had tumors ≥ 5 cm, and 32 (59.2%) had mitotic counts ≥ 5/50 high power fields (HPF).