Stromal Tumors

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Clinicopathological characteristics and prognosis of primary appendiceal stromal tumors

Clinicopathological characteristics and prognosis of primary appendiceal stromal tumors

Complete surgical resection with negative microscopic margins is the standard treatment for GISTs [30, 40].Vassos et al [8] found that simple appendectomy was the standard treatment for most cases that were located in the body or tail of the appendix. In some cases, resec- tion of adjacent tissue and organs or the base of the cecum may be necessary for complete removal of the tumor to minimize the risk of local recurrence. Chinese guidelines for the diagnosis and treatment of gastrointes- tinal stromal tumors indicate that lesions of less than 5 cm in diameter located in favorable anatomic sites, such as the greater curvature or anterior wall of gastric body and fundus, can be considered by laparoscopic method [41]. Considering the pathological features of cases in this study, 11 were small stromal tumors (45.8%) and more than half (54.2%) were located in the body or tail; thus, laparoscopic appendectomy may be feasible. However, relevant prospective clinical studies are needed to further confirm the feasibility and safety of laparoscopic surgery of PASTs. Since tumor rupture is an independent adverse prognostic factor [2, 28], surgery should follow the principle of “no touch, less compres- sion.” Endoscopic application of an “extract bag” to avoid tumor rupture and spillage should be performed [41–43], and open surgery for resectable and over-sized stromal tumors is necessary.
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Update on imatinib for gastrointestinal stromal tumors: duration of treatment

Update on imatinib for gastrointestinal stromal tumors: duration of treatment

Abstract: Gastrointestinal stromal tumors (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, gastrointestinal stromal tumors, imatinib
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Original Article Clinical features and prognosis of extragastrointestinal stromal tumors

Original Article Clinical features and prognosis of extragastrointestinal stromal tumors

Kaplan-Meier univariate analysis (Figure 2) showed that the primary tumor site, tumor size, and tumor cell nuclear pleomorphism are important factors affecting the prognosis of EGIST patients. Tumor size is widely considered to be an important factor affecting the progno- sis of stromal tumors, and therefore has been included in the risk rating system for stromal tumors. We will discuss in detail below the rela- tionship between primary tumor sites and prog- nosis. It has been previously reported in the literature that EGISTs are often found in the mesentery, omentum and retroperitoneum and that they can also occur in the pancreas, blad- der and female reproductive system [8]. The data from our hospital showed that the inci- dence of tumors in the mesentery was 50% (11/22), that in the retroperitoneum was 36.4 (8/22), and that in the omentum was 13.6 (3/22). Stratified survival analysis showed that EGISTs that originated from the omentum had the best prognosis and that those from the ret- roperitoneum had the worst prognosis. After reviewing the previous literature, we believe that the above observation may be due to the following reasons. First, this observation could be due to the biological characteristics of EGISTs in the lesser omental sac being similar to those of gastric stromal tumors, and the morphological and biological characteristics of mesenteric stromal tumors being similar to those of small intestinal stromal tumors; there- fore, GISTs with the origin in the mesentery have a poor prognosis [9, 10]. Second, it could be related to the thoroughness of surgical treatment. The omentum is a free intraperito- neal organ, which facilitates complete tumor resection, whereas the distribution of blood vessels and nerves inherent to the mesentery can affect complete resection of the tumor [11]. Furthermore, the data from our hospital data showed that the median diameter of tumors in the retroperitoneum (10 cm) was sig- nificantly greater than those of tumors originat- ing from the mesentery (8 cm) and omentum. This result suggests that the symptoms of EGISTs originating from the retroperitoneum appear at a late stage, leading to larger tumors and more advanced staging.
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Syndromic gastrointestinal stromal tumors

Syndromic gastrointestinal stromal tumors

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 gastrointestinal stromal tumors. A report from the National Institutes of Health Gastrointestinal Stromal 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.
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Transvaginal excision of rectal stromal tumors: case reports and a literature review

Transvaginal excision of rectal stromal tumors: case reports and a literature review

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Rectal locations are very rare, and minimally invasive surgery is a good choice for the treatment of rectal GISTs. Case presentation: Two women each had a mass located on the lower vaginal-rectal space as determined by transvaginal ultrasound (TV-US), pelvis MR imaging, and colonoscopy. The patients successfully underwent transvaginal excision. The spindle-shaped cells were found in pathological test. The immunohistochemical analysis showed that CD117 and Dog-1 were stained positively. These results confirmed the masses as GISTs. The postoperative period was uneventful without anal dysfunction. Two patients were received adjuvant treatment with imatinib after surgery. Conclusion: Transvaginal excision could be a minimally invasive and safe alternative treatment in the management of rectal GISTs in lower locations.
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Management Colorectal Gastrointestinal Stromal Tumors (Gists) in Surabaya

Management Colorectal Gastrointestinal Stromal Tumors (Gists) in Surabaya

Introduction: Colorectal gastrointestinal stromal tumors (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 gastrointestinal stromal 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 gastrointestinal stromal 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 gastrointestinal stromal tumors are very rare and can present as mass abdomen. Resection and chemotherapy are the treatment of choice.
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Management of hemorrhage in gastrointestinal stromal tumors: a review

Management of hemorrhage in gastrointestinal stromal tumors: a review

Therefore, TCB and FNA are not recommended if the patient is not being considered for conversion therapy, or if the clini- cian needs to differentiate GISTs from other tumors, for the following reasons: 1) stromal tumors are generally relatively easy to remove, 2) tumor rupture should be prevented in case of implantation metastasis, and 3) because of the presence of tumor capsule, it is difficult to get sufficient tissue to make a definite diagnosis using these modalities. 23 An MRI is useful

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Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors

Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors

Approximately 85% to 90% of all cases of gastrointestinal stromal tumors (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) [1]. Imatinib, a small-molecule inhibitor of Kit and PDGFRα, represents an effective first-line ther- apy option for patients with advanced GIST [6]. 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
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Gastrointestinal Stromal Tumors  in the 21st Century

Gastrointestinal Stromal Tumors in the 21st Century

Gastrointestinal stromal tumors 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.
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Gastrointestinal Stromal Tumors: Review Article

Gastrointestinal Stromal Tumors: Review Article

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 gastrointestinal stromal tumors: North American Intergroup phase III trial ACOSOG Z9001 .Proc Am Soc Clin Oncol 2007; 25(18s) Abstract 10079.

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Gastrointestinal stromal tumors: three decades of lessons

Gastrointestinal stromal tumors: three decades of lessons

Gastrointestinal stromal tumors 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.
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Clinicopathological spectrum of ovarian sex cord-stromal tumors; 20 years’ retrospective study in a developing country

Clinicopathological spectrum of ovarian sex cord-stromal tumors; 20 years’ retrospective study in a developing country

We performed a retrospective analysis of all patients diagnosed with ovarian sex cord stromal tumors from January 1, 1992 to December 31, 2012, whose specimens were received at Histopathology section, Department of Pathology and Microbiology, Aga Khan University Hospital, Karachi. Patients were identified from a prospectively main- tained departmental database, Integrated Lab. Management System, with keywords search. As this is an observational study and the confidentiality was thoroughly maintained, ethical review committee’s approval was not required, which is mandatory in experimental research according to Helniski’s declaration.
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Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach

Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach

Ménétrier disease and gastrointestinal stromal tumors (GISTs) are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases (RTKs). In Ménétrier disease, overexpression of TGF-a, 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
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Efficacy and Tolerability of Imatinib Mesylate In Advanced Gastrointestinal Stromal Tumors

Efficacy and Tolerability of Imatinib Mesylate In Advanced Gastrointestinal Stromal Tumors

Imatinib mesylate is a selective inhibitor of certain protein tyrosine kinases: the intracellular ABL kinase, the chimeric BCR-ABL fusion oncoprotein of chronic myeloid leukemia, the trans-membrane receptor KIT, and the platelet-derived growth factor receptors. Imatinib is highly active in patients with chronic myeloid leukemia and other Philadelphia chromosome–positive leukemias, in which it inhibits the dysregulated kinase activity of the BCR-ABL fusion protein. Imatinib blocks the constitutive activity of KIT receptor tyrosine kinase in the cells of gastrointestinal stromal tumors. This was supported by pre-clinical and clinical trials. Exposure of these cells to Imatinib blocked the kinase activity of KIT, arrested proliferation, and caused apoptotic cell death. 3
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Promising novel therapeutic approaches in the management of gastrointestinal stromal tumors.

Promising novel therapeutic approaches in the management of gastrointestinal stromal tumors.

Primary and secondary resistance to currently available licensed tyrosine kinase inhibitors poses a real clinical challenge in the management of advanced gastrointestinal stromal tumors. 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 gastrointestinal stromal tumor.
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Gastrointestinal Stromal Tumors: Experience from a Single Surgical Unit

Gastrointestinal Stromal Tumors: Experience from a Single Surgical Unit

Although gastrointestinal stromal tumors (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 [1]. 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) [2]. 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 [5].
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Targeting gastrointestinal stromal tumors: the role of regorafenib

Targeting gastrointestinal stromal tumors: the role of regorafenib

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

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Update on the treatment of gastrointestinal stromal tumors (GISTs): role of imatinib

Update on the treatment of gastrointestinal stromal tumors (GISTs): role of imatinib

possible. Patients were categorized based on response to TKI at the time of surgery (stable disease which included patients initially with unresectable or metastatic GIST who achieved a drug response to render all disease resectable and whose tumors were not growing at the time of surgery, limited disease progression or generalized disease progression) and surgical result (no evidence of disease, minimal residual disease or bulky residual disease). Results of this single center study sug- gested that response to TKI was significantly associated with surgical outcome. Seventy-eight percent of patients with stable disease at the time of surgery were rendered radiographically disease-free post-operatively, as compared to 25% and 7% of patients with limited progression and generalized progression respectively. Conversely bulky residual disease remained after surgery in 4%, 16%, and 43% of these patients respectively. One-year progression-free survival in patients with stable dis- ease, limited progression and generalized progression was 80%, 33%, and 0%. The median time to progression for patients with limited and generalized disease progression was 7.7 months and 2.9 months respectively, while the median time to progression for patients with stable disease has not been reached after a median follow-up of 14.6 months (range, 0.5 to 36.4 months). One-year overall survival was 95%, 86%, 0% respectively. The authors concluded that patients with advanced GISTs exhibiting stable disease or limited progression on TKI have prolonged survival after debulking procedures while surgery has little to offer in the setting of generalized progression. While it is clear that patients with generalized disease progression are unlikely to benefit from surgery, it is unclear from this study whether the improved progression-free and overall survival seen in patients with stable disease and limited disease progression was a result of surgical intervention or inherent tumor biology and response to TKI.
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Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications.

Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications.

In the Multinational European ConticaGIST Database analysis KIT p.W557_K558del mutants equally segregated in gastric and nongastric sites (55 vs 45%). KIT p.W557_K558del was more frequently identified in patients younger than 60 years of age (59 vs 42.4%), in tumors’ >5 cm (84.5 vs 57.7%), with MI >5/50 HPF (68.9 vs 39.4%), and classified as high risk (70.2 vs 38.9%), when compared with other KIT exon 11 mutated tumors. It was an important obser- vation that the clinicopathologic characteristics of tumors bearing KIT p.W557_K558del were comparable with the group of tumors with KIT delinc557/558, within which tumor size, mitotic rate and fraction of high-risk tumors were also significantly higher than in tumors with other KIT exon 11 mutants. KIT delinc557/558 was associated with an increased risk for tumor pro- gression with a hazard ratio (HR) of 1.45 and an inferior disease-free survival (DFS; median DFS 45.5 months; 5-year DFS 33.1%). The relatively high number of KIT del-inc557/558 mutants equally distributed in gastric and nongastric sites enabled the researchers to analyze the pos- sible impact of this genotype on DFS, depend- ing on the anatomical site of GISTs. In clear contrast with other KIT exon 11, KIT exon 9 and PDGFRA exon 18 mutations, the poor prog- nostic impact of KIT del-inc557/558 on patients’ survival was only significant in GIST localized to the stomach (p < 0.001), but not in tumors’ with nongastric origin (p < 0.26). The same asso- ciations were also evident when comparing KIT del-inc557/558 mutants with other exon11 KIT mutations, overall (p < 0.0001; or comparing gastric (p < 0.0001) and nongastric (p < 0.599) GIST. This phenomenon might be related to the observation that gastric GIST with KIT del-inc557/558 had a larger size (7 vs 5.8 cm) and a higher mitotic rate (6 vs 4/50 HPF) when Table 2. KIT and PDGFRA ‘hot spot’ mutation landscape.
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Epidemiology, survival, and costs of localized gastrointestinal stromal tumors

Epidemiology, survival, and costs of localized gastrointestinal stromal tumors

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).
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