Features Of Gastrointestinal Stromal Tumors Research Articles

Su1551 Digital Image Analysis Is Helpful in Diagnosing Gastric Mesenchymal Tumors

Endoscopic ultrasonography (EUS) is a valuable imaging tool for evaluating subepithelial lesions in the stomach. However, there are few studies on differentiation between gastrointestinal stromal tumors (GISTs) and benign mesenchymal tumors, such as leiomyoma or schwannoma, with the use of EUS. In addition, there are limitations in the analysis of the characteristic features of such tumors due to poor interobserver agreement as a result of subjective interpretation of EUS images. Therefore, the aim of this study was to evaluate the role of digital image analysis in distinguishing the features of GISTs from those of benign mesenchymal tumors on EUS.

Application and value of mutation detection in diagnosis and treatment of gastrointestinal stromal tumor

Mutation of c-kit and platelet-derived growth factor receptor alpha (PDGFRA) is the most important molecular feature of gastrointestinal stromal tumor (GIST). Mutation detection of these two genes is of great significance when establishing the diagnosis of a kit-negative GIST, or when predicting response to tyrosine kinase inhibitor. Furthermore, more and more researches focus on the feasibility of the mutation status using as a prognostic factor in recent years.

Surgicel® (oxidized regenerated cellulose) granuloma mimicking local recurrent gastrointestinal stromal tumor: A case report

Unexpected clinical and/or imaging evidence of the recurrence of gastrointestinal stromal tumors soon after surgical resection may be complicated due to certain biological behavioral features of gastrointestinal stromal tumors. However, local hemostatic materials routinely used in abdominal surgery to achieve hemostasis intraoperatively may cause a foreign-body reaction, which appears to be indistinguishable from recurrent tumors in imaging studies. Thus, a second examination may be necessary to settle the true nature of the findings in such cases. If the resection and examination reveals a recurrent tumor, further proper oncological treatment is warranted, whereas if a foreign-body reaction is observed, radical or potentially harmful therapy may be withheld or cancelled. The present study retrospectively analyzes the case of an 83-year-old male patient who presented with a recurrent gastrointestinal stromal tumor four months after surgical resection, which was later identified as an intra-abdominal foreign-body granuloma caused by retained Surgicel® residue. The present study aimed to demonstrate why foreign-body granuloma induced by local hemostatic materials should be incorporated into the differential diagnosis of recurrent gastrointestinal stromal tumors post-operatively, particularly soon after surgical resection has been performed.

Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are usually driven by mutations in KIT or PDGFRA, although 15% of GISTs in adults and >90% in children lack such mutations. The majority of gastric KIT/PDGFRA wild-type GISTs show distinctive morphological and clinical features and loss of expression of succinate dehydrogenase (SDH) B. Only a small subset of SDHB-deficient GISTs carries loss-of-function mutations in SDHB, SDHC, or SDHD. Because of the complexity of its locus (15 exons) and the presence of three pseudogenes, SDHA is rarely analyzed. Recently, mutations in SDHA were shown to lead to loss of expression of SDHA in a small group of paragangliomas. We sought to determine whether immunohistochemistry for SDHA could identify GISTs with SDHA mutations. Tumors (n=33) with pathological features of SDH-deficient GIST were analyzed for expression of SDHA and SDHB by immunohistochemistry, and SDHA exons were sequenced from tumors lacking SDHA expression. Exons harboring somatic mutations were examined in DNA from corresponding normal tissue. All 33 tumors showed loss of SDHB expression. A total of 9 out of 33 (27%) tumors also lacked expression of SDHA. SDHA-deficient GISTs affected five men and four women (median age 38 years). SDHA expression was intact in the 24 remaining tumors, including those with known SDHB (n=3) or SDHC (n=2) mutations. Nonsense (n=8) or missense (n=1) mutations in SDHA were identified in all SDHA-deficient tumors. Heterozygous mutations were also found in DNA from normal tissues from six patients with available material. Somatic loss of the second allele has been found in seven tumors, five by loss of heterozygosity, one by a 13-bp deletion, and one by a missense mutation. Loss of SDHA expression in GIST reliably predicts the presence of SDHA mutations, which represent a relatively common cause of SDH-deficient GIST in adults. Immunohistochemistry for SDHA can be used to select patients for SDHA-specific genetic testing.

Gastrointestinal Stromal Tumors Associated with Neurofibromatosis 1: A Single Centre Experience and Systematic Review of the Literature Including 252 Cases

Aims. The objectives of this study were (a) to report our experience regarding the association between neurofibromatosis type 1 (NF1) and gastrointestinal stromal tumors (GISTs); (b) to provide a systematic review of the literature in this field; and (c) to compare the features of NF1-associated GISTs with those reported in sporadic GISTs. Methods. We reported two cases of NF1-associated GISTs. Moreover we reviewed 23 case reports/series including 252 GISTs detected in 126 NF1 patients; the data obtained from different studies were analyzed and compared to those of the sporadic GISTs undergone surgical treatment at our centre. Results. NF1 patients presenting with GISTs had a homogeneous M/F ratio with a mean age of 52.8 years. NF1-associated GISTs were often reported as multiple tumors, mainly incidental, localized at the jejunum, with a mean diameter of 3.8 cm, a mean mitotic count of 3.0/50 HPF, and KIT/PDGFRα wild type. We reported a statistical difference comparing the age and the symptoms at presentation, the tumors' diameters and localizations, and the risk criteria of the NF1-associated GISTs comparing to those documented in sporadic GISTs. Conclusions. NF1-associated GISTs seem to have a distinct phenotype, specifically younger age, distal localization, small diameter, and absence of KIT/PDGRFα mutations.

Cytomorphology of gastrointestinal stromal tumors and extra-gastrointestinal stromal tumors: A comprehensive morphologic study

Background:The term gastrointestinal stromal tumors (GIST) is used to refer to those mesenchymal neoplasms of the gastrointestinal tract (GIT) which express CD117, a c-kit proto-oncogene protein.Aims:To study the cytological features of GIST and extra-gastrointestinal stromal tumors (EGIST), to correlate them with histology and to determine cytological indicators of malignancy.Materials and Methods:Cytological smears from patients diagnosed as GIST/EGIST on histology were retrieved. From Jan 2000 to July 2010, 26 GIST (13 primary, 12 metastatic, one recurrent) and seven EGIST (5 primary, one metastatic, one recurrent) cytologic samples from 27 patients were identified.Results:The patients included 20 males and 7 females with a mean age of 50.6 years. Tumor sites included stomach (5), duodenum (5), ileum (2), ileocecal (1), rectum (1), liver (9), retroperitoneum (5), mesentery (1), subcutaneous nodule (1), supra-penile lump (1), ascitic (1) and pleural fluids (1). The smears were cellular with cohesive to loosely cohesive thinly spread irregularly outlined cell clusters held together by thin calibre vessels. The tumor cells were mild to moderately pleomorphic, spindle to epithelioid with variable chromatin pattern and variable cytoplasm. Cellular dyscohesion, nuclear pleomorphism, intranuclear pseudoinclusions, prominent nucleoli, mitosis and necrosis were more prominent in malignant, metastatic and recurrent tumors.Conclusions:GISTs show a wide spectrum of cytological features and the presence of mitosis, necrosis and nuclear pleomorphism can help in prediction of malignant behavior. Further, cytology is a very useful screening modality in patients of GIST and EGIST to detect early recurrence and metastasis at follow-up.

MicroRNA Involvement in Gastrointestinal Stromal Tumor Tumorigenesis

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The molecular mechanism of GIST formation is among the best characterized of all human tumors. Activating mutations of the c-Kit-kinase (KIT), a member of the receptor tyrosine kinase III family, are present in 80% of GISTs. Gain-of-function mutations of platelet-derived growth factor receptor A (PDGFRA), a member of the same kinase family, are present in 35% of GISTs that lack KIT mutations. These mutations induce the overexpression and autophosphorylation of KIT and PDGFRA, and result in the activation of downstream signaling pathways. Imatinib, a KIT receptor inhibitor, was developed to treat GIST patients by inactivating signaling pathways. However, some GISTs, especially cases with mutations in exon 13 and 17 of KIT, are resistant to imatinib treatment. Therefore, another approach is needed to develop drugs for GIST treatment. Data also support dysregulation of microRNAs in the progression of many types of cancers. Studies demonstrate that microRNAs directly regulate KIT expression levels in GISTs, and inhibit GIST cell proliferation. This review summarizes the characteristics of GISTs, their molecular and clinical implications, the role of microRNAs in GIST tumorigenesis, and their possible therapeutic potential.

Prognostic factors in gastrointestinal stromal tumors: multicenter experience of 333 cases from Turkey.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract. In an attempt to survey the approximate incidence, clinicopathological characteristics, and immunophenotypic features of GISTs in Turkey, we conducted a clinicopathological and immunohistochemical analysis of GISTs. Three hundred and thirty-three patients with GIST from nine institutions in Turkey were retrospectively evaluated. Between January 2001 and March 2011, a total of 333 patients with GISTs were included; of these, 204 (61.2%) were male and 129 (38.8%) were female. The median age was 55 years (range; 22-102 years). At the median follow-up of 26 months (range; 4-166 months), the 1-, 3- and 5-year OS rates of the 333 patients were 96.9%, 85.8% and 78.5%, respectively. The 5-year DFS rate was 40%. The 5-year OS rate and median OS time for the patients with R0 resection were significantly higher than for patients with metastatic diseases (79.7 vs. 75.7% and not reached vs. 115 months, respectively, p=0.04). Although our results should be confirmed by prospective studies, we believe that they contribute to the literature because the study included both resectable and metastatic or unresectable GIST patients and multicenter findings from Turkey.

Primary esophageal gastrointestinal stromal tumor with PDGFRA mutation

Gastrointestinal stromal tumors (GISTs) of the esophagus are a rare entity. Diagnosis of GIST is currently based on immunohistochemical staining of c-KIT or CD34. However, some tumors have clinicopathologic features of GIST but do not express c-KIT or CD34. A few GISTs contain mutations within a receptor tyrosine kinase protein, platelet-derived growth factor receptor alpha (PDGFRA). We herein report a case of esophageal GIST that was KIT negative and had a PDGFRA mutation. A 75-year-old male who had a giant submucosal tumor in the lower part of the thoracic esophagus underwent surgical resection. Immunohistochemical staining of the tumor revealed that it was uniformly negative for KIT, but partially positive for CD34, and negative for S-100 protein and smooth muscle actin (SMA), which led to the final diagnosis of GIST. PDGFRA genetic testing revealed a mutation in exon 12. The mitotic index was over 5/50 high-power fields, and necrotic changes were noted. Adjuvant chemotherapy using imatinib mesylate was administered. The patient has been disease free for 2 years. To the best of our knowledge, this is the only reported case of esophageal GIST that was KIT negative and had a PDGFRA mutation. In cases of digestive submucosal tumor that are difficult to diagnose because of c-KIT or CD34 negativity despite being suspicious for GIST, PDGFRA genetic testing may help for diagnosis of this minority type of GIST.

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

Succinate dehydrogenase-deficient gastrointestinal stromal tumors (GISTs) demonstrate unique pathological and clinical features, including the absence of activating mutations of KIT and PDGFRA, and primary resistance to imatinib. They arise exclusively in the stomach and account for 5–7.5% of all adult stomach GISTs and the great majority of these tumors in childhood. Insulin-like growth factor 1 receptor (IGF1R) overexpression has been associated with wild-type and pediatric GISTs. We propose that IGF1R overexpression is a feature of succinate dehydrogenase-deficient GISTs as a group. We assessed succinate dehydrogenase complex subunit B (SDHB) and IGF1R expression by immunohistochemistry in eight known succinate dehydrogenase-deficient GISTs, three GISTs arising in the setting of neurofibromatosis type 1 syndrome and 40 unselected GISTs. Selected KIT and PDGFRA exons were amplified and sequenced from formalin-fixed paraffin-embedded tumor samples. All eight succinate dehydrogenase-deficient tumors were wild-type for KIT and PDGFRA, succinate dehydrogenase B negative and demonstrated IGF1R overexpression. The three neurofibromatosis-related tumors were succinate dehydrogenase B positive and IGF1R negative. Of the 40 unselected upper GISTs, five were wild-type for KIT and PDGFRA in the selected exons. Two of the wild-type GISTs were succinate dehydrogenase B negative and showed IGF1R overexpression and three were succinate dehydrogenase B positive and IGF1R negative. We conclude that IGF1R overexpression is a feature of succinate dehydrogenase deficient GIST as a group, rather than pediatric or wild-type GIST per se. Therefore, IGF1R inhibition represents a potential rational therapeutic approach in this recently recognized subgroup of GIST.

Histologie et biologie moléculaire des GIST

Gastrointestinal stromal tumors (GIST) are the most frequent sarcomas but were underdiagnosed until the beginning of this century. GIST derive from interstitial cells of Cajal and may develop all along the digestive tract. GIST are characterized by the expression of KIT (CD117), and also DOG-1, which was recently discovered by transcriptome analysis. Gain-of-function mutations of the tyrosine kinase receptors KIT and PDGFRA are present in 85% of cases. More than 150 different mutations have been reported, mostly located in exon 11 of the KIT gene. Detection of these mutations may be useful to confirm the diagnosis and to evaluate the prognosis. Mutations also have predictive value. For example, patients with metastatic GIST and a duplication of KIT exon 9 should receive twice the usual dose of imatinib, while GIST with the PDGFRA p. D842 V mutation are resistant to imatinib. This article presents the main pathologic characteristics of GIST and the important insights that GIST research has provided for oncology in general.

Gastrointestinal Stromal Tumors and Other Malignancies: a Case Series

This paper aims to review the clinical and pathological features of gastrointestinal stromal tumors (GISTs) occurring with other malignancies. A retrospective analysis has been worked out considering all consecutive patients with GISTs referred to our institution between February 2002 and June 2010. We analyzed the relationship among clinical and biological characteristics of the disease and the occurrence of second cancer. Twenty-four patients with GIST have been recorded: in eight cases (33.3%), a second cancer was diagnosed and was synchronous in six patients. In the subgroup of synchronous malignancy, GISTs (four of stomach and one of ileum) were discovered during surgery for other gastrointestinal cancers, whereas one case (arising in the duodenum) was diagnosed during the staging procedure for another primary cancer. In the subgroup of GISTs associated with a second cancer, median age at diagnosis was higher (69 vs. 65 years), patients were more frequently male (62.5% vs. 43.8%), GISTs were smaller (median size 3 vs. 8 cm), and spindle cell histology was less frequent (25% vs. 69.2%); all cases were CD117-positive. Other characteristics were similar in the two subgroups, with the exception of risk category, with low or very low cases higher (75% vs. 20%), even if not statistically, in the subgroup of cases associated with other cancers. Because of the limited number of cases, we cannot exclude an incidental relationship, but this association should be considered, especially during disease staging or surgery for other gastrointestinal cancer, when lesions in other intestinal tracts are detected. Larger studies are needed.

Gastrointestinal stromal tumors (GISTs): Diagnostic value of multi-detector computed tomography

BackgroundGISTs are considered the commonest mesenchymal neoplasms of the GIT originating from the gastrointestinal tract, mesentery, omentum, or retroperitoneum. They arise within the gut musculosa having exophytic growth pattern. They characteristically have hemorrhage, necrosis, or cyst formation that appears as focal areas of low attenuation on computed tomographic images.With multidetector CT (MDCT) capabilities, the exact origin of the GIST can be easily confirmed to differentiate it from other mesenchymal origin tumors. Materials and methodsRetrospective search for GIST cases in the digital archives of our institute, during a 15months duration (April 2010 to July 2011). Workstation reviewing of their imaging features. ResultsThis study included 24 pathologically proved GISTs (12 gastric, 8 small intestinal, two colonic, one mesenteric and one anorectal) demonstrating the radiologic features of GISTs depending on tumor size and organ of origin. ConclusionMDCT with its multiplanar capabilities and isotropic z-axis resolution allows the radiologist to examine the detailed relation of the mass to the surrounding bowel wall, vessels and other structures. It also helps to map the vascular pedicle in cases of hypervascular GIST’s, which may be crucial for trans-catheter embolization in cases presenting with acute gastrointestinal bleeding.

Unusual Appearance of a Pendulated Gastric Tumor: Always Think of GIST

Objective. To investigate the clinicopathological characteristics of gastrointestinal stromal tumor (GIST) with significant cystic changes and to assess the molecular genetic characteristics. Methods. In a 68-year-old man, a large abdominal tumoral mass was discovered incidentally. Computed tomography (CT) and magnetic resonance imaging (MRI) confirmed the presence of a large cystic lesion with multiple contrast-enhancing septae and papillary projections. No clear connection with any of the surrounding organs was identified. Malignancy could not be excluded, and surgery was indicated. During surgery, the large mass was found to be attached by a narrow stalk to the large curvature of the stomach. Results. The histological features and immunohistiochemical profile of the tumor cells (positivity for CD117 and CD34) were consistent with a gastrointestinal stromal tumor with a high risk of progressive disease according to the Fletcher classification. Diagnosis was confirmed by mutational analysis; this demonstrated mutation in exon 14 of PDGFRA. During the followup of 97 months, the patient had a cancer-free survival. Conclusions. This case demonstrates that gastrointestinal stromal tumors (GISTs) with extensive cystic degeneration should be considered in the differential diagnosis of a cystic abdominal mass.

Signet-Ring Cell Carcinoma Mimicking Gastric Gastrointestinal Stromal Tumor Confirmed by Endoscopic Ultrasound-Guided Trucut Biopsy

A submucosal gastric adenocarcinoma, especially the signet ring cell type, is rare. The histologic evaluation techniques for this lesion has not been established; however, histologic confirmation is very important for decision of treatment method. Here, we report a 57-year-old man with a 12-cm gastric submucosal signet ring cell type adenocarcinoma, diagnosed by an endoscopic ultrasound-guided Trucut biopsy and immunochemical studies. This case suggests that the endoscopic ultrasound-guided Trucut biopsy might be a useful diagnostic method in cases of gastric adenocarcinoma with features of gastrointestinal stromal tumor.

Gastrointestinal Stromal Tumor in the Cecum of a Horse

Gastrointestinal stromal tumors (GISTs) are defined as specific CD117-(Kit, stem cell factor receptor) expressing tumors of the gastrointestinal (GI) tract. They are believed to originate from the interstitial pacemaker cells of Cajal (ICC) or their progenitor cells. In horses only a few cases of GISTs are described in the literature. In the present paper the macroscopical, histological, immunohistochemical, and ultrastructural features of an equine cecal GIST are described.

Gastrointestinal Stromal tumor of the stomach and retroperitoneal paraganglioma in Saudi woman, “A case report”

Gastrointestinal stromal tumor (GIST) and paraganglioma are uncommon tumors; mostly occur in a sporadic and isolated form. They are occasionally components of 3 clinical syndromes, familial paraganglioma and gastric GIST, neurofibromatosis type 1 and Carney triad. The latter does not show genetic mutations and affects young women predominantly. This article reports the occurrence of GIST and retroperitoneal paraganglioma in young Saudi woman aged 22 years. The initial clinical presentation was acute severe gastric bleeding. Gastric mass with retroperitoneal mass was discovered during surgical exploration. Histological and immunohistochemical study of both masses showed features of GIST and paraganglioma. The combination of GIST and retroperitoneal paraganglioma in the reported case may be incomplete expression of Carney triad or be coincidental occurrence.

Gastrointestinal Stromal tumor of the stomach and retroperitoneal paraganglioma in Saudi woman, “A case report”

Gastrointestinal stromal tumor (GIST) and paraganglioma are uncommon tumors; mostly occur in a sporadic and isolated form. They are occasionally components of 3 clinical syndromes, familial paraganglioma and gastric GIST, neurofibromatosis type 1 and Carney triad. The latter does not show genetic mutations and affects young women predominantly. This article reports the occurrence of GIST and retroperitoneal paraganglioma in young Saudi woman aged 22 years. The initial clinical presentation was acute severe gastric bleeding. Gastric mass with retroperitoneal mass was discovered during surgical exploration. Histological and immunohistochemical study of both masses showed features of GIST and paraganglioma. The combination of GIST and retroperitoneal paraganglioma in the reported case may be incomplete expression of Carney triad or be coincidental occurrence.

Clinicopathological features and prognosis of cystic gastrointestinal stromal tumor

To investigate the clinicopathological and molecular genetic characteristics of gastrointestinal stromal tumor (GISTs) with significant cystic changes, and to assess their biological behavior. Clinicopathological features of 7 patients with cystic GISTs treated at the Zhongshan Hospital of Fudan University from February 2005 to January 2010 were summarized retrospectively. The mutations status of c-kit and PDGFR-α were analyzed. There were 2 males and 5 females aged from 46 to 76 years old. Primary site of GISTs included stomach(n=4), duodenum(n=1), and small intestinal(n=2). Tumor size ranged from 6 to 16 cm with obviously cystic changes. Tumor cells were found in the solid components under microscope, of which epithelioid cell type were found in 4 case and spindle cell type in 3 cases. The mitotic figures were no more than 3/50 HPF in all the patients. According to the NIH criteria, 4 were high-risk and 3 were low-risk. Based on morphological characteristics, 3 cases were as borderline tumor, 3 moderate-risk, and 1 moderate-risk. Gene mutation of exon 11 of c-kit were identified in 3 cases. During the follow up ranging from 9 to 80 months, all the 7 patients had cancer-free survival. The biological behavior of cystic GIST is indolent with a low risk of malignancy and favorable prognosis.

Beginning of personalized medicine in Panama: Molecular and pathological characteristics of gastrointestinal stromal tumors from archival paraffin-embedded tissue

This is the first study from Central America to analyze genetic mutations and histopathological features associated with gastrointestinal stromal tumors (GIST). Mutations found in the tyrosine kinase membrane receptors c-kit and pdgfra are associated with clinical and pathological characteristics of GIST. New drugs that inhibit the expression of these oncogenes at the molecular level substantially improve the quality of life for patients with this tumor. It is therefore essential for patient care in Panama that genetic analysis of GIST tumors continues to develop from the pilot study presented herein into routine clinical use. This study evaluated 39 cases of GIST in Panama, using samples archived at the Instituto Oncológico Nacional from 1994 to 2004. DNA from paraffin‑embedded tumor tissues was isolated and amplified for the exons of c-kit and pdgfra associated with a high frequency of mutations. Direct PCR sequencing of specific exons was performed, and those with different alleles were cloned and re-sequenced. Amino acid sequences were inferred from DNA and aligned to Genbank reference sequences to determine the position and type of mutation. The highest frequency of mutations was found in exon 11 of the c-kit gene (70%). Mutations found in this exon were heterogeneous, while only one type of mutation (p.A502_Y503dup) was observed in c-kit exon 9. Mutations in the pdgfra gene constituted several substitutions, with the deletion p.D842V being observed most frequently. The observed GIST-associated mutations were previously described. Four patients with mutations associated with familial GIST were also found. The majority (66%) of patients with mutations in exon 11 (residues 550-591) were considered to be at high risk and 75% of patients with mutations specifically within residues 556-560 (exon 11) were considered to have high-risk GIST. This is the first molecular study of GIST in Central America. It was performed to gain a better understanding of the cancer-associated mutations of KIT and platelet‑derived growth factor receptorα (PDGFRA) receptors. This may aid in the prediction of clinical evolution and guide the use of specific drug treatments in patients with GIST in Panama.