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Yan J, He X, Shen C, Zou Y, Chen H, Tang Y. Clinicopathological and mutational characteristics of primary double mutant gastrointestinal stromal tumor: a single center study with review of the literature. BMC Cancer 2023; 23:217. [PMID: 36890498 PMCID: PMC9993699 DOI: 10.1186/s12885-023-10684-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 02/27/2023] [Indexed: 03/10/2023] Open
Abstract
AIMS Primary double KIT/PDGFRA mutations are very rare in gastrointestinal stromal tumours (GISTs) but have not been comprehensively studied to date. In the present study, we investigated the clinicopathologic and genetic features of eight cases of primary double-mutant GISTs, and we reviewed the literature. METHODS AND RESULTS The tumours occurred in six males and two females (age range 57-83 years) and involved the small intestine (n = 4), stomach (n = 2), rectum (n = 1) and retroperitoneum (n = 1). Clinical manifestations were variable, ranging from indolent (no symptoms) to aggressive disease (tumour rupture and haemorrhage). All patients underwent surgical excision, and six of them were treated with imatinib. No one experienced recurrence or other complications during the follow-up time (10 to 61 months). Histologically, all the tumours exhibited mixed cell types, accompanied by variable interstitial changes. KIT mutations were detected in all cases, and the majority of them were present in different exons (n = 5). No PDGFRA exon 12, 14 or 18 mutations were found. All the mutations were validated by next-generation sequencing, and two additional variants with comparatively low allelic fractions were identified in one case. Two of the cases had available allele distribution data, one with an in cis compound mutation and the other with an in trans compound mutation. CONCLUSION Primary double-mutant GISTs have distinctive clinicopathologic and mutational features. Studies of more cases are necessary for a better understanding of these tumours.
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Affiliation(s)
- Jiaqi Yan
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xin He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chaoyong Shen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yan Zou
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Huijiao Chen
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuan Tang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Wong NACS, Garcia-Petit C, Dangoor A, Andrew N. A literature review and database of how the primary KIT/PDGFRA variant of a gastrointestinal stromal tumour predicts for sensitivity to imatinib. Cancer Genet 2022; 268-269:46-54. [PMID: 36155382 DOI: 10.1016/j.cancergen.2022.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/18/2022] [Accepted: 09/05/2022] [Indexed: 01/25/2023]
Abstract
It is well recognized that the primary KIT or PDGFRA variant of a gastrointestinal stromal tumour (GIST) can predict sensitivity to imatinib. However, these data are currently spread across a wide range of publications and have not been collated as one reference. A broad-ranging literature search was therefore performed to assemble such a database which should help optimize imatinib-based management of GIST patients henceforth. Having excluded wild type GISTs and results for imatinib used as adjuvant therapy, 79 publications (dated August 2001 to March 2022) underwent data extraction. These data on imatinib sensitivity were either derived from in vitro studies, predicted by in silico analysis or based on in vivo clinical patient response. Data interpretation carried some caveats: there was a potential for replication of patient-derived data between older and new publications; only predicted protein sequences were presented; the criteria used to record clinical response were not uniform across all publications; and imatinib dosage could vary between different clinical publications. However, these data showed broad agreement of imatinib sensitivity amongst similar subtypes of KIT or PDGFRA variant. There was also agreement between in vivo versus in vitro/in silico derived sensitivity data for most variants when both data types were available.
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Affiliation(s)
- Newton A C S Wong
- Department of Cellular Pathology, Southmead Hospital, Bristol, United Kingdom, BS10 5NB.
| | - Christel Garcia-Petit
- East of Scotland Regional Genetic Service, Ninewells Hospital, Dundee, United Kingdom, DD1 9SY
| | - Adam Dangoor
- Bristol Haematology and Oncology Centre, University Hospitals Bristol & Weston NHS Trust, Bristol, United Kingdom, BS2 8ED
| | - Nicola Andrew
- East of Scotland Regional Genetic Service, Ninewells Hospital, Dundee, United Kingdom, DD1 9SY
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3
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Morini M, Gentilini F, Turba ME, Gobbo F, Mandrioli L, Bettini G. Mutational Analysis of c-KIT and PDGFRA in Canine Gastrointestinal Stromal Tumors (GISTs). Vet Sci 2022; 9:vetsci9070376. [PMID: 35878393 PMCID: PMC9323380 DOI: 10.3390/vetsci9070376] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 11/16/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the canine gastrointestinal tract and are diagnosed by the immunohistochemical expression of the receptor tyrosine kinase (RTK) KIT. Activating mutations of the proto-oncogenes c-KIT and PDGFRA drive GIST oncogenesis and are used to predict the response to RTK-inhibitors in human oncology. Currently, the frequency and significance of these mutations in canine GIST have not been adequately explored. Therefore, we investigated the mutational status of c-KIT (exons 9, 11 and 13) and PDGFRA (exons 12 and 18) genes by PCR followed by fragment analysis for c-KIT deletions and PCR followed by screening with DHPLC and direct sequencing confirmation for single nucleotide variations in 17 formalin-fixed paraffin-embedded canine GISTs confirmed by KIT immunopositivity. c-KIT mutations were detected in 47% of cases, with a mutation detection rate significantly higher (p = 0.0004, Fisher’s exact test) and always involving exon 11. A PDGFRA gene mutation (exon 18) was identified in one case. Even if follow-up data were not available for all cases, four cases with documented abdominal metastases displayed c-KIT mutations. These data confirm that c-KIT exon 11 mutations occur frequently in canine GISTs, and identify the presence of a PDGFRA mutation similar to human GISTs. This study also suggests a potential association of c-KIT mutation with more aggressive biological behavior.
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Affiliation(s)
- Maria Morini
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (F.G.); (F.G.); (L.M.); (G.B.)
- Correspondence:
| | - Fabio Gentilini
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (F.G.); (F.G.); (L.M.); (G.B.)
| | | | - Francesca Gobbo
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (F.G.); (F.G.); (L.M.); (G.B.)
| | - Luciana Mandrioli
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (F.G.); (F.G.); (L.M.); (G.B.)
| | - Giuliano Bettini
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (F.G.); (F.G.); (L.M.); (G.B.)
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Huber AR, DeRoche TC. Gastric Perineurioma: A Case Report and Review of the Literature. Int J Surg Pathol 2022; 31:301-306. [PMID: 35635199 DOI: 10.1177/10668969221101872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Perineuriomas of the gastrointestinal tract, formerly known as benign fibroblastic polyps, most commonly occur as polyps on screening colonoscopy, particularly in the distal colon. Gastric examples are exceedingly rare. We report the sixth patient with a gastric perineurioma in a 57-year-old female. Histologically, the lesion was composed of bland spindle cells without cytologic atypia or mitotic activity located in the gastric lamina propria. The spindled cells were strongly positive for GLUT1 and focally reactive for epithelial membrane antigen (EMA). The morphologic and immunophenotypic findings were those of gastric perineurioma.
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Affiliation(s)
- Aaron R. Huber
- University of Rochester Medical Center, Rochester, NY, USA
| | - Tom C. DeRoche
- Kaiser Airport Way Regional Laboratory, Portland, OR, USA
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Kim DH, Park CH, Park SY, Cho E, Kim HS, Choi SK. Diagnostic yields of endoscopic ultrasound-guided fine-needle tissue acquisition according to the gastric location. Medicine (Baltimore) 2021; 100:e26477. [PMID: 34160458 PMCID: PMC8238348 DOI: 10.1097/md.0000000000026477] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/01/2021] [Accepted: 06/08/2021] [Indexed: 01/04/2023] Open
Abstract
The diagnostic accuracy of endoscopic ultrasound-guided fine-needle tissue acquisition (EUS-FNTA) according to the gastric location of subepithelial tumors (SETs) has not been well established. We aimed to evaluate the efficacy of EUS-FNTA for the diagnosis of gastric SETs according to tumor location.Thirty-three patients diagnosed with gastric SETs via EUS-FNTA from January 2016 to May 2018 were analyzed retrospectively. Patient demographics, diagnostic yields, and complications were evaluated.Nineteen patients (57.6%) were female, with a mean age of 57.7 years. Endoscopic ultrasound revealed a mean longitudinal diameter of 25.6 mm. The most common location of SETs was in the gastric body (n = 18, 54.5%), followed by cardia and fundus (n = 10, 30.3%), and antrum (n = 5, 15.2%). A 20-gauge biopsy needle was most frequently used (90.9%). The diagnostic yield was obtained in 23 patients (69.7%). The most common diagnosis was gastrointestinal stromal tumor (73.9%), followed by leiomyoma (17.4%). The diagnostic yield of SETs in gastric antrum (0/5, 0%) was significantly lower than that in the gastric body and cardia (23/28, 82.1%, P = .001). A case of immediate bleeding after EUS-FNTA occurred in 1 patient (3.0%) who recovered uneventfully. According to related literature, the overall diagnostic yield of SETs in gastric antrum was significantly lower than that in the gastric body, fundus, and cardia (29.7% vs 71.4%, P < .001, n = 191).EUS-FNTA is ineffective in the diagnosis of SETs in the gastric antrum. Although EUS-FNTA is an advanced diagnostic tool for gastric SETs, it is essential to develop more effective methods for the diagnosis of antral SETs.
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Fudalej MM, Badowska-Kozakiewicz AM. Improved understanding of gastrointestinal stromal tumors biology as a step for developing new diagnostic and therapeutic schemes. Oncol Lett 2021; 21:417. [PMID: 33841578 DOI: 10.3892/ol.2021.12678] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
A gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract, with an estimated incidence of 10-15 per 1 million per year. While preparing holistic care for patients with GIST diagnosis, scientists might face several difficulties - insufficient risk stratification, acquired or secondary resistance to imatinib, or the need for an exceptional therapy method associated with wild-type tumors. This review summarizes recent advances associated with GIST biology that might enhance diagnostic and therapeutic strategies. New molecules might be incorporated into risk stratification schemes due to their proven association with outcomes; however, further research is required. Therapies based on the significant role of angiogenesis, immunology, and neural origin in the GIST biology could become a valuable enhancement of currently implemented treatment schemes. Generating miRNA networks that would predict miRNA regulatory functions is a promising approach that might help in better selection of potential biomarkers and therapeutical targets in cancer, including GISTs.
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Affiliation(s)
- Marta Magdalena Fudalej
- Department of Cancer Prevention, Medical University of Warsaw, 02-091 Warsaw, Poland.,Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
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7
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Gao L, Tang X, Qu H, He Q, Sun G, Shi J, Ye J, Liang Y. Primary gastric squamous cell carcinoma presenting as a large submucosal mass: A case report and literature review. Medicine (Baltimore) 2020; 99:e22125. [PMID: 32899097 PMCID: PMC7478421 DOI: 10.1097/md.0000000000022125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
RATIONALE Primary gastric squamous cell carcinoma (SCC) is rarely encountered clinically. SCC, which presents as a submucosal tumor, is even rarer. Without the support of pathological evidence, it is difficult to make a correct preoperative diagnosis. Due to limited clinical data, the pathogenesis and treatment of gastric SCC remain unclear. PATIENT CONCERNS A 69-year-old man was admitted to our hospital with unexplained weight loss. Endoscopy revealed a submucosal mass without any ulcer on its surface located on the body of the stomach. The results of 2 gastroscopic mucosal biopsies were chronic inflammation. DIAGNOSES The clinical diagnosis by computed tomography (CT) and gastroscopy was gastrointestinal stromal tumor (GIST) preoperatively. The postoperative pathological examination demonstrated this tumor as moderately differentiated SCC. INTERVENTIONS Total gastrectomy, distal pancreatectomy, and splenectomy were performed. OUTCOMES The patient was discharged 7 days after the surgery without any complications. The follow-up CT scan showed no evidence of metastatic disease 6 months after surgery. LESSONS Large primary gastric SCC could present as a submucosal mass. Gastroscopic mucosal biopsy may not be able to get tumor tissue due to inflammatory reaction.
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Affiliation(s)
- Lei Gao
- Qilu Medical College of Shandong University
| | - Xiaolong Tang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan China
| | - Hui Qu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan China
| | - Qingsi He
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan China
| | - Guorui Sun
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan China
| | - Jingbo Shi
- Qilu Medical College of Shandong University
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Wong NACS, Giger OT, Ten Hoopen R, Casey RT, Russell K, Faulkner C. Next-generation sequencing demonstrates the rarity of short kinase variants specific to quadruple wild-type gastrointestinal stromal tumours. J Clin Pathol 2020; 74:194-197. [PMID: 32646927 DOI: 10.1136/jclinpath-2020-206613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/12/2020] [Accepted: 06/20/2020] [Indexed: 11/04/2022]
Abstract
AIM There is no known specific biomarker or genetic signal for quadruple wild-type (qWT) gastrointestinal stromal tumours (GISTs). By next-generation sequencing (NGS) of different GIST subgroups, this study aimed to characterise such a biomarker especially as a potential therapeutic target. METHODS AND RESULTS An NGS panel of 672 kinase genes was applied to DNA extracted from 11 wild-type GISTs (including three qWT GISTs) and 5 KIT/PDGFRA mutated GISTs. Short variants which were present in qWT GISTs but no other GIST subgroup were shortlisted. After removing common population variants, in silico-classified deleterious variants were found in CSNK2A1, MERTK, RHEB, ROCK1, PIKFYVE and TRRAP. None of these variants were demonstrated in a separate cohort of four qWT GISTs. CONCLUSIONS Short kinase variants which are specific to qWT GISTs are rare and are not universally demonstrated by this whole subgroup. It is therefore possible that the current definition of qWT GIST still covers a heterogenous population.
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Affiliation(s)
- Newton A C S Wong
- Department of Cellular Pathology, Southmead Hospital, Bristol, UK .,South West Genomic Laboratory Hub, Southmead Hospital, Bristol, UK
| | - Olivier T Giger
- Department of Pathology, University of Cambridge, Cambridge, UK
| | | | - Ruth T Casey
- Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Kirsty Russell
- South West Genomic Laboratory Hub, Southmead Hospital, Bristol, UK
| | - Claire Faulkner
- South West Genomic Laboratory Hub, Southmead Hospital, Bristol, UK
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Xu J, Yan Y, Xiang X, Jiang P, Hu X, Yang W. Gastric Perivascular Epithelioid Cell Tumor (PEComa). Am J Clin Pathol 2019; 152:221-229. [PMID: 31141597 DOI: 10.1093/ajcp/aqz040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES To review the clinicopathologic, immunophenotypic, and molecular features of gastric perivascular epithelioid cell tumor (PEComa). METHODS We identified two new cases of gastric PEComa and summarized the clinical and pathologic characteristics of this rare neoplasm. RESULTS The first case was a 48-year-old woman who was treated with an endoscopic submucosal dissection (ESD), and the second case was a 64-year-old man who received a distal gastrectomy. Microscopic examination showed one tumor was composed of purely epithelioid cells, while the other was composed of epithelioid and spindle cells. Both tumors were immunoreactive for melanocytic markers (HMB45 and Melan-A), smooth muscle actin, and vimentin. No TFE3 gene rearrangement was identified by fluorescence in situ hybridization in either case. CONCLUSIONS Gastric PEComa is an exceedingly rare neoplasm, with only seven other reported cases to date. We are the first to report the results of molecular assays for the TFE3 gene rearrangement associated with gastric PEComa.
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Affiliation(s)
- Jinghong Xu
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Yan
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xueping Xiang
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peter Jiang
- University of Florida College of Medicine, Gainesville
| | - Xiangrong Hu
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Wenjun Yang
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
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10
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Gastrointestinal Stromal Tumor: Genotype Frequency and Prognostic Relevance. Appl Immunohistochem Mol Morphol 2019; 26:153-160. [PMID: 27258566 DOI: 10.1097/pai.0000000000000395] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Genotyping has an important role in the prognosis and prediction of response to tyrosine kinase inhibitor therapy. KIT exon 11 deletions serve as an adverse prognostic marker. Gastrointestinal stromal tumor (GIST) genotype has been described in developed countries; however, data from India are lacking. The aim of this study was to determine the genotype frequency and its prognostic relevance. MATERIALS AND METHODS Eighty consecutive cases of resected GIST were evaluated for histologic and immunohistochemical findings. Mutation analysis for exons 9, 11, 13, and 17 of KIT and 12 and 18 of PDGFRA was carried out by PCR-Sanger sequencing. Genotypes were correlated with risk groups, recurrence, and imatinib therapy. RESULTS Forty-seven of 80 cases (58.7%) showed mutations, including 30 cases (37.5%) in KIT exon 11, 9 cases (11.2%) in KIT exon 9, and 8 cases (10%) in PDGFRA exon 18. Codon 557-558 deletion was present in 15 cases. D842E was the most common in PDGFRA, with similar histologic features as D842V. KIT exon 11 deletion had higher mitotic rate, larger tumor size, high-risk stratification, and lower recurrence-free survival. Recurrences were seen in 12 (16.4%) patients. Nine patients (75%) with recurrence were on imatinib therapy. CONCLUSIONS GIST genotype frequency is lower in Indians. KIT exon 11 deletion is associated with poor prognosis compared with wild-type and other missense mutations. D842E is a common PDGFRA mutation in Indian patients. Patients with a wild genotype are not suitable candidates for imatinib therapy. Genotyping can serve as an important prognostic marker.
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Adachi Y, Mita H, Sasaki Y, Himori R, Onodera K, Nakamura M, Kikuchi T, Yamashita K, Yoshida Y, Ishii Y, Endo T. Malignant paraganglioma of the posterior mediastinum: A case report with genetic analysis. Mol Clin Oncol 2019; 10:10-16. [PMID: 30655972 PMCID: PMC6313888 DOI: 10.3892/mco.2018.1758] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 09/21/2018] [Indexed: 11/07/2022] Open
Abstract
Paraganglioma and pheochromocytoma are rare neuroendocrine neoplasms that originate from chromaffin cells. In many of these tumors, several mutations are reported to occur in the genes of germline and/or somatic cells. A case of paraganglioma in the posterior mediastinum with highly malignant potential is reported. The patient had a rapid clinical course, and it was difficult to reach the final diagnosis. The initial diagnosis on fine-needle aspiration biopsy was a gastrointestinal stromal tumor (GIST) arising from the esophagus. Although radiation therapy was effective for the main tumor, the lung metastases did not respond sufficiently to several tyrosine kinase inhibitors. Autopsy and immunohistochemical examination using a battery of different markers resulted in a final diagnosis of malignant paraganglioma. Next-generation sequencing revealed several gene mutations and copy number variations, including of fumarate hydratase (FH), neurofibromatosis type-1 (NF1) and RET. Those gene alterations may contribute to the pathogenesis of this malignant phenotype to a certain extent. To confirm this, further cases and studies are required. In addition, it should be noted that histological examination of a small piece of tumor might have sampling bias and could cause misdiagnosis.
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Affiliation(s)
- Yasushi Adachi
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Hokkaido 062-0052, Japan
| | - Hiroaki Mita
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Hokkaido 062-0052, Japan
| | - Yasushi Sasaki
- Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Hokkaido 060-8556, Japan
| | - Ryogo Himori
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Hokkaido 062-0052, Japan
| | - Kei Onodera
- Department of Gastroenterology, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan
| | - Masahiro Nakamura
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Hokkaido 062-0052, Japan
| | - Takefumi Kikuchi
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Hokkaido 062-0052, Japan
| | - Kentaro Yamashita
- Department of Gastroenterology, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan
| | - Yukinari Yoshida
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Hokkaido 062-0052, Japan
| | - Yoshifumi Ishii
- Department of Pathology, Sapporo Shirakaba-dai Hospital, Sapporo, Hokkaido 062-0052, Japan
| | - Takao Endo
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba-dai Hospital, Sapporo, Hokkaido 062-0052, Japan
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12
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Richman SD, Fairley J, Hall JA, Nataraj N, Bhide M, Lau A, Norman KL, Deans ZC. Results of the UK NEQAS for Molecular Genetics reference sample analysis. J Clin Pathol 2018; 71:989-994. [PMID: 30030291 PMCID: PMC6225803 DOI: 10.1136/jclinpath-2018-205277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/02/2018] [Accepted: 07/04/2018] [Indexed: 02/06/2023]
Abstract
Aims In addition to providing external quality assessment (EQA) schemes, United Kingdom National External Quality Assessment service (UK NEQAS) for Molecular Genetics also supports the education of laboratories. As an enhancement to the Molecular Pathology EQA scheme, a human cell-line reference sample, manufactured by Thermo Fisher Scientific (AcroMetrix), was provided for analysis. This contained many variants, present at frequencies between 1% and 17.9%. Methods One hundred and one laboratories submitted results, with a total of 2889 test results on 53 genes being reported. Known polymorphisms, 46/2889 (1.59%) results, were excluded. Variants detected in the seven most commonly reported (and clinically relevant) genes, KRAS, NRAS, BRAF, EGFR, PIK3CA, KIT and PDGFRA, are reported here, as these genes fall within the scope of UK NEQAS EQA schemes. Results Next generation sequencing (NGS) was the most commonly performed testing platform. There were between 5 and 27 validated variants in the seven genes reported here. Eight laboratories correctly reported all five NRAS variants, and two correctly reported all eight BRAF variants. The validated mean variant frequency was lower than that determined by participating laboratories, with single-gene testing methodologies showing less variation in estimated frequencies than NGS platforms. Laboratories were more likely to correctly identify clinically relevant variants. Conclusions Over 100 laboratories took the opportunity to test the ‘educational reference sample’, showing a willingness to further validate their testing platforms. While it was encouraging to see that the most widely reported variants were those which should be included in routine testing panels, reporting of variants was potentially open to interpretation, thus clarity is still required on whether laboratories selectively reported variants, by either clinical relevance or variant frequency.
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Affiliation(s)
- Susan D Richman
- Department of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, St James University Hospital, Leeds, UK
| | - Jennifer Fairley
- UK NEQAS for Molecular Genetics, Department of Laboratory Medicine, The Royal Infirmary, Edinburgh, UK
| | - Jacqueline A Hall
- UK NEQAS for Molecular Genetics, Department of Laboratory Medicine, The Royal Infirmary, Edinburgh, UK
| | | | - Mrudul Bhide
- Thermo Fisher Scientific, Fremont, California, USA
| | - Aron Lau
- Thermo Fisher Scientific, Fremont, California, USA
| | | | - Zandra C Deans
- UK NEQAS for Molecular Genetics, Department of Laboratory Medicine, The Royal Infirmary, Edinburgh, UK
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Gastrointestinal Stromal Tumor With Multiple Primary Tyrosine Kinase Mutations-Clinicopathologic and Molecular Characterization. Appl Immunohistochem Mol Morphol 2018; 27:461-465. [PMID: 29734250 DOI: 10.1097/pai.0000000000000660] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
A unique cohort of chemo-naive gastrointestinal stromal tumors (GISTs) with double-primary tyrosine kinase mutations was characterized particularly to determine whether coexistent mutations represent a single mutational event. Up to 2013, 4 UK centers reported 9 GISTs with 2 primary tyrosine kinase mutations. In each of 8 cases validated by next generation sequencing, both mutations were present in the same allele of the same exon (KIT exon 11 or 17, or PDGFRA exon 18). One case showed the second mutation only on some of the mutant alleles. Seven cases showed both mutations in all the reads, but in 2 cases, additional variants were found only in some reads. Clinicopathologic features of the 8 cases were similar to GISTs with single-primary mutations. When GIST genotyping rarely uncovers multiple tyrosine kinase variants in an exon, they occur in the same allele but are likely to represent separate mutational events and lack clinical significance.
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Mucinous Carcinomatosis: A Rare Association between an Ovarian Tumor and an E-GIST. Case Rep Surg 2018; 2018:6897372. [PMID: 29593930 PMCID: PMC5821968 DOI: 10.1155/2018/6897372] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 12/03/2017] [Indexed: 12/29/2022] Open
Abstract
Pseudomyxoma peritonei (PMP) and extragastrointestinal stromal tumors (E-GISTs) are both rare entities. Most of the time, PMP is associated with an appendiceal tumor. An ovarian mucinous tumor can mimic appendiceal metastases. E-GIST is a mesenchymal tumor that can arise from the omentum, retroperitoneum, mesentery, or pleura. We present a case of an 87-year-old woman with mucinous carcinomatosis and acute intestinal occlusion submitted to an emergency laparotomy. She has found to have a borderline mucinous tumor of the ovary from the intestinal type with several lesions of pseudomyxoma peritonei and an E-GIST from the epiploons retrocavity (intermediated risk). In the literature, no relation was found between these two rare tumors. E-GIST was an incidental finding in the context of a mucinous carcinomatosis.
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Thymosin beta-4 overexpression correlates with high-risk groups in gastric gastrointestinal stromal tumors: A retrospective analysis by immunohistochemistry. Pathol Res Pract 2017; 213:1139-1143. [PMID: 28756979 DOI: 10.1016/j.prp.2017.07.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 06/01/2017] [Accepted: 07/02/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Thymosin beta-4 (Tβ4) is a protein that is linked to a number of important biological actions and recently tumor progression and poor prognosis of some tumors. The aim of this study was to evaluate Tβ4 expression in gastric GISTs and correlate with some clinicopathological characteristics related with prognosis and clinical outcome in order to add further data to the current literature. METHODS Tβ4 antibody was applied to the 4μm-thick paraffin sections of 57 gastric GISTs by immunohistochemistry. RESULTS Tβ4 expression was found to be directly corrrelated with higher risk groups, tumor size, mitotic count, cellularity, and necrosis while it was inversely correlated with overall survival (OS) by univariate analysis (p=0.000, p=0.001, p=0.000, p=0.025, p=0.023, and p=0.042, respectively). The direct association between Tβ4 expression and risk groups were also supported by multivariate analysis (p=0.000, β=0.497, t=4.374). CONCLUSION Overexpression of Tβ4 was found to be related with predictive characteristics for tumor progression and adverse prognosis. Thus, we suggest that overexpression of Tβ4 might play a role in the progression of gastric GISTs and might be used as a potential prognostic tool as well as a target for novel therapies.
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Kosemehmetoglu K, Kaygusuz G, Fritchie K, Aydin O, Yapicier O, Coskun O, Karatayli E, Boyacigil S, Guler G, Dervisoglu S, Kuzu I. Clinical and pathological characteristics of gastrointestinal stromal tumor (GIST) metastatic to bone. Virchows Arch 2017; 471:77-90. [PMID: 28488171 DOI: 10.1007/s00428-017-2138-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 03/11/2017] [Accepted: 04/26/2017] [Indexed: 12/16/2022]
Abstract
Our aim in this study was to describe the clinical, morphological, and molecular profile of gastrointestinal stromal tumor (GIST) metastatic to bone. We analyzed the morphological, phenotypic, and molecular characteristics of seven cases, and in addition reviewed 17 cases from literature. Sequence analysis of KIT and PDGFRA genes was possible for six cases. For the GIST cases with bone metastasis, the most common primaries were small intestine (29%), stomach (25%), and rectum (21%). Sites of bone metastases were vertebrae (11), pelvis (8), femur (8), ribs (6), humerus (5), skull (3), scapula (1), and mandible (1). The size ranged from 1.5 to 13 cm (median, 3.8 cm). Bone metastases without involvement of any other organ were seen in 17% of the cases and were solitary in 14 (58%). Adjacent soft tissue involvement was present in nearly half of the patients. Bone metastasis was either manifest at the time of diagnosis (28%) or occurred after a mean period of 4.7 years (3 months-20 years). Morphologically, neoplastic cells were spindle in 67%, epithelioid in 13%, and mixed epithelioid and spindle in 20%. CD117, DOG1, and CD34 were positive in 88, 86, and 85% of the cases, respectively. KIT Exon 11 mutations were the most frequent gene alteration (78%), followed by KIT Exon 13 mutations. Of 17 of the cases with available follow-up information, 7 (41%) patients developed bone metastasis under imatinib therapy. Five patients (29%) died of disease within a mean of 17 months. Bone metastases from GIST are usually found in patients with advanced disease and typically present as lytic masses with occasional soft tissue involvement. We could not identify any KIT or PDGFRA alterations predisposing to bone metastasis.
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Affiliation(s)
- Kemal Kosemehmetoglu
- Department of Pathology, Hacettepe University School of Medicine, Ankara, Turkey.
| | - Gulsah Kaygusuz
- Department of Pathology, Ankara University School of Medicine, Ankara, Turkey
| | - Karen Fritchie
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Ovgu Aydin
- Department of Pathology, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey
| | - Ozlem Yapicier
- Department of Pathology, Acıbadem University School of Medicine, Istanbul, Turkey
| | - Oznur Coskun
- Department of Pathology, Ankara University School of Medicine, Ankara, Turkey
| | | | - Senay Boyacigil
- Department of Pathology, Ankara University School of Medicine, Ankara, Turkey
| | | | - Sergulen Dervisoglu
- Department of Pathology, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey
| | - Isinsu Kuzu
- Department of Pathology, Ankara University School of Medicine, Ankara, Turkey
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Lin LF, Jin JS, Chen JC, Huang CC, Sheu JH, Chen W, Tsao TY, Hsu CW. Positive cyclin T expression as a favorable prognostic factor in treating gastric gastrointestinal stromal tumors. Mol Clin Oncol 2016; 4:971-975. [PMID: 27284431 DOI: 10.3892/mco.2016.835] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 10/26/2015] [Indexed: 12/13/2022] Open
Abstract
Positive transcriptional elongation factor b (P-TEFb) contains the catalytic subunit cyclin-dependent kinase 9 (Cdk9) and the regulatory subunit cyclin T. Cyclin T1 and Cdk9 are the key factors of the PTEFb pathways and are overexpressed in the human head and neck carcinoma cell line. However, there have been limited studies regarding the role of cyclin T1 and Cdk9 in gastric gastrointestinal stromal tumors (GISTs). The aim of the present study was to assess the association between cyclin T1 and Cdk9 and their clinical significance in gastric GISTs. A total of 30 gastric GIST patients who underwent either laparoscopic or laparotomic partial gastrectomy were enrolled in the study. The surgical tissue slides were stained with Cdk9 and cyclin T1 antibodies, and the immunohistochemistry scores and disease-free survival (DFS) were analyzed. Ten patients were cyclin T1-positive, and 20 were negative. All 11 patients with recurrent tumors or distant metastases were cyclin T1-negative patients. Old age, large tumor size, a high Ki67 IHC staining score, high mitotic count and negative cyclin T1 staining revealed a worse clinical outcome in univariate analysis. By contrast, the Cdk9 score was not associated with clinical parameters. The Kaplan-Meier survival curve illustrated that the DFS rate of the patients with negative cyclin T1 staining was significantly lower than that of the patients with positive cyclin T1 staining. Positive expression of cyclin T1 was a good prognostic factor in patients with gastric GISTs.
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Affiliation(s)
- Lien-Fu Lin
- Division of Gastroenterology, Department of Internal Medicine, Tungs' Taichung MetroHarbor Hospital, Taichung 435, Taiwan R.O.C
| | - Jong-Shiaw Jin
- Department of Pathology, Tungs' Taichung MetroHarbor Hospital, Taichung 435, Taiwan R.O.C
| | - Jui-Chang Chen
- Department of Applied Chemistry, National Chia-Yi University, Chia-Yi 600, Taiwan R.O.C
| | - Chia-Chi Huang
- Center of Nano Bio-Detection, National Chung Cheng University Chia-Yi, Chia-Yi 621, Taiwan R.O.C
| | - Jeng-Horng Sheu
- Department of Applied Chemistry, National Chia-Yi University, Chia-Yi 600, Taiwan R.O.C
| | - Wenlung Chen
- Department of Applied Chemistry, National Chia-Yi University, Chia-Yi 600, Taiwan R.O.C
| | - Tang-Yi Tsao
- Department of Pathology, Tungs' Taichung MetroHarbor Hospital, Taichung 435, Taiwan R.O.C
| | - Chih-Wei Hsu
- Department of Applied Chemistry, National Chia-Yi University, Chia-Yi 600, Taiwan R.O.C.; Division of General Surgery, Department of Surgery, Tungs' Taichung MetroHarbor Hospital, Taichung 435, Taiwan R.O.C
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Novel Use for DOG1 in Discriminating Breast Invasive Carcinoma from Noninvasive Breast Lesions. DISEASE MARKERS 2016; 2016:5628176. [PMID: 27041791 PMCID: PMC4793094 DOI: 10.1155/2016/5628176] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 01/27/2016] [Accepted: 02/08/2016] [Indexed: 12/03/2022]
Abstract
Aims. DOG1 has proven to be a useful marker of gastrointestinal stromal tumors (GISTs). Recently, DOG1 expression has also been reported in some non-GIST malignant tumors, but the details related to DOG1 expression in breast tissue remain unclear. The aim of this study was to detect the expression of DOG1 in the human breast and to evaluate the feasibility of using DOG1 to discriminate between invasive breast carcinoma and noninvasive breast lesions. Methods and Results. A total of 210 cases, including both invasive and noninvasive breast lesions, were collected to assess DOG1 expression immunohistochemically. DOG1 expression was consistently positive in breast myoepithelial cells (MECs), which was similar to the results obtained for three other MEC markers: calponin, smooth muscle myosin heavy chain (SMMHC), and P63 (P > 0.05 in all). Importantly, DOG1 was useful in discriminating invasive breast carcinoma from noninvasive breast lesions (P < 0.05). Conclusions. DOG1 is a useful marker of breast MECs, and adding DOG1 to the MEC identification panel will provide more sophisticated information when diagnosing uncertain cases in the breast.
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Güler B, Özyılmaz F, Tokuç B, Can N, Taştekin E. Histopathological Features of Gastrointestinal Stromal Tumors and the Contribution of DOG1 Expression to the Diagnosis. Balkan Med J 2015; 32:388-96. [PMID: 26740899 DOI: 10.5152/balkanmedj.2015.15912] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Accepted: 05/09/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GIST) have KIT or platelet-derived growth factor receptor α (PDGFRα) mutations affecting receptor tyrosine kinase activity and do not benefit from classic treatment regimens. AIMS The aim of this study was to review the algorithm that may be followed for the diagnosis and differential diagnosis in GISTs by investigating the histomorphological parameters and expression characteristics of classical immunohistochemical antibodies used in routine tests in addition to DOG1 expression. STUDY DESIGN Diagnostic accuracy study. METHODS We reevaluated the histological and immunohistochemical parameters of 37 GISTs. The standard immunohistochemical diagnosis and differential diagnosis panel antibodies (CD117, PDGFRα, CD34, vimentin, desmin, SMA, S-100, and Ki67) were studied on the tumor sections. We also used the popular marker DOG1 antibody with accepted sensitivity for GISTs in recent years and the PDGFRα immune marker for which the benefit in routine practice is discussed. RESULTS Classification according to progressive disease risk groups of the 37 cases revealed that 54% were in the high risk, 19% in the moderate risk, 16% in the low risk, 8% in the very low risk and 8% in the no risk group. Cytological atypia, necrosis, mucosal invasion and the Ki67 index were found to be related to the progressive disease risk groups of the tumors (p<0.05). Positive immunoreaction was observed with CD117 and PDGFRα in all GISTs in the study (100%). Positivity with the DOG1 antibody was found in 33 (89%) cases. CD34 was positive in 62% (23) of the cases. CONCLUSION The CD117 antibody still plays a key role in GIST diagnosis. However, the use of DOG1 and PDGFRα antibodies combined with CD117 as sensitive markers can be beneficial.
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Affiliation(s)
- Beril Güler
- Department of Pathology, Bezmialem Vakıf University Faculty of Medicine, İstanbul, Turkey
| | - Filiz Özyılmaz
- Department of Pathology, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Burcu Tokuç
- Department of Public Health, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Nuray Can
- Department of Pathology, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Ebru Taştekin
- Department of Pathology, Trakya University Faculty of Medicine, Edirne, Turkey
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Basilio-de-Oliveira RP, Nunes Pannain VL. Prognostic angiogenic markers (endoglin, VEGF, CD31) and tumor cell proliferation (Ki67) for gastrointestinal stromal tumors. World J Gastroenterol 2015; 21:6924-6930. [PMID: 26078569 PMCID: PMC4462733 DOI: 10.3748/wjg.v21.i22.6924] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 02/23/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the correlation between the immunoexpression of angiogenic markers [CD31, CD105 and vascular endothelial growth factor (VEGF)], proliferative index (Ki67), and prognosis of patients with gastrointestinal stromal tumors (GIST).
METHODS: This is a retrospective study of 54 GIST cases. Medical records were searched to obtain the GIST patients’ demographic and clinical data, and paraffin-embedded blocks of tumor samples were retrieved from the hospital archives to conduct a new immunohistochemical evaluation. The tumor samples of GIST patients were subject to immunohistochemical evaluation for endoglin (CD105), CD31, VEGF, and Ki67 expression. The CD105 and CD31 intratumoral microvascular density (IMVD) was measured using automated analysis. We determined the correlation between the immunoexpression of CD105, CD31, VEGF, Ki67 and prognosis. In addition, we conducted a cutoff analysis using the receiver-operating characteristic curve. VEGF positivity was classified as either null/weak or strong. Ki67 was evaluated using a cutoff of 5% positive cells. The prognosis was classified as good (patient alive without recurrence) or poor (patient with recurrence/death).
RESULTS: The distribution of tumor sites among the 54 analyzed samples was as follows: 27 (50%) in the stomach, 20 (37.1%) in the small intestine, 6 (11.1%) in the colon, and 1 (1.8%) in the esophagus. The size of the tumors ranged from 2 to 33 cm (median: 8 cm); in 12 cases (22.2%), the tumor was below 5 cm at the largest diameter, but in 42 cases (77.7%), the tumor was larger than 5 cm. The means of CD105 and CD31 were significantly higher in the group with poor prognosis (P < 0.001). The cut-off values of CD105 (> 1.2%) and CD31 (> 2.5%) in the receiver-operating characteristic curve were related to a poorer prognosis. Cases with a better prognosis showed significantly null/weak staining for VEGF (P < 0.001). Ki-67 expression of ≥ 5% was strongly correlated with a worse prognosis (P < 0.001). In the multivariate analysis, CD105 was the variable that most strongly correlated with prognosis.
CONCLUSION: The IMVD cutoff values for the angiogenic markers CD105 and CD31, may be prognostic factors for GIST, in addition to VEGF and Ki67.
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de Oliveira RPB, Portari Filho PE, Iglesias AC, de Oliveira CAB, Pannain VLN. Comparative study of the different degrees of risk of gastrointestinal stromal tumor. Rev Col Bras Cir 2015; 42:32-6. [PMID: 25992698 DOI: 10.1590/0100-69912015001007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Accepted: 04/18/2014] [Indexed: 01/19/2023] Open
Abstract
OBJECTIVE To evaluate the applicability of the main categories of risk and morphological factors in the prognosis of gastrointestinal stromal tumors. METHODS we retrospectively studied fifty-four cases of GIST, assessing the main prognostic factors of this neoplasis: risk levels, topography, size, mitotic index, necrosis, histological subtype and immunophenotype. We also verified their association and the reduction of overall survival. RESULTS Univariate analysis showed that tumors with mitoses number greater than 5 per 50CGA (high-power fields), the presence of necrosis and a high risk for both the systems proposed by Fletcher and Miettinen had a significant association with reduced survival (p = 0.00001, 0.0056, 0.03 and 0.009, respectively). The remaining analyzed factors (size, histological subtype, topography and immunophenotype) had no such association. Multivariate analysis (Jacard index) showed that the Miettinen degree of risk was the one that best correlated with prognosis. CONCLUSION the risk criteria of Fletcher and Miettinen are important in assessing the prognosis of patients with gastrointestinal stromal tumors, especially the latter, which adds to the mitotic index and the presence of tumor necrosis.
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Affiliation(s)
- Rodrigo Panno Basilio de Oliveira
- Department of Pathology and Clinical Support, School of Medicine and Surgery, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro Eder Portari Filho
- Department of General and Specialized Surgery, School of Medicine and Surgery, UNIRIO, Rio de Janeiro, Brazil
| | | | | | - Vera Lucia Nunes Pannain
- Department of Pathology, Faculty of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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22
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Wong NACS, Wingate J, Gradhand E. An immunohistochemical study of potential diagnostic and therapeutic biomarkers of wild-type gastrointestinal stromal tumours. Histopathology 2015; 67:378-85. [DOI: 10.1111/his.12667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 02/02/2015] [Indexed: 12/26/2022]
Affiliation(s)
| | - Jenny Wingate
- Department of Histopathology; Bristol Royal Infirmary; Bristol UK
| | - Elise Gradhand
- Department of Histopathology; Bristol Royal Infirmary; Bristol UK
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Wong NACS, Campbell F, Shepherd NA. Abdominal monophasic synovial sarcoma is a morphological and immunohistochemical mimic of gastrointestinal stromal tumour. Histopathology 2015; 66:974-81. [PMID: 25346074 DOI: 10.1111/his.12593] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 10/17/2014] [Indexed: 12/12/2022]
Abstract
AIMS Synovial sarcomas may arise within retroperitoneal or pelvic tissues or, more rarely, within the luminal gastrointestinal tract. This case series aims to demonstrate how such primary abdominal synovial sarcomas may particularly mimic gastrointestinal stromal tumour (GIST) on both morphological and immunohistochemical grounds. METHODS AND RESULTS Four cases of primary abdominal synovial sarcoma were reviewed morphologically and with immunohistochemistry, fluorescence in-situ hybridization with an SS18 break-apart probe, and KIT/PDGFRA mutation analysis. The four patients comprised two males and two females, with a median age of 42 years (range: 17-59 years). Two synovial sarcomas arose within the stomach, one within the small-intestine mesentery, and the fourth within the retroperitoneum. All four tumours showed only a monophasic spindle cell component in the tissues available for review. All four tumours showed DOG1 immunopositivity, and three coexpressed CD117. Three tested cases did not show activating KIT or PDGFRA mutations, whereas all four cases showed chromosomal rearrangement of SS18. CONCLUSIONS A diagnosis of synovial sarcoma should be considered particularly if an abdominal spindle cell neoplasm shows a haemangiopericytomatous pattern and diffuse CD99 and CD56 immunopositivity. A confident distinction between abdominal synovial sarcoma and GIST requires KIT/PDGFRA mutation analyses and specific molecular testing for synovial sarcoma.
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Affiliation(s)
| | - Fiona Campbell
- Department of Pathology, Royal Liverpool University Hospital, Liverpool, UK
| | - Neil A Shepherd
- Gloucestershire Cellular Pathology Laboratory, Cheltenham General Hospital, Cheltenham, UK
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Wang M, Xu J, Zhang Y, Tu L, Qiu WQ, Wang CJ, Shen YY, Liu Q, Cao H. Gastrointestinal stromal tumor: 15-years' experience in a single center. BMC Surg 2014; 14:93. [PMID: 25403624 PMCID: PMC4254179 DOI: 10.1186/1471-2482-14-93] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 09/16/2014] [Indexed: 12/11/2022] Open
Abstract
Background Gastrointestinal stromal tumor (GIST) is known for its wide variability in biological behaviors and it is difficult to predict its malignant potential. The aim of this study is to explore the characteristics and prognostic factors of GIST. Methods Clinical and pathological data of 497 GIST patients in our center between 1997 and 2012 were reviewed. Results Patients were categorized into very low-, low-, intermediate- and high-risk groups according to modified National Institutes of Health (NIH) consensus classification system. Among the 401 patients untreated with imatinib mesylate (IM), 5-year overall survival (OS) in very low-, low-, intermediate- and high-risk groups was 100%, 100%, 89.6% and 65.9%; and 5-year relapse-free survival (RFS) was 100%, 98.1%, 90.9% and 44.5%, respectively. Univariate analysis revealed that sex, tumor size, mitotic rate, risk grade, CD34 expression, and adjacent involvement were predictors of OS or RFS. COX hazard proportional model (Forward LR) showed that large tumor size, high mitotic rate, and high risk grade were independent risk factors to OS, whereas high mitotic rate, high risk grade and adjacent organ involvement were independent risk factors to RFS. The intermediate-high risk patients who received IM adjuvant therapy (n = 87) had better 5-year OS and RFS than those who did not (n = 188) (94.9% vs. 72.1; 82.3% vs. 56.3%, respectively). Similarly, advanced GIST patients underwent IM therapy (n = 45) had better 3-year OS and 1-year progression-free survival (PFS) than those who didn’t (n = 42) (75.6% vs. 6.8%; 87.6% vs. 12.4%, respectively). Conclusions Very low- and low-risk GISTs can be treated with surgery alone. Large tumor size, high mitotic rate, high risk grade, and adjacent organ involvement contribute to the poor outcome. IM therapy significantly improves the survival of intermediate-high risk or advanced GIST patients. Electronic supplementary material The online version of this article (doi:10.1186/1471-2482-14-93) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Hui Cao
- Department of General Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Floor 11, Building 7, NO, 1630, Dongfang Road, Shanghai 200127, China.
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Yamashita D, Usami Y, Toyosawa S, Hirota S, Imai Y. A case of diffuse infiltrating gastrointestinal stromal tumor of sigmoid colon with perforation. Pathol Int 2014; 64:34-8. [PMID: 24471968 DOI: 10.1111/pin.12124] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 11/29/2013] [Indexed: 12/22/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and typically present as discrete well-circumscribed but non-encapsulated tumor masses. In this report, we describe a case of colonic perforation caused by an unusual form of GIST. A 72-year-old Japanese woman presented to the emergency department with acute abdominal pain. Under the provisional diagnosis of sigmoid colon perforation, a laparoscopic sigmoidectomy was performed. Although the tumor mass was undetectable during the preoperative examination, a spindle cell lesion with a diffuse longitudinal growth pattern replacing the muscularis propria was revealed by microscopic examination. The spindle cell lesion was exposed at the perforation, suggesting a causal relationship between the lesion and the perforation. The spindle cell lesion was KIT-positive and had a mutation in the C-KIT gene at exon 11. We diagnosed it as diffuse infiltrating GIST. We consider that the lesion would be a cause of the colonic perforation, and emphasize the importance of accurate diagnosis of the lesion by histological, immunohistochemical and genetic examinations.
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Affiliation(s)
- Daisuke Yamashita
- Department of Clinical Pathology, Kobe City Medical Center General Hospital, Kobe, Japan
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26
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Yip D, Zalcberg J, Ackland S, Barbour AP, Desai J, Fox S, Kotasek D, McArthur G, Smithers BM. Controversies in the management of gastrointestinal stromal tumors. Asia Pac J Clin Oncol 2014; 10:216-227. [PMID: 24673914 DOI: 10.1111/ajco.12187] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2014] [Indexed: 12/15/2022]
Abstract
Major advances in the medical treatment of gastrointestinal tumors (GISTs) have improved survival for both patients with advanced disease and those diagnosed with high-risk primary tumors. The Consensus approaches to best practice management of gastrointestinal stromal tumors, published in this journal in 2008, provided guidance for the management of GIST to both clinicians and regulatory authorities. Since then, clinical trials have demonstrated the benefit of adjuvant imatinib in high-risk patients, and mature data from advanced GIST studies suggest that a small but significant proportion of patients with advanced disease can achieve long-term benefit with ongoing imatinib treatment. Other evolving management strategies include the controversial use of palliative or debulking surgery to improve outcomes in advanced GIST and the development of promising new multikinase inhibitors, such as regorafenib, which has established benefit in the third-line setting. This review provides an update of recent developments in GIST management and discusses new controversies that these advances have generated.
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Affiliation(s)
- Desmond Yip
- Department of Medical Oncology, The Canberra Hospital, Canberra, Australian Capital Territory, Australia; ANU Medical School, Australian National University, Canberra, Australian Capital Territory, Australia
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Salah W, Faigel DO. When to puncture, when not to puncture: Submucosal tumors. Endosc Ultrasound 2014; 3:98-108. [PMID: 24955339 PMCID: PMC4064168 DOI: 10.4103/2303-9027.131038] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Accepted: 11/20/2013] [Indexed: 12/19/2022] Open
Abstract
Subepithelial masses of the gastrointestinal (GI) tract are a frequent source of referral for endosonographic evaluation. Subepithelial tumors most often appear as protuberances in the GI tract with normal overlying mucosa. When there is a need to obtain a sample of the mass for diagnosis, endoscopic ultrasound (EUS) - guided fine-needle aspiration (FNA) is superior to other studies and should be the first choice to investigate any subepithelial lesion. When the decision is made to perform EUS-guided FNA several technical factors must be considered. The type and size of the needle chosen can affect diagnostic accuracy, adequacy of sample size and number of passes needed. The use of a stylet or suction and a fanning or standard technique during EUS-guided FNA are other factors that must be considered. Another method proposed to improve the efficacy of EUS-guided FNA is having an on-site cytopathologist or cytotechnician. Large or well-differentiated tumors may be more difficult to diagnose by standard EUS-FNA and the use of a biopsy needle can be used to acquire a histopathology sample. This can allow preservation of tissue architecture and cellularity of the lesion and may lead to a more definitive diagnosis. Alternatives to FNA such as taking bite-on-bite samples and endoscopic submucosal resection (ESMR) have been studied. Comparison of these two techniques found that ESMR has a significantly higher diagnostic yield. Most complications associated with EUS-FNA such as perforation, infection and pancreatitis are rare and the severity and incidence of these adverse events is not known. Controversy exists as to the optimal method in which to perform EUS-FNA and larger prospective trials are needed.
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Affiliation(s)
- Wajeeh Salah
- Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ 85054, USA
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Schoppmann SF, Vinatzer U, Popitsch N, Mittlböck M, Liebmann-Reindl S, Jomrich G, Streubel B, Birner P. Novel Clinically Relevant Genes in Gastrointestinal Stromal Tumors Identified by Exome Sequencing. Clin Cancer Res 2013; 19:5329-39. [DOI: 10.1158/1078-0432.ccr-12-3863] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Kara T, Serinsoz E, Arpaci RB, Gubur O, Orekici G, Ata A, Colak T, Arican A. Contribution of DOG1 expression to the diagnosis of gastrointestinal stromal tumors. Pathol Res Pract 2013; 209:413-7. [PMID: 23722018 DOI: 10.1016/j.prp.2013.04.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Revised: 03/11/2013] [Accepted: 04/16/2013] [Indexed: 12/25/2022]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, and the majority contain KIT or PDGFRA-activating mutations. However, up to 10% of GISTs are c-kit-negative. Antibodies with increased sensitivity and specificity for the detection of c-kit-negative GIST cases may be of value, especially because some of these cases may also benefit from tyrosine kinase inhibitor therapy. Hematoxylin and Eosin sections of 33 GISTs were re-examined in order to define histopathological criteria used in risk assessment of these tumors. Immunohistochemistry with a panel of antibodies [c-kit, DOG1 (discovered on GIST 1), CD34, smooth muscle actin (SMA), Desmin, S100 and Ki67] was performed on 5μm-thick paraffin sections of all tumors. Statistical analysis of immunohistochemical studies showed that DOG1 and CD117 were the most sensitive and specific antibodies in the diagnosis of GISTs. Other antibodies were unhelpful in confirming a diagnosis of GIST, but were particularly useful in the differential diagnosis. Reactivity for DOG1 may aid in the diagnosis of GISTs, which fail to express c-kit antigen, and lead to appropriate treatment with imatinib mesylate, an inhibitor of the KIT tyrosine kinase.
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Affiliation(s)
- Tuba Kara
- Mersin University, Medical School, Department of Pathology, Turkey.
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Oudijk L, Gaal J, Korpershoek E, van Nederveen FH, Kelly L, Schiavon G, Verweij J, Mathijssen RHJ, den Bakker MA, Oldenburg RA, van Loon RLE, O'Sullivan MJ, de Krijger RR, Dinjens WNM. SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors. Mod Pathol 2013; 26:456-63. [PMID: 23174939 DOI: 10.1038/modpathol.2012.186] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in KIT or platelet-derived growth factor receptor-α. However, a small subset of GISTs lacks such mutations and is termed 'wild-type GISTs'. Germline mutation in any of the subunits of succinate dehydrogenase (SDH) predisposes individuals to hereditary paragangliomas and pheochromocytomas. However, germline mutations of the genes encoding SDH subunits A, B, C or D (SDHA, SDHB, SDHC or SDHD; collectively SDHx) are also identified in GISTs. SDHA and SDHB immunohistochemistry are reliable techniques to identify pheochromocytomas and paragangliomas with mutations in SDHA, SDHB, SDHC and SDHD. In this study, we investigated if SDHA immunohistochemistry could also identify SDHA-mutated GISTs. Twenty-four adult wild-type GISTs and nine pediatric/adolescent wild-type GISTs were analyzed with SDHB, and where this was negative, then with SDHA immunohistochemistry. If SDHA immunohistochemistry was negative, sequencing analysis of the entire SDHA coding sequence was performed. All nine pediatric/adolescent GISTs and seven adult wild-type GISTs were negative for SDHB immunohistochemistry. One pediatric GIST and three SDHB-immunonegative adult wild-type GISTs were negative for SDHA immunohistochemistry. In all four SDHA-negative GISTs, a germline SDHA c.91C>T transition was found leading to a nonsense p.Arg31X mutation. Our results demonstrate that SDHA immunohistochemistry on GISTs can identify the presence of an SDHA germline mutation. Identifying GISTs with deficient SDH activity warrants additional genetic testing, evaluation and follow-up for inherited disorders and paragangliomas.
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Affiliation(s)
- Lindsey Oudijk
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, The Netherlands.
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Al-Sajee D, Huizinga JD. Interstitial Cells of Cajal: Pathology, injury and repair. Sultan Qaboos Univ Med J 2012; 12:411-21. [PMID: 23275836 DOI: 10.12816/0003165] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2011] [Revised: 02/08/2012] [Accepted: 02/12/2012] [Indexed: 12/30/2022] Open
Abstract
Interstitial cells of cajal (ICC) are specialised cells located within the musculature of the gastrointestinal tract (GIT). Although they form only 5% of the cells in the musculature of the GIT, they play a critical role in regulating smooth muscle function and GIT motility in coordination with the enteric nervous system. C-kit is a transmembrane glycoprotein that plays a critical role in ICC development and maturation. Physiological conditions such as ageing, as well as pathological conditions that have different disease processes, negatively affect ICC networks and function. Absent or disordered ICC networks can be associated with disorders in GIT motility. This review highlights the mechanism of ICC recovery from various types of injury which entails understanding the development of ICC and the factors affecting it. ICC transformation into malignant tumours (gastrointestinal stromal tumours) and their potential as contributors to therapeutic resistance is also discussed.
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Abstract
AIMS DOG1 is a recently described marker of gastrointestinal stromal tumour (GIST) which is considered to be extremely sensitive and, among mesenchymal neoplasms, quite specific for this tumour type. Following the identification of DOG1 immunoreactivity in a uterine leiomyosarcoma, we wished to ascertain how prevalent DOG1 immunoreactivity was in this tumour type. METHODS We stained a series of uterine leiomyosarcomas (n=26) with DOG1 and with CD117 (c-kit), another marker of GIST. Staining with both markers was classified as negative, focal (<50% tumour cells positive) or diffuse (≥50% tumour cells positive). RESULTS DOG1 immunoreactivity was present in seven of 26 (27%) leiomyosarcomas. Staining was focal in five cases and diffuse in two. CD117 was positive in three of 26 (11.5%) cases, two focal and one diffuse. Two cases were positive with DOG1 and CD117. One of five uterine leiomyomas was focally positive with DOG1, and one extrauterine pelvic leiomyoma was diffusely positive with this marker. CONCLUSIONS Since GISTs have rarely been described as primary uterine neoplasms, the presence of DOG1 immunoreactivity in a uterine leiomyosarcoma may result in diagnostic confusion, and a panel of markers is necessary for diagnosis. Uterine leiomyosarcomas should be added to the list of mesenchymal neoplasms which may be DOG1 positive.
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Affiliation(s)
- Shatrughan P Sah
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland
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Endosonographic large-bore biopsy of gastric subepithelial tumors: a prospective multicenter study. Eur J Gastroenterol Hepatol 2012; 24:1135-44. [PMID: 22797706 DOI: 10.1097/meg.0b013e328356eae2] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Once gastric subepithelial lesions (SEL) are found, tissue diagnosis is required, considering the possible differential diagnosis of gastrointestinal stromal tumors (GIST). Previous studies have shown insufficient accuracy of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) using cytologic analysis. METHODS The feasibility and yield of EUS-FNA-based histologic tissue acquisition for gastric SEL, using 19 G large-bore needles, was assessed in a 4-year multicenter, prospective study. All consecutive patients, who were referred for EUS-FNA for all SEL greater than 1 cm, were included. RESULTS Of 100 patients with suspected gastric SEL, 71 lesions were found to be eligible. Endoscopic biopsies or resections or surgery were used alternatively for a variety of reasons in 25 patients. EUS-FNA using the 19 G needle was finally performed in 46/71 cases (65%) with one to four needle passes. Sufficient material for a definite or a suspected histological diagnosis was obtained in 52 and 7% of the cases, respectively. In 41%, the samples were not informative. Immunohistochemistry was possible in 91% of cases with sufficient amounts of tissue; 30% were GIST. Self-limited, mild hemorrhage occurred in 22%; one patient developed a fatal abscess. CONCLUSION Even when intended, EUS-guided 19 G FNA is only feasible in 46% of gastric SEL. The diagnostic yield of 19 G FNA was only 52%, but with excellent differentiation between GIST and leiomyoma. Infectious complications must be prevented.
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Alkhatib AA, Faigel DO. Endoscopic ultrasonography-guided diagnosis of subepithelial tumors. Gastrointest Endosc Clin N Am 2012; 22:187-205, vii. [PMID: 22632943 DOI: 10.1016/j.giec.2012.04.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Subepithelial lesions are frequently discovered during routine endoscopic examinations. These lesions represent a wide spectrum of heterogeneous benign to malignant conditions. Most of these lesions are asymptomatic. There is no consensus regarding how to manage these lesions. Over the last 2 decades, the approach to these lesions has significantly improved owing to the introduction of endoscopic ultrasonography, fine-needle aspiration, immunohistochemical staining methods, and different treatment options. This article discusses the nature of subepithelial lesions, focusing on the most recent developments that use endoscopic ultrasonography to diagnose and manage these lesions.
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Affiliation(s)
- Amer A Alkhatib
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
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Reece-Smith AM, MacGoey P, Shah MA, Leeder P, Andrew DR, McCulloch T, Parsons SL. A multi-centre analysis of the impact of updated risk stratification on follow-up of gastric gastro-intestinal stromal tumours in the post-imatinib era. Eur J Surg Oncol 2012; 38:484-9. [PMID: 22342866 DOI: 10.1016/j.ejso.2012.01.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 11/16/2011] [Accepted: 01/26/2012] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Previously Gastro-Intestinal Stromal Tumours (GISTs) have been risk stratified histologically according to their size and mitotic index. However, gastric GISTs have a lower likelihood of recurrence and so the Miettinen criteria are now used to risk stratify patients. Records were reviewed from multiple centres to determine if these changes altered patients' clinical care and also to determine the survival of patients following the introduction of imatinib therapy. METHODS Prospective databases of GISTs undergoing surgical resection and those reviewed by the regional sarcoma MDT were cross-referenced and added to by searching a variety of clinical and pathology coding datasets, to identify patients diagnosed between January 2000 and March 2010. Patients undergoing resection for localised disease were re-scored using Miettinen criteria and Kaplan-Meier analysis was used to determine survival outcomes. RESULTS The search identified 203 patients; including 132 gastric GISTs, 89 of which had resections of untreated localised disease. These were reassessed, of which approximately one third were scored as intermediate risk. Following reclassification, 26 of 29 of intermediate risk cases moved to low risk groups, representing 27.7% of all those remaining in follow-up at the time of audit. Median survival was not reached after a median follow-up of 3.85 years and 4-year survival was estimated at 72%. CONCLUSIONS Clinicians involved in the follow-up of gastric GISTs should reassess the pathology of all intermediate and high risk patients in order to decrease patient exposure to stressful interventions, as well as hospital workload, and expenditure on unnecessary observation.
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Affiliation(s)
- A M Reece-Smith
- Joint GI Directorate, Nottingham University Hospitals, Nottingham City Hospital, Hucknall Rd, Nottingham NG5 1PB, UK.
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