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Chen L, Lu Y, Qian J, Qiu J, Wu C, Qiao Z, Ma Y, Yu F. Clinical characteristics and prognosis of non-metastatic multiple gastrointestinal stromal tumors: a population-based study. Discov Oncol 2025; 16:643. [PMID: 40304924 PMCID: PMC12043539 DOI: 10.1007/s12672-025-02454-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/21/2025] [Indexed: 05/02/2025] Open
Abstract
PURPOSE Multiple gastrointestinal stromal tumors (MGISTs) are relatively rare and may exhibit distinct clinical characteristics and prognosis compared to solitary GISTs (SGISTs). The objective of this study was to investigate the clinical features and prognosis of MGISTs. MATERIALS AND METHODS The Surveillance, Epidemiology, and End Results (SEER) database was used to identify all GIST patients diagnosed between 2010 and 2019. Multiple imputation (MI) was utilized to address missing data, while propensity score matching (PSM) was conducted to mitigate selection bias. The impact of demographic and clinical factors on overall survival (OS) was evaluated using Kaplan-Meier analyses and Cox proportional hazards models. RESULTS A total of 6241 patients were included in the study, with 4546 having SGISTs and 1695 having MGISTs. MGISTs have a higher prevalence in males, Caucasians, and elderly patients. Compared to MGISTs, the OS of SGISTs is significantly better (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.44-0.55, P < 0.001). After PSM, 3390 patients (equally distributed between the SGISTs and MGISTs groups) were matched for comparison. The OS of SGISTs is still better than that of MGISTs (HR 0.65, 95% CI 0.56-0.75, P < 0.001). Age, sex, site, surgery, marital status, mitotic rate, and chemotherapy were independent risk factors for OS in MGISTs patients. The OS of MGISTs patients who underwent surgery was significantly better than those who did not (P < 0.001). Similarly, chemotherapy-treated MGISTs patients showed improved OS compared to those who did not receive it (P = 0.045). CONCLUSIONS MGISTs have unique clinical characteristics and show worse OS compared to SGISTs. Surgical intervention and chemotherapy has the potential to ameliorate the prognosis of patients with MGISTs.
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Affiliation(s)
- Liang Chen
- Department of General Surgery, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Ye Lu
- Department of Endocrinology, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Jiawei Qian
- Department of General Surgery, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Jie Qiu
- Department of General Surgery, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Chuanfu Wu
- Department of General Surgery, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Zhenguo Qiao
- Department of Gastroenterology, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China.
| | - Yimin Ma
- Departments of Gastroenterology, Gaochun People's Hospital of Nanjing, Nanjing, China.
| | - Feng Yu
- Department of General Surgery, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China.
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Iasella MP, Ruttens D, Hompes D, Vandecaveye V, Sciot R, Deroose C, Douchy T, Decramer T, Jacobs S, Denayer E, Van Calenbergh F, Legius E, Brems H. Close Follow-Up of Patients with Neurofibromatosis Type 1 Reduces the Incidence of Malignant Peripheral Nerve Sheath Tumour. Cancers (Basel) 2025; 17:1306. [PMID: 40282482 PMCID: PMC12025940 DOI: 10.3390/cancers17081306] [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: 03/06/2025] [Revised: 04/03/2025] [Accepted: 04/04/2025] [Indexed: 04/29/2025] Open
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition with a birth incidence of one in 2000 to one in 3000 [...].
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Affiliation(s)
- Maria Pia Iasella
- Centre for Human Genetics, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium
| | - Dries Ruttens
- Department of Paediatric Oncology, University Hospitals Leuven, 3000 Leuven, Belgium
- Department of Paediatric Oncology, Princess Máxima Centre for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
| | - Daphne Hompes
- Department of Surgical Oncology, University Hospitals Leuven, 3000 Leuven, Belgium
| | | | - Raf Sciot
- Department of Pathology, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium
| | - Christophe Deroose
- Nuclear Medicine, University Hospitals Leuven, and Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, 3000 Leuven, Belgium
| | - Thomas Douchy
- Department of Surgical Oncology, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Thomas Decramer
- Department of Neurosurgery, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Sandra Jacobs
- Department of Paediatric Oncology, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Ellen Denayer
- Centre for Human Genetics, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium
| | | | - Eric Legius
- Centre for Human Genetics, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium
| | - Hilde Brems
- Centre for Human Genetics, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium
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Mavroeidis L, Kalofonou F, Casey R, Napolitano A, Bulusu R, Jones RL. Identifying and managing rare subtypes of gastrointestinal stromal tumors. Expert Rev Gastroenterol Hepatol 2025; 19:549-561. [PMID: 40156874 DOI: 10.1080/17474124.2025.2486304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 02/23/2025] [Accepted: 03/26/2025] [Indexed: 04/01/2025]
Abstract
INTRODUCTION A subset of gastrointestinal stromal tumors (GISTs) lacks the common mutations in KIT/PDGFRa genes. This is a rare and heterogeneous group of challenging GISTs due to their diversity and absence of sensitivity to the tyrosine kinase inhibitor (TKI) imatinib. AREAS COVERED In this manscript, we review the pathogenesis, natural history, diagnostic features and management of KIT/PDGFRa wild-type (WT) GISTs, including SDH-deficient GISTs, GISTs with mutations in the RAS/RAF pathway, and quadruple WT GISTs which lack mutations in either KIT/PDGFRa and SDH genes or components of the RAS/RAF pathway, and syndromic GISTs as well as GISTs with rare KIT/PDGFRa mutations. EXPERT OPINION Patients should be managed in reference centers. There has been progress in the understanding of the biology of these GISTs, and promising therapeutic targets have been identified. In SDH-deficient GISTs, the TKI olverembatinib has shown encouraging clinical activity but requires further clinical validation, while the HIF2a inhibitor bezultifan and temozolomide alone or in combination with the death receptor agonist 5 are under clinical investigation. Targeting the RAS/RAF pathway in RAS/RAF-mutated GISTs warrants evaluation in clinical trials. Rare molecular alterations in quadruple WT GISTs require investigation for their oncogenic potential. Collaborative research and patient advocacy is critical for these extremely rare tumors.
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Affiliation(s)
- Leonidas Mavroeidis
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
- Department of Oncology, Oxford University Hospitals, Oxford, UK
| | - Foteini Kalofonou
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - Ruth Casey
- Department of Endocrinology for Ruth Casey and Department of Oncology for Ramesh Bulusu, Cambridge University Hospitals, Cambridge, UK
| | - Andrea Napolitano
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - Ramesh Bulusu
- Department of Endocrinology for Ruth Casey and Department of Oncology for Ramesh Bulusu, Cambridge University Hospitals, Cambridge, UK
| | - Robin L Jones
- Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, UK
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Honda M, Iwamuro M, Tanaka T, Yamasaki Y, Kawano S, Hiraoka S, Kawahara Y, Otsuka M. Frequency and Characteristics of Gastrointestinal Diseases in Patients With Neurofibromatosis. JGH Open 2025; 9:e70151. [PMID: 40247846 PMCID: PMC12003917 DOI: 10.1002/jgh3.70151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/03/2025] [Accepted: 03/31/2025] [Indexed: 04/19/2025]
Abstract
Background and Aim Patients with neurofibromatosis (NF) frequently experience gastrointestinal symptoms, but the specific characteristics of these lesions are not well understood. Methods To investigate the prevalence and nature of gastrointestinal diseases in this population, we analyzed the gastrointestinal lesions identified through endoscopic examinations in patients with NF. Results We included 225 patients with NF type 1 (NF1) and 15 with NF type 2 (NF2). None of the NF2 patients underwent endoscopy. Among the NF1 patients, 27 received endoscopies, and 13 (59%) had gastrointestinal lesions. These 13 patients were predominantly male (10 males and three females), with a median age of 53 years (range: 19-76 years). The identified lesions included colorectal polyps (n = 6), gastrointestinal stromal tumors ([GIST], n = 4), subepithelial lesions (n = 3), gastric fundic gland polyps (n = 3), diffuse intestinal ganglioneuromatosis (n = 2), esophageal polyps (n = 2), a Schwann cell hamartoma (n = 1), esophageal cancer (n = 1), and a gastric hyperplastic polyp (n = 1). All GISTs and one case of diffuse intestinal ganglioneuromatosis were surgically resected. Interestingly, six out of 13 patients were asymptomatic. Additionally, all patients who required surgery were 40 years of age or older. Conclusions These findings suggest that routine endoscopic examinations, along with imaging techniques like computed tomography and magnetic resonance imaging, could be beneficial for the early detection of gastrointestinal lesions in NF1 patients aged 40 and above.
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Affiliation(s)
- Manami Honda
- Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Masaya Iwamuro
- Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Takehiro Tanaka
- Department of PathologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
| | - Yasushi Yamasaki
- Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Seiji Kawano
- Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Sakiko Hiraoka
- Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
- Inflammatory Bowel Disease CenterOkayama University HospitalOkayamaJapan
| | - Yoshiro Kawahara
- Department of Practical Gastrointestinal EndoscopyOkayama University HospitalOkayamaJapan
| | - Motoyuki Otsuka
- Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
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Bai GY, Shan KS, Li CS, Wang XH, Feng MY, Gao Y. Gastric gastrointestinal stromal tumor in a patient with neurofibromatosis type I presenting with anemia: A case report. World J Gastrointest Oncol 2025; 17:99304. [PMID: 40092932 PMCID: PMC11866250 DOI: 10.4251/wjgo.v17.i3.99304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/24/2024] [Accepted: 01/02/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are caused by mutations in the KIT and platelet derived growth factor receptor alpha genes in approximately 90% of cases. A minority of wild-type GISTs are associated with neurofibromatosis type 1 (NF1), an autosomal dominant genetic disease resulting from pathogenic mutations in the NF1 gene, which encodes the neurofibromin protein. NF1 patients often exhibit multi-system involvement, with café-au-lait macules and neurofibromas being characteristic symptoms. GISTs are a rare complication of NF1, with the tumors most frequently occurring in the small intestine (90% of cases), while occurrences in the stomach are rare. CASE SUMMARY A 51-year-old woman presented to the emergency department with complaints of dizziness, fatigue, chest tightness, and dark stools. Initial examination revealed a red blood cell count of 1.99 × 1012/L and a hemoglobin level of 43 g/L. She underwent blood transfusions and fluid replacement to stabilize her condition. Further investigations identified typical café-au-lait macules on her trunk, limbs, and face, along with neurofibromas. Endoscopy showed coffee-colored fluid in the gastric cavity, a large submucosal elevation with an exudative covering, and ulcer formation on the gastric fundus. Exploratory laparoscopy confirmed the tumor's origin in the gastric fundus, and resection of the giant GIST was performed. Pathological analysis revealed a necrotic GIST measuring 18 cm × 14 cm, classified as high-risk, with approximately 5 mitotic figures per 10 high-power fields and no tumor at the margins. Immunohistochemistry results were CD117 (+), delay of germination 1 (+), CD34 (+), and succinate dehydrogenase complex iron sulfur subunit B intact expression. Genetic testing using next-generation sequencing confirmed an NF1 gene mutation. The patient underwent successful tumor resection and was discharged home with postoperative regorafenib therapy. A follow-up at one year showed no recurrence. CONCLUSION Given the diversity of clinical symptoms associated with NF1 and the complexity of NF1-related GISTs, surgical resection with complete tumor removal remains the preferred treatment option. However, the absence of a standardized treatment protocol for adjuvant therapy presents numerous challenges for clinicians.
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Affiliation(s)
- Guang-Yang Bai
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Ke-Shu Shan
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Chen-Sheng Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Xiang-Hua Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Ming-Yang Feng
- Department of Gastrointestinal Surgery, Yinan County People’s Hospital, Linyi 276399, Shandong Province, China
| | - Yan Gao
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
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Cuvelier C, Brahmi M, Sobhani I, Verret B, Grancher A, Penel N, Toulmonde M, Lahlou W, Dupuis H, Calavas L, Muller M, Watson S, Bruyat D, Poumeaud F, Chaigneau L, Manfredi S, Lecomte T, Bertucci F, Ghiringhelli F, Pracht M, Mourthadhoi F, Monceau-Baroux L, Helyon M, Kurtz JE, Roquin G, Regenet N, Vinches M, Tougeron D, Wolkenstein P, Blay JY, Bouche O, Hautefeuille V. Clinical description and development of a prognostic score for neurofibromatosis type 1 (NF1)-associated GISTs: a retrospective study from the NETSARC. ESMO Open 2025; 10:104477. [PMID: 40043354 PMCID: PMC11928958 DOI: 10.1016/j.esmoop.2025.104477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 01/30/2025] [Accepted: 02/02/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) occur in ∼7% of neurofibromatosis type 1 (NF1) patients. Data about their natural history remain scarce and neither risk classifications, prognosis model nor adjuvant treatment have been validated in this population. METHODS This national retrospective study included consecutive operated NF1-GIST cases from 31 reference centers in France, mostly from the NETSARC+ network. Factors associated with relapse were used to build a new prognostic score (RECKGIST). To address potential bias between adjuvant group and follow-up group, a propensity score was used. RESULTS A total of 119 patients were included between 2008 and 2023, of whom 61% were women. Median age was 53 years (range 20-78 years). The main primary location was the small bowel (86%) and the stomach (11%). Median size and mitotic count (mit) were 45 mm [95% confidence interval (CI) 45-58 mm] and 2 mit/5 mm2 (95% CI 3-9 mit/5 mm2), respectively. The vast majority were KIT/PDGFRA wild type (mutation KIT 2%, PDGFRA 3%). The median follow-up was 6 years. For GISTs <30 mm (n = 35), none relapsed. For GISTS >30 mm (n = 84), 18 developed metastases (21%). There was no difference in relapse according to tumor location (P = 0.45) or tumor rupture (P = 0.11), whereas KIT/PDGFRA-mutated GISTs were at higher risk of relapse [recurrence-free survival (RFS) at 10 years of 30% versus 82.5% for wild type, P = 0.03]. Miettinen and Joensuu classification did not predict relapse accurately. For the RECKGIST score A (size ≤30 mm, n = 34) group, 10-year RFS was 100%; it was 78.5% in the RECKGIST B group (size >30 mm and 0 < mit ≤ 5, n = 60), and 45.5% in the RECKGIST C group (size >30 mm and mit >5, n = 20) (P < 0.0001). After matching, 10-year RFS was similar between adjuvant and surveillance groups (P = 0.34). CONCLUSIONS For NF1-GISTs <30 mm, prognosis without relapse is excellent. RECKGIST score accurately predicts recurrence and needs to be validated in an external cohort, but it may help treatment decision making. No efficacy of adjuvant treatment was observed.
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Affiliation(s)
- C Cuvelier
- Department of Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France
| | - M Brahmi
- Department of Medical Oncology, Centre Leon Berard, Lyon, France
| | - I Sobhani
- Department of Gastroenterology, Henri Mondor Hospital, Créteil, France
| | - B Verret
- Department of Medical Oncology, Gustave Roussy Cancer Campus, Paris Saclay University, Villejuif, France
| | - A Grancher
- Department of Gastroenterology and Digestive Oncology, Rouen University Hospital, Rouen, France
| | - N Penel
- Department of Medical Oncology, Centre Oscar-Lambret, ULR-2694 - METRICS: Evaluation des technologies de santé et des pratiques médicales, CHU de Lille, University of Lille, Lille, France
| | - M Toulmonde
- Department of Medical Oncology, Bergonié Institute, Bordeaux, France
| | - W Lahlou
- Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, AP-HP, Paris-Cité University, Paris, France
| | - H Dupuis
- Department of Endocrinology, Diabetology, Metabolism and Nutrition, Huriez Hospital, Lille University Hospital, Lille, France
| | - L Calavas
- Department of Gastroenterology and Digestive Oncology, Hospices Civils de Lyon, Lyon University Hospital, Lyon, France
| | - M Muller
- Department of Gastroenterology and Digestive Oncology, Nancy University Hospital, Vandoeuvre-lès-Nancy, France
| | - S Watson
- Department of Medical Oncology and INSERM U830, Institut Curie, Paris, France
| | - D Bruyat
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - F Poumeaud
- Department of Medical Oncology, Oncopole Claudius Regaud, Toulouse, France
| | - L Chaigneau
- Department of Medical Oncology, University Hospital of Besançon Jean Minjoz, Besançon, France
| | - S Manfredi
- Gastroenterology and Digestive Oncology Unit, University Hospital Dijon-Bourgogne, University of Burgundy, INSERM U1231, Dijon, France
| | - T Lecomte
- Department of Hepatogastroenterology and Digestive Oncology, Trousseau Hospital, Tours, France; INSERM UMR 1069, Tours University, Tours, France
| | - F Bertucci
- Department of Medical Oncology, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France
| | - F Ghiringhelli
- Department of Medical Oncology, Georges François Leclerc, Dijon, France
| | - M Pracht
- Department of Medical Oncology, Eugène Marquis Center, Rennes, France
| | - F Mourthadhoi
- Department of Digestive Surgery and Oncology, CHU Saint-Etienne, Saint-Priest-en-Jarez, France
| | - L Monceau-Baroux
- Department of Medical Oncology, CHRU Brest Morvan Hospital, Brest, France
| | - M Helyon
- Department of Digestive Surgery, Clermont Ferrand University Hospital, Clermont-Ferrand, France
| | - J-E Kurtz
- ICANS Cancer Institute, Strasbourg, France
| | - G Roquin
- Gastroenterology and Digestive Oncology, Angers University Hospital, Angers, France
| | - N Regenet
- Department of Digestive Surgery, Nantes University Hospital, Nantes, France
| | - M Vinches
- Department of Medical Oncology, Cancer Institute of Montpellier, Montpellier, France
| | - D Tougeron
- Department of Gastroenterology and Hepatology, Poitiers University Hospital, Poitiers, France
| | - P Wolkenstein
- Department of Dermatology, Henri Mondor Hospital, Créteil, France
| | - J Y Blay
- Department of Medical Oncology, Centre Leon Berard, Lyon, France
| | - O Bouche
- Department of Gastroenterology and Digestive Oncology, CHU Reims, University Reims Champagne Ardennes, Reims, France
| | - V Hautefeuille
- Department of Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France.
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Cao L, Tian W, Zhao Y, Song P, Zhao J, Wang C, Liu Y, Fang H, Liu X. Gene Mutations in Gastrointestinal Stromal Tumors: Advances in Treatment and Mechanism Research. Glob Med Genet 2024; 11:251-262. [PMID: 39176108 PMCID: PMC11341198 DOI: 10.1055/s-0044-1789204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2024] Open
Abstract
Although gastrointestinal stromal tumors (GISTs) has been reported in patients of all ages, its diagnosis is more common in elders. The two most common types of mutation, receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor a (PDGFRA) mutations, hold about 75 and 15% of GISTs cases, respectively. Tumors without KIT or PDGFRA mutations are known as wild type (WT)-GISTs, which takes up for 15% of all cases. WT-GISTs have other genetic alterations, including mutations of the succinate dehydrogenase and serine-threonine protein kinase BRAF and neurofibromatosis type 1. Other GISTs without any of the above genetic mutations are named "quadruple WT" GISTs. More types of rare mutations are being reported. These mutations or gene fusions were initially thought to be mutually exclusive in primary GISTs, but recently it has been reported that some of these rare mutations coexist with KIT or PDGFRA mutations. The treatment and management differ according to molecular subtypes of GISTs. Especially for patients with late-stage tumors, developing a personalized chemotherapy regimen based on mutation status is of great help to improve patient survival and quality of life. At present, imatinib mesylate is an effective first-line drug for the treatment of unresectable or metastatic recurrent GISTs, but how to overcome drug resistance is still an important clinical problem. The effectiveness of other drugs is being further evaluated. The progress in the study of relevant mechanisms also provides the possibility to develop new targets or new drugs.
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Affiliation(s)
- Lei Cao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Wencong Tian
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Yongjie Zhao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Peng Song
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Jia Zhao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Chuntao Wang
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Yanhong Liu
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Hong Fang
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Xingqiang Liu
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
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Garland K, Parikh S, Goodwin R. Hemorrhagic Shock Due to a Gastrointestinal Stromal Tumor in a Patient With Neurofibromatosis Type 1: A Case Report. Cureus 2024; 16:e76028. [PMID: 39835036 PMCID: PMC11743592 DOI: 10.7759/cureus.76028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 01/22/2025] Open
Abstract
Gastrointestinal stromal tumors (GISTs), though rare, are associated with neurofibromatosis (NF) type 1 and may cause significant gastrointestinal bleeding. A 42-year-old male with NF1 presented with severe hematochezia and underwent initial non-contrast CT, which was negative for abnormalities. Subsequent endoscopies and PillCam studies also revealed no clear bleeding source. Due to persistent bleeding and hemodynamic instability, a contrast-enhanced CT was eventually performed, revealing a hyper-enhancing mass in the proximal ileum. Emergent surgical exploration identified a 1.5-cm jejunal GIST, which was resected successfully, stabilizing the patient who was discharged without the need for adjuvant therapy. This case highlights the importance of early contrast-enhanced imaging in NF1 patients presenting with acute bleeding to facilitate timely diagnosis, reduce hospital resource utilization, and avoid unnecessary invasive procedures.
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Affiliation(s)
- Kenneth Garland
- Trauma Institute, Saint Francis Health System, Tulsa, USA
- Orthopedics, Oklahoma State University Medical Center, Tulsa, USA
| | - Sarthak Parikh
- Trauma Institute, Saint Francis Health System, Tulsa, USA
| | - Robert Goodwin
- Trauma Institute, Saint Francis Health System, Tulsa, USA
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Ali RH, Alsaber AR, Mohanty AK, Alnajjar A, Mohammed EMA, Alateeqi M, Jama H, Almarzooq A, Benobaid N, Alqallaf Z, Ahmed AA, Bahzad S, Alkandari M. Molecular Profiling of KIT/PDGFRA-Mutant and Wild-Type Gastrointestinal Stromal Tumors (GISTs) with Clinicopathological Correlation: An 18-Year Experience at a Tertiary Center in Kuwait. Cancers (Basel) 2024; 16:2907. [PMID: 39199677 PMCID: PMC11352935 DOI: 10.3390/cancers16162907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/20/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024] Open
Abstract
In gastrointestinal stromal tumors (GISTs), identifying prototypical mutations in the KIT/PDGFRA oncogenes, or in rare alternate genes, is essential for prognostication and predicting response to tyrosine kinase inhibitors. Conversely, wild-type GISTs (WT-GIST), which lack known mutations, have limited treatment options. Data on the mutational landscape of GISTs and their impact on disease progression are very limited in Kuwait. Using a targeted next-generation sequencing panel, we investigated the spectrum and frequency of KIT, PDGFRA, and RAS-pathway-related mutations in 95 out of 200 GISTs diagnosed at Kuwait Cancer Center from 2005 to 2023 and assessed their correlation with clinicopathological parameters. Among the 200 tumors (median age 55 years; 15-91), 54% originated in the stomach, 33% in the small bowel, 7% in the colorectum, 1.5% in the peritoneum, and 4.5% had an unknown primary site. Of the 95 molecularly profiled cases, 88% had a mutation: KIT (61%), PDGFRA (25%), NF1 (2%), and one NTRK1 rearrangement. Ten WT-GISTs were identified (stomach = 6, small bowel = 2, and colorectum = 2). WT-GISTs tended to be smaller (median 4.0 cm; 0.5-8.0) (p = 0.018), with mitosis ≤5/5 mm2, and were of lower risk (p = 0.019). KIT mutations were an adverse indicator of disease progression (p = 0.049), while wild-type status did not significantly impact progression (p = 0.934). The genetic landscape in this cohort mirrors that of global studies, but regional collaborations are needed to correlate outcomes with genetic variants.
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Affiliation(s)
- Rola H. Ali
- Department of Pathology, College of Medicine, Kuwait University, Safat 13110, Kuwait
- Histopathology Laboratory, Sabah Hospital, Sabah Medical District, Safat 13001, Kuwait
| | - Ahmad R. Alsaber
- Department of Management, College of Business and Economics, American University of Kuwait, Safat 13034, Kuwait;
| | - Asit K. Mohanty
- Department of Medical Oncology, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (A.K.M.); (A.A.)
| | - Abdulsalam Alnajjar
- Department of Medical Oncology, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (A.K.M.); (A.A.)
| | - Eiman M. A. Mohammed
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Mona Alateeqi
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Hiba Jama
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Ammar Almarzooq
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Noelle Benobaid
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Zainab Alqallaf
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Amir A. Ahmed
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Shakir Bahzad
- Molecular Genetics Laboratory, Kuwait Cancer Center, Sabah Medical District, Safat 13001, Kuwait; (E.M.A.M.); (M.A.); (H.J.); (A.A.); (N.B.); (Z.A.); (A.A.A.); (S.B.)
| | - Mohammad Alkandari
- Histopathology Laboratory, Farwaniya Hospital, Sabah Al Nasser Area 92426, Kuwait;
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10
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Fukuda M, Mukohara T, Kuwata T, Sunami K, Naito Y. Efficacy of Trametinib in Neurofibromatosis Type 1-Associated Gastrointestinal Stromal Tumors: A Case Report. JCO Precis Oncol 2024; 8:e2300649. [PMID: 39116355 PMCID: PMC11371073 DOI: 10.1200/po.23.00649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 05/14/2024] [Accepted: 07/02/2024] [Indexed: 08/10/2024] Open
Abstract
Trametinib, an MEK inhibitor, may offer a new therapeutic option for patients with NF1-related GIST.
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Affiliation(s)
- Misao Fukuda
- Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Toru Mukohara
- Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Genetic Medicine and Services, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takeshi Kuwata
- Department of Genetic Medicine and Services, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kuniko Sunami
- Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan
| | - Yoichi Naito
- Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Department of General Internal Medicine, National Cancer Center Hospital East, Kashiwa, Japan
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11
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Medrano Guzman R, Lopez Lara X, Arias Rivera AS, Garcia Rios LE, Brener Chaoul M. Neoadjuvant Imatinib in Gastrointestinal Stromal Tumors (GIST): The First Analysis of a Mexican Population. Cureus 2024; 16:e65001. [PMID: 39161479 PMCID: PMC11333017 DOI: 10.7759/cureus.65001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/20/2024] [Indexed: 08/21/2024] Open
Abstract
Introduction Gastrointestinal stromal tumors (GISTs) are neoplasms originating from the interstitial cells of Cajal, pacemaker cells responsible for intestinal motility. Patients with locally advanced GISTs and those with borderline resections due to the proximity of vital anatomical structures, which could result in unacceptable post-surgical morbidity, require special therapeutic consideration. Imatinib, a tyrosine kinase inhibitor, has demonstrated significant success in the non-surgical management of metastatic GIST, and its favorable impact on overall survival in the adjuvant setting makes it logical to speculate on the benefit it could provide as a neoadjuvant medication in patients with locally advanced disease. Methods Patients aged 18-90 years with a diagnosis of GIST confirmed by immunohistochemistry (CD117 positivity) who were treated at the Oncology Hospital of Centro Médico Nacional Siglo XXI in Mexico City from January 2012 to December 2016 were included in the study. It is a retrospective study with a duration of four years. Clinical data were collected from the medical records, which included sex, age, tumor location, initial resectability, reason for unresectability, initial tumor size, and mitotic rate. In the case of unresectable disease, patients who were evaluated by medical oncology and who had received treatment with 400 mg of imatinib daily were evaluated. Results A total of 312 patients diagnosed with GIST were analyzed. One hundred thirty-one were men (42%) with a mean age of 57 years, and 181 were women (58%) with a mean age of 59 years. The most frequent anatomical location was the stomach (n=185, 59.2%). At the time of diagnosis, 210 patients (67.3%) presented with resectable disease, while n=102 patients (32.7%) had unresectable disease. A total of 102 patients with unresectable disease received therapy with 400 mg of imatinib per day. Sixteen patients (15.7%) presented a reduction in tumor dimensions and underwent surgery. Conclusion The study highlights the importance of complete surgical resection and the potential benefit of neoadjuvant imatinib therapy in converting unresectable to resectable disease. The results suggest that imatinib can be effective in converting unresectable GISTs to resectable ones, allowing for a complete resection to be performed and obtaining an R0 resection in 93.7% of these cases.
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Affiliation(s)
| | - Xavier Lopez Lara
- Surgical Oncology, Centro Médico Nacional Siglo XXI, Mexico City, MEX
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Medrano Guzman R, Perez Ventura EF, Arias Rivera AS, Piña-Sanchez P, Brener Chaoul M. Clinicopathological Characteristics and the First Mutational Analysis of Gastrointestinal Stromal Tumors From Mexico: A Single Institution Experience. Cureus 2024; 16:e62594. [PMID: 39027749 PMCID: PMC11256735 DOI: 10.7759/cureus.62594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2024] [Indexed: 07/20/2024] Open
Abstract
Background Gastrointestinal stromal tumors (GISTs) arise from Cajal's interstitial cell precursors and display a variety of genetic mutations, primarily in the KIT and PDGFRA genes. These mutations are linked to tumor location, prognosis, and response to treatment. This study delves into the mutational patterns of GISTs in a Mexican population and their impact on overall survival (OS) and disease-free survival (DFS). Methodology This retrospective study examined 42 GIST cases diagnosed at the Oncology Hospital of the National Medical Center XXI Century between January 2018 and December 2020. Clinical, histological, and immunohistochemical data were gathered, and mutational analysis of KIT and PDGFRA genes was conducted using second-generation sequencing. Results The study group consisted of 52.4% females and 47.6% males, with an average age of 62.6 years. The most common tumor site was the stomach (59.5%), followed by the small intestine (26.2%). KIT mutations were detected in 71.4% of cases, predominantly involving exon 11. PDGFRA mutations were observed in 7.1% of cases. Recurrence was noted in 9.5% of patients, all with high-risk tumors. No significant link was identified between specific mutations and OS or DFS. Conclusions This investigation sheds light on the genetic landscape of GISTs in the Mexican population. While no significant association was established between particular mutations and survival outcomes, the study emphasizes the importance of molecular profiling in treatment decision-making. Further studies with larger sample sizes and longer follow-up periods are necessary to validate these results and explore their clinical relevance.
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Affiliation(s)
- Rafael Medrano Guzman
- Surgical Oncology, Unidad Médica de Alta Especialidad (UMAE) Hospital de Oncologia Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, MEX
| | - Edgar F Perez Ventura
- Surgical Oncology, Unidad Médica de Alta Especialidad (UMAE) Hospital de Oncologia Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, MEX
| | | | - Patricia Piña-Sanchez
- Medical Research Unit in Oncological Diseases, Unidad Médica de Alta Especialidad (UMAE) Hospital de Oncologia Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, MEX
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13
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Nishida T, Naito Y, Takahashi T, Saito T, Hisamori S, Manaka D, Ogawa K, Hirota S, Ichikawa H. Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors. Cancer Sci 2024; 115:894-904. [PMID: 38178783 PMCID: PMC10920999 DOI: 10.1111/cas.16058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 10/22/2023] [Accepted: 12/06/2023] [Indexed: 01/06/2024] Open
Abstract
Approximately 10% of gastrointestinal stromal tumors (GISTs) harbor reportedly no KIT and PDGFRA mutations (wild-type GISTs). The clinicopathological features and oncologic outcomes of wild-type GISTs based on molecular profiles are unknown. We recruited 35 wild-type GIST patients from the two registry studies of high-risk GISTs between 2012 and 2015 and primary GISTs between 2003 and 2014. Molecular profiling of wild-type GISTs was performed by targeted next-generation sequencing (NGS) using formalin-fixed paraffin-embedded tumor samples. Among 35 wild-type GISTs, targeted NGS analysis detected NF1, SDH, or BRAF mutation: 16 NF1-GISTs with various NF1 mutations, 12 SDH-GISTs (4 with SDHA mutations, 4 with SDHB mutations, and 4 with SDHB-negative staining), and 5 BRAF-GISTs with the V600E mutation. Two GISTs showed no mutations based on our targeted NGS analysis. Additional gene mutations were infrequent in primary wild-type GISTs and found in TP53, CREBBP, CDKN2A, and CHEK2. Most NF1-GISTs were located in the small intestine (N = 12; 75%) and showed spindle cell features (N = 15; 94%) and multiple tumors (N = 6, 38%) with modest proliferation activities. In contrast, SDH-GISTs were predominantly found in the stomach (N = 11; 92%), exhibiting epithelioid cell (N = 6; 50%) and multiple (N = 6, 50%) features. The overall survival of patients with SDH-GISTs appeared to be better than that of BRAF-GISTs (p = 0.0107) or NF1-GISTs (p = 0.0754), respectively. In conclusion, major molecular changes in wild-type GISTs include NF1, SDH, and BRAF. NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.
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Affiliation(s)
- Toshirou Nishida
- Department of SurgeryJapan Community Health‐care Organization Osaka HospitalOsakaJapan
- Department of SurgeryNational Cancer Center HospitalTokyoJapan
- National Institute of Biomedical Innovation, Health and Nutrition, Laboratory of Nuclear Transport DynamicsIbarakiJapan
| | - Yoichi Naito
- Department of General Internal MedicineNational Cancer Center Hospital EastKashiwaJapan
- Department of Experimental TherapeuticsNational Cancer Center Hospital EastKashiwaJapan
- Department of Medical OncologyNational Cancer Center Hospital EastKashiwaJapan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
| | - Takuro Saito
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
- Department of SurgeryOsaka Police HospitalOsakaJapan
| | - Shigeo Hisamori
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Dai Manaka
- Department of SurgeryKyoto Katsura HospitalKyotoJapan
| | - Katsuhiro Ogawa
- Department of SurgerySaiseikai Kumamoto HospitalKumamotoJapan
| | - Seiichi Hirota
- Department of Surgical PathologyHyogo Medical University School of MedicineNishinomiyaJapan
| | - Hitoshi Ichikawa
- Department of Clinical GenomicsNational Cancer Center Research InstituteTokyoJapan
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Fueng-Hin Liang R, Chau CYP, Lim WC. Neurofibromatosis Type 1 Presenting as Bleeding Jejunal Gastrointestinal Stromal Tumour. Case Rep Gastroenterol 2024; 18:299-305. [PMID: 38895585 PMCID: PMC11185854 DOI: 10.1159/000538688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 03/24/2024] [Indexed: 06/21/2024] Open
Abstract
Introduction Gastrointestinal stromal tumours (GISTs) are an important, though uncommon, cause of obscure gastrointestinal bleeding and may rarely be associated with genodermatoses such as neurofibromatosis type 1 (NF1). NF1-related GISTs have unique phenotypic features compared with sporadic GISTs and may elude diagnosis due to their predilection for the small bowel. Case Presentation We report a case of a 45-year-old Singaporean woman with café-au-lait macules and cutaneous neurofibromas who presented with occult obscure gastrointestinal bleeding and was eventually discovered to have a bleeding jejunal GIST. This finding, considered together with her cutaneous signs, eventually led to the diagnosis of NF1. Conclusion Genodermatoses and their gastrointestinal complications are likely under-reported in adult Southeast Asian populations and deserve greater awareness from gastroenterologists practising in this region.
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Affiliation(s)
- Raymond Fueng-Hin Liang
- Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | | | - Wee Chian Lim
- Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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15
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Li C, Wang Q, Jiang KW, Ye YJ. Hallmarks and novel insights for gastrointestinal stromal tumors: A bibliometric analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:107079. [PMID: 37826966 DOI: 10.1016/j.ejso.2023.107079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 09/13/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND Due to the increasing recognition of gastrointestinal stromal tumor (GIST), novel insights have appeared in both preclinical and clinical research and begun to reshape the field. This study aims to map the research landscape through bibliometric analysis and provide a brief overview for the future of the GIST field. METHODS We searched the Web of Science Core Collection without publication data restrictions for GISTs and performed a bibliometric analysis with CiteSpace and VOSviewer software. RESULTS In sum, 5,911 of 13,776 records were included, and these studies were published in 948 journals and written by 24,965 authors from 4,633 institutions in 100 countries. Referring to published reviews and bibliometric analysis, we classified the future trends in four groups. In epidemiological study, precise incidence and clinicopathological features in different regions and races might become potential hotspots. Novel therapy, such as drugs, modified strategies, radioligand therapy, was persistent hotspots in GIST fields, and ctDNA-guided diagnosis, monitoring, and treatment might meet future clinical needs. The debate over serosa surgery vs. mucosa surgery will remain active for a long time in GIST surgery, and function reserve surgery, biology-based surgery will play an important role in future. Moreover, rare GIST type, like NF-1-associated GIST, Carney triads and SDH mutant GIST, need more studies in pathogenesis and genetic mutation to provide appropriate treatment for this orphan GIST patients. CONCLUSIONS Potential hotspots in future GIST trends might involve epidemiology, agents, resection therapy and rare type GIST, moreover, researchers could pay more attention in these four fields.
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Affiliation(s)
- Chen Li
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, 100044, China
| | - Quan Wang
- Ambulatory Surgery Center, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, China
| | - Ke-Wei Jiang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, 100044, China.
| | - Ying-Jiang Ye
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, 100044, China.
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Nagano H, Ohyama S, Sato A, Igarashi J, Yamamoto T, Kadoya M, Kobayashi M. Jejunal gastrointestinal stromal tumor that developed in a patient with neurofibromatosis type 1: a case report. Diagn Pathol 2023; 18:110. [PMID: 37789344 PMCID: PMC10546696 DOI: 10.1186/s13000-023-01398-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 09/28/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND Neurofibromatosis type 1 (NF1) is known to be associated with the frequent occurrence of unique gastrointestinal stromal tumors (GISTs), preferably occurring in the small intestine, with no mutations in the c-kit proto-oncogene or platelet-derived growth factor receptor-alpha (PDGFRA), with a high tendency for multifocal development, indolent nature, with low proliferation activity and favorable prognosis. CASE PRESENTATION A woman in her forties visited her local doctor complaining of menstrual pain; a large mass was detected in her lower abdomen, and she was referred to our hospital. The patient had hundreds of skin warts and café au lait spots. The patient's mother had been diagnosed with type 1 neurofibromatosis. The patient met the diagnostic criteria for NF1 and was diagnosed with NF1. Ultrasonography showed a large heterogeneous cystic mass with various echo patterns, solid compartments and multiple septations. Magnetic resonance imaging showed a multilocular cystic mass with liquid content exhibiting various intensities, including that of blood. A small round solid mass was also observed close to the cystic tumor. Contrast-enhanced computed tomography showed that the round solid mass showed strong enhancement in the early phase, unlike the cystic tumor component. Open laparotomy revealed a multicystic exophytic tumor measuring 11.5 cm originating from the jejunal wall, 20 cm distal to the duodenojejunal flexure. A solid tumor measuring 2.1 cm was also found on the anal side of the large tumor. We resected the short segment of the jejunum, including the two lesions. Microscopic findings revealed that the cystic and solid tumors consisted of spindle-shaped tumor cells showing little atypia with a fascicular or bundle arrangement. Nuclear mitosis was scarce. Immunostaining of the tumor cells showed positive staining for KIT and DOG1 and negative staining for S100 and desmin. The NF1 patient was diagnosed with multiple GISTs accompanied by intratumoral hemorrhagic denaturation arising from the jejunum. The TNM staging was pT4N0M0, stage IIIA. CONCLUSION We report a case of GISTs associated with NF1 that showed a jejunal origin, multifocal development and few mitotic figures. The recurrence risk, survival prognosis and need for adjuvant chemotherapy, particularly in cases where the initial GIST exhibits a very indolent pathology in NF1-related GISTs, remain to be elucidated.
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Affiliation(s)
- Hideki Nagano
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan.
| | - Shigekazu Ohyama
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Atsushi Sato
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Jun Igarashi
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Tomoko Yamamoto
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Masumi Kadoya
- Department of Radiology, Marunouchi Hospital, Matsumoto Nagano, Japan
| | - Mikiko Kobayashi
- Department of Pathology, Marunouchi Hospital, Matsumoto Nagano, Japan
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Dupuis H, Chevalier B, Cardot-Bauters C, Jannin A, Do Cao C, Ladsous M, Cortet C, Merlen E, Drouard M, Aubert S, Vidaud D, Espiard S, Vantyghem MC. Prevalence of Endocrine Manifestations and GIST in 108 Systematically Screened Patients With Neurofibromatosis Type 1. J Endocr Soc 2023; 7:bvad083. [PMID: 37409183 PMCID: PMC10318875 DOI: 10.1210/jendso/bvad083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Indexed: 07/07/2023] Open
Abstract
Context In patients with neurofibromatosis type 1 (NF1), guidelines suggest screening for pheochromocytoma by metanephrine measurement and abdominal imaging, which may lead to the discovery of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and their differential diagnosis, gastrointestinal stromal tumors (GISTs). Other endocrine manifestations such as follicular thyroid carcinoma and primary hyperparathyroidism have also been reported in a few cases. Objective This study aimed to describe prevalence and clinical presentation of these manifestations through systematic screening in a large cohort of patients. Methods In this monocentric retrospective study, 108 patients with NF1 were included and screened for endocrine manifestations and GISTs. Clinical, laboratory, molecular profile, pathology, and morphologic (abdominal computed tomography scan and/or magnetic resonance imaging) and functional imaging were collected. Results Twenty-four patients (22.2% of the cohort, 16 female, mean age 42.6 years) presented with pheochromocytomas that were unilateral in 65.5%, benign in 89.7%, and with a ganglioneural component in 20.7%. Three female patients (2.8% of the cohort, aged 42-63 years) presented with well-differentiated GEP-NETs, and 4 (3.7%) with GISTs. One patient had primary hyperparathyroidism, 1 patient had medullary microcarcinoma, and 16 patients had goiter, multinodular in 10 cases. There was no correlation between pheochromocytoma and other NF1 tumoral manifestations, nor correlations between pheochromocytoma and NF1 genotype, despite a familial clustering in one-third of patients. Conclusion The pheochromocytoma prevalence in this NF1 cohort was higher (>20%) than previously described, confirming the interest of systematic screening, especially in young women. The prevalence of GEP-NETs and GISTs was about 3%, respectively. No phenotype-genotype correlation was observed.
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Affiliation(s)
- Hippolyte Dupuis
- Correspondence: Dr Hippolyte Dupuis, MD, MSc, Department of Endocrinology, Diabetology, Metabolism and Nutrition, Huriez Hospital, Lille University Hospital, 1 Rue Michel Polonowski, 59037 Lille Cedex, France. ; or Pr Marie-Christine Vantyghem, MD, PhD, Department of Endocrinology, Diabetology, Metabolism and Nutrition, Huriez Hospital, Lille University Hospital, 1 Rue Michel Polonovski, 59037 Lille Cedex, France.
| | - Benjamin Chevalier
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
- University of Lille, F-59000 Lille, France
- Department of Nuclear Medicine, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Catherine Cardot-Bauters
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Arnaud Jannin
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
- University of Lille, F-59000 Lille, France
- Canther Laboratory U1277 Inserm—Team “Mucins, Cancer and drug resistance” team, Oncolille Institute, F-59000 Lille, France
| | - Christine Do Cao
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Miriam Ladsous
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Christine Cortet
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Emilie Merlen
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Magali Drouard
- Department of Dermatology, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Sébastien Aubert
- Department of Pathology, Lille University Hospital, F-59000 Lille, France
| | - Dominique Vidaud
- Department of Genetic Medicine of System and Organ Diseases, Cochin Hospital, Federation of Genomic Medicine, Assistance Publique—Hôpitaux de Paris, AP-HP, Paris University Center, F-75014 Paris, France
| | | | - Marie-Christine Vantyghem
- Correspondence: Dr Hippolyte Dupuis, MD, MSc, Department of Endocrinology, Diabetology, Metabolism and Nutrition, Huriez Hospital, Lille University Hospital, 1 Rue Michel Polonowski, 59037 Lille Cedex, France. ; or Pr Marie-Christine Vantyghem, MD, PhD, Department of Endocrinology, Diabetology, Metabolism and Nutrition, Huriez Hospital, Lille University Hospital, 1 Rue Michel Polonovski, 59037 Lille Cedex, France.
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Giraud JS, Bièche I, Pasmant É, Tlemsani C. NF1 alterations in cancers: therapeutic implications in precision medicine. Expert Opin Investig Drugs 2023; 32:941-957. [PMID: 37747491 DOI: 10.1080/13543784.2023.2263836] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 09/24/2023] [Indexed: 09/26/2023]
Abstract
INTRODUCTION NF1 is a tumor suppressor gene encoding neurofibromin, an inhibitor of the RAS/MAPK and PI3K-AKT-mTOR signaling pathways. NF1 germline pathogenic variants cause the tumor predisposition syndrome neurofibromatosis type 1. Targeted therapies (MEK inhibitors) have been approved for benign nerve sheath tumors in neurofibromatosis type 1 patients. NF1 somatic alterations are present in ~5% of all human sporadic cancers. In melanomas, acute myeloid leukemias and lung adenocarcinomas, the NF1 somatic alteration frequency is higher (~15%). However, to date, the therapeutic impact of NF1 somatic alterations is poorly investigated. AREAS COVERED This review presents a comprehensive overview of targeted therapies and immunotherapies currently developed and evaluated in vitro and in vivo for NF1-altered cancer treatment. A PubMed database literature review was performed to select relevant original articles. Active clinical trials were researched in ClinicalTrials.gov database in August 2022. TCGA and HGMD® databases were consulted. EXPERT OPINION This review highlights the need to better understand the molecular mechanisms of NF1-altered tumors and the development of innovative strategies to effectively target NF1-loss in human cancers. One of the current major challenges in cancer management is the targeting of tumor suppressor genes such as NF1 gene. Currently, most studies are focusing on inhibitors of the RAS/MAPK and PI3K-AKT-mTOR pathways and immunotherapies.
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Affiliation(s)
- Jean-Stéphane Giraud
- Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France
| | - Ivan Bièche
- Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France
- Genetic Department, Curie Institute, Paris, France
| | - Éric Pasmant
- Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France
- Genetic Department, Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France
| | - Camille Tlemsani
- Institut Cochin, Inserm U1016, CNRS UMR8104, Université Paris Cité, CARPEM, Paris, France
- Oncology Department, Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France
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19
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Maehara T, Yamazaki A, Kawabata-Iwakawa R, Fukuoka K, Akazawa A, Okura N, Nishiyama M, Nassiri F, Wang JZ, Zadeh G, Kikuta K, Oka H, Hirato J, Yokoo H, Nobusawa S. Hyperplasia of Arachnoid Trabecular Cells: A Hitherto Undescribed Lesion Observed in the Setting of Neurofibromatosis Type 1. Am J Surg Pathol 2023; 47:819-825. [PMID: 37226836 DOI: 10.1097/pas.0000000000002056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Central nervous system manifestations, a variety of benign and malignant tumors as well as non-neoplastic abnormalities, are found in over 70% of neurofibromatosis type 1 (NF1) patients. Herein, we report hitherto undescribed space-occupying lesions in the setting of NF1. We aimed to clarify their characteristics, especially whether they represent neoplastic or non-neoplastic (hyperplastic) lesions. All 3 cases were preoperatively assessed as non-neoplastic; 2 and 1 cases were suspected to be arachnoid cysts and dilation of subarachnoid space, respectively. However, all lesions were revealed to be whitish jelly-like masses by operation, and the histology composed of spindle cells resembling arachnoid trabecular cells with moderate cellularity and cellular uniformity gave an impression that these lesions may be neoplastic. In contrast, electron microscopic analysis showed that the characteristics of these cells were compatible with those of normal arachnoid trabecular cells. Furthermore, whole-exome sequencing and array comparative genomic hybridization did not show any obvious alterations suggestive of their neoplastic nature. DNA methylation analysis demonstrated that these lesions were epigenetically distinct not only from meningiomas but also from normal healthy meninges. In conclusion, considering the clinicopathologic aspects of the present lesions and the results of the molecular analysis that failed to suggest their neoplastic nature, they may represent previously unrecognized rare hyperplasia of arachnoid trabecular cells, which may be associated with NF1.
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Affiliation(s)
- Tatsuro Maehara
- Department of Human Pathology, Gunma University Graduate School of Medicine
| | - Ayako Yamazaki
- Department of Human Pathology, Gunma University Graduate School of Medicine
| | - Reika Kawabata-Iwakawa
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Gunma University
| | - Kohei Fukuoka
- Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama
| | - Ayumi Akazawa
- Department of Neurosurgery, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui
| | - Naoki Okura
- Department of Radiology, International University of Health and Welfare, School of Medicine, Narita
| | | | - Farshad Nassiri
- Division of Neurosurgery, Department of Surgery, University of Toronto
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto
- Division of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
| | - Justin Z Wang
- Division of Neurosurgery, Department of Surgery, University of Toronto
| | - Gelareh Zadeh
- Division of Neurosurgery, Department of Surgery, University of Toronto
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto
- Division of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
| | - Kenichiro Kikuta
- Department of Neurosurgery, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui
| | - Hidehiro Oka
- Department of Neurosurgery, Kitasato University Medical Center, Kitamoto
| | - Junko Hirato
- Department of Human Pathology, Gunma University Graduate School of Medicine
- Department of Pathology, Public Tomioka General Hospital, Tomioka, Japan
| | - Hideaki Yokoo
- Department of Human Pathology, Gunma University Graduate School of Medicine
| | - Sumihito Nobusawa
- Department of Human Pathology, Gunma University Graduate School of Medicine
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20
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Yao MQ, Jiang YP, Yi BH, Yang Y, Sun DZ, Fan JX. Neurofibromatosis type 1 with multiple gastrointestinal stromal tumors: A case report. World J Clin Cases 2023; 11:2336-2342. [PMID: 37122520 PMCID: PMC10131015 DOI: 10.12998/wjcc.v11.i10.2336] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/01/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND Neurofibromatosis type 1 (NF1) is characterized by café-au-lait patches on the skin and the presence of neurofibromas. Gastrointestinal stromal tumor (GIST) is the most common non-neurological tumor in NF1 patients. In NF1-associated GIST, KIT and PDGFRA mutations are frequently absent and imatinib is ineffective. Surgical resection is first-line treatment.
CASE SUMMARY A 56-year-old woman with NF1 was hospitalized because of an incidental pelvic mass. Physical examination was notable for multiple café-au-lait patches and numerous subcutaneous soft nodular masses of the skin of the head, face, trunk, and limbs. Her abdomen was soft and nontender. No masses were palpated. Digital rectal examination was unremarkable. Abdominal computed tomography was suspicious for GIST or solitary fibrous tumor. Laparoscopy was performed, which identified eight well-demarcated masses in the jejunum. All were resected and pathologically diagnosed as GISTs. The patient was discharged on day 7 after surgery without complications. No tumor recurrence was evident at the 6-mo follow-up.
CONCLUSION Laparoscopy is effective for both diagnosis and treatment of NF1-associated GIST.
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Affiliation(s)
- Min-Quan Yao
- Department of Gastrointestinal Surgery, Tongxiang First People’s Hospital, Jiaxing 314500, Zhejiang Province, China
| | - Yu-Peng Jiang
- Department of Gastrointestinal Surgery, Tongxiang First People’s Hospital, Jiaxing 314500, Zhejiang Province, China
| | - Bing-Hong Yi
- Department of Gastrointestinal Surgery, Tongxiang First People’s Hospital, Jiaxing 314500, Zhejiang Province, China
| | - Yong Yang
- Department of Gastrointestinal Surgery, Tongxiang First People’s Hospital, Jiaxing 314500, Zhejiang Province, China
| | - Da-Zhuang Sun
- Department of Gastrointestinal Surgery, Tongxiang First People’s Hospital, Jiaxing 314500, Zhejiang Province, China
| | - Jin-Xing Fan
- Endoscopy Center, Tongxiang First People’s Hospital, Jiaxing 314500, Zhejiang Province, China
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Catalano F, Cremante M, Dalmasso B, Pirrone C, Lagodin D’Amato A, Grassi M, Comandini D. Molecular Tailored Therapeutic Options for Advanced Gastrointestinal Stromal Tumors (GISTs): Current Practice and Future Perspectives. Cancers (Basel) 2023; 15:cancers15072074. [PMID: 37046734 PMCID: PMC10093725 DOI: 10.3390/cancers15072074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumors characterized by different molecular alterations that lead to specific clinical presentations and behaviors. In the last twenty years, thanks to the discovery of these mutations, several new treatment options have emerged. This review provides an extensive overview of GISTs’ molecular pathways and their respective tailored therapeutic strategies. Furthermore, current treatment strategies under investigation and future perspectives are analyzed and discussed.
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Affiliation(s)
- Fabio Catalano
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Malvina Cremante
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Bruna Dalmasso
- Genetica dei Tumori Rari, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Chiara Pirrone
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | | | - Massimiliano Grassi
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Correspondence:
| | - Danila Comandini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
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22
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Carton C, Evans DG, Blanco I, Friedrich RE, Ferner RE, Farschtschi S, Salvador H, Azizi AA, Mautner V, Röhl C, Peltonen S, Stivaros S, Legius E, Oostenbrink R, ERN GENTURIS NF1 Tumour Management Guideline Group BrunetJoanVan CalenberghFrankCassimanCatherineCzechThomasGavarrete de LeónMaría JoséGieleHenkHenleySusieLazaroConxiLipkovskayaVeraMaherEamonn R.MartinVanessaMathijssenIreneOpocherEnricoPiresAna ElisabetePletschkoThomasPoupakiEireneRidolaVitaRietmanAndreRosenbaumThorstenSanthouseAlastairSehestedAstridSimmonsIanTaalWalterWagnerAnja. ERN GENTURIS tumour surveillance guidelines for individuals with neurofibromatosis type 1. EClinicalMedicine 2023; 56:101818. [PMID: 36684394 PMCID: PMC9845795 DOI: 10.1016/j.eclinm.2022.101818] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 12/16/2022] [Accepted: 12/22/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder, predisposing development of benign and malignant tumours. Given the oncogenic potential, long-term surveillance is important in patients with NF1. Proposals for NF1 care and its specific manifestations have been developed, but lack integration within routine care. This guideline aims to assimilate available information on NF1 associated tumours (based on evidence and/or expert opinion) to assist healthcare professionals in undertaking tumour surveillance of NF1 individuals. METHODS By comprehensive literature review, performed March 18th 2020, guidelines were developed by a NF1 expert group and patient representatives, conversant with clinical care of the wide NF1 disease spectrum. We used a modified Delphi procedure to overcome issues of variability in recommendations for specific (national) health care settings, and to deal with recommendations based on indirect (scarce) evidence. FINDINGS We defined proposals for personalised and targeted tumour management in NF1, ensuring appropriate care for those in need, whilst reducing unnecessary intervention. We also incorporated the tumour-related psychosocial and quality of life impact of NF1. INTERPRETATION The guideline reflects the current care for NF1 in Europe. They are not meant to be prescriptive and may be adjusted to local available resources at the treating centre, both within and outside EU countries. FUNDING This guideline has been supported by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS). ERN GENTURIS is funded by the European Union. DGE is supported by the Manchester NIHRBiomedical Research Centre (IS-BRC-1215-20007).
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Affiliation(s)
- Charlotte Carton
- Laboratory for Neurofibromatosis Research, Department of Human Genetics, University of Leuven, KU Leuven, Belgium
| | - D. Gareth Evans
- Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, MAHSC, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Ignacio Blanco
- Clinical Genetics Department, Hospital Germans Trias I Pujol, Barcelona, Spain
| | | | - Rosalie E. Ferner
- Neurofibromatosis Centre, Department of Neurology, Guy's & St Thomas' NHS Foundation Trust, London, UK
| | | | - Hector Salvador
- Sant Joan de Déu, Barcelona Children's Hospital, Barcelona, Spain
| | - Amedeo A. Azizi
- Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria
| | - Victor Mautner
- Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | | | - Sirkku Peltonen
- University of Turku and Turku University Hospital, Turku, Finland
- Sahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Stavros Stivaros
- Academic Unit of Paediatric Radiology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
- Geoffrey Jefferson Brain Research Centre, Northern Care Alliance NHS Group, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Eric Legius
- University Hospital Leuven, Department of Human Genetics, University of Leuven, KU Leuven, Belgium
| | - Rianne Oostenbrink
- ENCORE-NF1 Expertise Center, ErasmusMC-Sophia, Rotterdam, the Netherlands
- Corresponding author. Department General Pediatrics, ErasmusMC-Sophia, Room Sp 1549, Dr Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands.
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23
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Gunawardene A, Fischer J. Obscure gastrointestinal bleeding in a patient with neurofibromatosis type 1. ANZ J Surg 2022; 92:3105-3106. [PMID: 35212097 PMCID: PMC9790566 DOI: 10.1111/ans.17573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/08/2022] [Accepted: 02/09/2022] [Indexed: 12/30/2022]
Affiliation(s)
- Ashok Gunawardene
- Department of General SurgeryWaikato District Health BoardHamiltonNew Zealand,Department of SurgeryUniversity of AucklandAucklandNew Zealand
| | - Jesse Fischer
- Department of General SurgeryWaikato District Health BoardHamiltonNew Zealand,Department of SurgeryUniversity of AucklandAucklandNew Zealand
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24
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Qian H, Yan N, Hu X, Jiang J, Cao Z, Shen D. Molecular Portrait of GISTs Associated With Clinicopathological Features: A Retrospective Study With Molecular Analysis by a Custom 9-Gene Targeted Next-Generation Sequencing Panel. Front Genet 2022; 13:864499. [PMID: 35547262 PMCID: PMC9081536 DOI: 10.3389/fgene.2022.864499] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/03/2022] [Indexed: 01/04/2023] Open
Abstract
Objectives: The study aims to investigate genetic characterization of molecular targets and clinicopathological features with gastrointestinal stromal tumors based on targeted next-generation sequencing. Materials and Methods: We selected 106 patients with GISTs from Sir Run Run Shaw Hospital between July 2019 and March 2021. FFPE samples and paired blood samples were obtained from these patients who underwent excision of the tumor. A customized targeted-NGS panel of nine GIST-associated genes was designed to detect variants in the coding regions and the splicing sites of these genes. Results: In total, 106 patients with a GIST were included in the study which presented with various molecular driver alterations in this study. KIT mutations occurred most often in GISTs (94/106, 95.92%), followed by point mutations in PDGFRA. KIT or PDGFRA mutations were detected to be mutually exclusive in the GIST. A total of eight patients with wide-type KIT/PDGFRA were characterized as WT-GISTs, according to clinical diagnosis which included six quadruple-WT GISTs, 1 BRAF-mutant, and 1 NF1-mutant GIST. In KIT exon 11, the most common mutation type was the codon Mutation (in-frame deletion or indels), whereas the missense mutation was the dominant type in KIT exon 13 and KIT exon 17. All variations in KIT exon 11 observed in this study were concentrated at a certain position of codon 550 to codon 576. Mutation in KIT exon 9 was mostly located at codon 502–503. Two germline pathogenic mutations were detected: NF1-R681* and KRAS-T58I. NF1-L591P was a germline mutation to be identified for the first time and is not recorded in the database. The frequency of driving mutations differed between the primary anatomical site in the GIST (p = 0.0206). KIT exon 11 mutants had a lower proliferation index of Ki67 (68.66%,≤5%), while 50.00% of KIT exon 9 mutants had the Ki67 status greater than 10%. Conclusion: The occurrence and development of a GIST is driven by different molecular variations. Resistance to TKIs arises mainly with resistance mutations in KIT or PDGFRA when they are the primary drivers. Targeted NGS can simultaneously and efficiently detect nine GIST-related gene mutations and provide reference for clinicians’ individualized diagnosis and treatment. Our results have important implications for clinical management.
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Affiliation(s)
- Haoran Qian
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Na Yan
- Dian Diagnostics Group Co., Ltd., Hangzhou, China.,Key Laboratory of Clinical in Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China
| | - Xiaotong Hu
- Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Junchang Jiang
- Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhengzheng Cao
- Dian Diagnostics Group Co., Ltd., Hangzhou, China.,Key Laboratory of Clinical in Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China
| | - Dan Shen
- Dian Diagnostics Group Co., Ltd., Hangzhou, China.,Key Laboratory of Clinical in Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China
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25
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Lin Y, Wang C, Chiu Y, Lin R, Mo L. Small intestine gastrointestinal stromal tumor and malignant peripheral nerve sheath tumor in a patient with neurofibromatosis type 1: A case report. ADVANCES IN DIGESTIVE MEDICINE 2021. [DOI: 10.1002/aid2.13235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Yu‐Hung Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation) Tainan Taiwan
| | - Chun‐Hsiang Wang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation) Tainan Taiwan
| | - Yin‐I Chiu
- Department of General Surgery Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation) Tainan Taiwan
| | - Ruey‐Chang Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation) Tainan Taiwan
| | - Lein‐Ray Mo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation) Tainan Taiwan
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26
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Shimizu T, Hondo N, Miyagawa Y, Kitazawa M, Muranaka F, Tokumaru S, Nakamura S, Koyama M, Yamamoto Y, Ehara T, Miyazaki S, Iijima Y, Iwaya M, Soejima Y. A case of appendiceal ganglioneuroma in neurofibromatosis type 1. Surg Case Rep 2021; 7:218. [PMID: 34581917 PMCID: PMC8479022 DOI: 10.1186/s40792-021-01299-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/09/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Neurofibromatosis type 1 is an autosomal dominant inherited disease associated with multiple skin neurofibromas or other neurogenic tumors, such as nodular plexiform neurinoma or cerebrospinal tumor. Gastrointestinal stromal tumors are often complicated in patients with neurofibromatosis type 1, although involvement of the appendix is rare, and there have been few reports of appendiceal ganglioneuroma. CASE PRESENTATION The patient was a 29-year-old man diagnosed with neurofibromatosis type 1 based on physical findings and his family history. During the follow-up of neurofibromatosis, computed tomography was performed to detect neurological tumors, such as neurofibromas in the brain, spinal cord, and gastrointestinal tract. Computed tomography showed a markedly thickened appendix wall, and an appendiceal tumor was suspected. Laparoscopic appendectomy was performed, and a 50 × 35 mm appendiceal submucosal tumor was resected with a negative resection margin. At histopathological examination, the tumor was diagnosed as ganglioneuroma; it showed short spindle-shaped cells and ganglion cells diffusely infiltrated into the proper muscle layer and fibrous tissue that grew around nerve cells. The patient was discharged on the 5th postoperative day without postoperative complications and was doing well at 13 months following the operation. CONCLUSIONS Gastrointestinal stromal tumor and neurofibroma are the most common gastrointestinal tumors associated with neurofibromatosis type 1, but ganglioneuroma of the appendix is rare. Appendiceal neurogenic tumors should be considered in patients with neurofibromatosis type 1, and surgical resection is necessary because of the risk of malignancy.
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Affiliation(s)
- Tadaaki Shimizu
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Nao Hondo
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Yusuke Miyagawa
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Masato Kitazawa
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
| | - Futoshi Muranaka
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Shigeo Tokumaru
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Satoshi Nakamura
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Makoto Koyama
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Yuta Yamamoto
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Takehito Ehara
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Satoru Miyazaki
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Yasuhiro Iijima
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Mai Iwaya
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Nagano, 390-8621, Japan
| | - Yuji Soejima
- Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
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Mishra A, Gyawali S, Kharel S, Mishra A, Pathak N, Subedi N, Gaire P. Multiple jejunal gastrointestinal stromal tumors and Neurofibromatosis type 1: A rare association. Int J Surg Case Rep 2021; 85:106178. [PMID: 34274754 PMCID: PMC8319367 DOI: 10.1016/j.ijscr.2021.106178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/04/2021] [Accepted: 07/06/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION AND IMPORTANCE The association between gastrointestinal stromal tumor (GIST), mesenchymal tumor arising from the interstitial cells of cajal and Neurofibromatosis type 1 (NF1), an autosomal dominant disease has been reported in the literature. GIST in NF1 patients are multiple and located in the small intestine. Tumorigenesis in NF1 associated GIST is different to that of sporadic GIST and hence the treatment. Here we report a rare case of an NF1 patient with multiple jejunal GISTs. CASE PRESENTATION We here present a rare case of a 57-year-old male diagnosed with NF1 30 years back, presented in our emergency department with complaints of black, tarry stools later diagnosed to have multiple GIST in jejunum. Contrast enhanced computed tomography (CECT) of the abdomen showed a large 10.1 × 7.33 × 6.2 cm heterogeneous, exophytic, solid mass with cystic areas originating from the jejunum. The microscopic examination of the specimen showed spindle shaped tumor cells while immunohistochemistry showed CD117 (c-KIT) and DOG-1 positivity. The primary treatment was complete surgical excision of the tumor. CLINICAL DISCUSSION The incidence of GISTs in NF1 patient is around 6-7%; however, concomitant presence of multiple GISTs is rare. CECT of abdomen along with histopathological and immunohistochemistry studies are diagnostic. The management of GIST includes surgical and adjuvant therapy methods based on the tumorigenesis and recurrent risk stratification. CONCLUSION Early clinical suspicion and imaging aids in early detection of the tumor in patients with NF1 presenting with gastrointestinal symptoms. Postoperatively, screening for recurrence with radiology is of utmost importance.
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Affiliation(s)
- Aakash Mishra
- Kathmandu Medical College Teaching Hospital, Kathmandu, Nepal.
| | - Sandesh Gyawali
- Department of General Surgery, National Academy of Medical Sciences, Bir Hospital, Kathmandu, Nepal
| | - Sanjeev Kharel
- Maharajgunj Medical Campus, Institute of Medicine, Maharajgunj, Kathmandu, Nepal.
| | - Aman Mishra
- Maharajgunj Medical Campus, Institute of Medicine, Maharajgunj, Kathmandu, Nepal.
| | - Nibesh Pathak
- Maharajgunj Medical Campus, Institute of Medicine, Maharajgunj, Kathmandu, Nepal.
| | - Nirajan Subedi
- Department of GI and General Surgery, Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal
| | - Prabin Gaire
- Department of Pathology, Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal
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Recent Progress and Challenges in the Diagnosis and Treatment of Gastrointestinal Stromal Tumors. Cancers (Basel) 2021; 13:cancers13133158. [PMID: 34202544 PMCID: PMC8268322 DOI: 10.3390/cancers13133158] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Gastrointestinal stromal tumors (GIST) are potentially malignant tumors and require evidence-based surgical and/or medical treatment. Laparoscopy has similar safety and prognostic outcomes to those of laparotomy and is currently a standard procedure for localized GISTs. However, surgery for gastric GISTs less than 2 cm may be re-evaluated due to the indolent nature of the GIST and other competing risks among GIST patients. A work-up with endoscopy and endoscopic ultrasonography as well as endoscopic or percutaneous biopsy is important for the preoperative diagnosis of GISTs. Medical treatment with tyrosine kinase inhibitors is the mainstay for recurrent/metastatic GISTs. The activity of an individual drug is well correlated with gene alterations, and, in the era of precision medicine, cancer genome profiling should be considered before medical treatment. Abstract Gastrointestinal stromal tumors (GISTs) are the most frequent malignant mesenchymal tumors in the gastrointestinal tract. The clinical incidence of GISTs is estimated 10/million/year; however, the true incidence is complicated by frequent findings of tiny GISTs, of which the natural history is unknown. The initial work-up with endoscopy and endoscopic ultrasonography plays important roles in the differential diagnosis of GISTs. Surgery is the only modality for the permanent cure of localized GISTs. In terms of safety and prognostic outcomes, laparoscopy is similar to laparotomy for GIST treatment, including tumors larger than 5 cm. GIST progression is driven by mutations in KIT or PDGFRA or by other rare gene alterations, all of which are mutually exclusive. Tyrosine kinase inhibitors (TKIs) are the standard therapy for metastatic/recurrent GISTs. Molecular alterations are the most reliable biomarkers for TKIs and for other drugs, such as NTRK inhibitors. The pathological and genetic diagnosis prior to treatment has been challenging; however, a newly developed endoscopic device may be useful for diagnosis. In the era of precision medicine, cancer genome profiling by targeted gene panel analysis may enable potential targeted therapy even for GISTs without KIT or PDGFRA mutations.
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Xiao K, Swierczynski S, Xiao G. Small, low-grade ampullary neuroendocrine tumor presenting with metastasis and multiple synchronous tumors in a patient with neurofibromatosis type 1: a case report with literature review. J Surg Case Rep 2021; 2021:rjab076. [PMID: 33815755 PMCID: PMC8007178 DOI: 10.1093/jscr/rjab076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 02/09/2021] [Accepted: 02/13/2021] [Indexed: 12/28/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is a tumor syndrome and one of the most common genetic disorders. Patients have an increased risk of developing neurologic and gastrointestinal (GI) neoplasms, but GI lesions are often underrecognized since most cases are asymptomatic. It is extremely rare to see multiple types of abdominal tumors synchronously in NF1. In this case, we describe a patient presenting with a small, low-grade periampullary neuroendocrine tumor (NET) that underwent endoscopic submucosal dissection and later pancreaticoduodenectomy (Whipple procedure). This led to findings of lymph node and distant metastasis of her NET, and the incidental discovery of gastrointestinal stromal tumors, extensive pancreatic intraepithelial neoplasia, and main duct and side branch intraductal pancreatic mucinous neoplasm. The synchronous presence of these lesions has not been reported in the literature.
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Affiliation(s)
- Kevin Xiao
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | | | - Gary Xiao
- Department of Surgery, Transplant and Hepato-Pancreato-Biliary Surgery, Reading Hospital, West Reading, PA, USA
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Abstract
Gastrointestinal stromal tumours (GIST) have an incidence of ~1.2 per 105 individuals per year in most countries. Around 80% of GIST have varying molecular changes, predominantly mutually exclusive activating KIT or PDGFRA mutations, but other, rare subtypes also exist. Localized GIST are curable, and surgery is their standard treatment. Risk factors for relapse are tumour size, mitotic index, non-gastric site and tumour rupture. Patients with GIST with KIT or PDGFRA mutations sensitive to the tyrosine kinase inhibitor (TKI) imatinib that are at high risk of relapse have improved survival with adjuvant imatinib treatment. In advanced disease, median overall survival has improved from 18 months to >70 months since the introduction of TKIs. The role of surgery in the advanced setting remains unclear. Resistance to TKIs arise mainly from subclonal selection of cells with resistance mutations in KIT or PDGFRA when they are the primary drivers. Advanced resistant GIST respond to second-line sunitinib and third-line regorafenib, as well as to the new broad-spectrum TKI ripretinib. Rare molecular forms of GIST with alterations involving NF1, SDH genes, BRAF or NTRK genes generally show primary resistance to standard TKIs, but some respond to specific inhibitors of the activated genes. Despite major advances, many questions in both advanced and localized disease remain unanswered.
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Affiliation(s)
- Jean-Yves Blay
- Department of Medicine, Centre Leon Berard, UNICANCER & University Lyon I, Lyon, France.
| | - Yoon-Koo Kang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Toshiroo Nishida
- Surgery Department, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
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A case of planar-type gastrointestinal stromal tumor of the transverse colon with perforation. Clin J Gastroenterol 2021; 14:1157-1162. [PMID: 33728873 DOI: 10.1007/s12328-021-01385-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/08/2021] [Indexed: 10/21/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the human gastrointestinal tract. They usually develop in the stomach and small intestine, but extremely rarely in the colon. Although most GISTs form a mass, some cases showing a flatly proliferating lesion called planar-type GIST have been reported in the sigmoid colon and small intestine. Those are often associated with diverticular lesion and/or perforation. We present here a case of planar-type GIST of the transverse colon with perforation. A 49-year-old Japanese woman abruptly complained of abdominal pain, and was clinically diagnosed as perforation of the transverse colon. Partial resection of the transverse colon including the perforated site was done, and no apparent mass lesion was present. Histology showed that spindle cells flatly proliferated around the perforated area and replaced the layers from submucosa to subserosa. Immunohistochemistry revealed that the spindle cells were KIT-, DOG1- and CD34-positive. Codons 557 and 558 of exon 11 of the c-kit gene were heterozygously deleted at the lesional tissue but not at the normal mucosal tissue. Planar-type GIST of the transverse colon has not been reported yet, and the literature search for the similar cases was done.
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Wu J, Zhou H, Yi X, He Q, Lei T, Tan F, Liu H, Li B. Targeted Deep Sequencing Reveals Unrecognized KIT Mutation Coexistent with NF1 Deficiency in GISTs. Cancer Manag Res 2021; 13:297-306. [PMID: 33469372 PMCID: PMC7811451 DOI: 10.2147/cmar.s280174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/10/2020] [Indexed: 01/16/2023] Open
Abstract
Purpose NF1-deficient GISTs account for about 1% of gastrointestinal stromal tumors (GISTs) and are usually considered as a subtype of KIT/PDGFRA wild-type GISTs that have no detectable KIT and PDGFRA mutations. Some KIT/PDGFRA wild-type GISTs actually have cryptic KIT mutations (mKIT). So we investigate whether concurrent mKIT existed in NF1-associated GISTs. Patients and Methods Three independent cohorts were retrospectively analyzed. KIT/PDGFRA wild-type GISTs in Xiangya Hospital between May 2017 and Oct 2019 were investigated by next-generation sequencing (NGS) approach targeted 1021 cancer-related genes regions. GISTs cases in Gene+ dataset from May 2017 to May 2020 were collected from the platform of this company. The genotypes of GISTs in MSKCC cohort were downloaded from cBioPortal. Results A total of 290 cases including 23 KIT/PDGFRA wild-type GISTs in Xiangya Hospital, 136 GISTs in Gene+ database, and 131 GISTs in MSKCC were enrolled. Twenty-six cases have NF1 mutations (mNF1), and 48% (12/26) of NF1-mutated GISTs have concurrent mKIT. Compared with MSKCC (2/10, 20%), a higher ratio of mKIT in NF1-associated GISTs was detected in Xiangya Hospital (3/5, 60%) and Gene+ (7/11, 64%) (p<0.05). No mutation hotspot existed in mNF1. Most of mKIT centered within exon 11 (7/12, 58%) and others including exon 17 (3/12, 25%), exon 9(1/12, 8%), exon 13 (1/12, 8%) and exon 21 (1/12, 8%). No differences in age, gender, and location were detected between NF1-related GISTs with mKIT and those without mKIT. Three GIST cases of type I neurofibromatosis, skin neurofibromas and micro-GISTs (≤1 cm) were devoid of mKIT, but all the mini-GISTs (1~2 cm) and clinic GIST lesions (>2 cm) in two cases harbored mKIT. Conclusion mKIT was not unusual in NF1-associated GISTs, especially in Chinese populations. The gain-of-function mKIT possibly facilitated the progression of NF1-deficient lesions to clinic GISTs, however, the underlying mechanism warrants further studies.
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Affiliation(s)
- Jinchun Wu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Haiyan Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Xiaoping Yi
- Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Qiongzhi He
- Geneplus-Beijing Institute, Beijing, People's Republic of China
| | - Tianxiang Lei
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Fengbo Tan
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Heli Liu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Bin Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
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Small bowel gastrointestinal stromal tumor presenting with gastrointestinal bleeding in patient with type 1 Neurofibromatosis: Management and laparoscopic treatment. Case report and review of the literature. Int J Surg Case Rep 2021; 79:84-90. [PMID: 33444965 PMCID: PMC7808908 DOI: 10.1016/j.ijscr.2020.12.095] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 12/30/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION AND IMPORTANCE Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. It may be asymptomatic; nevertheless, gastrointestinal bleeding is the most frequent symptom, due to mucosal erosion. Its poor lymph node metastatic spread makes GIST often suitable of minimally invasive surgical approach. The importance of this study is to increase the awareness among physicians about this condition in particular scenarios as in our case and to stress the role of laparoscopic surgery. CASE PRESENTATION A 74-year-old female patient presented to the emergency department with hematemesis, followed by haematochezia and melena. The patient had a medical history of type 1 Neurofibromatosis (NF1). She underwent, after CT scan, esophagogastroduodenoscopy, and endoscopic haemostasis. Finally, we performed a laparoscopic resection of a mass of the first jejunal loop. The postoperative period was predominantly uneventful. Pathological examination confirmed a low-risk GIST. CLINICAL DISCUSSION Proximal jejunal GIST may cause an upper and lower gastrointestinal bleeding. A multidisciplinary team approach is mandatory for the correct management of this disease and its complications (bleeding). GISTs are indicated as the most commonly gastrointestinal NF1 associated tumours. In case of localised and resectable GIST surgical treatment is the mainstay and laparoscopic surgery is a valid alternative. CONCLUSION In case of abdominal bleeding mass in a NF1 patient, it is important to keep in mind the well-known association between NF1 and GIST to facilitate the diagnosis and to quickly perform the appropriate treatment. Laparoscopic approach is safe and effective if the oncological radicality is respected.
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Yasuda K, Nobeyama Y, Ishiji T, Ota A, Asahina A. Effects of imatinib mesylate on cutaneous neurofibromas associated with neurofibromatosis type 1. Clin Case Rep 2020; 8:2125-2128. [PMID: 33235741 PMCID: PMC7669387 DOI: 10.1002/ccr3.3071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 06/04/2020] [Indexed: 11/13/2022] Open
Abstract
Imatinib mesylate seemed to inhibit development of cutaneous neurofibromas (c-NFs) and promote growth of pre-existing c-NFs in our neurofibromatosis type 1 case. This report potentially provides new findings in the effects of imatinib mesylate.
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Affiliation(s)
- Ken‐ichi Yasuda
- Department of DermatologyThe Jikei University School of MedicineTokyoJapan
| | - Yoshimasa Nobeyama
- Department of DermatologyThe Jikei University School of MedicineTokyoJapan
| | - Takaoki Ishiji
- Department of DermatologyThe Jikei University School of MedicineTokyoJapan
| | - Arihito Ota
- Department of DermatologyThe Jikei University School of MedicineTokyoJapan
| | - Akihiko Asahina
- Department of DermatologyThe Jikei University School of MedicineTokyoJapan
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35
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Gokozan HN, Bomeisl P. Succinate dehydrogenase-deficient gastrointestinal stromal tumor of stomach diagnosed by endoscopic ultrasound-guided fine-needle biopsy: Report of a distinct subtype in cytology. Diagn Cytopathol 2020; 48:1328-1332. [PMID: 32870601 DOI: 10.1002/dc.24591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/06/2020] [Accepted: 08/03/2020] [Indexed: 02/04/2023]
Abstract
Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) are characterized by the lack of mutations in KIT receptor tyrosine kinase complex and platelet derived growth factor receptor-alpha (PDGFRA) that are commonly found in the majority of GISTs. SDH-deficient GISTs comprise approximately 5%-10% of all GISTs. This subset may be associated with Carney Triad and Carney-Stratakis syndrome. SDH-deficient GISTs show unique demographic, radiologic, morphologic findings, clinical behavior, and treatment response. To our knowledge, the identification and characterization of this subset of GISTs have not yet been described in the cytopathology literature. By understanding the clinical as well as the other unique features of this tumor, in addition to the rapidly evolving identification of specific molecular alterations and targeted therapies, cytopathologists may play an important role in the diagnosis and work-up of these patients to allow clinicians to better manage and treat them. We present a young female with gastric SDH-deficient GIST diagnosed by fine-needle biopsy with supporting surgical pathology follow-up and molecular confirmation. This report suggests that the diagnosis of SDH-deficient GIST can be made on cytology in the appropriate clinical setting by using cytomorphologic features and demonstrating SDH loss by IHC on the cell block. In addition, molecular testing may be possible on the cytology cell block or supernatant to confirm the diagnosis.
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Affiliation(s)
- Hamza Numan Gokozan
- Department of Pathology, University Hospitals Cleveland Medical Center/ Case Western Reserve University, Cleveland, Ohio, USA
| | - Philip Bomeisl
- Department of Pathology, University Hospitals Cleveland Medical Center/ Case Western Reserve University, Cleveland, Ohio, USA
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36
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Dare AJ, Gupta AA, Thipphavong S, Miettinen M, Gladdy RA. Abdominal neoplastic manifestations of neurofibromatosis type 1. Neurooncol Adv 2020; 2:i124-i133. [PMID: 32642738 PMCID: PMC7317050 DOI: 10.1093/noajnl/vdaa032] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome, with a wide clinicopathologic spectrum. It is defined by characteristic central nervous system, cutaneous and osseous manifestations, and by mutations in the NF1 gene, which is involved in proliferation via p21, RAS, and MAP kinase pathways. Up to 25% of NF1 patients develop intra-abdominal neoplastic manifestations including neurogenic (commonly plexiform neurofibromas and malignant peripheral nerve sheath tumors), interstitial cells of Cajal (hyperplasia, gastrointestinal stromal tumors), neuroendocrine, and embryonal tumors (rhabdomyosarcoma). Nonspecific symptoms, multifocal disease, or coexistence of 2 or more tumor types make patients challenging to diagnose and manage. Screening for intra-abdominal tumors in NF1 patients remains controversial, and currently no guidelines are established. Management decisions are complex and often informed by single-center experiences or case studies in the literature, though the field is rapidly evolving. Thus, NF1 patients should be followed in specialist centers familiar with their wide spectrum of pathology and with multidisciplinary care including specialized pathology and radiology. This review will (1) provide a contemporaneous synthesis of the literature and our multi-institutional clinical experiences with intra-abdominal neoplasms in NF1 patients, (2) present a classification framework for this heterogeneous group of disorders, and (3) outline approaches to screening, surveillance, diagnosis, and management.
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Affiliation(s)
- Anna J Dare
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Abha A Gupta
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.,Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Seng Thipphavong
- Department of Medical Imaging, Women's College Hospital, Toronto, Ontario, Canada
| | - Markku Miettinen
- Laboratory of Pathology, National Cancer Institute/Center for Cancer Research, Bethesda, Maryland, USA
| | - Rebecca A Gladdy
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.,Department of Surgical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
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Shintaku Y, Asano Y, Watanabe T, Kihara T, Ishikawa E, Jiayin Y, Kimura N, Kinoshita K, Hirota S. A case of planar-type GIST of the sigmoid colon showing diverticular structure with perforation. World J Surg Oncol 2020; 18:125. [PMID: 32527279 PMCID: PMC7291680 DOI: 10.1186/s12957-020-01906-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 06/03/2020] [Indexed: 01/28/2023] Open
Abstract
Background Gastrointestinal stromal tumors (GISTs) generally form well-defined mass lesions. However, some cases of the flatly distributed and muscularis propria-replacing GISTs have been reported so far. We experienced an additional case of planar-type GIST of the sigmoid colon accompanied by a diverticulum with perforation. Case presentation A 68-year-old Japanese male with sudden onset of abdominal pain was clinically diagnosed with gastrointestinal perforation, and an emergency abdominal operation was performed. A diverticulum with rupture was found in the sigmoid colon, but no apparent tumor was observed. Histological examination revealed bland spindle cells flatly proliferating and diffusely replacing the muscularis propria at the diverticular structure. The spindle cells were positive for KIT, DOG1, and CD34. Mutational analysis of the c-kit gene revealed that the lesion had a heterozygous deletion of 2 amino acids at codons 557 and 558 of exon 11. The mutation was not observed in the normal mucosa of the surrounding tissue. Conclusion We diagnosed this case as an unusual planar-type GIST. Some similar cases have been reported in the sigmoid colon and other sites. We discuss the mechanism of development of the planar-type GISTs associated with the diverticulum.
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Affiliation(s)
- Yuka Shintaku
- Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Yuya Asano
- Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Takahiro Watanabe
- Department of Pathology, Chibune Hospital, 3-4-39 Fuku-machi, Nishi-yodogawaku, Osaka, Osaka, 555-0034, Japan
| | - Takako Kihara
- Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Eri Ishikawa
- Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Yuan Jiayin
- Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Neinei Kimura
- Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Koji Kinoshita
- Department of Surgery, Nomura-Kaihin Hospital, 2-1-41 Sumaura-dori, Suma-ku, Kobe, Hyogo, 654-0055, Japan
| | - Seiichi Hirota
- Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
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A Huge Pelvic-Abdominal Malignant GIST Tumour in a Patient with Neurofibromatosis Type 1: Case Report and Literature Review. Case Rep Oncol Med 2020; 2020:6590307. [PMID: 31984144 PMCID: PMC6964723 DOI: 10.1155/2020/6590307] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 08/25/2019] [Accepted: 12/23/2019] [Indexed: 11/18/2022] Open
Abstract
Gastrointestinal stromal tumours are rare tumours of the gastrointestinal tract (GIT) accounting for 0.1%–3% of all gastrointestinal tumours. The most common location is the stomach (55%) followed by the small bowel (31.8%), colon (6%), other various locations (5.5%), and the oesophagus (0.7%). They may also occur in extraintestinal locations. The signs and symptoms of GIST depend on the tumour's location and size. Gastrointestinal bleeding is one of the most common symptoms. Other signs and symptoms include abdominal discomfort, pain or distention; intestinal obstruction, and weight loss. The association between the development of GISTs and neurofibromatosis 1 (NF1) has been established. NF1-associated GISTs tend to have a distinct phenotype, and the absence of KIT/PDGRFα mutations in turn has implications on further management when they do not respond well to imatinib treatment. Here, we present one of the largest GISTs reported in the literature with a total volume of 25.3 × 20 × 14 cm + 27.9 × 23 × 8 cm and an overall weight of 7.3 kg, which developed in a 43-year-old female patient with NF1 and was resected on an emergency basis due to the rapid deterioration and development of abdominal compartment syndrome. Pathology assessment showed a malignant GIST composed of spindle cells with elongated nuclei with necrosis, marked pleomorphism and numerous giant cell. The mitotic count was >15/50 HPF, Ki 67 was 80%, and the lymphovascular invasion was clear. Immunohistochemistry investigations showed that Vimentin, CD117, and DOG1 were positive, while BCL-2 and CD99 were focal positives. Pan-CK, S-100, CD34, Desmin, SMA, and HMB-45 were negatives.
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Minkiewicz I, Wilbrandt-Szczepańska E, Jendrzejewski J, Sworczak K, Korwat A, Śledziński M. CO-OCCURRENCE OF ADRENOCORTICAL CARCINOMA AND GASTROINTESTINAL STROMAL TUMOR IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1 AND A HISTORY OF ENDOMETRIAL CANCER. ACTA ENDOCRINOLOGICA-BUCHAREST 2020; 16:353-358. [PMID: 33363659 DOI: 10.4183/aeb.2020.353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Neurofibromatosis type 1 (NF-1) is an autosomal dominant inherited syndrome affecting 1 per 3000-4000 individuals. Patients with the neurofibromin gene mutation are more likely to develop malignancies. We report the case of a 57-year-old female with NF-1 who presented during her lifetime three neoplasms: endometrial cancer, adrenocortical carcinoma (ACC) and gastrointestinal stromal tumor (GIST). We describe the clinical, radiological and histopathological features of this rare condition. There have been reported only 10 cases of ACC together with NF-1 and 18 cases of ACC with other tumors. To the best of our knowledge it is the first reported case of NF-1 diagnosed with three cancers. Our report indicates the importance of careful and all-embracing care of patients with NF-1 in order to make a thorough investigation of any symptoms that might be a manifestation of a malignant disease.
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Affiliation(s)
- I Minkiewicz
- Medical University of Gdansk - Department of Endocrinology and Internal Medicine, Gdansk, Poland
| | - E Wilbrandt-Szczepańska
- Medical University of Gdansk - Department of Endocrinology and Internal Medicine, Gdansk, Poland
| | - J Jendrzejewski
- Medical University of Gdansk - Department of Endocrinology and Internal Medicine, Gdansk, Poland
| | - K Sworczak
- Medical University of Gdansk - Department of Endocrinology and Internal Medicine, Gdansk, Poland
| | - A Korwat
- Medical University of Gdansk - Department of Pathology, Gdansk, Poland
| | - M Śledziński
- Medical University of Gdansk - Department of General, Endocrine and Transplant Surgery, Gdansk, Poland
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Ylä-Outinen H, Loponen N, Kallionpää RA, Peltonen S, Peltonen J. Intestinal tumors in neurofibromatosis 1 with special reference to fatal gastrointestinal stromal tumors (GIST). Mol Genet Genomic Med 2019; 7:e927. [PMID: 31397088 PMCID: PMC6732307 DOI: 10.1002/mgg3.927] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 07/23/2019] [Accepted: 07/26/2019] [Indexed: 12/18/2022] Open
Abstract
Background Type 1 neurofibromatosis (NF1) is a genetic tumor predisposing Rasopathy. NF1 patients have an increased risk for developing benign and malignant tumors, but the occurrence of intestinal tumors has not been investigated at the population level. Methods In this retrospective register‐based total population study, diagnoses of gastrointestinal tract tumors were retrieved from the Finnish Care Register for Health Care for 1,410 NF1 patients and 14,030 reference persons. We also reviewed the death certificates of 232 NF1 patients who died during years 1987–2013, and specifically searched for diagnosis of gastrointestinal stromal tumor (GIST). Results The register analysis revealed an increased overall hazard ratio (HR) of 2.6 (95% CI 1.9–3.6) for intestinal tumors in NF1 compared to general population. The highest HR of 15.6 (95% CI 6.9–35.1) was observed in the small intestine. The focused analysis of NF1 death certificates and GISTs demonstrated that the GIST was the primary cause of death in seven patients. Conclusion This study emphasizes the need for careful evaluation of NF1 patients with gastrointestinal complaints. The challenge in diagnosis is that the tumors preferably occur at the small intestine, which is difficult target for diagnostic procedures. We also show that the NF1 GISTs may lead to fatal outcome despite of benign histopathological findings at the time of the diagnosis.
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Affiliation(s)
- Heli Ylä-Outinen
- Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.,Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland
| | - Niina Loponen
- Department of Cell Biology and Anatomy, University of Turku, Turku, Finland
| | - Roope A Kallionpää
- Department of Cell Biology and Anatomy, University of Turku, Turku, Finland
| | - Sirkku Peltonen
- Department of Dermatology, Turku University Hospital, Turku, Finland
| | - Juha Peltonen
- Department of Cell Biology and Anatomy, University of Turku, Turku, Finland
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Li Y, Gao ZD, Yang XD, Ye YJ, Wang S, Jiang KW. Gastrointestinal Stromal Tumors with KIT Mutation Coexisting with Wild-type Gastrointestinal Stromal Tumors in a Patient with Neurofibromatosis Type 1. Chin Med J (Engl) 2019; 131:2244-2245. [PMID: 30203805 PMCID: PMC6144858 DOI: 10.4103/0366-6999.240814] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Yang Li
- Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing 100044, China
| | - Zhi-Dong Gao
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Xiao-Dong Yang
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Ying-Jiang Ye
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Shan Wang
- Laboratory of Surgical Oncology, Peking University People's Hospital, Beijing 100044, China
| | - Ke-Wei Jiang
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing 100044, China
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Kays JK, Sohn JD, Kim BJ, Goze K, Koniaris LG. Approach to wild-type gastrointestinal stromal tumors. Transl Gastroenterol Hepatol 2018; 3:92. [PMID: 30603728 DOI: 10.21037/tgh.2018.10.13] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 10/29/2018] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) arise from the intestinal pacemaker cells of Cajal. Wild-type gastrointestinal stromal tumors (WT-GIST) are a unique and uncommon subtype of GISTs that lack activating mutations in the tyrosine kinase c-KIT or platelet derived growth factor receptor alpha (PDGFRA) receptors. The lack of these growth-stimulating mutations renders tyrosine kinase receptor inhibitors, such as imatinib mesylate, relatively ineffective against these tumors. WT-GIST arises most commonly due to underlying alternate proliferative signals associated with germ-line, genetic mutations. WT-GIST frequently arises in patients with BRAF mutations, Carney's Triad or neurofibromatosis type-1 (NF-1). All patients with WT-GIST require a careful examination for germ-line mutations and very close observation for recurrent tumors. Surgery remains a mainstay therapy for these patients. This review aims to discuss the most recent data available on the diagnosis and treatment of WT-GIST.
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Affiliation(s)
- Joshua K Kays
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jeffrey D Sohn
- Monmouth Medical Center, Robert Wood Johnson Barnabas Health, Long Branch, NJ, USA
| | - Bradford J Kim
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Katherine Goze
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Leonidas G Koniaris
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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de la Fuente N, Rodríguez Blanco M, Cerdán G, Artigas V. Acute gastrointestinal bleeding, multiple GIST and intestinal ganglioneuromatosis in a patient with neurofibromatosis. Cir Esp 2018; 97:237-239. [PMID: 30293759 DOI: 10.1016/j.ciresp.2018.08.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/26/2018] [Accepted: 08/13/2018] [Indexed: 11/20/2022]
Affiliation(s)
- Noa de la Fuente
- Unidad de Cirugía Hepatobiliopancreática y Cirugía Oncológica, Servicio de Cirugía General y del Aparato Digestivo, Hospital de la Santa Creu i Sant Pau, Barcelona, España.
| | - Manuel Rodríguez Blanco
- Unidad de Cirugía Hepatobiliopancreática y Cirugía Oncológica, Servicio de Cirugía General y del Aparato Digestivo, Hospital de la Santa Creu i Sant Pau, Barcelona, España
| | - Gemma Cerdán
- Unidad de Cirugía Hepatobiliopancreática y Cirugía Oncológica, Servicio de Cirugía General y del Aparato Digestivo, Hospital de la Santa Creu i Sant Pau, Barcelona, España
| | - Vicenç Artigas
- Unidad de Cirugía Hepatobiliopancreática y Cirugía Oncológica, Servicio de Cirugía General y del Aparato Digestivo, Hospital de la Santa Creu i Sant Pau, Barcelona, España
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Taranu I, Marin DE, Braicu C, Pistol GC, Sorescu I, Pruteanu LL, Berindan Neagoe I, Vodnar DC. In Vitro Transcriptome Response to a Mixture of Lactobacilli Strains in Intestinal Porcine Epithelial Cell Line. Int J Mol Sci 2018; 19:ijms19071923. [PMID: 29966337 PMCID: PMC6073849 DOI: 10.3390/ijms19071923] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 06/20/2018] [Accepted: 06/26/2018] [Indexed: 12/23/2022] Open
Abstract
Background: Food and feed supplements containing microorganisms with probiotic potential are of increasing interest due to their healthy promoting effect on human and animals. Their mechanism of action is still unknown. Using a microarray approach, the aim of this study was to investigate the differences in genome-wide gene expression induced by a mixture of three Lactobacillus strains (L. rhamnosus, L. plantarum, and L. paracasei) in intestinal porcine epithelial cells (IPEC-1) and to identify the genes and pathways involved in intestinal barrier functions. Methods: Undifferentiated IPEC-1 cells seeded at a density of 2.0 × 105/mL in 24-wells culture plates were cultivated at 37 °C and 5% CO2 until they reached confluence (2–3 days). Confluent cells monolayer were then cultivated with 1 mL of fresh lactobacilli (LB) mixture suspension prepared for a concentration of approximately 3.3 × 107 CFU/mL for each strain (1 × 108 CFU/mL in total) for 3 h and analyzed by microarray using Gene Spring GX v.11.5. Results: The functional analysis showed that 1811 of the genes modulated by LB treatment are involved in signaling (95% up-regulation, 121 genes with a fold change higher than 10). The most enhanced expression was registered for AXIN2 (axis inhibition protein 2-AXIN2) gene (13.93 Fc, p = 0.043), a negative regulator of β-catenin with a key role in human cancer. LB affected the cellular proliferation by increasing 10 times (Fc) the NF1 gene encoding for the neurofibromin protein, a tumor suppressor that prevent cells from uncontrolled proliferation. The induction of genes like serpin peptidase inhibitor, clade A member 3 (SERPINA 3), interleukin-20 (IL-20), oncostatin M(OSM), granulocyte-macrophage colony-stimulating factor (GM-CSF), and the suppression of chemokine (C-X-C motif) ligand 2/macrophage inflammatory protein 2-alpha (CXCL-2/MIP-2), regulator of G-protein signaling 2 (RGS2), and of pro-inflammatory interleukin-18 (IL-18) genes highlights the protective role of lactobacilli in epithelial barrier function against inflammation and in the activation of immune response. Conclusion: Gene overexpression was the predominant effect produced by lactobacilli treatment in IPEC-1 cells, genes related to signaling pathways being the most affected. The protective role of lactobacilli in epithelial barrier function against inflammation and in the activation of immune response was also noticed.
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Affiliation(s)
- Ionelia Taranu
- Laboratory of Animal Biology, National Institute for Research and Development for Biology and Animal Nutrition, Calea Bucuresti No. 1, Balotesti, 077015 Ilfov, Romania.
| | - Daniela Eliza Marin
- Laboratory of Animal Biology, National Institute for Research and Development for Biology and Animal Nutrition, Calea Bucuresti No. 1, Balotesti, 077015 Ilfov, Romania.
| | - Cornelia Braicu
- Department of Functional Genomics and Experimental Pathology, Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Str. V. Babes, No. 8, 400000 Cluj-Napoca, Romania.
| | - Gina Cecilia Pistol
- Laboratory of Animal Biology, National Institute for Research and Development for Biology and Animal Nutrition, Calea Bucuresti No. 1, Balotesti, 077015 Ilfov, Romania.
| | - Ionut Sorescu
- Laboratory of Animal Biology, National Institute for Research and Development for Biology and Animal Nutrition, Calea Bucuresti No. 1, Balotesti, 077015 Ilfov, Romania.
| | - Lavinia Laura Pruteanu
- Department of Chemistry, Lensfield Road, Centre for Molecular Science Informatics, University of Cambridge, Cambridge CB2 1EW, UK.
- MEDFUTURE-Research Center for Advanced Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, 23 Marinescu Street, 400015 Cluj-Napoca, Romania.
| | - Ioana Berindan Neagoe
- Department of Functional Genomics and Experimental Pathology, Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Str. V. Babes, No. 8, 400000 Cluj-Napoca, Romania.
- MEDFUTURE-Research Center for Advanced Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, 23 Marinescu Street, 400015 Cluj-Napoca, Romania.
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute "Prof. Dr. Ion Chiricuta", Republicii 34 Street, 400015 Cluj-Napoca, Romania.
| | - Dan Cristian Vodnar
- Department of Food Science, University of Agricultural Sciences and Veterinary Medicine, Calea Manastur, No. 3-5, 400372 Cluj-Napoca, Romania.
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Al Momani LA, Abughanimeh O, Shipley LC, Phemister J, Swenson J, Young M. Recurrent Gastric Gastrointestinal Stromal Tumor in a Patient with Neurofibromatosis. Cureus 2018; 10:e2854. [PMID: 30148007 PMCID: PMC6104896 DOI: 10.7759/cureus.2854] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder characterized by a mutation of the neurofibromin 1 (NF1) gene, resulting in increased susceptibility for multiple tumors, namely, gastrointestinal stromal tumors (GISTs)—the most common types of mesenchymal neoplasms in the gastrointestinal tract. Despite these tumors' predilection for the stomach, it seems to be the least likely part of the gastrointestinal (GI) tract to be affected in cases of neurofibromatosis. Herein, we report a case of a 61-year-old male patient with known neurofibromatosis, who presented with acute blood loss anemia due to a recurrent gastric GIST, requiring partial gastrectomy due to its size and multiple recurrences.
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Affiliation(s)
- Laith A Al Momani
- Department of Internal Medicine, East Tennessee State University, Johnson City, USA
| | - Omar Abughanimeh
- Department of Internal Medicine, University of Missouri Kansas City School of Medicine, Kansas City, USA
| | - Lindsey C Shipley
- Department of Internal Medicine, University of Alabama, Birmingham, USA
| | - Jennifer Phemister
- Department of Gastroenterology, East Tennessee State University, Johnson City, USA
| | - James Swenson
- Department of Gastroenterology, Mountain Home Veterans Affairs Hospital, Mountain Home, USA
| | - Mark Young
- Department of Gastroenterology, East Tennessee State University, Johnson City, USA
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Hammami A, Hasnaoui B, Guerfala M, Mabrouk MB, Farhat W, Ksiaa M, Jaziri H, Elleuch N, Brahem A, Ajmi S, Ali AB, Sriha B, Slama AB, Jmaa A. Gastrointestinal stromal tumor (GIST) inpatient with Von Recklinghausen's disease. Presse Med 2018; 47:404-408. [PMID: 29588106 DOI: 10.1016/j.lpm.2018.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Revised: 01/16/2018] [Accepted: 02/19/2018] [Indexed: 10/17/2022] Open
Affiliation(s)
- Aya Hammami
- Departement of Gastroenterology, Sahloul City, Tunisia.
| | | | | | | | - Waad Farhat
- Departement of Surgery, Sahloul City, Tunisia
| | - Mehdi Ksiaa
- Departement of Gastroenterology, Sahloul City, Tunisia
| | - Hanen Jaziri
- Departement of Gastroenterology, Sahloul City, Tunisia
| | - Nour Elleuch
- Departement of Gastroenterology, Sahloul City, Tunisia
| | - Ahlem Brahem
- Departement of Gastroenterology, Sahloul City, Tunisia
| | - Salem Ajmi
- Departement of Gastroenterology, Sahloul City, Tunisia
| | - Ali Ben Ali
- Departement of Surgery, Sahloul City, Tunisia
| | | | | | - Ali Jmaa
- Departement of Gastroenterology, Sahloul City, Tunisia
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Abdominal Imaging Findings in Neurocutaneous Syndromes: Looking Below the Diaphragm. AJR Am J Roentgenol 2017; 209:1197-1208. [PMID: 28981355 DOI: 10.2214/ajr.17.18404] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Nishida T. Therapeutic strategies for wild-type gastrointestinal stromal tumor: is it different from KIT or PDGFRA-mutated GISTs? Transl Gastroenterol Hepatol 2017; 2:92. [PMID: 29264430 DOI: 10.21037/tgh.2017.11.05] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 11/06/2017] [Indexed: 12/16/2022] Open
Affiliation(s)
- Toshirou Nishida
- Department of Surgery, National Cancer Center Hospital, Tokyo, Japan
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Hakozaki Y, Sameshima S, Tatsuoka T, Okuyama T, Yamagata Y, Noie T, Oya M, Fujii A, Ueda Y, Shimura C, Katagiri K. Rectal carcinoma and multiple gastrointestinal stromal tumors (GIST) of the small intestine in a patient with neurofibromatosis type 1: a case report. World J Surg Oncol 2017; 15:160. [PMID: 28835241 PMCID: PMC5569513 DOI: 10.1186/s12957-017-1231-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 08/14/2017] [Indexed: 12/13/2022] Open
Abstract
Background Neurofibromatosis type 1 (NF1) is an autosomally dominant inherited disorder characterized by multiple pigmented skin spots (café-au-lait spots) and neurofibroma. NF1 is associated with a wide variety of benign or malignant tumors. We report a NF1 patient who received surgical treatment for rectal carcinoma and multifocal small intestinal gastrointestinal stromal tumors (GISTs). Case presentation A 70-year-old female patient with NF1 was referred to our hospital after a positive fecal occult blood test. Locally advanced rectal carcinoma was detected in the upper rectum using colonoscopy. A submucosal tumor 20 mm in diameter was detected in the duodenal bulb during the upper gastrointestinal endoscopy. The biopsy specimen from the duodenum was GIST with positive immunostaining of KIT and CD34 microscopically. Laparoscopic low anterior resection for rectal carcinoma and local excision of the duodenal GIST were performed successfully. During the operation, five white small nodules were found on the serosa of the jejunum. One nodule was excised for histological examination. The resected rectal tumor was a well-differentiated adenocarcinoma with multiple lymph nodes metastases according to the histology. The duodenal tumor was found to be low-risk GIST. Moreover, the nodule from the jejunum was very low risk GIST. An excised skin wart was neurofibroma according to the histology. Conclusions GIST or carcinomas have been reported to occasionally occur in the digestive tract of the patients with NF1. We present a rare case of a NF1 patient with GISTs and colorectal carcinoma.
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Affiliation(s)
- Yuhei Hakozaki
- Department of Surgery, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Shinichi Sameshima
- Department of Surgery, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan.
| | - Teppei Tatsuoka
- Department of Surgery, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Takashi Okuyama
- Department of Surgery, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Yukinori Yamagata
- Department of Surgery, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Tamaki Noie
- Department of Surgery, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Masatoshi Oya
- Department of Surgery, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Akiko Fujii
- Department of Pathology, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Yoshihiko Ueda
- Department of Pathology, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Chieko Shimura
- Department of Dermatology, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Kazumoto Katagiri
- Department of Dermatology, Dokkyo Medical University Koshigaya Hospital, 2-1-50, Minami Koshigaya, Koshigaya, Saitama, 343-8555, Japan
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姚 思, 罗 庆. 野生型胃肠间质瘤分子机制研究进展. Shijie Huaren Xiaohua Zazhi 2017; 25:1166-1172. [DOI: 10.11569/wcjd.v25.i13.1166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
胃肠道间质瘤(gastrointestinal stromal tumor, GIST)是消化系最常见的间叶源性肿瘤, 80%-95%GIST存在KIT或PDGFRA基因突变, 未突变者称为野生型GIST(WT-GIST). 目前证实, 突变型GIST对酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)分子靶向治疗有效. 但WT-GIST通常对TKI类药物不敏感, 其分子理论基础、发生机制需明确阐述.
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