|
1
|
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.
Collapse
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.
| |
Collapse
|
|
2
|
Sadhu G, Dalal DC. Effects of Non-linear Interaction Between Oxygen and Lactate on Solid Tumor Growth Under Cyclic Hypoxia. Bull Math Biol 2025; 87:41. [PMID: 39934358 DOI: 10.1007/s11538-025-01420-6] [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: 11/18/2024] [Accepted: 01/27/2025] [Indexed: 02/13/2025]
Abstract
Oxygen is a crucial element for cellular respiration. Based on oxygen concentration, tumor regions can be categorized as normoxic, hypoxic, and necrotic. Hypoxic tumor cells switch their metabolism from aerobic glycolysis to anaerobic glycolysis. As a result, lactate is produced in hypoxic regions and is used as an alternative metabolic fuel by normoxic tumor cells. The consumption of lactate and oxygen by tumor cells does not follow a linear pattern. Scientific studies suggest that oxygen consumption and lactate production are non-linear phenomena. In this study, we propose a two-dimensional mathematical model to investigate lactate dynamics in avascular tumors with various initial shapes, such as circular, elliptical, and petal, and to explore its growth patterns in the context of non-linear interactions between oxygen and lactate. In certain human tumors, particularly in kidney, skin, and liver, multiple tumors may emerge within a tissue domain simultaneously. We also examine how the growth patterns of multiple tumors evolve within a shared domain. Cyclic hypoxia, commonly observed in solid tumors, results from oxygen fluctuations over time at the tumor site. Additionally, we analyze lactate dynamics and tumor growth patterns in environments with cyclic hypoxia. In order to simulate the proposed model, we use finite element based COMSOL Multiphysics 6.0 interface. The simulated results show excellent agreement with experimental data. Our findings reveal that the initial tumor shape significantly influences the lactate distribution and the tumor's internal structure. Furthermore, the simulations indicate that multiple tumors eventually merge into a single tumor. We also observe that cyclic hypoxia with short periodicity increases tumor volume.
Collapse
Affiliation(s)
- Gopinath Sadhu
- Department of Mathematics, Indian Institute of Technology, Guwahati, Assam, 781039, India.
| | - D C Dalal
- Department of Mathematics, Indian Institute of Technology, Guwahati, Assam, 781039, India
| |
Collapse
|
|
3
|
Li C, Li W, Shang M, Wang P, Hu X. Case report: detection of multiple sporadic gastrointestinal stromal tumors by dual-time 18 F-FDG PET/CT. Front Oncol 2024; 14:1321179. [PMID: 38606109 PMCID: PMC11007083 DOI: 10.3389/fonc.2024.1321179] [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: 10/13/2023] [Accepted: 03/18/2024] [Indexed: 04/13/2024] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors affecting the gastrointestinal tract. Typically, GISTs are solitary; however, in rare cases, they may be multiple and appear in one or more organs. Multiple GISTs can appear in familial GISTs, children, or certain tumor syndromes such as neurofibromatosis type 1, Carney syndrome, and Carney-Stratakis syndrome. However, the diagnosis of primary multiple sporadic GISTs is often more difficult than that of these diseases. Herein, we report a case of multiple primary sporadic GISTs in a 64-year-old man, affecting the abdominal cavity and retroperitoneum, as identified through dual-time point positron emission tomography (PET) with 18F-labeled fluoro-2-deoxyglucose (18F-FDG) and computed tomography (18F-FDG PET/CT). Notably, the dual-time-point PET/CT revealed the migration of masses near the lower abdomen into the abdominal cavity. Furthermore, a significant increase in radioactive uptake of the mass 3 h after 18F-FDG injection compared with that 1 h after injection may be an important cue for its diagnosis.
Collapse
Affiliation(s)
| | | | | | - Pan Wang
- Affiliated Hospital of Zunyi Medical University, Department of Nuclear Medicine, Zunyi, China
| | - Xianwen Hu
- Affiliated Hospital of Zunyi Medical University, Department of Nuclear Medicine, Zunyi, China
| |
Collapse
|
|
4
|
Serrano C, Martín-Broto J, Asencio-Pascual JM, López-Guerrero JA, Rubió-Casadevall J, Bagué S, García-del-Muro X, Fernández-Hernández JÁ, Herrero L, López-Pousa A, Poveda A, Martínez-Marín V. 2023 GEIS Guidelines for gastrointestinal stromal tumors. Ther Adv Med Oncol 2023; 15:17588359231192388. [PMID: 37655207 PMCID: PMC10467260 DOI: 10.1177/17588359231192388] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 07/19/2023] [Indexed: 09/02/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.
Collapse
Affiliation(s)
- César Serrano
- Sarcoma Translational Research Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Carrer de Natzaret, 115-117, Barcelona 08035, Spain
| | - Javier Martín-Broto
- Medical Oncology Department, Fundación Jimenez Diaz University Hospital, Madrid, Spain
- University Hospital General de Villalba, Madrid, Spain Instituto de investigación Sanitaria Fundación Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain
| | - José Manuel Asencio-Pascual
- Department of General Surgery, Gregorio Marañón University Hospital, Madrid, Spain
- Department of Surgery, Universidad Complutense de Madrid, Madrid, Spain
| | | | - Jordi Rubió-Casadevall
- Department of Medical Oncology, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | - Silvia Bagué
- Department of Pathology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
| | - Xavier García-del-Muro
- Department of Medical Oncology, Institut Català d’Oncologia, IDIBELL and University of Barcelona, Barcelona, Spain
| | | | - Luís Herrero
- GIST advocacy group – Colectivo GIST, Valladolid, Spain
| | - Antonio López-Pousa
- Department of Pathology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
| | - Andrés Poveda
- Initia Oncologia, Hospital Quironsalud, Valencia, Spain
| | | |
Collapse
|
|
5
|
Hamed H, Wahab MA, Elmahdy Y, El-Wahab RMA, El-Magd ESA. Gastrointestinal stromal tumors of the small intestine: the challenge of diagnosis and the outcome of management. World J Surg Oncol 2023; 21:85. [PMID: 36894972 PMCID: PMC9996990 DOI: 10.1186/s12957-023-02968-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
PURPOSES Gastrointestinal stromal tumor (GIST) is a rare small intestinal tumor. Most patients usually report long-period complaints due to difficult diagnoses. A high grade of suspicion is required for early diagnosis and initiation of the proper management. METHODS A retrospective study of all patients with small intestinal GIST who were operated in the period between January 2008 and May 2021 at Mansoura University Gastrointestinal Surgical Center (GIST). RESULTS Thirty-four patients were included in the study with a mean age of 58.15 years (± 12.65) with a male to female ratio of 1.3:1. The mean duration between onset of symptoms and diagnosis was 4.62 years (± 2.34). Diagnosis of a small intestinal lesion was accomplished through abdominal computed tomography (CT) in 19 patients (55.9%). The mean size of the tumor was 8.76 cm (± 7.76) ranging from 1.5 to 35 cm. The lesion was of ileal origin in 20 cases (58.8%) and jejunal in 14 cases (41.2%). During the scheduled follow-up period, tumor recurrence occurred in one patient (2.9%). No mortality was encountered. CONCLUSION Diagnosis of a small bowel GISTs requires a high grade of suspicion. Implementing new diagnostic techniques like angiography, capsule endoscopy, and enteroscopy should be encouraged when suspecting these lesions. Surgical resection is always associated with an excellent postoperative recovery profile and very low recurrence rates.
Collapse
Affiliation(s)
- Hosam Hamed
- Department of General Surgery, Faculty of Medicine, Gastrointestinal Surgical Center GISC, Mansoura University, Gehan Street, Al Dakahlia Governorate, 35511, Mansoura, Egypt
| | - Mohamed Abdel Wahab
- Department of General Surgery, Faculty of Medicine, Gastrointestinal Surgical Center GISC, Mansoura University, Gehan Street, Al Dakahlia Governorate, 35511, Mansoura, Egypt
| | - Youssif Elmahdy
- Department of General Surgery, Faculty of Medicine, Gastrointestinal Surgical Center GISC, Mansoura University, Gehan Street, Al Dakahlia Governorate, 35511, Mansoura, Egypt
| | - Rihame M Abd El-Wahab
- Department of General Surgery, Faculty of Medicine, Gastrointestinal Surgical Center GISC, Mansoura University, Gehan Street, Al Dakahlia Governorate, 35511, Mansoura, Egypt
| | - El-Sayed Abou El-Magd
- Department of General Surgery, Faculty of Medicine, Gastrointestinal Surgical Center GISC, Mansoura University, Gehan Street, Al Dakahlia Governorate, 35511, Mansoura, Egypt.
| |
Collapse
|
|
6
|
Miller D, Hosna A, Makhoul K, Amin T, Fuchs D. Gastrointestinal Stromal Tumor With a Rare Associated Meningioma: A Case Report. Cureus 2022; 14:e31361. [DOI: 10.7759/cureus.31361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2022] [Indexed: 11/13/2022] Open
|
|
7
|
Tarallo M, Carruezzo C, Dentice Di Accadia FM, Del Gaudio A, Caruso D, Polici M, Crocetti D, Costi U, Polistena A, Panzuto F, Laghi A, Cavallaro G, Fiori E. A Case Report of Multiple Gastrointestinal Stromal Tumors: Imaging Findings, Surgical Approach, and Review of the Literature. Front Surg 2022; 9:886135. [PMID: 36017517 PMCID: PMC9396543 DOI: 10.3389/fsurg.2022.886135] [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: 02/28/2022] [Accepted: 04/25/2022] [Indexed: 12/02/2022] Open
Abstract
INTRODUCTION Multiple gastrointestinal stromal tumors (GISTs) are rare tumors. Differential diagnosis between metastatic and multiple GISTs represents a challenge for a proper workup, prediction prognosis, and therapeutic strategy. CASE PRESENTATION We present the case of 67-year-old man with computed tomography (CT) evidence of multiple exophytic lesions in the abdomen, reaching diameters ranging from 1 to 9 cm, without any signs of organs infiltration, and resulting positive at 18F-FDG-PET/CT. Laparoscopic biopsy revealed multiple GISTs, and surgical resection by using an open approach was performed to achieve radicality. Moreover, an extensive review of the current literature was performed. RESULTS Small GISTs (<5 cm) can be treated by the laparoscopic approach, while in the case of large GISTs (>5 cm), tumor location and size should be taken into account to reach the stage of radical surgery avoiding tumor rupture. For metastatic GISTs, Imatinib represents the first choice of treatment, and surgery should be considered only in a few selected cases when all lesions are resectable. CONCLUSION Sporadic multiple GISTs are a rare event, imaging findings are not specific for GISTs, and biopsy requires a secure diagnosis and proper management. In the case of large lesions, with a high risk of vessels injury, laparotomy excision should be considered to achieve radicality and to avoid tumor rupture.
Collapse
Affiliation(s)
- Mariarita Tarallo
- Department of Surgery Pietro Valdoni, University of Rome Sapienza, Rome, Italy
| | - Cristina Carruezzo
- Department of Surgery Pietro Valdoni, University of Rome Sapienza, Rome, Italy
| | | | - Antonella Del Gaudio
- Department of Medical Surgical Sciences and Translational Medicine, Radiology Unit, Sant’Andrea University Hospital, University of Rome Sapienza, Rome, Italy
| | - Damiano Caruso
- Department of Medical Surgical Sciences and Translational Medicine, Radiology Unit, Sant’Andrea University Hospital, University of Rome Sapienza, Rome, Italy
| | - Michela Polici
- Department of Medical Surgical Sciences and Translational Medicine, Radiology Unit, Sant’Andrea University Hospital, University of Rome Sapienza, Rome, Italy
| | - Daniele Crocetti
- Department of Surgery Pietro Valdoni, University of Rome Sapienza, Rome, Italy
| | - Umberto Costi
- Department of Surgery Pietro Valdoni, University of Rome Sapienza, Rome, Italy
| | - Andrea Polistena
- Department of Surgery Pietro Valdoni, University of Rome Sapienza, Rome, Italy
| | - Francesco Panzuto
- Department of Medical Surgical Sciences and Translational Medicine, Radiology Unit, Sant’Andrea University Hospital, University of Rome Sapienza, Rome, Italy
- Department of Medical Surgical Sciences and Translational Medicine, Digestive Disease Unit, Sant'Andrea University Hospital, University of Rome Sapienza, Rome, Italy
| | - Andrea Laghi
- Department of Medical Surgical Sciences and Translational Medicine, Radiology Unit, Sant’Andrea University Hospital, University of Rome Sapienza, Rome, Italy
| | - Giuseppe Cavallaro
- Department of Surgery Pietro Valdoni, University of Rome Sapienza, Rome, Italy
| | - Enrico Fiori
- Department of Surgery Pietro Valdoni, University of Rome Sapienza, Rome, Italy
| |
Collapse
|
|
8
|
Heo JH, Choi EJ, Yu SJ, Park YH, Choi JS. Neuroendocrine Tumor with Metachronous Gastrointestinal Stromal Tumor in a Patient: A Case Report. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2022; 79:72-76. [PMID: 35232922 DOI: 10.4166/kjg.2022.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 11/03/2022]
Abstract
Neuroendocrine tumors (NETs) that arise from neuroendocrine cells can develop in most organs; however, it is rarely found in the duodenal papilla. Conversely, gastrointestinal stromal tumors (GISTs), which are mostly asymptomatic and detected incidentally, are usually found in the stomach and very rarely occur metachronously with NETs. A 42-year-old female with no specific underlying disease underwent gastroscopy due to epigastric pain. Biopsy of enlarged major and minor duodenal papilla confirmed the diagnosis of a NET. Endoscopic papillectomy of the major and minor papillae was performed. Multiple duodenal and jejunal submucosal nodules were seen on biliary CT performed at the 30 months follow-up. Pylorus-preserving pancreaticoduodenectomy was performed due to the suspicion of multiple recurrent NETs and muscularis propria involvement on endoscopic ultrasound. Surgical specimen biopsy confirmed the diagnosis of multiple duodenal and jejunal GIST lesions and a metastatic NET in the duodenal lymph node. We report a rare case of a GIST detected in the duodenum during follow-up after the diagnosis and papillectomy of duodenal papilla NET.
Collapse
Affiliation(s)
- Jae Hyuk Heo
- Division of Gastroenterology, Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Eun Jeong Choi
- Division of Gastroenterology, Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Seung Jung Yu
- Division of Gastroenterology, Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Yo Han Park
- Department of Surgery, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Jung Sik Choi
- Division of Gastroenterology, Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| |
Collapse
|
|
9
|
Haider A, Mehershahi S, Siddiqa A, Sharma M, Patel H. Imatinib-Resistant Gastrointestinal Stromal Tumor Presenting as a Large Abdominal Mass. Case Rep Gastroenterol 2021; 15:736-741. [PMID: 34594174 PMCID: PMC8436722 DOI: 10.1159/000518122] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 06/11/2021] [Indexed: 01/21/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the stromal or mesenchymal neoplasms affecting the gastrointestinal tract. Although they constitute 1% of primary gastrointestinal tumors, they are the most common nonepithelial tumors involving the gastrointestinal tract. They mostly present as overt or occult gastrointestinal bleeding. We present a case in which a 77-year-old female presented with a large abdominal mass. The origin of the mass was unclear on CT and MRI scan of the abdomen. Upper gastrointestinal endoscopic ultrasonography showed a cystic lesion in the perigastric region. A fine-needle biopsy of the lesion was performed, which was consistent with spindle type GIST. After the initial failure of imatinib therapy, the tumor was managed surgically.
Collapse
Affiliation(s)
- Asim Haider
- Internal Medicine, BronxCare Health System, Bronx, New York, USA
| | - Shehriyar Mehershahi
- Internal Medicine, BronxCare Health System, Bronx, New York, USA.,Gastroenterology, BronxCare Health System, Bronx, New York, USA
| | - Ayesha Siddiqa
- Internal Medicine, BronxCare Health System, Bronx, New York, USA
| | - Madhav Sharma
- Internal Medicine, BronxCare Health System, Bronx, New York, USA
| | - Harish Patel
- Internal Medicine, BronxCare Health System, Bronx, New York, USA.,Gastroenterology, BronxCare Health System, Bronx, New York, USA
| |
Collapse
|
|
10
|
Wu H, Li C, Li H, Shang L, Jing HY, Liu J, Fang Z, Du FY, Liu Y, Fu MD, Jiang KW, Li LP. Clinicopathological characteristics and longterm survival of patients with synchronous multiple primary gastrointestinal stromal tumors: A propensity score matching analysis. World J Gastroenterol 2021; 27:6128-6141. [PMID: 34629824 PMCID: PMC8476333 DOI: 10.3748/wjg.v27.i36.6128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 07/26/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple gastrointestinal stromal tumors (MGISTs) are specific and rare. Little is known about the impact of MGISTs on the survival of patients with gastrointestinal stromal tumors (GIST). The diagnosis, treatment and follow-up strategies of MGISTs is not specifically described in guidelines.
AIM To compare the clinicopathological characteristics and prognosis of MGISTs and solitary GISTs (SGISTs)
METHODS Patients diagnosed with primary GISTs from March 2010 to January 2020 were included. Due to the inhomogeneous distribution of several baseline characteristics and uneven MGIST and SGIST group sizes, propensity score matching was performed according to comorbidities, body mass index, tumor location, mitotic index, sex, age and American Society of Anesthesiologists score. Differences in clinicopathological characteristics and prognosis between patients with MGISTs and patients with SGISTs were compared.
RESULTS Among the entire cohort of 983 patients, the incidence of MGISTs was 4.17%. Before matching, patients with MGISTs and those with SGISTs had disparities in body mass index, surgical approach, tumor size and mitotic index. After 1:4 ratio matching, the clinical baseline data were comparable. The 5-year progression-free survival rate was 52.17% in the MGIST group and 75.00% in the SGIST group (P = 0.031). On multivariate analysis, tumor location, tumor size, mitotic index, imatinib treatment and MGISTs (hazard ratio = 2.431, 95% confidence interval = 1.097-5.386, P = 0.029) were identified as independent prognostic factors of progression-free survival. However, overall survival was similar between the SGIST and MGIST groups.
CONCLUSION Patients with MGISTs had poorer progression-free survival than patients with SGISTs. Risk criteria and diagnostic and treatment strategies should be developed to achieve personalized precision therapy and maximize the survival benefit.
Collapse
Affiliation(s)
- Hao Wu
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Chen Li
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China
| | - Han Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Liang Shang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
- Department of Digestive Tumor Translational Medicine, Engineering Laboratory of Shandong Province, Shandong Provincial Hospital, Jinan 250021, Shandong Province, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250021, Shandong Province, China
| | - Hai-Yan Jing
- Department of Pathology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Jin Liu
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Zhen Fang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Feng-Ying Du
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Yang Liu
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Meng-Di Fu
- Department of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Ke-Wei Jiang
- Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing 100044, China
| | - Le-Ping Li
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
- Department of Digestive Tumor Translational Medicine, Engineering Laboratory of Shandong Province, Shandong Provincial Hospital, Jinan 250021, Shandong Province, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250021, Shandong Province, China
| |
Collapse
|
|
11
|
Li C, Yang KL, Wang Q, Tian JH, Li Y, Gao ZD, Yang XD, Ye YJ, Jiang KW. Clinical features of multiple gastrointestinal stromal tumors: A pooling analysis combined with evidence and gap map. World J Gastroenterol 2020; 26:7550-7567. [PMID: 33384554 PMCID: PMC7754550 DOI: 10.3748/wjg.v26.i47.7550] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/09/2020] [Accepted: 11/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple gastrointestinal stromal tumors (MGISTs) are a very rare type of gastrointestinal stromal tumor (GIST) and are usually observed in syndrome.
AIM The paper aimed to describe the clinical and oncological features of MGISTs and to offer evidence for the diagnosis and treatment.
METHODS Data of consecutive patients with MGISTs who were diagnosed at Peking University People’s Hospital (PKUPH) from 2008 to 2019 were retrospectively evaluated. Further, a literature search was conducted by retrieving data from PubMed, EMBASE, and the Cochrane library databases from inception up to November 30, 2019.
RESULTS In all, 12 patients were diagnosed with MGISTs at PKUPH, and 43 published records were ultimately included following the literature review. Combined analysis of the whole individual patient data showed that female (59.30%), young (14.45%), and syndromic GIST (63.95%) patients comprised a large proportion of the total patient population. Tumors were mainly located in the small intestine (58.92%), and both CD117 and CD34 were generally positive. After a mean 78.32-mo follow-up, the estimated median overall survival duration (11.5 years) was similar to single GISTs, but recurrence-free survival was relatively poorer.
CONCLUSION The clinical and oncological features are potentially different between MGISTs and single GIST. Further studies are needed to explore appropriate surgical approach and adjuvant therapy.
Collapse
Affiliation(s)
- Chen Li
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Ke-Lu Yang
- Evidence-Based Nursing Center, School of Nursing, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Quan Wang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Jin-Hui Tian
- Evidence Based Medicine Center, School of Basic Medical Science of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yang Li
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Zhi-Dong Gao
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Xiao-Dong Yang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Ying-Jiang Ye
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Ke-Wei Jiang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| |
Collapse
|
|
12
|
Shen YY, Ma XL, Yang LX, Zhao WY, Tu L, Zhuang C, Ni B, Liu Q, Wang M, Cao H. Clinicopathologic characteristics, diagnostic clues, and prognoses of patients with multiple sporadic gastrointestinal stromal tumors: a case series and review of the literature. Diagn Pathol 2020; 15:56. [PMID: 32408889 PMCID: PMC7222320 DOI: 10.1186/s13000-020-00939-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/11/2020] [Indexed: 12/28/2022] Open
Abstract
Background Most sporadic gastrointestinal stromal tumors (GISTs) occur as solitary tumors, while multiple sporadic GISTs are extremely rare and often misdiagnosed as metastatic GISTs, leading to inappropriate treatment. This study aimed to investigate the clinicopathological characteristics, diagnostic clues, and prognoses of multiple sporadic GISTs. Methods Twenty-seven patients with multiple sporadic GISTs and 11 patients with metastatic GISTs mimicking sporadic GISTs were analyzed. The clinicopathological characteristics, genetic mutation types, and prognoses were summarized. In addition, 1066 cases of primary GISTs with a single lesion diagnosed at the same hospital were included as controls. Results Compared with 1066 cases of primary GIST with a single lesion, multiple sporadic GISTs occurred at an older age, were more common in women than in men, and were located mainly in the stomach. They were generally small in size, had a low mitotic index and were more often rated as very low risk/low risk. Mutation analysis of all available lesions revealed different KIT/PDGFRA mutation patterns among tumors from the same patients. No patient relapsed during the follow-up period. Among 11 patients with metastatic GISTs that mimicked multiple sporadic GISTs, multiple lesions from the same patient always had concordant pathological and mutational characteristics; namely, they carried an identical KIT/PDGFRA mutation, and the mitotic index was usually high. Conclusions The prognoses of patients with multiple sporadic GISTs were not worse than those of patients with a single lesion of the same risk under the same treatment. When it was difficult to distinguish multiple sporadic GISTs from metastatic GISTs, multiple lesions in the same patient carried different KIT/PDGFRA mutation patterns, which supported tumor multiplicity, while the concordant hypermitotic phase in multiple lesions of GISTs suggested that the tumor was metastatic.
Collapse
Affiliation(s)
- Yan-Ying Shen
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China.,Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Xin-Li Ma
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Lin-Xi Yang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Wen-Yi Zhao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Lin Tu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Chun Zhuang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Bo Ni
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Qiang Liu
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Ming Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China.
| | - Hui Cao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China.
| |
Collapse
|
|
13
|
Yasuda T, Eto K, Yoshida N, Iwagami S, Hiyoshi Y, Nagai Y, Iwatsuki M, Ishimoto T, Baba Y, Miyamoto Y, Shiota T, Mikami Y, Baba H. Multiple heterochronic gastrointestinal stromal tumors in the stomach detected 6 years after resection: a case report. Surg Case Rep 2020; 6:48. [PMID: 32146688 PMCID: PMC7060937 DOI: 10.1186/s40792-020-00812-1] [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: 01/11/2020] [Accepted: 02/26/2020] [Indexed: 11/16/2022] Open
Abstract
Background To date, only a few cases of multiple GISTs with different clones in different organs have been published. However, a case of multiple GISTs with different clones occurring in a single organ has never been reported. Case presentation A 41-year-old patient underwent laparoscopic partial gastrectomy for gastric gastrointestinal stromal tumor (GIST) in 2012. The pathological findings showed high-risk characteristics for recurrence, so he received adjuvant therapy with imatinib for 3 years. In 2018, 3 years after completing the adjuvant therapy, tumor lesions at residual gastric cardia were incidentally identified by follow-up computed tomography (CT). The pathological findings of the tumor biopsy revealed gastric GIST. He underwent secondary laparoscopic partial gastrectomy and was diagnosed with high-risk GIST. Adjuvant therapy with imatinib was restarted immediately. The two gastric GISTs had the same exon 11 mutations in the c-kit gene, but they had different missense mutations. This molecular heterogeneity suggested that they were derived from different origins. Conclusion We reported a multiple heterochronic GIST in the stomach detected 6 years after resection. There may be a possibility that another heterochronic GIST will occur in the remnant stomach in the future, so close follow-up will be needed.
Collapse
Affiliation(s)
- Tadahito Yasuda
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Kojiro Eto
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Naoya Yoshida
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Shiro Iwagami
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yukiharu Hiyoshi
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Youhei Nagai
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yoshifumi Baba
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yuji Miyamoto
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Takuya Shiota
- Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yoshiki Mikami
- Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterology, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
| |
Collapse
|
|
14
|
Feng X, Xu H, Dela Cruz N. Mucosal Schwann Cell Hamartoma in sigmoid colon – A rare case report and review of literature. HUMAN PATHOLOGY: CASE REPORTS 2020. [DOI: 10.1016/j.ehpc.2019.200337] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
|
|
15
|
Li K, Tjhoi W, Shou C, Yang W, Zhang Q, Liu X, Yu J. Multiple gastrointestinal stromal tumors: analysis of clinicopathologic characteristics and prognosis of 20 patients. Cancer Manag Res 2019; 11:7031-7038. [PMID: 31413638 PMCID: PMC6662863 DOI: 10.2147/cmar.s197560] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 06/18/2019] [Indexed: 12/16/2022] Open
Abstract
Purpose Multiple gastrointestinal stromal tumors (GISTs) are rare. The aim of this study was to investigate the clinicopathologic characteristics and prognosis of multiple GISTs. Patients and methods Between May 2003 and June 2018, patients who underwent surgery for multiple GISTs were retrospectively analyzed. Exons 9, 11, 13, and 17 of the KIT gene, and exons 12, and 18 of the PDGFRA gene were examined in 34 tumors from 20 patients. Results A total of 20 patients with multiple GISTs were enrolled. There were 11 females and nine males with a median age of 59 years (range: 37–80 years). Of these cases, 16 were sporadic cases and four were associated with GIST syndromes (two cases of Carney triad and two cases of neurofibromatosis type 1 [NF1]). The most common presentation was gastrointestinal bleeding. Carney triad GISTs did not exhibit KIT/PDGFRA mutations. One of the NF1 patients was a KIT/PDGFRA wild-type, and the other patient had a PDGFRA mutation. Of the sporadic cases, one shared the same KIT gene mutation within each GIST and one had two lesions that were both wild-type for KIT and PDGFRA. Different KIT mutations among individual tumors were detected in seven patients. During the median follow-up period of 66 months (range: 3–183 months), four patients developed liver or abdominal metastases, three of whom expired due to the disease. The rates of recurrence-free survival and overall surviva at 5 years were 65.8% and 76.7%, respectively. Conclusion Multiple GISTs may occur as sporadic tumors or as an additional component of specific syndromes (eg, Carney triad and NF1) that display different clinicopathologic characteristics based on their particular underlying mechanisms. The overall prognosis of patients with multiple GISTs is comparable to that of patients with only a single GIST.
Collapse
Affiliation(s)
- Kai Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Weh Tjhoi
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Chunhui Shou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Weili Yang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Qing Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Xiaosun Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jiren Yu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| |
Collapse
|
|
16
|
Schöffski P, Sciot R, Debiec-Rychter M, Van Ongeval J, D'Hoore A, Merckx L, Joniau S. Successful Perioperative and Surgical Treatment of a Rare Case of Extra-Gastrointestinal Stromal Tumor Arising in the Prostate Gland. Case Rep Oncol 2019; 12:183-191. [PMID: 39263341 PMCID: PMC11387946 DOI: 10.1159/000496686] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 01/04/2019] [Indexed: 09/13/2024] Open
Abstract
We report a very uncommon case of a primary, non-metastatic gastrointestinal stromal tumor (GIST) arising in the prostate gland in a 60-year-old patient. The morphology and immunohistochemical profile of the disease resembled GIST of gastrointestinal origin, and the molecular driver of this malignancy was a double mutation in exons 11 and 13 of the KIT gene. The tumor was proliferating slowly, did respond to neoadjuvant therapy with the KIT-inhibiting agent imatinib and was cured by radical, retro-pubic prostatectomy followed by adjuvant imatinib treatment. We postulate that primary GIST tumors of the prostate can arise from prostatic interstitial cells, which are the pacemakers of smooth muscle contractility in the gland, and possibly share a common precursor with typical GIST and the interstitial cells of Cajal in the gastrointestinal tract.
Collapse
Affiliation(s)
- Patrick Schöffski
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
| | - Raf Sciot
- Department of Pathology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
| | - Maria Debiec-Rychter
- Department of Human Genetics, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
| | - Johan Van Ongeval
- Department of Gastroenterology, General Hospital Sint-Lucas, Ghent, Belgium
| | - André D'Hoore
- Department of Abdominal Surgery, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
| | - Luc Merckx
- Department of Urology, General Hospital Sint-Lucas, Ghent, Belgium
| | - Steven Joniau
- Department of Urology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
| |
Collapse
|
|
17
|
Serrano-Candelas E, Ainsua-Enrich E, Navinés-Ferrer A, Rodrigues P, García-Valverde A, Bazzocco S, Macaya I, Arribas J, Serrano C, Sayós J, Arango D, Martin M. Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth. Mol Oncol 2018; 12:1383-1397. [PMID: 29885053 PMCID: PMC6068349 DOI: 10.1002/1878-0261.12332] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 05/18/2018] [Accepted: 05/28/2018] [Indexed: 12/13/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) represent about 80% of the mesenchymal neoplasms of the gastrointestinal tract. Most GISTs contain oncogenic KIT (85%) or PDGFRA (5%) receptors. The kinase inhibitor imatinib mesylate is the preferential treatment for these tumors; however, the development of drug resistance has highlighted the need for novel therapeutic strategies. Recently, we reported that the adaptor molecule SH3 Binding Protein 2 (SH3BP2) regulates KIT expression and signaling in human mast cells. Our current study shows that SH3BP2 is expressed in primary tumors and cell lines from GIST patients and that SH3BP2 silencing leads to a downregulation of oncogenic KIT and PDGFRA expression and an increase in apoptosis in imatinib-sensitive and imatinib-resistant GIST cells. The microphthalmia-associated transcription factor (MITF), involved in KIT expression in mast cells and melanocytes, is expressed in GISTs. Interestingly, MITF is reduced after SH3BP2 silencing. Importantly, reconstitution of both SH3BP2 and MITF restores cell viability. Furthermore, SH3BP2 silencing significantly reduces cell migration and tumor growth of imatinib-sensitive and imatinib-resistant cells in vivo. Altogether, SH3BP2 regulates KIT and PDGFRA expression and cell viability, indicating a role as a potential target in imatinib-sensitive and imatinib-resistant GISTs.
Collapse
Affiliation(s)
- Eva Serrano-Candelas
- Biochemistry Unit, Biomedicine Department, Faculty of Medicine, University of Barcelona, Spain.,Laboratory of Clinic and Experimental Immunoallergy, IDIBAPS, Barcelona, Spain
| | - Erola Ainsua-Enrich
- Biochemistry Unit, Biomedicine Department, Faculty of Medicine, University of Barcelona, Spain.,Laboratory of Clinic and Experimental Immunoallergy, IDIBAPS, Barcelona, Spain
| | - Arnau Navinés-Ferrer
- Biochemistry Unit, Biomedicine Department, Faculty of Medicine, University of Barcelona, Spain.,Laboratory of Clinic and Experimental Immunoallergy, IDIBAPS, Barcelona, Spain
| | - Paulo Rodrigues
- Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Autonomous University of Barcelona, Spain
| | | | - Sarah Bazzocco
- Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Autonomous University of Barcelona, Spain
| | - Irati Macaya
- Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Autonomous University of Barcelona, Spain
| | - Joaquín Arribas
- Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.,The Catalan Institute of Research and Advanced Studies (ICREA), Barcelona, Spain.,CIBERONC, Barcelona, Spain.,Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona, Bellaterra, Spain
| | - César Serrano
- Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.,Vall d'Hebron University Hospital, Barcelona, Spain
| | - Joan Sayós
- Immune Regulation and Immunotherapy Group, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Autonomous University of Barcelona, Spain
| | - Diego Arango
- Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Autonomous University of Barcelona, Spain
| | - Margarita Martin
- Biochemistry Unit, Biomedicine Department, Faculty of Medicine, University of Barcelona, Spain.,Laboratory of Clinic and Experimental Immunoallergy, IDIBAPS, Barcelona, Spain
| |
Collapse
|
|
18
|
Tokunaga M, Nanjo S, Yoshita H, Fujinami H, Watanabe T, Ishii Y, Kobayashi S, Akashi M, Takagi H, Mihara H, Kajiura S, Ando T, Hashimoto I, Hojo S, Okumura T, Sugiyama T. Multiple Synchronous Sporadic Gastrointestinal Stromal Tumors in the Stomach and Jejunum. Intern Med 2018; 57:1719-1723. [PMID: 29434135 PMCID: PMC6047988 DOI: 10.2169/internalmedicine.0229-17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
A 77-year-old patient was admitted to our hospital for the further examination of melena. A computed tomography scan detected two submucosal tumors (SMTs) in the stomach and jejunum. Double-balloon endoscopy revealed the presence of a delle on the jejunal SMT, suggesting that the SMT was the origin of the gastrointestinal bleeding. Both tumors were surgically resected and subsequently diagnosed via histology as gastrointestinal stromal tumors (GISTs). Furthermore, the two GISTs had different mutations in the c-kit gene, suggesting that they were derived from different clonal origins. This report depicts an extremely rare case of multiple synchronous sporadic GISTs in the stomach and jejunum.
Collapse
Affiliation(s)
- Mami Tokunaga
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Sohachi Nanjo
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Hiroki Yoshita
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Haruka Fujinami
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Tohru Watanabe
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Yoko Ishii
- Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Saito Kobayashi
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Momoko Akashi
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Hiroaki Takagi
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Hiroshi Mihara
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Shinya Kajiura
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Takayuki Ando
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Isaya Hashimoto
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Shozo Hojo
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Tomoyuki Okumura
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| | - Toshiro Sugiyama
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
| |
Collapse
|
|
19
|
Sanchez-Hidalgo JM, Duran-Martinez M, Molero-Payan R, Rufian-Peña S, Arjona-Sanchez A, Casado-Adam A, Cosano-Alvarez A, Briceño-Delgado J. Gastrointestinal stromal tumors: A multidisciplinary challenge. World J Gastroenterol 2018; 24:1925-1941. [PMID: 29760538 PMCID: PMC5949708 DOI: 10.3748/wjg.v24.i18.1925] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/27/2018] [Accepted: 05/06/2018] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors located in the alimentary tract. Its usual manifestation is gastrointestinal bleeding. However, small asymptomatic lesions are frequently detected as incidental finding. Characteristically, most GISTs (> 95%) are positive for the KIT protein (CD117) by IHC staining and approximately 80%-90% of GISTs carry a mutation in the c-KIT or PDGFRA genes. Mutational analysis should be performed when planning adjuvant and neoadjuvant therapy, due to its possible resistance to conventional treatment. The arise of tyrosine kinase inhibitor has supposed a revolution in GISTs treatment being useful as adjuvant, neoadjuvant or recurrence disease treatment. That is why a multidisciplinary approach to this disease is required. The correct characterization of the tumor at diagnosis (the diagnosis of recurrences and the evaluation of the response to treatment with tyrosine kinase inhibitors) is fundamental for facing these tumors and requires specialized Endoscopist, Radiologists and Nuclear Medicine Physician. Surgery is the only potentially curative treatment for suspected resectable GIST. In the case of high risk GISTs, surgery plus adjuvant Imatinib-Mesylate for 3 years is the standard treatment. Neoadjuvant imatinib-mesylate should be considered to shrink the tumor in case of locally advanced primary or recurrence disease, unresectable or potentially resectable metastasic tumors, and potentially resectable disease in complex anatomic locations to decrease the related morbidity. In the case of Metastatic GIST under Neoadjuvant treatment, when there are complete response, stable disease or limited disease progression, complete cytoreductive surgery could be a therapeutic option if feasible.
Collapse
Affiliation(s)
- Juan Manuel Sanchez-Hidalgo
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Avda. Menéndez Pidal s/n, Cordoba 14004, Spain
| | - Manuel Duran-Martinez
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Avda. Menéndez Pidal s/n, Cordoba 14004, Spain
| | - Rafael Molero-Payan
- Department of Intern Medicine, Reina Sofia University Hospital, Avda. Menéndez Pidal s/n, Cordoba 14004, Spain
- Lipids and Atherosclerosis Research Unit, IMIBIC/Hospital Universitario Reina Sofía/Universidad de Córdoba, Cordoba 14004, Spain
| | - Sebastian Rufian-Peña
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Avda. Menéndez Pidal s/n, Cordoba 14004, Spain
| | - Alvaro Arjona-Sanchez
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Avda. Menéndez Pidal s/n, Cordoba 14004, Spain
| | - Angela Casado-Adam
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Avda. Menéndez Pidal s/n, Cordoba 14004, Spain
| | - Antonio Cosano-Alvarez
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Avda. Menéndez Pidal s/n, Cordoba 14004, Spain
| | - Javier Briceño-Delgado
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Avda. Menéndez Pidal s/n, Cordoba 14004, Spain
| |
Collapse
|
|
20
|
Chen Q, Li R, Zhang ZG, Deng QT, Li K, Wang H, Yang XX, Wu YS. Oncogene mutational analysis in Chinese gastrointestinal stromal tumor patients. Onco Targets Ther 2018; 11:2279-2286. [PMID: 29719410 PMCID: PMC5916380 DOI: 10.2147/ott.s155214] [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: 12/15/2022] Open
Abstract
Background Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors and exhibit a high frequency of oncogenic KIT or PDGFRA mutations. Tyrosine kinase inhibitors (TKIs) have been mainly used in the treatment of GISTs bearing KIT/PDGFRA mutations. However, other mutation profiles have been found to affect the sensitivity to and effectiveness of TKIs in the treatment of GISTs. Purpose The aim of the present study was to describe the mutational status of multiple genes in GIST samples and to provide information for finding potential predictive markers of therapeutic targets in Chinese GIST patients. Patients and methods MassARRAY spectrometry was used to test 40 Chinese GIST patients for 238 mutations affecting 19 oncogenes. Results A total of 14 oncogenes with 43 mutations were detected in 38 samples, with a mutation frequency of 95%. Among these mutation samples, 26 GISTs were found for KIT or PDGFRA mutations, while 12 were KIT/PDGFRA wild-type. Approximately half of the GIST samples harbored multiple mutations. The most frequent mutations were found in KIT (62.5%), CDK4 (17.5%), NRAS (15%) and EGFR (12.5%). Other mutations included PIK3CA and AKT1 (10%), BRAF and ABL1 (7.5%), PDGFRA, ERBB2 and HRAS (5%), and AKT2, FLT3 and KRAS (2.5%). New mutated genes (CDK4, AKT2, FLT3, ERBB2, ABL1 and AKT1), a higher BRAF mutation frequency (7.5%) and new BRAF mutation sites (G464E) were found in Chinese GIST patients. Conclusion This study demonstrated useful mutations in a small fraction of Chinese GIST, but targeted therapeutics on these potential predictive markers need to be investigated in depth especially in Oriental populations.
Collapse
Affiliation(s)
- Qiong Chen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, People's Republic of China
| | - Rong Li
- Department of Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhi-Gao Zhang
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, People's Republic of China
| | - Qiao-Ting Deng
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, People's Republic of China
| | - Kun Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, People's Republic of China
| | - Hao Wang
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, People's Republic of China
| | - Xue-Xi Yang
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, People's Republic of China
| | - Ying-Song Wu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, People's Republic of China
| |
Collapse
|
|
21
|
Rossi S, Sbaraglia M, Dell'Orto MC, Gasparotto D, Cacciatore M, Boscato E, Carraro V, Toffolatti L, Gallina G, Niero M, Pilozzi E, Mandolesi A, Sessa F, Sonzogni A, Mancini C, Mazzoleni G, Romeo S, Maestro R, Dei Tos AP. Concomitant KIT/BRAF and PDGFRA/BRAF mutations are rare events in gastrointestinal stromal tumors. Oncotarget 2017; 7:30109-18. [PMID: 27097112 PMCID: PMC5058667 DOI: 10.18632/oncotarget.8768] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 04/04/2016] [Indexed: 01/13/2023] Open
Abstract
AIM The BRAF mutation is a rare pathogenetic alternative to KIT/PDGFRA mutation in GIST and causes Imatinib resistance. A recent description of KIT and BRAF mutations co-occurring in an untreated GIST has challenged the concept of their being mutually exclusive and may account for ab initio resistance to Imatinib, even in the presence of Imatinib-sensitive KIT mutations. BRAF sequencing is generally limited to KIT/PDGFRA wild-type cases. Hence, the frequency of concomitant mutations may be underestimated. METHODS We screened for KIT (exon 9, 11, 13, 17), PDGFRA (exon 12,14, 18) and BRAF (exon 15) mutations a series of 407 GIST. Additionally, we evaluated the BRAF V600E mutation-specific antibody, VE1, as a surrogate for V600E mutation, on a series of 313 GIST (24 on whole sections, 288 cases on tissue array), including 6 cases molecularly ascertained to carry the BRAF V600E mutation. RESULTS No concomitant KIT/BRAF or PDGFRA/BRAF mutations were detected. BRAF mutation was detected only in one case, wild-type for KIT/PDGFRA. All the 6 BRAF-mutant cases stained positive with the VE1 antibody. A weak VE1 expression was observed in 14/287 (4.9%) BRAF wild-type cases, as observed also in 2/6 BRAF-mutant cases. Overall in our series, sensitivity and specificity of the VE1 antobody were 100% and 95.1%, respectively. CONCLUSION The concomitance of BRAF mutation with either KIT or PDGFRA mutation is rare in GIST. In these tumors, moderate/strong VE1 immunoreactivity is a valuable surrogate for molecular analysis. Instead, genotyping is warranted in the presence of weak VE1 staining.
Collapse
Affiliation(s)
- Sabrina Rossi
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Marta Sbaraglia
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Marta Campo Dell'Orto
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | | | - Matilde Cacciatore
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Elena Boscato
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Valentina Carraro
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Luisa Toffolatti
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Giovanna Gallina
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Monia Niero
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Emanuela Pilozzi
- Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Rome, Italy
| | - Alessandra Mandolesi
- Department of Pathology, University of Marche, Ancona School of Medicine, Ancona, Italy
| | - Fausto Sessa
- Department of Pathology, Macchi Fondation, Varese, Italy
| | | | - Cristina Mancini
- Department of Pathology, Azienda Ospedaliera-Universitaria, Parma, Italy
| | | | - Salvatore Romeo
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | | | - Angelo P Dei Tos
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| |
Collapse
|
|
22
|
|
|
23
|
Poveda A, García Del Muro X, López-Guerrero JA, Cubedo R, Martínez V, Romero I, Serrano C, Valverde C, Martín-Broto J. GEIS guidelines for gastrointestinal sarcomas (GIST). Cancer Treat Rev 2017; 55:107-119. [PMID: 28351781 DOI: 10.1016/j.ctrv.2016.11.011] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 11/25/2016] [Indexed: 02/06/2023]
Abstract
Gastrointestinal stromal sarcomas (GISTs) are the most common mesenchymal tumours originating in the digestive tract. They have a characteristic morphology, are generally positive for CD117 (c-kit) and are primarily caused by activating mutations in the KIT or PDGFRA genes(1). On rare occasions, they occur in extravisceral locations such as the omentum, mesentery, pelvis and retroperitoneum. GISTs have become a model of multidisciplinary work in oncology: the participation of several specialties (oncologists, pathologists, surgeons, molecular biologists, radiologists…) has forested advances in the understanding of this tumour and the consolidation of a targeted therapy, imatinib, as the first effective molecular treatment in solid tumours. Following its introduction, median survival of patients with advanced or metastatic GIST increased from 18 to more than 60months. Sunitinib and Regorafenib are two targeted agents with worldwide approval for second- and third-line treatment, respectively, in metastatic GIST.
Collapse
Affiliation(s)
- Andrés Poveda
- Instituto Valenciano de Oncología, Calle del Profesor Beltrán Bàguena, 8, 46009 Valencia, Spain.
| | - Xavier García Del Muro
- Institut Català d'Oncologia, Avinguda de la Granvia de l'Hospitalet, 199-203, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
| | | | - Ricardo Cubedo
- Hospital Puerta de Hierro, Calle Manuel de Falla, 1, 28222 Majadahonda, Madrid, Spain
| | | | - Ignacio Romero
- Instituto Valenciano de Oncología, Calle del Profesor Beltrán Bàguena, 8, 46009 Valencia, Spain
| | - César Serrano
- Hospital Vall d'Hebrón, Passeig de la Vall d'Hebrón, 119-129, 08035 Barcelona, Spain
| | - Claudia Valverde
- Hospital Vall d'Hebrón, Passeig de la Vall d'Hebrón, 119-129, 08035 Barcelona, Spain
| | | | | |
Collapse
|
|
24
|
[Gastrointestinal stromal tumors of the stomach and precursor lesions]. DER PATHOLOGE 2017; 38:105-111. [PMID: 28243730 DOI: 10.1007/s00292-017-0275-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract although they are much less frequent than epithelial tumors. In more than 60% of cases they occur in the stomach. Especially small lesions measuring ≤1 cm in diameter, so-called microscopic GIST can occur multifocally, frequently in the proximal stomach wall and sometimes as an incidental finding in a gastrectomy specimen resected for gastric cancer. The multicentricity of GIST alone is not proof of a metastatic behavior or a syndromal or hereditary disease. Multiple sporadic synchronous and metachronous GIST are characterized by different primary mutations mostly in the KIT or PDGFRA genes and are often less aggressive. It is speculative whether a field effect is responsible or whether still unknown GIST-promoting factors may facilitate the development of several independent lesions. If KIT or PDGFRA mutations are lacking, a succinate dehydrogenase (SDH) deficient GIST has to be considered, either hereditary as Carney-Stratakis syndrome or syndromal as part of a Carney triad.
Collapse
|
|
25
|
Jasek K, Buzalkova V, Minarik G, Stanclova A, Szepe P, Plank L, Lasabova Z. Detection of mutations in the BRAF gene in patients with KIT and PDGFRA wild-type gastrointestinal stromal tumors. Virchows Arch 2016; 470:29-36. [PMID: 27864688 DOI: 10.1007/s00428-016-2044-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 10/19/2016] [Accepted: 11/10/2016] [Indexed: 02/06/2023]
Abstract
Gastrointestinal stromal tumors (GISTs) are characterized by mutations in exons 9, 11, 13, and 17 of KIT or exons 12, 14, and 18 of PDGFRA gene. However, approximately 10 to 15 % of GISTs lack the mutations in KIT and PDGFRA, and these are referred to as wild-type GISTs which are less sensitive to tyrosine-kinase inhibitors. The aim of this study was to detect BRAF mutations in patients with wild-type GISTs. We applied a sensitive allele-specific PCR, which was optimized using the V600E mutation-harboring cell line RKO, followed by verification of the results by dideoxy sequencing. We selected 149 GIST patients without detectable mutations in KIT and PDGFRA genes from the Slovak national GIST register and analyzed biopsy specimens for the presence of BRAF mutations in exon 15. We identified nine patients with the V600E mutation. The BRAF-driven GISTs were primary gastric (n = 3), small intestinal (n = 3), colon (n = 1), and of uncertain origin (n = 1). We also included a liver metastasis of a patient with a simultaneous KIT exon 11-mutated intra-abdominal metastasis. We conclude that genome analysis of wild-type GISTs for mutations should include the BRAF gene, as its mutation status contributes to understanding of pathogenesis and might be important for decisions on therapy.
Collapse
Affiliation(s)
- Karin Jasek
- Department of Pathological Anatomy, Jessenius Faculty of Medicine and University Hospital in Martin, Comenius University in Bratislava, Kollarova 2, 03601, Martin, Slovakia.,Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Malá hora 4C, 03601, Martin, Slovakia
| | - Veronika Buzalkova
- Department of Pathological Anatomy, Jessenius Faculty of Medicine and University Hospital in Martin, Comenius University in Bratislava, Kollarova 2, 03601, Martin, Slovakia
| | - Gabriel Minarik
- Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 81108, Bratislava, Slovakia
| | - Andrea Stanclova
- Department of Pathological Anatomy, Jessenius Faculty of Medicine and University Hospital in Martin, Comenius University in Bratislava, Kollarova 2, 03601, Martin, Slovakia
| | - Peter Szepe
- Department of Pathological Anatomy, Jessenius Faculty of Medicine and University Hospital in Martin, Comenius University in Bratislava, Kollarova 2, 03601, Martin, Slovakia
| | - Lukas Plank
- Department of Pathological Anatomy, Jessenius Faculty of Medicine and University Hospital in Martin, Comenius University in Bratislava, Kollarova 2, 03601, Martin, Slovakia
| | - Zora Lasabova
- Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Malá hora 4C, 03601, Martin, Slovakia. .,Department of Molecular Biology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4C, 03601, Martin, Slovakia.
| |
Collapse
|
|
26
|
Brenca M, Rossi S, Polano M, Gasparotto D, Zanatta L, Racanelli D, Valori L, Lamon S, Dei Tos AP, Maestro R. Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. J Pathol 2016; 238:543-9. [PMID: 26606880 DOI: 10.1002/path.4677] [Citation(s) in RCA: 146] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 10/06/2015] [Accepted: 11/18/2015] [Indexed: 01/28/2023]
Abstract
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The vast majority of GISTs are driven by oncogenic activation of KIT, PDGFRA or, less commonly, BRAF. Loss of succinate dehydrogenase complex activity has been identified in subsets of KIT/PDGFRA/BRAF-mutation negative tumours, yet a significant fraction of GISTs are devoid of any of such alterations. To address the pathobiology of these 'quadruple-negative' GISTs, we sought to explore the possible involvement of fusion genes. To this end we performed transcriptome sequencing on five KIT/PDGFRA/BRAF-mutation negative, SDH-proficient tumours. Intriguingly, the analysis unveiled the presence of an ETV6-NTRK3 gene fusion. The screening by FISH of 26 additional cases, including KIT/PDGFRA-mutated GISTs, failed to detect other ETV6 rearrangements beside the index case. This was a 'quadruple-negative' GIST located in the rectum, an uncommon primary site for GIST development (∼4% of all GISTs). The fusion transcript identified encompasses exon 4 of ETV6 and exon 14 of NTRK3 and therefore differs from the canonical ETV6-NTRK3 chimera of infantile fibrosarcomas. However, it retains the ability to induce IRS1 phosphorylation, activate the IGF1R downstream signalling pathway and to be targeted by IGF1R and ALK inhibitors. Thus, the ETV6-NTRK3 fusion might identify a subset of GISTs with peculiar clinicopathological characteristics which could be eligible for such therapies. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Monica Brenca
- Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy
| | - Sabrina Rossi
- Department of Pathology, Treviso General Hospital, Italy
| | - Maurizio Polano
- Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy
| | - Daniela Gasparotto
- Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy
| | - Lucia Zanatta
- Department of Pathology, Treviso General Hospital, Italy
| | - Dominga Racanelli
- Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy
| | - Laura Valori
- Department of Pathology, Treviso General Hospital, Italy
| | - Stefano Lamon
- Department of Oncology, Treviso General Hospital, Italy
| | | | - Roberta Maestro
- Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy
| |
Collapse
|
|
27
|
Unique case of sporadic multiple gastro intestinal stromal tumour. Int J Surg Case Rep 2015; 9:98-100. [PMID: 25746950 PMCID: PMC4392183 DOI: 10.1016/j.ijscr.2015.01.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 01/13/2015] [Accepted: 01/13/2015] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and they derived from transformed neoplastic precursors of Cajal's interstitial cell (ICC). PRESENTATION OF THE CASE We are presenting a sporadic and exemplary case of 42 multiple GISTs in a young female patient. Our patient showed anemia for the gastric GIST bleeding and only after other tumors were instrumentally and intra-surgery discovered. The patient showed genetic mutation V559A/1676 T>C of the juxtamembrane domain of the exon 11 causing the replacement of Valine with Alanine in the 559 codon. DISCUSSION GISTS estimated annual incidence is 12-14 per million. Multiple GISTs associated with familiarity or hereditary syndromes are described only in few case reports and sporadic mGISTs have not been studied yet. Literature review has been done. CONCLUSION We are presenting a sporadic and exemplary case of 42 multiple GISTs in a young female patient localized trough out all the gastrointestinal tract. This is the only case of sporadic multiple GISTs reported in literature.
Collapse
|
|
28
|
Jones DH, Caracciolo JT, Hodul PJ, Strosberg JR, Coppola D, Bui MM. Familial Gastrointestinal Stromal Tumor Syndrome: Report of 2 Cases with KIT Exon 11 Mutation. Cancer Control 2015; 22:102-8. [DOI: 10.1177/107327481502200113] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- Derek H. Jones
- University of South Florida Morsani College of Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jamie T. Caracciolo
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Pamela J. Hodul
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jonathan R. Strosberg
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Domenico Coppola
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Marilyn M. Bui
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Department of Sarcoma, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| |
Collapse
|
|
29
|
Poveda A, del Muro XG, López-Guerrero JA, Martínez V, Romero I, Valverde C, Cubedo R, Martín-Broto J. GEIS 2013 guidelines for gastrointestinal sarcomas (GIST). Cancer Chemother Pharmacol 2014; 74:883-98. [PMID: 25193432 PMCID: PMC4209233 DOI: 10.1007/s00280-014-2547-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 07/19/2014] [Indexed: 02/06/2023]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. Correct diagnosis with thorough use of pathologic and molecular tools of GIST mutations has been of the foremost importance. GIST are usually (95 %) KIT positive and harbor frequent KIT or platelet-derived growth factor receptor α-activating mutations. This deep molecular understanding has allowed the correct classification into risk groups with implications regarding prognosis, essential use in the development of targeted therapies and even response prediction to this drugs. Treatment has been evolving and an update to include lessons learned from recent trials in advanced disease as well as controversies in the adjuvant setting that are changing daily practice, is reviewed here. An effort from the Spanish Group for Sarcoma Research with investigators from the group has been undertaken to launch this third version of the GIST guidelines and provide a practical means for the different disciplines that treat this complex disease.
Collapse
Affiliation(s)
- Andrés Poveda
- Instituto Valenciano de Oncología, Calle del Profesor Beltrán Bàguena, 8, 46009, Valencia, Spain,
| | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Synchronous gastric gastrointestinal stromal tumor and colon adenocarcinoma: a case report. Case Rep Oncol Med 2014; 2014:305848. [PMID: 25197591 PMCID: PMC4150523 DOI: 10.1155/2014/305848] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Revised: 07/21/2014] [Accepted: 07/24/2014] [Indexed: 01/13/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) represent the majority of primary mesenchymal tumors of the gastrointestinal tract. They are generally considered to be solitary tumors and therefore the synchronous occurrence with other primary malignancies of gastrointestinal track is considered a rare event. Here we present the case of a 75-year-old man admitted to our hospital with a 10-day history of gastrointestinal bleeding. Colonoscopy revealed an ulcerative mass of 4 cm in diameter in the ascending colon. Gastroscopy revealed a bulge in the gastric body measuring 1 cm in diameter with normal overlying mucosa. Surgical intervention was suggested and ileohemicolectomy with regional lymph node resection along with gastric wedge resection was performed. Pathologic examination of the ascending colon mass showed an invasive moderately differentiated adenocarcinoma stage III B (T3N1M0). Grossly resected wedge of stomach showed a well circumscribed intramural tumor which microscopically was consistent with essentially benign gastrointestinal stromal tumor (according to Miettinen criteria). The patient did not receive additional treatment. Two years later the patient showed no evidence of recurrence or metastasis.
Collapse
|
|
31
|
Blandamura S, Alessandrini L, Bertorelle R, Simonato F, Guzzardo V, Valentini E, Angriman I, Fassina A. Multiple sporadic gastrointestinal stromal tumors concomitant with ampullary adenocarcinoma: a case report with KIT and PDGFRA mutational analysis and miR-221/222 expression profile. Pathol Res Pract 2014; 210:392-6. [PMID: 24674454 DOI: 10.1016/j.prp.2014.01.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/08/2014] [Accepted: 01/23/2014] [Indexed: 12/11/2022]
Abstract
GISTs originating multifocally at different GI sites, in patients lacking familial syndromes, could be interpreted as recurrent/metastatic disease. MiR-221/222 have recently been identified as regulators of KIT expression in GISTs. We report the first case of synchronous GISTs in the stomach and duodenum concomitant with an ampullary adenocarcinoma. Different CD117 expression patterns could be related to different KIT mutational status in the two lesions: gastric GIST showed a dot-like pattern and lacked KIT mutations; duodenal GIST had a strong membranous expression pattern, likely due to KIT exon 9 duplication, which is associated with lower response to imatinib. MiR-221/222 were downregulated in GISTs as compared with normal tissue (p<0.05) and expressed increased levels in the gastric GIST as compared with duodenal one (p<0.05). Our data support an independent origin of the two GISTs. Determining whether these tumors are multiple primaries or recurrencies is helpful to predict their malignancy and to select proper treatment.
Collapse
Affiliation(s)
- Stella Blandamura
- Surgical Pathology and Cytopathology Unit, Department of Medicine, DIMED University of Padova, Padova, Italy
| | - Lara Alessandrini
- Surgical Pathology and Cytopathology Unit, Department of Medicine, DIMED University of Padova, Padova, Italy.
| | | | - Francesca Simonato
- Surgical Pathology and Cytopathology Unit, Department of Medicine, DIMED University of Padova, Padova, Italy
| | - Vincenza Guzzardo
- Surgical Pathology and Cytopathology Unit, Department of Medicine, DIMED University of Padova, Padova, Italy
| | - Elisa Valentini
- Surgical Pathology and Cytopathology Unit, Department of Medicine, DIMED University of Padova, Padova, Italy
| | - Imerio Angriman
- Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Ambrogio Fassina
- Surgical Pathology and Cytopathology Unit, Department of Medicine, DIMED University of Padova, Padova, Italy
| |
Collapse
|
|
32
|
Corless CL. Gastrointestinal stromal tumors: what do we know now? Mod Pathol 2014; 27 Suppl 1:S1-16. [PMID: 24384849 DOI: 10.1038/modpathol.2013.173] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 06/15/2013] [Accepted: 06/17/2013] [Indexed: 12/15/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.
Collapse
Affiliation(s)
- Christopher L Corless
- Department of Pathology (L471) and Knight Diagnostic Laboratories, Oregon Health and Science University, Portland, OR, USA
| |
Collapse
|
|
33
|
Barnett CM, Corless CL, Heinrich MC. Gastrointestinal stromal tumors: molecular markers and genetic subtypes. Hematol Oncol Clin North Am 2013; 27:871-88. [PMID: 24093165 DOI: 10.1016/j.hoc.2013.07.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Mutation-activated signaling from the KIT and PDGFRA kinases has been successfully targeted in gastrointestinal stromal tumors (GISTs), with subtle differences between the mutations serving to refine prognosis and more precisely tailor therapy. There is a growing understanding of the molecular drivers of GISTs lacking mutations in KIT or PDGFRA, so called wild-type GISTs, further aiding in management decisions. This article provides an overview of all the known molecular subtypes of GIST and provides information about clinical correlates, treatment, and prognosis depending on the subtype.
Collapse
Affiliation(s)
- Christine M Barnett
- Hematology and Medical Oncology, Division of Hematology/Oncology, Portland VA Medical Center, OHSU Knight Cancer Institute, Oregon Health & Science University, Mail Code L586, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
| | | | | |
Collapse
|
|
34
|
Nakayama Y, Kadowaki K, Higure A, Hisaoka M, Yamaguchi K. Synchronous sporadic gastrointestinal stromal tumors in the stomach and jejunum: report of a case. Case Rep Gastroenterol 2013; 7:69-74. [PMID: 23626506 PMCID: PMC3617895 DOI: 10.1159/000348754] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
This report describes a patient with synchronous sporadic gastrointestinal stromal tumors (GISTs) in the stomach and jejunum. A 71-year-old Japanese male presented with a 2-year history of occasional melena and general fatigue. Computed tomography of the abdomen demonstrated an enhanced extramural gastric tumor, 4 cm in diameter. Endoscopic examination revealed a jejunal submucosal tumor. He was referred to the surgical outpatient clinic for surgical treatment of an extramural gastric tumor and a jejunal submucosal tumor. Laparotomy allowed the identification of a nut-sized extramural tumor at the stomach and a thumb's head-sized tumor on the jejunum. Partial resections of the stomach and jejunum were performed. Histopathological and immunohistochemical examination revealed that these tumors were GISTs. Although no molecular analysis was performed, the immunohistochemical staining patterns of these two tumors were different from each other. Therefore, the final diagnosis was synchronous sporadic GISTs in the stomach and jejunum. This patient has survived without recurrence for approximately 12 years since complete resection.
Collapse
Affiliation(s)
- Yoshifumi Nakayama
- Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Japan
- Department of Gastroenterological and General Surgery, Wakamatsu Hospital of University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kouji Kadowaki
- Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Aiichirou Higure
- Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Masanori Hisaoka
- Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Koji Yamaguchi
- Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Japan
| |
Collapse
|
|
35
|
Nannini M, Biasco G, Pallotti MC, Di Battista M, Santini D, Paterini P, Maleddu A, Mandrioli A, Lolli C, Saponara M, Di Scioscio V, Zompatori M, Catena F, Fusaroli P, Dei Tos AP, Pantaleo MA. Late recurrences of gastrointestinal stromal tumours (GISTs) after 5 years of follow-up. Med Oncol 2012; 29:144-150. [PMID: 21258878 DOI: 10.1007/s12032-010-9806-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Accepted: 12/24/2010] [Indexed: 12/27/2022]
Abstract
In practice, relapses of gastrointestinal stromal tumours after long time of surgical resection occur. However, few published data are available for duration, intensity and imaging sources of follow-up in radically excised patients with localized disease. Therefore, every single institution chooses the surveillance schedule according to its experience. The aim of this study was to describe the late recurrences of disease 5 years after the primary tumour's excision in a series of patients with recurrent GIST from our institution. We retrospectively reviewed 42 patients with "recurrent" GIST, collected since 2001. Ten patients were always followed at our institution, and 32 patients came to our attention at the time of recurrence. The analysed series were divided into two groups: patients who developed recurrence before 5 years and patients who developed recurrence 5 years after the primary tumour's excision. Among 42 patients, 36 patients developed the recurrence within 5 years of the primary tumour excision, whereas 6 patients developed the recurrence 5 years after primary tumour excision diagnosed during follow-up or casually for other reasons. All patients had distant recurrence, involving liver and peritoneum, whereas no local relapse was observed. These patients were heterogeneous in primary tumour site, risk classification and molecular analysis. Duration of the follow-up for radically excised patients with GIST remains still unsettled; however, the integration of every clinical, pathological and molecular parameter is essential to optimize the duration and intensity of the follow-up for each single patient.
Collapse
Affiliation(s)
- Margherita Nannini
- Department of Hematology and Oncology Sciences L A Seragnoli, S Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Pantaleo MA, Astolfi A, Nannini M, Ceccarelli C, Formica S, Santini D, Heinrich MC, Corless C, Dei Tos AP, Paterini P, Catena F, Maleddu A, Saponara M, Di Battista M, Biasco G. Differential expression of neural markers in KIT and PDGFRA wild-type gastrointestinal stromal tumours. Histopathology 2011; 59:1071-80. [PMID: 22175887 DOI: 10.1111/j.1365-2559.2011.04071.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
AIMS To compare the genomic signatures of wild-type (WT) and mutated GISTs and the murine interstitial cells of Cajal (ICCs) to find markers of cell differentiation and other functions that may identify cells that give rise to WT tumours. METHODS AND RESULTS We analysed the gene expression profiles of a total of 30 tumour samples (four WT GISTs and 26 mutated GISTs), selected the genes most differentially expressed (P < 0.001:448 probe sets) and validated these results by quantitative polymerase chain reaction (PCR) and immunohistochemistry. In addition, we conducted a meta-analysis merging data from human GISTs with a genomic data set from murine ICCs. The gene expression profiles of WT and mutated GISTs differed profoundly, especially in the expression of those genes restricted primarily to neural tissues. We found that mature ICCs are more similar to mutated GISTs than WT GISTs. CONCLUSIONS WT GISTs have different genomic profiles from both mutated GISTs and murine mature ICCs. Considering that IGF1R expression is common to both WT GISTs and putative precursor ICCs, this study suggests that WT GISTs may derive either from ICCs at a different step of differentiation or from a different cell of origin.
Collapse
Affiliation(s)
- Maria A Pantaleo
- Department of Hematology and Oncology Sciences, L A Seragnoli, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Abstract
Gastrointestinal stromal tumours (GISTs) are a paradigm for the development of personalized treatment for cancer patients. The nearly simultaneous discovery of a biomarker that is reflective of their origin and the presence of gain-of-function kinase mutations in these tumours set the stage for more accurate diagnosis and the development of kinase inhibitor therapy. Subsequent studies of genotype and phenotype have led to a molecular classification of GIST and to treatment optimization on the basis of molecular subtype. The study of drug-resistant tumours has advanced our understanding of kinase biology, enabling the development of novel kinase inhibitors. Further improvements in GIST treatment may require targeting GIST stem cell populations and/or additional genomic events.
Collapse
Affiliation(s)
- Christopher L Corless
- Knight Cancer Institute, Division of Haematology & Oncology, and Department of Pathology, Portland VA Medical Center and Oregon Health & Science University, Portland, OR 97239, USA
| | | | | |
Collapse
|
|
38
|
Fujimoto A, Kobayashi T, Uchida S, Ichinose Y, Sasaoki T, Goto K, Okabe H. Laparoscopic total gastrectomy for multiple sporadic gastric gastrointestinal stromal tumors: report of a case. Surg Today 2011; 42:84-8. [PMID: 22045229 DOI: 10.1007/s00595-011-0011-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Accepted: 12/17/2010] [Indexed: 01/02/2023]
Abstract
A 64-year-old man was admitted to our hospital with hematemesis. Emergency upper gastrointestinal endoscopy revealed bleeding from a submucosal tumor (SMT) in the antrum of the stomach, with two other SMTs at different sites. Based on his family history, we diagnosed familial multiple gastric gastrointestinal stromal tumors (GISTs) and performed laparoscopic total gastrectomy. Three distinct tumors were found: one in the fornix, one in the lesser curvature of the angle, and one in the antrum of the stomach. Microscopic examination of the resected specimens revealed different cytomorphologies, of the spindle and epithelioid type, as well as immunophenotypes in the tumors. Mutation analysis revealed different sites of mutation in c-kit and PDGFRA. No mutation was detected in the normal tissue of the stomach. These findings confirmed a diagnosis of multiple sporadic gastric GISTs. Thus, investigating germline mutation might assist in the preoperative diagnosis of multiple gastric GISTs.
Collapse
Affiliation(s)
- Akihisa Fujimoto
- Department of Surgery, Takatsuki Red Cross Hospital, 1-1-1 Abuno, Takatsuki, Osaka 569-1096, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
39
|
|
|
40
|
Pera M, Iglesias M, Puig S, Martínez-Avilés L, Bellosillo B. A sporadic multiple gastrointestinal stromal tumor with unique clinical and molecular features. Hum Pathol 2011; 42:1194-9. [DOI: 10.1016/j.humpath.2010.10.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Revised: 09/25/2010] [Accepted: 10/19/2010] [Indexed: 11/30/2022]
|
|
41
|
Yin TC, Yang SF, Wang JY. Multicentric gastrointestinal stromal tumor of the stomach with wild-type KIT and PDGFRA. GENOMIC MEDICINE, BIOMARKERS, AND HEALTH SCIENCES 2011; 3:81-85. [DOI: 10.1016/j.gmbhs.2011.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
|
|
42
|
|
|
43
|
Molecular and clinicopathologic characterization of gastrointestinal stromal tumors (GISTs) of small size. Am J Surg Pathol 2010; 34:1480-91. [PMID: 20861712 DOI: 10.1097/pas.0b013e3181ef7431] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Although Gastrointestinal stromal tumors (GISTs) affect about 0.0014% of the population, GISTs smaller than 1 cm (microGISTs) are detectable in about 20% to 30% of elderly individuals. This suggests that microGISTs likely represent premalignant precursors that evolve only in a minute fraction of cases toward overt GISTs. We sought histopathologic and molecular explanations for the infrequent clinical progression in small GISTs. To investigate the mechanisms of GIST progression and identify subsets with differential malignant potential, we carried out a thorough characterization of 170 GISTs <2 cm and compared their KIT/PDGFRA status with overt GISTs. The proliferation was lower in microGISTs compared with GISTs from 1 to 2 cm (milliGISTs). In addition, microGISTs were more frequently incidental, gastric, spindle, showed an infiltrative growth pattern, a lower degree of cellularity, and abundant sclerosis. The progression was limited to 1 ileal and 1 rectal milliGISTs. KIT/PDGFRA mutations were detected in 74% of the cases. The overall frequency of KIT/PDGFRA mutation and, particularly, the frequency of KIT exon 11 mutations was significantly lower in small GISTs compared with overt GISTs. Five novel mutations, 3 in KIT (p.Phe506Leu, p.Ser692Leu, p.Glu695Lys) 2 in PDGFRA (p.Ser847X, p.Ser667Pro), plus 4 double mutations were identified. Small GISTs share with overt GIST KIT/PDGFRA mutation. Nevertheless, microGISTs display an overall lower frequency of mutations, particularly canonical KIT mutations, and also carry rare and novel mutations. These molecular features, together with the peculiar pathologic characteristics, suggest that the proliferation of these lesions is likely sustained by weakly pathogenic molecular events, supporting the epidemiologic evidence that microGISTs are self-limiting lesions.
Collapse
|
|
44
|
Orsenigo E, Gazzetta P, Di Palo S, Tamburini A, Staudacher C. Experience on surgical treatment of gastrointestinal stromal tumor of the stomach. Updates Surg 2010; 62:101-104. [PMID: 20845009 DOI: 10.1007/s13304-010-0018-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In spite of their rarity, gastrointestinal stromal tumors (GISTs) represent a complex clinical problem, mainly diagnostic and therapeutic, for their unpredictable biological course and their long-term prognosis, the most involved site being the stomach. Although a great number of tyrosine-kinase inhibitors has been developed for blocking their proliferative pathways (constitutive CD117 and PDGFRa activation), surgical treatment still remains the only curative one. Nevertheless, their particular non-lymphatic spread and their tendency to peritoneal seeding have emphasized technical issues that are still greatly debated. The definition of the best surgical procedure aiming at the complete R0 resection of the tumor has changed in the recent years and, with the improvement of laparoscopic techniques, the minimally invasive approach of gastric GIST has become feasible in most cases. In this paper we present our experience on surgical treatment of 43 gastric GISTs observed from 2001 to 2008 taken from our case study (75 patients from 1994). The risk class, treatment and long-term follow-up (mean 36 months) has been analyzed. All patients underwent a surgical procedure; 10 of them were also treated with molecular tyrosine-kinase inhibitors as adjuvant treatment. Overall survival at 60 months was 89.3%, with a disease-free survival of 87.68%.
Collapse
Affiliation(s)
- Elena Orsenigo
- Chirurgia Gastroenterologica, Department of Surgery, San Raffaele Scientific Hospital, University Vita-Salute-San Raffaele, Via Olgettina, 60, 20132, Milan, Italy,
| | | | | | | | | |
Collapse
|
|
45
|
Hiraki M, Kitajima Y, Ohtsuka T, Kai K, Miyake S, Koga Y, Mori D, Noshiro H, Tokunaga O, Miyazaki K. Immunohistochemical and molecular genetic analyses of multiple sporadic gastrointestinal stromal tumors. World J Gastrointest Oncol 2010; 2:364-8. [PMID: 21160808 PMCID: PMC2999140 DOI: 10.4251/wjgo.v2.i9.364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Revised: 08/03/2010] [Accepted: 08/10/2010] [Indexed: 02/05/2023] Open
Abstract
A 77-year-old Japanese male patient was admitted to our hospital complaining of general fatigue and melena. A gastroduodenal endoscopic examination revealed no definitive localized lesions. However, both a large amount of cruor and blood flow from the small intestine into the ascending colon was observed during the colonoscopic examination. At least three tumors, believed to originate from the small intestine, were detected by abdominal computed tomography. Based on these findings, multiple and hemorrhagic small intestinal tumors were diagnosed and surgical treatment of the tumors planned. During the celiotomy, twelve tumors were found in the small intestine. Intestinal wedge or partial resection was applied. All excised specimens demonstrated morphology of a submucosal tumor and the largest tumor had a delle with coagulation on the mucosal face. In the histological findings, hematoxylin and eosin staining showed spindle cell morphology. The immunohistochemical examination revealed that the tumor cells were diffusely positive for KIT and CD34. The myenteric plexus layer of the small intestine was focal-positive for KIT and showed no intestinal cells of Cajal hyperplasia. The tumor sequencing results revealed an identical missense mutation in codon 642 of c-kit exon 13 leading to the replacement of lysine by glutamic acid and a silent germ-line mutation in exon 12 of the PDGFRA gene concerning whole blood, normal mucosa and tumors. We concluded that the current subject was categorized as having multiple sporadic-type gastrointestinal stromal tumor with identical mutational types. Although the patient did not receive any adjuvant chemotherapy, there has been no sign of recurrence over the 3 years since the surgery.
Collapse
Affiliation(s)
- Masatsugu Hiraki
- Masatsugu Hiraki, Yoshihiko Kitajima, Takao Ohtsuka, Shuusuke Miyake, Yasuo Koga, Hirokazu Noshiro, Kohji Miyazaki, Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Pancreatic expression of DOG1: a novel gastrointestinal stromal tumor (GIST) biomarker. Appl Immunohistochem Mol Morphol 2010; 17:413-8. [PMID: 19417627 DOI: 10.1097/pai.0b013e31819e4dc5] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The cDNA microarray gene profile of gastrointestinal stromal tumors (GISTs) revealed that DOG1 (TMEM16A) gene was mostly expressed in these neoplasms. Immunohistochemically, DOG1 protein was found positive in a significant proportion of GISTs. However, normal tissues' expression of DOG1 is not yet completely studied. Our study intended to identify the DOG1 protein expression in normal adult and fetal tissues, in comparison with that of GISTs, using an anti-DOG1 polyclonal serum. Fourteen CD117/CD34-positive GIST cases were tested for DOG1. Tissue samples from autopsies of 15 human fetuses and 11 adults were tested immunohistochemically on simple or double staining with antibodies raised against: DOG1, insulin, glucagon, somatostatin, NK1, PGP9.5, chromogranin A, and synaptophysin. All the tested GISTs were positive for DOG1, with a membranous and cytoplasmic location. The normal tissues showed a distinct positivity for DOG1 only in the endocrine pancreas, in both fetal and adult ones. The other tissues tested showed a weak or negative reaction. The DOG1 staining pattern in the pancreas islets was granular, like that of neuroendocrine markers. The location of DOG1 expression in pancreatic islets was partly similar to neuroendocrine markers chromogranin A, PGP9.5, and synaptophysin. The positive cells were situated centrally, in the vicinity of insulin-bearing cells as seen on double staining. DOG1 positivity in fetal and adult pancreatic islets suggests the strong antibody affinity for neuroendocrine cells. Before making a final conclusion regarding the suitability of DOG1 as a new neuroendocrine marker, a large survey of neuroendocrine lesions must be undertaken, including carcinoid tumors of various sites and pancreatic endocrine tumors. To the best of our knowledge, this particular localization has not been reported yet for DOG1.
Collapse
|
|
47
|
Zhang L, Smyrk TC, Young WF, Stratakis CA, Carney JA. Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol 2010; 34:53-64. [PMID: 19935059 PMCID: PMC3652406 DOI: 10.1097/pas.0b013e3181c20f4f] [Citation(s) in RCA: 148] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Carney triad, as originally described in 1977, was the association of 3 tumors: gastric epithelioid leiomyosarcoma [later renamed gastrointestinal stromal tumor (GIST)], extra-adrenal paraganglioma, and pulmonary chondroma. The disorder affected mostly young women and was not familial. We studied the clinical and pathologic features of the gastric neoplasm in 104 patients with the syndrome. Most (88%) were young women (mean age, 22 y), and the usual presentation was gastric bleeding. The tumors, commonly antral-based (61%), were multifocal, and ranged from 0.2 to 18.0 cm in dimension. Most (86%) featured round and polygonal (epithelioid) cells. Metastasis occurred in 49 patients (47%): to gastric lymph nodes (29%), liver (25%), and peritoneum (13%). Immunopositivity was detected in the tumors tested as follows: KIT, 100%; CD34, 75%; PKCtheta, 21%; PDGFRA, 90%; and smooth muscle actin, 6%. Fourteen patients (13%) died of metastatic GIST at a mean age of 45 years (range, 30 to 69 y). Estimated 10 and 40-year survivals were 100% and 73%, respectively. Median survival time was 26.5 years (range, 16 to 60 y). There was no correlation between the National Institutes of Health tumor risk classification and the tumor behavior. Compared with sporadic gastric GISTs, the gastric stromal tumor in Carney triad showed distinctive features: female predilection, young patient age, epithelioid cell predominance, multifocality, frequent lymph node metastasis, serial tumor occurrence, and unpredictable behavior. Thus, the Carney triad gastric stromal tumor is different clinically, pathologically, and behaviorally from sporadic gastric GIST.
Collapse
Affiliation(s)
- Lizhi Zhang
- Department of Laboratory Medicine and Pathology (J.A.C. Emeritus Member), Mayo Clinic, Rochester, MN
| | - Thomas C. Smyrk
- Department of Laboratory Medicine and Pathology (J.A.C. Emeritus Member), Mayo Clinic, Rochester, MN
| | - William F. Young
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN
| | | | - J. Aidan Carney
- Department of Laboratory Medicine and Pathology (J.A.C. Emeritus Member), Mayo Clinic, Rochester, MN
| |
Collapse
|
|
48
|
Agaimy A, Märkl B, Arnholdt H, Wünsch PH, Terracciano LM, Dirnhofer S, Hartmann A, Tornillo L, Bihl MP. Multiple sporadic gastrointestinal stromal tumours arising at different gastrointestinal sites: pattern of involvement of the muscularis propria as a clue to independent primary GISTs. Virchows Arch 2009; 455:101-8. [DOI: 10.1007/s00428-009-0803-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2009] [Revised: 06/07/2009] [Accepted: 06/08/2009] [Indexed: 12/18/2022]
|