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Chen L, Lu Y, Qian J, Qiu J, Wu C, Qiao Z, Ma Y, Yu F. Clinical characteristics and prognosis of non-metastatic multiple gastrointestinal stromal tumors: a population-based study. Discov Oncol 2025; 16:643. [PMID: 40304924 PMCID: PMC12043539 DOI: 10.1007/s12672-025-02454-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/21/2025] [Indexed: 05/02/2025] Open
Abstract
PURPOSE Multiple gastrointestinal stromal tumors (MGISTs) are relatively rare and may exhibit distinct clinical characteristics and prognosis compared to solitary GISTs (SGISTs). The objective of this study was to investigate the clinical features and prognosis of MGISTs. MATERIALS AND METHODS The Surveillance, Epidemiology, and End Results (SEER) database was used to identify all GIST patients diagnosed between 2010 and 2019. Multiple imputation (MI) was utilized to address missing data, while propensity score matching (PSM) was conducted to mitigate selection bias. The impact of demographic and clinical factors on overall survival (OS) was evaluated using Kaplan-Meier analyses and Cox proportional hazards models. RESULTS A total of 6241 patients were included in the study, with 4546 having SGISTs and 1695 having MGISTs. MGISTs have a higher prevalence in males, Caucasians, and elderly patients. Compared to MGISTs, the OS of SGISTs is significantly better (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.44-0.55, P < 0.001). After PSM, 3390 patients (equally distributed between the SGISTs and MGISTs groups) were matched for comparison. The OS of SGISTs is still better than that of MGISTs (HR 0.65, 95% CI 0.56-0.75, P < 0.001). Age, sex, site, surgery, marital status, mitotic rate, and chemotherapy were independent risk factors for OS in MGISTs patients. The OS of MGISTs patients who underwent surgery was significantly better than those who did not (P < 0.001). Similarly, chemotherapy-treated MGISTs patients showed improved OS compared to those who did not receive it (P = 0.045). CONCLUSIONS MGISTs have unique clinical characteristics and show worse OS compared to SGISTs. Surgical intervention and chemotherapy has the potential to ameliorate the prognosis of patients with MGISTs.
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Affiliation(s)
- Liang Chen
- Department of General Surgery, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Ye Lu
- Department of Endocrinology, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Jiawei Qian
- Department of General Surgery, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Jie Qiu
- Department of General Surgery, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Chuanfu Wu
- Department of General Surgery, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Zhenguo Qiao
- Department of Gastroenterology, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China.
| | - Yimin Ma
- Departments of Gastroenterology, Gaochun People's Hospital of Nanjing, Nanjing, China.
| | - Feng Yu
- Department of General Surgery, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China.
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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.
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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
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Agaimy A. [Mesenchymal tumors and tumor-like lesions of the gastrointestinal tract: an overview]. DER PATHOLOGE 2022; 43:31-44. [PMID: 34919183 DOI: 10.1007/s00292-021-01040-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/15/2021] [Indexed: 06/14/2023]
Abstract
Mesenchymal tumors and tumor-like lesions of the gastrointestinal (GI) tract are uncommon. They vary from reactive tumefactive lesions and benign neoplasms to highly aggressive sarcomas. Among them, GI stromal tumors (GISTs) are most common, followed, with less frequency, by smooth muscle and neurogenic tumors. The major challenge resides in correctly identifying GISTs and providing a comprehensive report (including risk assessment and genotyping) that represents the basis for an optimized surgical-oncological treatment and/or adjuvant therapy. On the other hand, the challenge of benign lesions is to find a good name (well understandable and reproducible diagnostic term) that helps avoid diagnostic ambiguity and prognostic uncertainty so that overprognostication and overtreatment can be prevented. Moreover, several recently described genetically defined benign and malignant entities need be correctly diagnosed due to their special "targeted" therapeutic options and to further characterize their clinicopathological and biological properties in the future. These recent entities include aggressive epithelioid inflammatory myofibroblastic sarcoma (ALK-RANBP2-driven), malignant gastrointestinal neuroectodermal tumor (EWSR1-ATF1/CREB-related), NTRK-rearranged neoplasms, and, most recently, colorectal NUTM1-rearranged sarcomas. This review highlights the major clinicopathological features of gastrointestinal mesenchymal lesions in light of recent developments.
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Affiliation(s)
- Abbas Agaimy
- Pathologisches Institut, Universitätsklinikum Erlangen, Krankenhausstraße 8-10, 91054, Erlangen, Deutschland.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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
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Abstract
With the increased use of modern next generation sequencing technologies in routine molecular pathology practice, the proportion of cancer cases with a definite or probable hereditary background seems to be steadily increasing. Currently, it is assumed that ≥10% of all malignancies develop in the setting of germline predisposition. Diagnosis and recognition of cancer predisposition syndromes relies not rarely on distinctive histopathological features that proved to be highly valuable and reproducible in uncovering those diseases that would otherwise have gone undetected by clinicians as being hereditary in nature. This is especially true in case of new mutations without suspicious family history. Example of such entities are fumarate hydratase-deficient renal cell carcinoma (RCC), succinate dehydrogenase-deficient RCC, hereditary gastrointestinal stromal tumor syndromes and many other diseases. It is remarkable that many of these inherited cancer syndromes do present as unifocal disease with highly variable age of onset so that many of them are misinterpreted as sporadic on clinical grounds. Availability of specialized cancer screening programs and disease-specific follow-up schemes for several hereditary cancer syndromes encourages the recognition of such disorders, so that "at risk patients" can be enrolled in such programs for early detection and timely intervention/ treatment of these malignancies which are in the majority of cases aggressive. In several conditions, as in familial adenomatous polyposis coli (FAP), well established prophylactic surgical interventions may be adopted to prevent the disease manifestations, highlighting the importance of the timely recognition of these potentially life-limiting neoplasms. In this review, the clinicopathological, demographic and histological features that are considered highly suggestive of a hereditary basis of "a neoplasm under consideration" are highlighted and discussed briefly. The details of some of these entities are in addition dealt with in reviews devoted to them in this special issue.
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Affiliation(s)
- Abbas Agaimy
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital, Erlangen, Germany.
| | - Arndt Hartmann
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital, Erlangen, Germany
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10
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Abstract
Benign and malignant soft tissue tumors usually develop de novo without identifiable risk factors or predisposing conditions. However, in recent decades, soft tissue tumors have been increasingly recognized to be associated with diverse hereditary tumor syndromes as a consequence of germline mutations involving mainly tumor suppressor genes, but rarely also affecting proto-oncogenes. This is mainly the consequence of increasing application of modern genetic analysis tools, such as next-generation sequencing (NGS) and whole genome analyses. Syndrome-associated soft tissue tumors frequently show distinctive clinicopathological features and peculiarities that facilitate and potentially enhance their recognition and identification during routine surgical pathology practice. As it is not uncommon that pathologists are the first medical specialists to recognize a potential hereditary etiology of neoplastic diseases on the basis of specific pathological features, it is mandatory that pathologists be familiar with the main features that characterize those soft tissue tumors with inherited etiology, at least the most common and important of them. This review summarizes the main syndromes and their associated soft tissue tumors and discusses their characteristic pathological features that help in the recognition of hereditary syndromes.
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Huss S, Pasternack H, Ihle MA, Merkelbach-Bruse S, Heitkötter B, Hartmann W, Trautmann M, Gevensleben H, Büttner R, Schildhaus HU, Wardelmann E. Clinicopathological and molecular features of a large cohort of gastrointestinal stromal tumors (GISTs) and review of the literature: BRAF mutations in KIT/PDGFRA wild-type GISTs are rare events. Hum Pathol 2017; 62:206-214. [PMID: 28159677 DOI: 10.1016/j.humpath.2017.01.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 01/03/2017] [Accepted: 01/05/2017] [Indexed: 12/27/2022]
Abstract
In KIT/PDGFRA wild-type gastrointestinal stromal tumors (wt-GISTs), BRAF mutations are regarded as alternative pathogenic events driving tumorigenesis. In our study, we aimed at analyzing a large cohort (n=444) of GISTs for BRAF mutations using molecular and immunohistochemical methods. More than 3000 GIST samples from caucasian patients were available in our GIST and Sarcoma Registry NRW. Of these, we selected 172 wt-GISTs to evaluate the frequency of BRAF mutations. Furthermore, 272 GISTs with a representative KIT and PDGFRA mutational status were selected. BRAF mutational status was evaluated by high-resolution melting analysis, Sanger sequencing, and VE1 immunohistochemistry. A BRAF mutation (p.V600E) was found in 7 cases (3.9%) of the wt-GIST cohort. In 2 cases, multiple synchronous tumors harbored the same somatic BRAF mutation. VE1 immunohistochemical staining had a sensitivity of 81.8% and a specificity of 97.5% to detect BRAF p.V600E mutations. Analyzing our cases and the cases reported in the literature (n=37), the percentage of intermediate and high-risk BRAF-mutated wt-GISTs (17/31; 54.8%) was comparable to that recorded for large GIST cohorts irrespective of the mutational status. BRAF mutations are rare events in wt-GISTs, and VE1 immunohistochemistry appears to be a valuable pre-screening tool for the detection of BRAF p.V600E mutations. BRAF mutations in GISTs do not seem to have a prognostic value per se. However, as BRAF inhibition represents a therapeutic option to control disease, we suggest the assessment of the BRAF mutational status, especially in the setting of advanced GIST disease.
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Affiliation(s)
- Sebastian Huss
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
| | - Helen Pasternack
- Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, Ratzeburger Allee 160, 23538 Luebeck, Germany.
| | - Michaela Angelika Ihle
- Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
| | - Sabine Merkelbach-Bruse
- Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
| | - Birthe Heitkötter
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
| | - Wolfgang Hartmann
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
| | - Marcel Trautmann
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
| | - Heidrun Gevensleben
- Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
| | - Reinhard Büttner
- Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
| | - Hans-Ulrich Schildhaus
- Institute of Pathology, University Hospital Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.
| | - Eva Wardelmann
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
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12
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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.
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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
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Huang Z, Li Y, Zhao H, Zhao JJ, Cai JQ. Prognositic factors and clinicopathologic characteristics of small gastrointestinal stromal tumor of the stomach: a retrospective analysis of 31 cases in one center. Cancer Biol Med 2013; 10:165-8. [PMID: 24379992 PMCID: PMC3860339 DOI: 10.7497/j.issn.2095-3941.2013.03.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 09/10/2013] [Indexed: 12/19/2022] Open
Abstract
Objective To analyze the clinicopathologic characteristics and prognostic factors of small gastrointestinal stromal tumor (GIST) of the stomach. Methods A total of 31 small gastric GIST patients, including 10 males and 21 females, with a median age of 58 years (37-81 years), who underwent surgery at any time from 1999 to 2012 were included in this study. The clinical records of the patients were analyzed retrospectively. Results Abdominal discomfort and pain (10 cases, 32.3%, respectively) were the two most common complaints among the patients. All patients received surgery, 11 received gastric wedge resection, 11 received subtotal gastrectomy, 5 received laparoscopic gastric wedge resection, and 4 received endoscopic submucosal dissection. No severe adverse complication was observed. A total of 29 patients (93.5%) were followed up. During the follow-up, 2 patients were found to exhibit tumor recurrence, and 1 patient had liver metastases. One patient died of tumor progression, while another died of another malignant tumor. Median progression free survival (PFS) time was 120.3 months, and median overall survival (OS) time was 130.4 months. Conclusion Small gastric GIST has better prognosis. Surgery is the best choice for therapy. Micro-invasive procedures are safe and effective for elective patients. Tumor necrosis, tumor bleeding, and muscle invasion are potential prognostic factors of small gastric GIST.
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Affiliation(s)
- Zhen Huang
- Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
| | - Yuan Li
- Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
| | - Hong Zhao
- Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
| | - Jian-Jun Zhao
- Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
| | - Jian-Qiang Cai
- Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
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GISTogram: a graphic presentation of the growing GIST complexity. Virchows Arch 2013; 463:481-7. [PMID: 23975171 DOI: 10.1007/s00428-013-1467-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 05/06/2013] [Accepted: 07/26/2013] [Indexed: 01/13/2023]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They have represented a paradigm of molecular-targeted therapies for solid tumors since the discovery of KIT mutations and KIT expression in GIST in 1998, which opened the way to the use of imatinib, a tyrosine kinase inhibitor able to inhibit the growth of cells expressing KIT-mutant isoforms. Since then, accumulating evidence revealed the rather heterogeneous nature of GIST, implying possible different diagnostic and therapeutic approaches for each specific case, leading to the development of drugs alternative to imatinib. In this brief commentary, we graphically represent the historical growing of genotype and phenotype evidence on GIST since 1998 in its increasing complexity by building up a graph, which we have called "GISTogram", that visually conveys most of GIST-characterizing features and the probability for each of them, either alone or in combination, to be observed in a single GIST case.
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Agaimy A. Risk assessment and pathological reporting of gastrointestinal stromal tumour. ACTA ACUST UNITED AC 2013. [DOI: 10.1016/j.mpdhp.2013.03.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Bareck E, Ba-Ssalamah A, Brodowicz T, Eisterer W, Häfner M, Högenauer C, Kastner U, Kühr T, Längle F, Liegl-Atzwanger B, Schoppmann SF, Widmann G, Wrba F, Zacherl J, Ploner F. Gastrointestinal stromal tumors: diagnosis, therapy and follow-up care in Austria. Wien Med Wochenschr 2013; 163:137-52. [PMID: 23508516 DOI: 10.1007/s10354-013-0187-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 01/31/2013] [Indexed: 12/16/2022]
Abstract
Optimal treatment for patients suffering from gastrointestinal stromal tumors (GIST) is based on an interdisciplinary treatment approach. Austrian representatives of Medical and Surgical Oncology, Pathology, Radiology, Nuclear Medicine, Gastroenterology, and Laboratory Medicine issued this manuscript on a consensual base within the context of currently available and published literature. This paper contains guidelines and recommendations for diagnosis, therapy, and follow-up of GIST patients in Austria.
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Affiliation(s)
- Evelyne Bareck
- Department of Surgery, General Hospital, Wiener Neustadt, Vienna, Austria.
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A novel germline SDHB mutation in a gastrointestinal stromal tumor patient without bona fide features of the Carney-Stratakis dyad. Fam Cancer 2012; 11:189-94. [PMID: 22160509 DOI: 10.1007/s10689-011-9499-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchyme neoplasms of the gastrointestinal tract. Gain-of-function somatic mutations of the KIT or PDGFRA genes represent the most prevalent molecular alterations in GISTs. In Carney-Stratakis dyad, patients portray germline mutations of the succinate dehydrogenase subunits B (SDHB), C (SDHC) and D (SDHD) and develop multifocal GISTs and multicentric paragangliomas (PGLs). We herein report a novel germline SDHB mutation (c.T282A--Ile44Asn) occurring in a 26 years-old patient diagnosed with a spindle cell intermediate risk GIST that did not present KIT/PDGFRA/BRAF gene mutations. Further analyses revealed loss of the wild-type SDHB allele and complete loss of SDHB expression in the tumor tissue. After genetic screening of other family members, we detected in the patient's mother a SDHB mutation without any clinical/laboratorial evidence of GIST or PGL. Altogether, our findings (germline SDHB mutation with absence of PGL in the index case and of GIST and/or PGL in his mother) raise the possibility that this familiar setting corresponds to an incomplete phenotype of the Carney-Stratakis dyad.
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18
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Molecular alterations and expression of succinate dehydrogenase complex in wild-type KIT/PDGFRA/BRAF gastrointestinal stromal tumors. Eur J Hum Genet 2012; 21:503-10. [PMID: 22948025 DOI: 10.1038/ejhg.2012.205] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, disclosing somatic KIT, PDGFRA and BRAF mutations. Loss of function of succinate dehydrogenase (SDH) complex is an alternative molecular mechanism in GISTs, namely in carriers of germline mutations of the SDH complex that develop Carney-Stratakis dyad characterized by multifocal GISTs and multicentric paragangliomas (PGLs). We studied a series of 25 apparently sporadic primary wild-type (WT) KIT/PDGFRA/BRAF GISTs occurring in patients without personal or familial history of PGLs, re-evaluated clinicopathological features and analyzed molecular alterations and immunohistochemistry expression of SDH complex. As control, we used a series of well characterized 49 KIT/PDGFRA/BRAF-mutated GISTs. SDHB expression was absent in 20% and SDHB germline mutations were detected in 12% of WT GISTs. Germline SDHB mutations were significantly associated to younger age at diagnosis. A significant reduction in SDHB expression in WT GISTs was found when compared with KIT/PDGFRA/BRAF-mutated GISTs. No significant differences were found when comparing DOG-1 and c-KIT expression in WT, SDHB-mutated and KIT/PDGFRA/BRAF-mutated GISTs. Our results confirm the occurrence of germline SDH genes mutations in isolated, apparently sporadic WT GISTs. WT KIT/PDGFRA/BRAF GISTs without SDHB or SDHA/SDHB expression may correspond to Carney-Stratakis dyad or Carney triad. Most importantly, the possibility of PGLs (Carney-Stratakis dyad) and/or pulmonary chondroma (Carney triad) should be addressed in these patients and their kindred.
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Abstract
PURPOSE To report an uncommon case of orbital gastrointestinal stromal tumor (GIST) metastasis. MATERIAL AND METHODS Observational case report. RESULTS A 65-year-old woman with metastatic GIST involving the left orbit with a history of two separate GIST nodules involving the stomach 6 years earlier. Computed tomography (CT) scan demonstrated a well-circumscribed enhancing lesion confined to the anterior orbit. Histopathology analysis of the tumor showed predominantly spindle cells with focal epithelioid forms. It also stained positive for c-KIT (CD117) on immunochemistry, confirming the diagnosis. Additional medical treatment was not required, and the patient was followed up regularly for disease recurrence. CONCLUSION GISTs typically occur as sporadic solitary tumors. In malignant cases, it usually metastasizes to the liver or other intraabdominal sites. Orbital involvement is extremely rare. This is the first case of metastatic GIST involving the anterior orbit with histopathological and immunochemical confirmation.
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Affiliation(s)
- David Woo
- Sydney Eye Hospital, Ophthalmology, 8 Macquarie Street, Sydney 2000, Australia.
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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.
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Affiliation(s)
- Akihisa Fujimoto
- Department of Surgery, Takatsuki Red Cross Hospital, 1-1-1 Abuno, Takatsuki, Osaka 569-1096, Japan.
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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]
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[Hereditary and non-hereditary syndromic gastointestinal stromal tumours]. DER PATHOLOGE 2011; 31:430-7. [PMID: 20848108 DOI: 10.1007/s00292-010-1354-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The majority of gastrointestinal stromal tumours (GISTs) present as solitary gastrointestinal masses in adults aged 50-70 years. A small subset of GISTs (≤5%) occurs in the setting of familial or idiopathic multitumour syndrome. In decreasing order of frequency, neurofibromatosis Recklinghausen (NF-1), Carney triad (gastric GIST, pulmonary chondroma and extra-adrenal paraganglioma), familial GIST syndromes resulting from germline mutations in c-Kit/PDGFRA and the Carney-Stratakis syndrome (hereditary GIST paraganglioma syndrome caused by germline mutations in the mitochondrial tumour suppressor gene pathway involving the succinate dehydrogenase subunits SDHD, SDHC and SDHB) represent the four most important GIST syndromes characterized to date. Since affected patients and their family members require special treatment and/or counseling and follow-up, early diagnosis and precise classification of this likely still underdiagnosed diseases is of the utmost importance. This review summarizes the pertinent clinicopathological and molecular features of the main GIST syndromes to facilitate their diagnosis and distinction from their non-syndromic mimics.
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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.
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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.
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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
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Liegl-Atzwanger B, Fletcher JA, Fletcher CDM. Gastrointestinal stromal tumors. Virchows Arch 2010; 456:111-27. [PMID: 20165865 DOI: 10.1007/s00428-010-0891-y] [Citation(s) in RCA: 152] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Accepted: 01/29/2010] [Indexed: 12/17/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) have emerged from being poorly defined, treatment-resistant tumors to a well-recognized, well-understood, and treatable tumor entity within only one decade. The understanding of GIST biology has made this tumor a paradigm for molecularly targeted therapy in solid tumors and provides informative insights into the advantages and limitations of so-called targeted therapeutics. Approximately 85% of GISTs harbor activating mutations in KIT or the homologous receptor tyrosine kinase PDGFRA gene. These mutations are an early event in GIST development and the oncoproteins serve as a target for the small molecule tyrosine kinase inhibitors imatinib and sunitinib. The existing and emerging treatment options demand exact morphologic classification and risk assessment. Although, KIT (CD117) immunohistochemistry is a reliable diagnostic tool in the diagnosis of GIST, KIT-negative GISTs, GISTs showing unusual morphology as well as GISTs which progress during or after treatment with imatinib/sunitinib can be a challenge for pathologists and clinicians. This review focuses on GIST pathogenesis, morphologic evaluation, promising new immunohistochemical markers, risk assessment, the role of molecular analysis, and the increasing problem of secondary imatinib resistance and its mechanisms.
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