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Hu Y, Zhang Y, He J, Rao H, Zhang D, Shen Z, Zhou C. ANO1: central role and clinical significance in non-neoplastic and neoplastic diseases. Front Immunol 2025; 16:1570333. [PMID: 40356890 PMCID: PMC12067801 DOI: 10.3389/fimmu.2025.1570333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 03/20/2025] [Indexed: 05/15/2025] Open
Abstract
Anoctamin 1 (ANO1), also known as TMEM16A, is a multifunctional protein that serves as a calcium-activated chloride channel (CaCC). It is ubiquitously expressed across various tissues, including epithelial cells, smooth muscle cells, and neurons, where it is integral to physiological processes such as epithelial secretion, smooth muscle contraction, neural conduction, and cell proliferation and migration. Dysregulation of ANO1 has been linked to the pathogenesis of numerous diseases. Extensive research has established its involvement in non-neoplastic conditions such as asthma, hypertension, and gastrointestinal (GI) dysfunction. Moreover, ANO1 has garnered significant attention for its role in the development and progression of cancers, including head and neck cancer, breast cancer, and lung cancer, where its overexpression correlates with increased tumor growth, metastasis, and poor prognosis. Additionally, ANO1 regulates multiple signaling pathways, including the epidermal growth factor receptor (EGFR) pathway, the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, among others. These pathways are pivotal in regulating cell proliferation, migration, and invasion. Given its central role in these processes, ANO1 has emerged as a promising diagnostic biomarker and therapeutic target. Recent advancements in ANO1 research have highlighted its potential in disease diagnosis and treatment. Strategies targeting ANO1, such as small molecule modulators or gene-silencing techniques, have shown preclinical promise in both non-neoplastic and neoplastic diseases. This review explores the latest findings in ANO1 research, focusing on its mechanistic involvement in disease progression, its regulation, and its therapeutic potential. Modulating ANO1 activity may offer novel therapeutic strategies for effectively treating ANO1-associated diseases.
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Affiliation(s)
- Yanghao Hu
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
- Health Science Center, Ningbo University, Ningbo, Zhejiang, China
| | - Yifei Zhang
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
- Health Science Center, Ningbo University, Ningbo, Zhejiang, China
| | - Jiali He
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
- Health Science Center, Ningbo University, Ningbo, Zhejiang, China
| | - Huihuang Rao
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
- Health Science Center, Ningbo University, Ningbo, Zhejiang, China
| | - Duomi Zhang
- Health Science Center, Ningbo University, Ningbo, Zhejiang, China
| | - Zhisen Shen
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Chongchang Zhou
- Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, China
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Zheng Y, Meng L, Qu L, Zhao C, Wang L, Ma J, Liu C, Shou C. Co-targeting TMEM16A with a novel monoclonal antibody and EGFR with Cetuximab inhibits the growth and metastasis of esophageal squamous cell carcinoma. J Transl Med 2024; 22:1046. [PMID: 39563381 DOI: 10.1186/s12967-024-05830-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 10/30/2024] [Indexed: 11/21/2024] Open
Abstract
The chloride channel transmembrane protein 16A (TMEM16A) possesses a calcium-activated property linked to tumor-promoting malignant phenotype and electrophysiological stability. Numerous studies have shown that TMEM16A exhibits aberrant amplification in various squamous cell carcinomas such as esophageal squamous cell carcinoma (ESCC) and is correlated with unfavorable outcomes of ESCC patients. Therefore, TMEM16A is considered as a promising therapeutic target for ESCC. Because of its intricate structure, the development of therapeutic antibodies directed against TMEM16A has not been documented. In this study, we produced a series of novel monoclonal antibodies targeting TMEM16A and identified mT16#5 as an antibody capable of inhibiting ESCC cells migration, invasion and TMEM16A ion channel activity. Additionally, based on the validation that TMEM16A was positively correlated with expression of EGFR and the interaction between them, the mT16#5 exhibited a synergistic inhibitory effect on ESCC metastasis and growth when administered in combination with Cetuximab in vivo. In terms of mechanism, we found that mT16A#5 inhibited the phosphorylation of PI3K, AKT and JNK. These results highlight the anti-growth and anti-metastasis capacity of the combination of mT16A#5 and Cetuximab in the treatment of ESCC by targeting TMEM16A and EGFR, and provide a reference for combinational antibody treatment in ESCC.
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Affiliation(s)
- Yutian Zheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
- Department of Pathology, National Center for Children's Health (NCCH), Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
| | - Lin Meng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Like Qu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Chuanke Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Lixin Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jiayi Ma
- Beijing National Day School, Beijing, 100039, China
| | - Caiyun Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Chengchao Shou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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3
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Li X, Wang Y, Zhang L, Yao S, Liu Q, Jin H, Tuo B. The role of anoctamin 1 in liver disease. J Cell Mol Med 2024; 28:e18320. [PMID: 38685684 PMCID: PMC11058335 DOI: 10.1111/jcmm.18320] [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: 11/08/2023] [Revised: 03/21/2024] [Accepted: 04/03/2024] [Indexed: 05/02/2024] Open
Abstract
Liver diseases include all types of viral hepatitis, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), cirrhosis, liver failure (LF) and hepatocellular carcinoma (HCC). Liver disease is now one of the leading causes of disease and death worldwide, which compels us to better understand the mechanisms involved in the development of liver diseases. Anoctamin 1 (ANO1), a calcium-activated chloride channel (CaCC), plays an important role in epithelial cell secretion, proliferation and migration. ANO1 plays a key role in transcriptional regulation as well as in many signalling pathways. It is involved in the genesis, development, progression and/or metastasis of several tumours and other diseases including liver diseases. This paper reviews the role and molecular mechanisms of ANO1 in the development of various liver diseases, aiming to provide a reference for further research on the role of ANO1 in liver diseases and to contribute to the improvement of therapeutic strategies for liver diseases by regulating ANO1.
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Affiliation(s)
- Xin Li
- Department of Gastroenterology, Digestive Disease HospitalAffiliated Hospital of Zunyi Medical UniversityZunyiChina
| | - Yongfeng Wang
- Department of Gastroenterology, Digestive Disease HospitalAffiliated Hospital of Zunyi Medical UniversityZunyiChina
| | - Li Zhang
- Department of Gastroenterology, Digestive Disease HospitalAffiliated Hospital of Zunyi Medical UniversityZunyiChina
| | - Shun Yao
- Department of Gastroenterology, Digestive Disease HospitalAffiliated Hospital of Zunyi Medical UniversityZunyiChina
| | - Qian Liu
- Department of Gastroenterology, Digestive Disease HospitalAffiliated Hospital of Zunyi Medical UniversityZunyiChina
| | - Hai Jin
- Department of Gastroenterology, Digestive Disease HospitalAffiliated Hospital of Zunyi Medical UniversityZunyiChina
- The Collaborative Innovation Center of Tissue Damage Repair and Regenerative Medicine of Zunyi Medical UniversityZunyiChina
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease HospitalAffiliated Hospital of Zunyi Medical UniversityZunyiChina
- The Collaborative Innovation Center of Tissue Damage Repair and Regenerative Medicine of Zunyi Medical UniversityZunyiChina
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Bhatt A, Mishra S, Glehen O. Histopathological Evaluation and Molecular Diagnostic Tests for Peritoneal Metastases with Unknown Primary Site-a Review. Indian J Surg Oncol 2023; 14:15-29. [PMID: 37359927 PMCID: PMC10284789 DOI: 10.1007/s13193-022-01612-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 07/26/2022] [Indexed: 11/25/2022] Open
Abstract
Cancer of unknown primary (CUP) is a well-studied entity with guidelines available for the management of patients with CUP. The peritoneum represents one of the metastatic sites in CUP, and peritoneal metastases (PM) could present as CUP. PM of unknown origin remains a poorly studied clinical entity. There is only one series of 15 cases, one population-based study, and few other case reports on this subject. Studies on CUP, in general, cover some common tumour histological types like adenocarcinomas and squamous carcinomas. Some of these tumours may have a good prognosis though majority have high-grade disease with a poor long-term outcome. Some of the histological tumour types commonly seen in the clinical scenario of PM like mucinous carcinoma have not been studied. In this review, we divide PM into five histological types-adenocarcinomas, serous carcinomas, mucinous carcinomas, sarcomas and other rare varieties. We provide algorithms to identify the primary tumour site using immunohistochemistry when imaging, and endoscopy fails to establish the primary tumour site. The role of molecular diagnostic tests for PM or unknown origin is also discussed. Current literature on site-specific systemic therapy based on gene expression profiling does not show a clear benefit of this approach over empirical systemic therapies.
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Affiliation(s)
- Aditi Bhatt
- Dept. of Surgical Oncology, Zydus Hospital, Thaltej, Ahmedabad 380054 India
| | - Suniti Mishra
- Dept. of Pathology, Sparsh Hospital, Bangalore, India
| | - Olivier Glehen
- Dept. of Surgical Oncology, Centre Hospitalier Lyon-Sud, Lyon, France
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5
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Muacevic A, Adler JR, Mohan SK, Singh K, Das A. DOG1-Positive Extragastrointestinal Stromal Tumor Presenting As Large Abdomino-Pelvic Mass: A Case Report. Cureus 2022; 14:e31670. [PMID: 36545171 PMCID: PMC9762496 DOI: 10.7759/cureus.31670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2022] [Indexed: 11/21/2022] Open
Abstract
Gastrointestinal stromal tumors (GIST) are mesenchymal tumors commonly arising from the GI tract. Only a small number of GIST originating outside the GI tract have been reported in the literature. They are termed extraintestinal GIST (E-GIST), with histological features similar to GIST. These commonly arise from the omentum, mesentery, or abdominal wall. Microscopic examination shows spindle or epitheloid morphology with immunohistochemistry (IHC) positivity for the cluster of differentiation 117, 34 (CD117, CD34), or discovered on GIST-1 (DOG1). This case series describes the presentation of two cases of E-GIST as an abdominopelvic mass with DOG1 positivity and CD117 negativity on IHC. Patient in the first case presented with a giant abdominopelvic mass, clinically arising from the pelvis with a misdiagnosis of midline desmoid tumor. It was completely excised with a histological surprise of E-GIST with DOG1 positivity on IHC. The second case presented a swelling in the groin region, separate from the testis but arising from the anterior abdominal wall, with histological features of E-GIST with DOG1 positivity. The cases reported here show further evidence regarding the existence of a distinct subset of GISTs characterized by extraintestinal localization, with negative immunohistochemical expression of receptor tyrosine kinases (KIT) and positive DOG1 expression, which appears to be rare and makes DOG1 an emerging marker for GIST.
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DOG1 as an Immunohistochemical Marker of Acinic Cell Carcinoma: A Systematic Review and Meta-Analysis. Int J Mol Sci 2022; 23:ijms23179711. [PMID: 36077107 PMCID: PMC9456024 DOI: 10.3390/ijms23179711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/20/2022] [Accepted: 08/24/2022] [Indexed: 12/04/2022] Open
Abstract
DOG1 is a transmembrane protein originally discovered on gastrointestinal stromal tumors and works as a calcium-activated chloride channel protein. There are a limited number of articles on the potential utility of this antibody in the diagnosis of salivary gland tumors in routine practice. In this study, we aimed to investigate the role of DOG1 as an immunohistochemical marker in patients with salivary acinic cell carcinoma (ACC) through meta-analysis. A literature search was performed of the PubMed, Scopus, and Web of Science databases for English-language studies published from January 2010 to September 2021. The literature search revealed 148 articles, of which 20 were included in the study. The overall rate of DOG1 expression in salivary acinic cell carcinoma was 55% (95% CI = 0.43–0.58). Although ACC is a challenging diagnosis, paying careful attention to the cytomorphological features in conjunction with DOG1 immunostaining can help to reach an accurate diagnosis.
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7
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Li H, Yu Z, Wang H, Wang N, Sun X, Yang S, Hua X, Liu Z. Role of ANO1 in tumors and tumor immunity. J Cancer Res Clin Oncol 2022; 148:2045-2068. [PMID: 35471604 DOI: 10.1007/s00432-022-04004-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 03/29/2022] [Indexed: 12/24/2022]
Abstract
Dysregulation of gene amplification, cell-signaling-pathway transduction, epigenetic and transcriptional regulation, and protein interactions drives tumor-cell proliferation and invasion, while ion channels also play an important role in the generation and development of tumor cells. Overexpression of Ca2+-activated Cl- channel anoctamin 1 (ANO1) is shown in numerous cancer types and correlates with poor prognosis. However, the mechanisms involved in ANO1-mediated malignant cellular transformation and the role of ANO1 in tumor immunity remain unknown. In this review, we discuss recent studies to determine the role of ANO1 in tumorigenesis and provide novel insights into the role of ANO1 in the context of tumor immunity. Furthermore, we analyze the roles and potential mechanisms of ANO1 in different types of cancers, and provide novel notions for the role of ANO1 in the tumor microenvironment and for potential use of ANO1 in clinical applications. Our review shows that ANO1 is involved in tumor immunity and microenvironment, and may, therefore, be an effective biomarker and therapeutic drug target.
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Affiliation(s)
- Haini Li
- Department of Gastroenterology, Qingdao Sixth People's Hospital, Qingdao, 266001, China
| | - Zongxue Yu
- Department of Endocrinology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266001, China
| | - Haiyan Wang
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China
| | - Ning Wang
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China
| | - Xueguo Sun
- Department of Gastroenterology, Qingdao University Affiliated Hospital, Qingdao, 266001, China
| | - Shengmei Yang
- Department of Gynecology, Qingdao University Affiliated Hospital, Qingdao, 266001, China
| | - Xu Hua
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China
| | - Zongtao Liu
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China.
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Chen W, Gu M, Gao C, Chen B, Yang J, Xie X, Wang X, Sun J, Wang J. The Prognostic Value and Mechanisms of TMEM16A in Human Cancer. Front Mol Biosci 2021; 8:542156. [PMID: 33681289 PMCID: PMC7930745 DOI: 10.3389/fmolb.2021.542156] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 01/11/2021] [Indexed: 12/24/2022] Open
Abstract
As a calcium ion-dependent chloride channel transmembrane protein 16A (TMEM16A) locates on the cell membrane. Numerous research results have shown that TMEM16A is abnormally expressed in many cancers. Mechanically, TMEM16A participates in cancer proliferation and migration by affecting the MAPK and CAMK signaling pathways. Additionally, it is well documented that TMEM16A exerts a regulative impact on the hyperplasia of cancer cells by interacting with EGFR in head and neck squamous cell carcinoma (HNSCC), an epithelial growth factor receptor in head and neck squamous cell carcinoma respectively. Meanwhile, as an EGFR activator, TMEM16A is considered as an oncogene or a tumor-promoting factor. More and more experimental data showed that down-regulation of TMEM16A or gene targeted therapy may be an effective treatment for cancer. This review summarized its role in various cancers and research advances related to its clinical application included treatment and diagnosis.
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Affiliation(s)
- Wenjian Chen
- Anhui Province Children's Hospital Affiliated to Anhui Medical University, Hefei, China.,School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China
| | - Meng Gu
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Chaobing Gao
- Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of AnHui Medical University, Hefei, China
| | - Bangjie Chen
- First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Junfa Yang
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Xiaoli Xie
- Anhui Medicine Centralized Procurement Service Center, Hefei, China
| | - Xinyi Wang
- First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Jun Sun
- Anhui Province Children's Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Jinian Wang
- Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Libertini M, Hallin M, Thway K, Noujaim J, Benson C, van der Graaf W, Jones RL. Gynecological Sarcomas: Molecular Characteristics, Behavior, and Histology-Driven Therapy. Int J Surg Pathol 2020; 29:4-20. [PMID: 32909482 DOI: 10.1177/1066896920958120] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Gynecological sarcomas represent 3% to 4% of all gynecological malignancies and 13% of all sarcomas. The uterus is the most frequent primary site (83%); less frequently sarcomas are diagnosed originating from the ovary (8%), vulva and vagina (5%), and other gynecologic organs (2%). As the classification of gynecologic sarcomas continues to diversify, so does the management. Accurate histopathologic diagnosis, utilizing appropriate ancillary immunohistochemical and molecular analysis, could lead to a more personalized approach. However, there are subtypes that require further definition, with regard to putative predictive markers and optimal management. The aim of this review is to highlight the importance of accurate diagnosis and classification of gynecologic sarcoma subtypes by the surgical pathologist in order to provide more tailored systemic treatment, and to highlight the increasing importance of close collaboration between the pathologist and the oncologist.
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Affiliation(s)
| | - Magnus Hallin
- Royal Marsden Hospital/Institute of Cancer Research, London, UK
| | - Khin Thway
- Royal Marsden Hospital/Institute of Cancer Research, London, UK
| | | | | | | | - Robin L Jones
- Royal Marsden Hospital/Institute of Cancer Research, London, UK
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10
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Jin M, Chowsilpa S, Ali SZ, Wakely PE. Mesenchymal neoplasms of the tubular gut and adjacent structures: experience with EUS-guided fine-needle aspiration cytopathology. J Am Soc Cytopathol 2020; 9:528-539. [PMID: 32622859 DOI: 10.1016/j.jasc.2020.05.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 05/23/2020] [Accepted: 05/26/2020] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Unlike epithelial malignancies, mesenchymal neoplasms arising within the tubular gut are less often encountered in endoscopic ultrasound-guided (EUS) fine-needle aspiration biopsies (FNABs). Nonetheless, preoperative diagnosis of such neoplasms has important therapeutic and prognostic value. We report our experience with this category of neoplasms from the past decade. MATERIALS AND METHODS We performed a 10-year retrospective search at our respective institutions to identify EUS-guided FNAB cases of mesenchymal neoplasms arising from the tubular gut wall and closely adjacent structures. Cytopathologic diagnoses were compared to corresponding surgical pathology (SP) when available. Cases with either no confirmatory cell block (CB) immunohistochemical (IHC) staining, or no SP were excluded. RESULTS Two-hundred eighty-two cases (M:F = 1:1; age range: 25-94 years, mean age = 60 years) of EUS-guided FNAB from the tubular gut met our criteria. Onsite adequacy was performed on nearly all cases. Case numbers: 209 gastrointestinal stromal tumors (GIST), 58 smooth muscle neoplasms, and 15 miscellaneous neoplasms. Of these, 188 (67%) had SP follow-up. We found that 258 (91%) aspirates had a correct specific diagnosis, 3 (1%) were nondiagnostic, 18 (6%) had indeterminate diagnoses, and 3 (1%) had incorrect diagnoses (2 leiomyosarcomas mistaken as leiomyoma, and 1 fibrosclerotic lesion mistaken as inflammatory pseudotumor). Of 94 cases with no SP, all had a specific cytologic diagnosis based on confirmatory IHC staining from the CB including 61 GISTs, 29 smooth muscle neoplasms, and 4 miscellaneous tumors. CONCLUSION This study endorses the clinical utility of EUS-guided FNAB in the diagnosis of tubular gut mesenchymal neoplasms. A definitive and accurate diagnosis is possible in over 90% of cases, chiefly when cytomorphology is coupled with optimal cellularity and IHC from a concurrent CB. EUS-guided FNAB diagnosis of mesenchymal tubular gut neoplasms may play an important role in determining neoadjuvant therapy as targeted therapy evolves.
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Affiliation(s)
- Ming Jin
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Sayanan Chowsilpa
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland
| | - Syed Z Ali
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland
| | - Paul E Wakely
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
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Kim JH, Nam SJ, Park SC, Lee SH, Kim TS, Lee M, Park JM, Choi DH, Kang CD, Lee SJ, Ryu YJ, Lee K, Park SY. Association between interstitial cells of Cajal and anti-vinculin antibody in human stomach. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2020; 24:185-191. [PMID: 32140042 PMCID: PMC7043993 DOI: 10.4196/kjpp.2020.24.2.185] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/01/2020] [Accepted: 02/04/2020] [Indexed: 02/06/2023]
Abstract
Interstitial cells of Cajal (ICC) are known as the pacemaker cells of gastrointestinal tract, and it has been reported that acute gastroenteritis induces intestinal dysmotility through antibody to vinculin, a cytoskeletal protein in gut, resulting in small intestinal bacterial overgrowth, so that anti-vinculin antibody can be used as a biomarker for irritable bowel syndrome. This study aimed to determine correlation between serum anti-vinculin antibody and ICC density in human stomach. Gastric specimens from 45 patients with gastric cancer who received gastric surgery at Kangwon National University Hospital from 2013 to 2017 were used. ICC in inner circular muscle, and myenteric plexus were counted. Corresponding patient's blood samples were used to determine the amount of anti-vinculin antibody by enzyme-linked immunosorbent assay. Analysis was done to determine correlation between anti-vinculin antibody and ICC numbers. Patients with elevated anti-vinculin antibody titer (above median value) had significantly lower number of ICC in inner circular muscle (71.0 vs. 240.5, p = 0.047), and myenteric plexus (12.0 vs. 68.5, p < 0.01) compared to patients with lower anti-vinculin antibody titer. Level of serum anti-vinculin antibody correlated significantly with density of ICC in myenteric plexus (r = −0.379, p = 0.01; Spearman correlation). Increased level of circulating anti-vinculin antibody was significantly correlated with decreased density of ICC in myenteric plexus of human stomach.
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Affiliation(s)
- Ji Hyun Kim
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Seung-Joo Nam
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Sung Chul Park
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Sang Hoon Lee
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Tae Suk Kim
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Minjong Lee
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Jin Myung Park
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Dae Hee Choi
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Chang Don Kang
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Sung Joon Lee
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Young Joon Ryu
- Department of Pathology, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - Kyungyul Lee
- Department of Pathology, Kangwon National University School of Medicine, Chuncheon 24289, Korea
| | - So Young Park
- Kangwon National University Institute of Medical Science, Chuncheon 24289, Korea
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12
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Ogun GO, Adegoke OO, Rahman A, Egbo OH. Gastrointestinal Stromal Tumours (GIST): A Review of Cases from Nigeria. J Gastrointest Cancer 2019; 51:729-737. [PMID: 31659675 DOI: 10.1007/s12029-019-00318-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Gastrointestinal stromal tumours (GIST) are rare and studies on GIST in Nigeria are extremely uncommon. This study aims to achieve a comprehensive systematic review of the cases of this tumour in Nigerians. METHODS A systematic search of all available literature on GIST published from Nigeria between January 2000 and December 2018 was done and reviewed. Simple descriptive data on all the cases are presented. RESULTS The search yielded 15 publications but 13 publications with a total of 67 patients were analysed. The other two studies centred on imatinib therapy and overall survival, and molecular characteristics respectively and were therefore reviewed independently. Age at diagnosis ranged from 9 to 75 years, with mean age being in the 50s and 60s across most studies. There is no gender disparity. Anatomical location of primary tumours showed gastric location as the most frequent (61%) followed by large intestine accounting for 15%, the small intestine (9%) and other locations (15%). Tumour size ranged from 5-39.5 cm. Over 85% of patients had tumour size greater than 10 cm at presentation, hence fell into intermediate or high-risk group irrespective of location of tumour. The overall survival of a cohort of 27 patients that had imatinib therapy was 69.5% after 4 years of follow-up. KIT exon 11 mutations were the only mutations detected from a small cohort of 12 patients. CONCLUSIONS Characteristics of GIST in Nigerians are fairly similar to other parts of the world. However, most of our patients present with large masses which are of poor prognostic characteristics.
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Affiliation(s)
- Gabriel O Ogun
- Department of Pathology, College of Medicine, University of Ibadan, Ibadan, Nigeria. .,Department of Pathology, University College Hospital, Ibadan, Nigeria.
| | - Omolade O Adegoke
- Department of Pathology, College of Medicine, University of Ibadan, Ibadan, Nigeria.,Department of Pathology, University College Hospital, Ibadan, Nigeria
| | - Adam Rahman
- Department of Pathology, University College Hospital, Ibadan, Nigeria
| | - Ojevwe H Egbo
- Department of Anatomical Pathology, College of Medical Sciences, Edo University Iyamho, Iyamho, Nigeria
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Detection of ANO1 mRNA in PBMCs is a promising method for GISTs diagnosis. Sci Rep 2019; 9:9525. [PMID: 31266974 PMCID: PMC6606646 DOI: 10.1038/s41598-019-45941-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 06/17/2019] [Indexed: 01/14/2023] Open
Abstract
ANO1 is a calcium-activated chloride channel protein that has been used to diagnose GISTs after tissue biopsy. Recently, ANO1 mRNA amplification in the blood has received considerable attention as a useful method for the diagnosis of GISTs. The aim of this study was to evaluate the diagnostic ability of ANO1 mRNA in distinguishing GIST patients from healthy subjects. We constructed a logistic regression model for examining the diagnostic ability of ANO1 mRNA in comparison with conventional tumor markers, including CEA, CA199, and CA724. Our results showed that ANO1 mRNA was significantly amplified in PBMCs, the average expression level and range of ANO1 mRNA in the blood were increased along with the expression of ANO1 in the tissues, and the extent of amplification of ANO1 was associated with tumor size. In addition, ROC curve analysis showed that ANO1 mRNA in the blood had the highest specificity when compared with conventional tumor markers. Moreover, a combined analysis with ANO1 mRNA and conventional tumor markers had the highest sensitivity in diagnosing GISTs. Our study indicated that detection of ANO1 mRNA in PBMCs is a promising method for diagnosis of GISTs in vitro.
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14
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Kunzelmann K, Ousingsawat J, Benedetto R, Cabrita I, Schreiber R. Contribution of Anoctamins to Cell Survival and Cell Death. Cancers (Basel) 2019; 11:E382. [PMID: 30893776 PMCID: PMC6468699 DOI: 10.3390/cancers11030382] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 03/13/2019] [Accepted: 03/16/2019] [Indexed: 02/07/2023] Open
Abstract
Before anoctamins (TMEM16 proteins) were identified as a family of Ca2+-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in more detail, and the role of ANO1 in cell proliferation and the development of different types of malignomas is now well established. While ANO5, ANO7, and ANO9 may also be relevant for growth of cancers, evidence has been provided for a role of ANO6 (TMEM16F) in regulated cell death. The cellular mechanisms by which anoctamins control cell proliferation and cell death, respectively, are just emerging; however, the pronounced effects of anoctamins on intracellular Ca2+ levels are likely to play a significant role. Recent results suggest that some anoctamins control membrane exocytosis by setting Ca2+i levels near the plasma membrane, and/or by controlling the intracellular Cl- concentration. Exocytosis and increased membrane trafficking induced by ANO1 and ANO6 may enhance membrane expression of other chloride channels, such as CFTR and volume activated chloride channels (VRAC). Notably, ANO6-induced phospholipid scrambling with exposure of phosphatidylserine is pivotal for the sheddase function of disintegrin and metalloproteinase (ADAM). This may support cell death and tumorigenic activity of IL-6 by inducing IL-6 trans-signaling. The reported anticancer effects of the anthelminthic drug niclosamide are probably related to the potent inhibitory effect on ANO1, apart from inducing cell cycle arrest through the Let-7d/CDC34 axis. On the contrary, pronounced activation of ANO6 due to a large increase in intracellular calcium, activation of phospholipase A2 or lipid peroxidation, can lead to ferroptotic death of cancer cells. It therefore appears reasonable to search for both inhibitors and potent activators of TMEM16 in order to interfere with cancer growth and metastasis.
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Affiliation(s)
- Karl Kunzelmann
- Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
| | - Jiraporn Ousingsawat
- Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
| | - Roberta Benedetto
- Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
| | - Ines Cabrita
- Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
| | - Rainer Schreiber
- Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
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15
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Salama R, Al-Obaidy KI, Perrino CM, Grignon DJ, Ulbright TM, Idrees MT. DOG1 immunohistochemical staining of testicular biopsies is a reliable tool for objective assessment of infertility. Ann Diagn Pathol 2019; 40:18-22. [PMID: 30849695 DOI: 10.1016/j.anndiagpath.2019.02.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 02/17/2019] [Indexed: 11/30/2022]
Abstract
Testicular biopsy may be a component of the work-up of male infertility. However, no reliable diagnostic tools are available for objective quantitative assessment of spermatogenic cells. It is well known that MAGE-A4 is selectively expressed in spermatogonia and our group has previously demonstrated that DOG1 differentially stains germ cells. Therefore, we performed DOG1 and a double stain cocktail (DOG1 and 57b murine monoclonal anti-MAGE-A4) immunohistochemical stains on 40 testicular infertility biopsies (10 each with active spermatogenesis, Sertoli cell-only, hypospermatogenesis, and maturation arrest), 25 benign seminiferous tubules from radical orchiectomies, and 5 spermatocytic tumors (ST). In biopsies/resections with active spermatogenesis, DOG1 stained spermatocytes and spermatids and was absent in spermatogonia, while MAGE-A4 stained spermatogonia and primary spermatocytes (weak). In hypospermatogenesis, DOG1 highlighted decreased spermatocytes/spermatids and MAGE-A4 highlighted decreased spermatogonia. DOG1 staining confirmed decreased to absent spermatocytes in maturation arrest and MAGE-A4 staining established the presence of preserved spermatogonia in all cases. All STs were negative for DOG1 and positive for MAGE-A4, while all Sertoli cell-only cases were negative for DOG1 and the double stain cocktail. In conclusion, we confirmed that DOG1 is expressed in spermatocytes and spermatids and MAGE-A4 highlights primarily spermatogonia. Usage of these stains facilitates confirmation of maturation arrest, assessment of the percentage of testis involvement in hypospermatogenesis and identification of mixed patterns. Finally, this study supports that the differentiation of STs is more closely related to spermatogonia than the more mature spermatocytes.
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Affiliation(s)
- Rasha Salama
- Department of Pathology, St. Elizabeth Healthcare, Edgewood, KY, USA
| | - Khaleel I Al-Obaidy
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - David J Grignon
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Thomas M Ulbright
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Muhammad T Idrees
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
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Alghamdi HM, Amr SS, Shawarby MA, Sheikh SS, Alsayyah AA, Alamri AM, Ismail MH, Almarhabi A, Alrefaee MA, Ahmed MI. Gastrointestinal stromal tumors. A clinicopathological study. Saudi Med J 2019; 40:126-130. [PMID: 30723856 PMCID: PMC6402471 DOI: 10.15537/smj.2019.2.23913] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 01/08/2019] [Indexed: 01/17/2023] Open
Abstract
OBJECTIVES To evaluate the clinical presentations and immunohistochemical (IHC) properties of gastrointestinal stromal tumors (GISTs) and to compare them to internationally published data. METHODS Thirty-six patients diagnosed with GISTs between January 1997 and December 2015 were retrospectively studied in 2 tertiary hospitals. Immunohistochemical staining was carried out prospectively when it has not been completed fully at the beginning. Results: The median age of patients was 54 years (range; 17-81 years). Predominantly, we found more females were affected. The male to female ratio was 1:1.7. The most frequently affected organs were the stomach (63.8%) followed by small bowel (25%) and colorectal region (8.4%). Abdominal pain was the most frequent presentation in 33.3% of the patients then gastrointestinal (GI) bleeding in 30.5%. Most of the gastric GISTs were at early stages at presentation: stage 1 and II (60.8%), while in non-gastric GISTs, the tumor stage was advanced: stage III and IV (69.3%). The IHC characteristic of GIST in descending order showed positivity for vimentin (88.9%), CD117 (83.3%), CD34 (77.8%), Ki67 (63.9%), SMA (38.9%), desmin (27.8%), and S100 (19.4%). CONCLUSION Gastrointestinal stromal tumors in our study demonstrates a major similar feature as the published international data. However, minor differences do exist in terms of clinical features and immunohistochemistry.
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Affiliation(s)
- Hanan M Alghamdi
- Department of Surgery, College of Medicine, King Fahad Hospital of the University, University of Imam Abdurahman Bin Faisal, Al Khobar, Kingdom of Saudi Arabia. E-mail.
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17
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Zhao J, Zhu D, Zhang X, Zhang Y, Zhou J, Dong M. TMEM206 promotes the malignancy of colorectal cancer cells by interacting with AKT and extracellular signal‐regulated kinase signaling pathways. J Cell Physiol 2018; 234:10888-10898. [DOI: 10.1002/jcp.27751] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 10/24/2018] [Indexed: 12/24/2022]
Affiliation(s)
- Jinbo Zhao
- Department of Gastrointestinal Surgery The First Affiliated Hospital of China Medical University Shenyang China
| | - Dehua Zhu
- Department of Gastrointestinal Surgery The First Affiliated Hospital of China Medical University Shenyang China
| | - Xiupeng Zhang
- Department of Pathology The First Affiliated Hospital of China Medical University Shenyang China
| | - Yong Zhang
- Department of Pathology Liaoning Provincial People's Hospital China Medical University Shenyang China
| | - Jianping Zhou
- Department of Gastrointestinal Surgery The First Affiliated Hospital of China Medical University Shenyang China
| | - Ming Dong
- Department of Gastrointestinal Surgery The First Affiliated Hospital of China Medical University Shenyang China
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18
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Ferreira J, Félix A, Lennerz JK, Oliva E. Recent advances in the histological and molecular classification of endometrial stromal neoplasms. Virchows Arch 2018; 473:665-678. [DOI: 10.1007/s00428-018-2470-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 09/29/2018] [Accepted: 10/03/2018] [Indexed: 12/20/2022]
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19
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Endometrial stromal sarcomas and related neoplasms: new developments and diagnostic considerations. Pathology 2018; 50:162-177. [DOI: 10.1016/j.pathol.2017.11.086] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 11/05/2017] [Indexed: 12/21/2022]
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20
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Atay S, Wilkey DW, Milhem M, Merchant M, Godwin AK. Insights into the Proteome of Gastrointestinal Stromal Tumors-Derived Exosomes Reveals New Potential Diagnostic Biomarkers. Mol Cell Proteomics 2017; 17:495-515. [PMID: 29242380 DOI: 10.1074/mcp.ra117.000267] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 10/21/2017] [Indexed: 12/13/2022] Open
Abstract
Developing tumors continuously release nano-sized vesicles that represent circulating "fingerprints" of the tumor's identity. In gastrointestinal stromal tumor (GIST), we have previously reported that these tumors release "oncosomes" carrying the constitutively activated tyrosine kinase (TK) receptor KIT. Despite the clinical utility of TK inhibitors, such as imatinib mesylate (IM), recurrence and metastasis are clinical problems that urge the need to identify new tumor-derived molecules. To this aim, we performed the first high quality proteomic study of GIST-derived exosomes (GDEs) and identified 1,060 proteins composing the core GDE proteome (cGDEp). The cGDEp was enriched in diagnostic markers (e.g. KIT, CD34, ANO1, PROM1, PRKCQ, and ENG), as well as proteins encoded by genes previously reported expressed in GIST (e.g. DPP4, FHL1, CDH11, and KCTD12). Many of these proteins were validated using cell lines, patient-derived KIT+ exosomes, and GIST tissues. We further show that in vitro and in vivo-derived GDE, carry proteins associated with IM response, such as Sprouty homolog 4 (SPRY4), surfeit 4 (SURF4), ALIX, and the cGMP-dependent 3',5'-cyclic phosphodiesterase 2A (PDE2A). Additionally, we report that the total exosome levels and exosome-associated KIT and SPRY4 protein levels have therapeutic values. In fact, molecular characterization of in vivo-derived KIT+ exosomes indicate significant sorting of p-KITTyr719, total KIT, and SPRY4 after IM-treatment of metastatic patients as compared with the pre-IM levels. Our data suggest that analysis of circulating exosomes levels and molecular markers of IM response in GIST patients with primary and metastatic disease is suitable to develop liquid based biopsies for the diagnosis, prognosis, and monitoring of response to treatment of these tumors. In summary, these findings provide the first insight into the proteome of GIST-derived oncosomes and offers a unique opportunity to further understand their oncogenic elements which contribute to tumorigenesis and drug resistance. Data are available via ProteomeXchange with identifier PXD007997.
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Affiliation(s)
- Safinur Atay
- From the ‡Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., 4005 WHE, MS3040, Kansas City, Kansas 66160;
| | - Daniel W Wilkey
- §University of Louisville Room 209, Donald Baxter Research Building, 570 S. Preston Street, Louisville, Kentucky 40202
| | - Mohammed Milhem
- ¶Division of Hematology, Oncology, Blood and Marrow Transplantation 200 Hawkins Drive, C32 GH Iowa City, Iowa 52242
| | - Michael Merchant
- §University of Louisville Room 209, Donald Baxter Research Building, 570 S. Preston Street, Louisville, Kentucky 40202
| | - Andrew K Godwin
- From the ‡Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., 4005 WHE, MS3040, Kansas City, Kansas 66160.,‖University of Kansas Cancer Center, 3901 Rainbow Blvd., 4005 WHE, MS3040, Kansas City, Kansas 66160
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21
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Charville GW, Longacre TA. Surgical Pathology of Gastrointestinal Stromal Tumors: Practical Implications of Morphologic and Molecular Heterogeneity for Precision Medicine. Adv Anat Pathol 2017; 24:336-353. [PMID: 28820749 DOI: 10.1097/pap.0000000000000166] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastrointestinal stromal tumor (GIST), the most common mesenchymal neoplasm of the gastrointestinal tract, exhibits diverse histologic and clinical manifestations. With its putative origin in the gastrointestinal pacemaker cell of Cajal, GIST can arise in association with any portion of the tubular gastrointestinal tract. Morphologically, GISTs are classified as spindled or epithelioid, though each of these subtypes encompasses a broad spectrum of microscopic appearances, many of which mimic other histologic entities. Despite this morphologic ambiguity, the diagnosis of GIST is aided in many cases by immunohistochemical detection of KIT (CD117) or DOG1 expression. The natural history of GIST ranges from that of a tumor cured by surgical resection to that of a locally advanced or even widely metastatic, and ultimately fatal, disease. This clinicopathologic heterogeneity is paralleled by an underlying molecular diversity: the majority of GISTs are associated with spontaneous activating mutations in KIT, PDGFRA, or BRAF, while additional subsets are driven by genetic lesions-often inherited-of NF1 or components of the succinate dehydrogenase enzymatic complex. Specific gene mutations correlate with particular anatomic or morphologic characteristics and, in turn, with distinct clinical behaviors. Therefore, prognostication and treatment are increasingly dictated not only by morphologic clues, but also by accompanying molecular genetic features. In this review, we provide a comprehensive description of the heterogenous molecular underpinnings of GIST, including implications for the practicing pathologist with regard to morphologic identification, immunohistochemical diagnosis, and clinical management.
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22
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Baskin Y, Kocal GC, Kucukzeybek BB, Akbarpour M, Kayacik N, Sagol O, Ellidokuz H, Oztop I. PDGFRA and KIT Mutation Status and Its Association With Clinicopathological Properties, Including DOG1. Oncol Res 2017; 24:41-53. [PMID: 27178821 PMCID: PMC7838738 DOI: 10.3727/096504016x14576297492418] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Most of the gastrointestinal stromal tumors (GISTs) have gain-of-function mutations in the KIT gene, which can be used as a prognostic marker for the biological behavior of tumors, predictive marker for the response of tyrosine kinase inhibitors, and diagnostic marker. Researchers have focused on PDGFRA mutations because of both their prognostic and predictive potential and DOG1 positivity for diagnosis on GISTs. The aim of this study is to investigate the effect DOG1, PDGFRA, and KIT mutations on the prediction of the outcome for GIST management. Polymerase chain reaction was performed for KIT gene exons 9, 11, 13, and 17 and PDGFRA gene exons 12 and 18 with the genomic DNA of 46 GIST patients, and amplicons were sequenced in both directions. Immunocytochemical stainings were done by using primary antibodies. Molecular analysis revealed that the KIT mutation was observed in 63% of all cases, while the PDGFRA mutation was observed in 23.9% of cases. Significant relationships were found between age and KIT mutation, tumor location and KIT mutations, and tumor location and PDGFRA mutations (p ≤ 0.05). DOG1 positivity was detected in 65.2% of all GISTs and DOG1-positive cells had a higher KIT mutation ratio than DOG1-negative cells (p ≤ 0.05). KIT gene exon 11 mutations in DOG1-positive cells was higher than DOG1-negative cells (p ≤ 0.05). Conversely, KIT gene exon 13 mutations were higher in DOG1-negative cells than DOG1-positive cells (p ≤ 0.05). In this study, KIT mutation frequency was found similar with the European population; conversely, PDGFRA mutation frequency was similar with an Asian-Chinese-based study. KIT/PDGFRA mutations and tumor location can be used for the prediction of tumor behavior and the management of disease in GISTs. DOG1 positivity might be a candidate marker to support KIT and PDGFRA mutations, due to the higher DOG1 positivity in KIT exon 11 mutant and stomach- and small intestine-localized GISTs.
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Affiliation(s)
- Yasemin Baskin
- Institute of Oncology, Department of Basic Oncology, Dokuz Eylul University, Izmir, Turkey
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Swalchick W, Shamekh R, Bui MM. Is DOG1 Immunoreactivity Specific to Gastrointestinal Stromal Tumor? Cancer Control 2016; 22:498-504. [PMID: 26678977 DOI: 10.1177/107327481502200416] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND DOG1 is a novel gene on gastrointestinal stromal tumors (GISTs) that encodes the chloride channel protein anoctamin 1, also known as discovered on GIST-1 (DOG1) protein. DOG1 antibodies are a sensitive and specific marker against GIST positive for CD117 and CD34 and negative for CD117 and CD34. DOG1 is also independent of KIT or PDGFRA mutation status and considered specific for GIST when it was first discovered in 2004. METHODS The previous 10 years of literature was searched for articles relating to DOG1. We critically reviewed 12 studies that showed DOG1 was positive in 250 cases of 2,360 tested non-GIST neoplasms (10.6%) at different anatomical sites using monoclonal, polyclonal, or nonspecified antibodies. Criteria for positivity varied between the studies. RESULTS Monoclonal and polyclonal DOG1 antibodies were reactive in various different non-GIST tumor types spanning 9 organ systems in addition to normal salivary and pancreatic tissues. The tumors included were renal oncocytoma (100%), renal cell carcinoma chromophobe type (86%), solid pseudopapillary neoplasm of the pancreas (51%), neoplastic salivary tissue (17%), synovial sarcoma (15%), leiomyoma (10%), pancreatic adenocarcinoma (7%), and leiomyosarcoma (4%). CONCLUSIONS By contrast to the original concept that DOG1 antibodies are specific to GIST neoplasms, the studies reviewed showed that the data suggest DOG1 positivity in select non-GIST tumors. Only in the appropriate clinical and pathological context is DOG1 positivity specific and helpful in the diagnosis of GIST.
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24
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Liu QY, Kan YZ, Zhang MY, Sun TY, Kong LF. Primary extragastrointestinal stromal tumor arising in the vaginal wall: Significant clinicopathological characteristics of a rare aggressive soft tissue neoplasm. World J Clin Cases 2016; 4:118-123. [PMID: 27099863 PMCID: PMC4832118 DOI: 10.12998/wjcc.v4.i4.118] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 12/30/2015] [Accepted: 02/16/2016] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal (GI) stromal tumor is the most common mesenchymal neoplasm of the GI tract but also occurs with a lower frequency in extragastrointestinal regions and is called extragastrointestinal stromal tumor (EGIST). We report an unusual case of EGIST presenting as a vaginal mass. A 41-year-old woman presented with a gradually enlarging vaginal mass for the last 2 years. Physical examination revealed an elliptical, non-tender mass about 7.5 cm × 7 cm in size in the posterior vaginal wall and was resected completely. Under histological examination, the tumor showed a spindle cell type with coagulation necrosis, hemorrhage and high mitotic count. Immunohistochemical analysis revealed tumor cells were positive for DOG1, CD117, CD34 and p53 protein. Ki-67 labeling was 8%. Genetic analysis showed a deletion of exon 11 of the c-kit gene at codons 557-558. EGISTs should be kept in mind in the differential diagnosis in patients presenting with solid mass of the vaginal wall.
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Novel Use for DOG1 in Discriminating Breast Invasive Carcinoma from Noninvasive Breast Lesions. DISEASE MARKERS 2016; 2016:5628176. [PMID: 27041791 PMCID: PMC4793094 DOI: 10.1155/2016/5628176] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 01/27/2016] [Accepted: 02/08/2016] [Indexed: 12/03/2022]
Abstract
Aims. DOG1 has proven to be a useful marker of gastrointestinal stromal tumors (GISTs). Recently, DOG1 expression has also been reported in some non-GIST malignant tumors, but the details related to DOG1 expression in breast tissue remain unclear. The aim of this study was to detect the expression of DOG1 in the human breast and to evaluate the feasibility of using DOG1 to discriminate between invasive breast carcinoma and noninvasive breast lesions. Methods and Results. A total of 210 cases, including both invasive and noninvasive breast lesions, were collected to assess DOG1 expression immunohistochemically. DOG1 expression was consistently positive in breast myoepithelial cells (MECs), which was similar to the results obtained for three other MEC markers: calponin, smooth muscle myosin heavy chain (SMMHC), and P63 (P > 0.05 in all). Importantly, DOG1 was useful in discriminating invasive breast carcinoma from noninvasive breast lesions (P < 0.05). Conclusions. DOG1 is a useful marker of breast MECs, and adding DOG1 to the MEC identification panel will provide more sophisticated information when diagnosing uncertain cases in the breast.
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26
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Guzel T, Mech K, Mazurkiewicz M, Dąbrowski B, Lech G, Chaber A, Słodkowski M. A very rare case of a small bowel leiomyosarcoma leading to ileocaecal intussusception treated with a laparoscopic resection: a case report and a literature review. World J Surg Oncol 2016; 14:48. [PMID: 26911738 PMCID: PMC4765121 DOI: 10.1186/s12957-016-0798-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 02/16/2016] [Indexed: 12/17/2022] Open
Abstract
Background Small bowel tumours are rare and comprise less than 2 % of all primary gastrointestinal neoplasms. Among these tumours, a leiomyosarcoma belonging to soft tissue sarcomas is extremely rare and accounts for about 1 % of malignant mesenchymal lesions in the gastrointestinal tract. Due to its aggressive nature and slow growth, it is often diagnosed at the late stage when curative treatment is impossible. Authors report a first case of leiomyosarcoma with chronic recurrent ileocaecal intussusception and literature review to analyse diagnosis and treatment features of the ileum mesenchymal tumours. Case presentation We present a case of an 87-year-old Caucasian man suffering from cramp-like abdominal pain for months. Due to lack of clinical signs and unspecific complaints, a diagnosis was delayed. Despite a detailed in-hospital examination, a proper diagnosis was established as late as during an operation. The patient was treated by surgery with good results. An uncommon laparoscopic resection of the small bowel with a tumour was performed. A histopathological investigation confirmed a very rare mesenchymal lesion of the distal ileum. The patient is under control with no recurrence for 1 year of the follow-up period. Conclusions Reported case indicates that a usually asymptomatic tumour can cause uncommon chronic recurrent ileus signs. CT and MRI scans are investigation of choice in such cases, but they are sometimes inconclusive. It might be worth highlighting the good results of laparoscopic leiomyosarcoma lesion resection with a very good outcome.
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Affiliation(s)
- Tomasz Guzel
- Department of General, Gastroenterological and Oncologic Surgery, Medical University of Warsaw, ul. Banacha 1a, 02-097, Warsaw, Poland.
| | - Katarzyna Mech
- Department of General, Gastroenterological and Oncologic Surgery, Medical University of Warsaw, ul. Banacha 1a, 02-097, Warsaw, Poland.
| | - Michał Mazurkiewicz
- Chair and Department of Pathomorphology, Medical University of Warsaw, ul.Pawińskiego 7, 02-097, Warsaw, Poland.
| | - Bohdan Dąbrowski
- Department of General, Gastroenterological and Oncologic Surgery, Medical University of Warsaw, ul. Banacha 1a, 02-097, Warsaw, Poland.
| | - Gustaw Lech
- Department of General, Gastroenterological and Oncologic Surgery, Medical University of Warsaw, ul. Banacha 1a, 02-097, Warsaw, Poland.
| | - Andrzej Chaber
- Department of General, Gastroenterological and Oncologic Surgery, Medical University of Warsaw, ul. Banacha 1a, 02-097, Warsaw, Poland.
| | - Maciej Słodkowski
- Department of General, Gastroenterological and Oncologic Surgery, Medical University of Warsaw, ul. Banacha 1a, 02-097, Warsaw, Poland.
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Abstract
Ca2+-activated Cl− channels (CaCCs) are a class of Cl− channels activated by intracellular Ca2+ that are known to mediate numerous physiological functions. In 2008, the molecular identity of CaCCs was found to be anoctamin 1 (ANO1/TMEM16A). Its roles have been studied in electrophysiological, histological, and genetic aspects. ANO1 is known to mediate Cl− secretion in secretory epithelia such as airways, salivary glands, intestines, renal tubules, and sweat glands. ANO1 is a heat sensor activated by noxious heat in somatosensory neurons and mediates acute pain sensation as well as chronic pain. ANO1 is also observed in vascular as well as airway smooth muscles, controlling vascular tone as well as airway hypersensitivity. ANO1 is upregulated in numerous types of cancers and thus thought to be involved in tumorigenesis. ANO1 is also found in proliferating cells. In addition to ANO1, involvement of its paralogs in pathophysiological conditions was also reported. ANO2 is involved in olfaction, whereas ANO6 works as a scramblase whose mutation causes a rare bleeding disorder, the Scott syndrome. ANO5 is associated with muscle and bone diseases. Recently, an X-ray crystal structure of a fungal TMEM16 was reported, which explains a precise molecular gating mechanism as well as ion conduction or phospholipid transport across the plasma membrane.
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Current management of gastrointestinal stromal tumors: Surgery, current biomarkers, mutations, and therapy. Surgery 2015; 158:1149-64. [DOI: 10.1016/j.surg.2015.06.027] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 06/18/2015] [Accepted: 06/24/2015] [Indexed: 12/11/2022]
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Güler B, Özyılmaz F, Tokuç B, Can N, Taştekin E. Histopathological Features of Gastrointestinal Stromal Tumors and the Contribution of DOG1 Expression to the Diagnosis. Balkan Med J 2015; 32:388-96. [PMID: 26740899 DOI: 10.5152/balkanmedj.2015.15912] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Accepted: 05/09/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GIST) have KIT or platelet-derived growth factor receptor α (PDGFRα) mutations affecting receptor tyrosine kinase activity and do not benefit from classic treatment regimens. AIMS The aim of this study was to review the algorithm that may be followed for the diagnosis and differential diagnosis in GISTs by investigating the histomorphological parameters and expression characteristics of classical immunohistochemical antibodies used in routine tests in addition to DOG1 expression. STUDY DESIGN Diagnostic accuracy study. METHODS We reevaluated the histological and immunohistochemical parameters of 37 GISTs. The standard immunohistochemical diagnosis and differential diagnosis panel antibodies (CD117, PDGFRα, CD34, vimentin, desmin, SMA, S-100, and Ki67) were studied on the tumor sections. We also used the popular marker DOG1 antibody with accepted sensitivity for GISTs in recent years and the PDGFRα immune marker for which the benefit in routine practice is discussed. RESULTS Classification according to progressive disease risk groups of the 37 cases revealed that 54% were in the high risk, 19% in the moderate risk, 16% in the low risk, 8% in the very low risk and 8% in the no risk group. Cytological atypia, necrosis, mucosal invasion and the Ki67 index were found to be related to the progressive disease risk groups of the tumors (p<0.05). Positive immunoreaction was observed with CD117 and PDGFRα in all GISTs in the study (100%). Positivity with the DOG1 antibody was found in 33 (89%) cases. CD34 was positive in 62% (23) of the cases. CONCLUSION The CD117 antibody still plays a key role in GIST diagnosis. However, the use of DOG1 and PDGFRα antibodies combined with CD117 as sensitive markers can be beneficial.
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Affiliation(s)
- Beril Güler
- Department of Pathology, Bezmialem Vakıf University Faculty of Medicine, İstanbul, Turkey
| | - Filiz Özyılmaz
- Department of Pathology, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Burcu Tokuç
- Department of Public Health, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Nuray Can
- Department of Pathology, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Ebru Taştekin
- Department of Pathology, Trakya University Faculty of Medicine, Edirne, Turkey
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Abd El-Rehim DM, Gayyed MF. Does Immunohistochemistry for Discovered on GIST1 and Minichromosome Maintenance Protein7 Provide Additional Clinicopathological Value in Gastrointestinal Stromal Tumors? World J Oncol 2015; 6:355-363. [PMID: 28983330 PMCID: PMC5624661 DOI: 10.14740/wjon918w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2015] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The aim of the study was to investigate the expression of discovered on GIST 1 (DOG1) and minichromosome maintenance protein 7 (MCM7) in addition to the traditional markers, C-KIT and Ki-67, in gastrointestinal stromal tumors (GISTs) to specify the diagnosis and to evaluate their clinicopathological significance in GIST patients. METHODS Hematoxylin and eosin sections of 43 GISTs were re-examined to review histopathological criteria and risk stratification of these tumors. Immunohistochemistry for DOG1, C-KIT, MCM7, Ki-67 antibodies was performed. RESULTS Positive DOG1 and C-KIT expressions were found in 42 (97.7%) and 39 (90.7%) of cases, respectively. DOG1 and C-KIT expression scores were significantly correlated (P < 0.001). Among four C-KIT-negative GISTs, three cases were DOG1-positive. DOG1 was more sensitive and specific than C-KIT in the diagnosis of GISTs. High DOG1 expression scores were significantly associated with tumor size (P = 0.023) and risk (P = 0.037). Significant positive correlation was noted between MCM7 and Ki-67 labeling indices (LIs) (P < 0.001, r = 0.885). MCM7 demonstrated higher proliferation LIs than Ki-67. Significant associations were found between MCM7 and Ki-67 LIs and tumor size (P = 0.001 and 0.003 respectively), mitotic rate (P < 0.001 both) and risk stratification (P < 0.001 both) with a stepwise increase in MCM7 LIs with increasing tumor risk. CONCLUSION DOG1 is an important diagnostic tool for GISTs particularly in C-KIT-negative tumors. It may have a role in GISTs tumorogenesis and progression. Despite the established clinicopathological value of Ki-67 in GISTs, detection of MCM7 expression is recommended as a prognostic adjunct, given its better sensitivity for cellular proliferation and stepwise association with tumor risk.
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Wollina U, Hansel G, Zimmermann F, Schönlebe J, Nowak A. Merkel cell carcinoma of the lower leg with retroperitoneal GIST: a very rare association. Wien Klin Wochenschr 2015; 127:402-5. [PMID: 25943418 DOI: 10.1007/s00508-014-0660-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 10/19/2014] [Indexed: 12/11/2022]
Abstract
Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. Although its association with other malignancies is well known, an association with gastrointestinal stromal tumor (GIST) has yet not been described.We report about a 65-year-old female patient who presented with a hypervascularized subcutaneous tumor mass of her left calf. Resection of the primary tumor and histopathological investigations confirmed the diagnosis of MCC. The patient was treated by delayed Mohs surgery, and tumor-free margins were obtained. Sentinel lymph node biopsy was negative for metastatic spread. Primary tumor and lymph node basin were treated by adjuvant radiotherapy. During staging of the patient, a second malignancy-a GIST-was detected. Neoadjuvant treatment with multikinase inhibitor imatinib induced a partial response of GIST that was eventually removed by surgery. However, 8 months later, the patient developed subcutaneous regional metastases of MCC, which were surgically removed. Adjuvant therapy was planned by oncologists.To the best of our knowledge, the occurrence of MCC and GIST in the same patient has yet not been reported. In contrast to GIST, MCC did not respond to imatinib, although c-kit mutations are common in MCC.
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Affiliation(s)
- Uwe Wollina
- Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067, Dresden, Germany,
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Yan F, Ma Y, Sun J, Zhu P. Reactive nodular fibrous pseudotumor involving the gastrointestinal tract and mesentery: A case report and review of the literature. Oncol Lett 2015; 9:1343-1346. [PMID: 25663910 PMCID: PMC4315131 DOI: 10.3892/ol.2015.2882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 12/12/2014] [Indexed: 12/26/2022] Open
Abstract
Reactive nodular fibrous pseudotumor (RNFP) is a tumor-like lesion that is characterized by reactive fibroblast/myofibroblast proliferation within collagenic hyalinized stroma, due to its association with injury or inflammation. The current study describes the case of a 60-year-old female with a history of abdominal surgery and abdominal pain. Upon laparoscopy, multiple nodules attached to the outer layer of the colon and mesentery were identified, and therefore, complete surgical excision was performed. Macroscopically, the nodules were well-circumscribed, firm, tan-white in color and ranged in size between 2.0–10.0 cm at the greatest dimension. Microscopically, the nodules were composed of spindle and stellate cells in a dense collagenic hyalinized background with sparse lymphocytic infiltration. Immunohistochemical analysis demonstrated positive staining for vimentin, smooth muscle actin and cluster of differentiation (CD) 117, and focally-positive keratin staining with AE1/AE3; however, no staining was observed for gastrointestinal stromal tumor 1, CD34, S-100, anaplastic lymphoma kinase or β-catenin. Therefore, it was proposed that the lesion may be most accurately described as an RNFP. The current study reports a rare case of RNFP, emphasizing its histopathological features and differential diagnoses to promote an improved and broader understanding of this poorly understood condition.
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Affiliation(s)
- Fei Yan
- Department of Oncology, Zhongshan Hospital of Hubei Province, Wuhan, Hubei 430000, P.R. China
| | - Yanli Ma
- Department of Oncology, Zhongshan Hospital of Hubei Province, Wuhan, Hubei 430000, P.R. China
| | - Jianhai Sun
- Department of Oncology, Zhongshan Hospital of Hubei Province, Wuhan, Hubei 430000, P.R. China
| | - Pengcheng Zhu
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Kakkar A, Mathur SR, Jain D, Iyer VK, Nalwa A, Sharma MC. Utility of DOG1 Immunomarker in Fine Needle Aspirates of Gastrointestinal Stromal Tumor. Acta Cytol 2015; 59:61-7. [PMID: 25632981 DOI: 10.1159/000370057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 11/21/2014] [Indexed: 12/28/2022]
Abstract
BACKGROUND Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. DOG1 is a sensitive and specific immunohistochemical marker for the diagnosis of GIST. To date, no study has reported the utility of DOG1 immunocytochemistry on aspirate smears. METHODS Aspirates with a cytological diagnosis of GIST were retrieved. DOG1 immunocytochemistry was performed on aspirates with adequate material. RESULTS 23 cases were included (11 primary, 2 recurrent, 10 metastatic). Primary tumors were most frequently located in the stomach; most metastatic tumors were in the liver. Tumor cells were arranged in cohesive clusters with high cellularity. Cells were spindled, had a low N:C ratio, and a moderate amount of cytoplasm, which was elongated and tapering. Characteristic nuclear features included elongated nuclei with blunt or tapering ends, fine chromatin, mild anisonucleosis, and longitudinal grooves. The mitotic count was low, including in metastatic tumors. DOG1 immunopositivity was noted in 57% of the cases examined. Histopathology was available in 5 cases, all diagnosed as GIST. CONCLUSION Cytology is a sensitive investigative modality for the preoperative diagnosis and confirmation of metastasis of GISTs. In ambiguous cases, DOG1 immunocytochemistry can serve as a valuable adjunct. Cytologic assessment, however, cannot predict malignant potential of GISTs as even metastatic tumors display bland nuclear features.
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Affiliation(s)
- Aanchal Kakkar
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
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Affiliation(s)
- Cheng-Han Lee
- Department of Laboratory Medicine and Pathology; Royal Alexandra Hospital; University of Alberta; Edmonton AB Canada
| | - Marisa R Nucci
- Department of Pathology; Brigham and Women's Hospital; Boston MA USA
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Atta IS, Al Qahtani FN. DOG1, alpha-amylase and p63 expression in acinic cell carcinoma of salivary gland; immunohistochemical, clinical and radiological study. Histol Histopathol 2015. [DOI: 10.7243/2055-091x-2-13] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Tang YL, Wong CF, Yap WM, Chuah KL. Discovered on gastrointestinal stromal tumours 1 (DOG1) expression in non-gastrointestinal stromal tumour (non-GIST) neoplasms. Histopathology 2014; 65:724-6. [DOI: 10.1111/his.12433] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Yee Lin Tang
- Department of Pathology; Tan Tock Seng Hospital; Singapore
| | - Chin Fong Wong
- Department of Pathology; Tan Tock Seng Hospital; Singapore
| | - Wai Ming Yap
- Department of Pathology; Tan Tock Seng Hospital; Singapore
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37
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Frequent expression of KIT in endometrial stromal sarcoma with YWHAE genetic rearrangement. Mod Pathol 2014; 27:751-7. [PMID: 24186140 DOI: 10.1038/modpathol.2013.199] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 09/08/2013] [Indexed: 12/15/2022]
Abstract
Endometrial stromal sarcomas with the YWHAE-NUTM2A/B genetic fusion characteristically contain high-grade round to epithelioid cell component that is strongly and diffusely cyclin D1-positive and it may or may not show an associated low-grade fibroblastic/myxoid cell component. They are clinically more aggressive than endometrial stromal sarcomas with the JAZF1-SUZ12 genetic fusion and frequently demonstrate extrauterine extension at initial clinical presentation. In this setting, the tumor may be misdiagnosed as gastrointestinal stromal tumor. This study examines the expression of KIT and ANO1 in 14 YWHAE-NUTM2A/B tumors by immunohistochemistry. Staining localization was determined as membranous and/or cytoplasmic, and the staining intensity was assessed (negative, weak, moderate and strong). Of the 14 tumors, 6 contained only a high-grade round cell component, 2 only a low-grade fibroblastic component and 6 had both components in the slides evaluated. The high-grade round cell component displayed moderate to strong membranous/cytoplasmic KIT staining in all tumors (12 of 12). The low-grade fibroblastic cell component showed only weak cytoplasmic KIT staining in 3 of 8 tumors. In contrast, ANO1 was negative in all 14 neoplasms, irrespective of the component evaluated. Sanger sequencing analysis (exons 9, 11, 13 and 17) and Ampliseq Cancer Panel mutation screen (Ion Torrent) demonstrated no KIT mutations in three KIT-positive YWHAE-NUTM2A/B tumors. This study shows that the high-grade round cell component of YWHAE-NUTM2A/B endometrial stromal sarcoma consistently expresses KIT but lacks KIT hotspot mutations. KIT expression may represent a potential diagnostic pitfall in the evaluation of YWHAE-NUTM2A/B endometrial stromal sarcoma presenting with pelvic/abdominal mass, particularly in situations where its uterine origin is not definitive, and thus a panel of antibodies that includes ANO1 and cyclin D1 is necessary.
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ANO1 contributes to Angiotensin-II-activated Ca2+-dependent Cl− current in human atrial fibroblasts. J Mol Cell Cardiol 2014; 68:12-9. [DOI: 10.1016/j.yjmcc.2013.12.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 12/03/2013] [Accepted: 12/31/2013] [Indexed: 01/04/2023]
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Qi J, Wang Y, Liu Y, Zhang F, Guan B, Zhang H. Development and validation of HTS assay for screening the calcium-activated chloride channel modulators in TMEM16A stably expressed CHO cells. Anal Bioanal Chem 2014; 406:1713-21. [PMID: 24448969 DOI: 10.1007/s00216-013-7550-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 11/30/2013] [Accepted: 12/02/2013] [Indexed: 12/18/2022]
Abstract
Calcium-activated chloride channels (CaCCs), for example TMEM16A, are widely expressed in a variety of tissues and are involved in many important physiological functions. We developed and validated an atomic absorption spectroscopy (AAS)-based detection system for high-throughput screening (HTS) of CaCC modulators. With this assay, Cl(-) flux from CHO cells stably transfected with TMEM16A is assayed indirectly, by measuring excess silver ions (Ag(+)) in the supernatant of AgCl precipitates. The screening process involved four steps: (1) TMEM16A CHO cells were incubated in high-K(+) and high-Cl(-) buffer with test compounds, and with ionomycin as Ca(2+) ionophore, for 12 min; (2) cells were washed with a low-K(+), Cl(-)-free and Ca(2+)-free buffer; (3) CaCC/TMEM16A were activated in high-K(+), Cl(-)-free buffer with ionomycin (10 μmol L(-1)) for 12 min; and (4) excess Ag(+) concentration was measured using an ion channel reader (ICR, an AAS system). The assay can be used to screen CaCC activators and inhibitors at the same time. With this assay, positive control drugs, including NPPB, CaCCinh-A01, flufenamic acid (Flu) and Eact, all had good concentration-dependent effects on CaCC/TMEM16A. NPPB and CaCCinh-A01 inhibited the CaCC/TMEM16A currents completely at 300 μmol L(-1), with IC50 values of 39.35 ± 4.72 μmol L(-1) and 6.35 ± 0.27 μmol L(-1), respectively; and Eact, activated CaCC/TMEM16A, with an EC50 value of 3.92 ± 0.87 μmol L(-1).
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Affiliation(s)
- Jinlong Qi
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, China
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Novel uses of immunohistochemistry in the diagnosis and classification of soft tissue tumors. Mod Pathol 2014; 27 Suppl 1:S47-63. [PMID: 24384853 DOI: 10.1038/modpathol.2013.177] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 07/30/2013] [Indexed: 12/13/2022]
Abstract
Immunohistochemistry plays a key role in the diagnosis of soft tissue tumors. Until recently, however, the primary purpose of immunohistochemistry in this context was simply to attempt to demonstrate a line of differentiation. Unfortunately, most traditional markers (predominantly directed against cytoplasmic determinants) show relatively limited specificity. Over the last decade or so, much more specific immunohistochemical markers for soft tissue tumors have been developed. This review will provide an update of some of the most useful new diagnostic markers, which are significantly changing clinical practice for surgical pathologists, separated into three general categories: (1) lineage-restricted transcription factors, (2) protein correlates of molecular alterations, and (3) diagnostic markers identified by gene expression profiling.
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Wada T, Tanabe S, Ishido K, Higuchi K, Sasaki T, Katada C, Azuma M, Naruke A, Kim M, Koizumi W, Mikami T. DOG1 is useful for diagnosis of KIT-negative gastrointestinal stromal tumor of stomach. World J Gastroenterol 2013; 19:9133-9136. [PMID: 24379641 PMCID: PMC3870569 DOI: 10.3748/wjg.v19.i47.9133] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Accepted: 10/22/2013] [Indexed: 02/06/2023] Open
Abstract
Approximately 80%-95% of gastrointestinal stromal tumors (GISTs) show positive staining for KIT, while the other 5%-20% show negative staining. If the tumor is negative for KIT, but is positive for CD34, a histological diagnosis is possible. However, if the tumor is negative for KIT, CD34, S-100, and SMA, a definitive diagnosis is often challenging. Recently, Discovered on GIST-1 (DOG1) has received considerable attention as a useful molecule for the diagnosis of GIST. DOG1, a membrane channel protein, is known to be overexpressed in GIST. Because the sensitivity and specificity of DOG1 are higher than those of KIT, positive staining for DOG1 has been reported, even in KIT-negative GISTs. KIT-negative GISTs most commonly arise in the stomach and are mainly characterized by epithelioid features histologically. We describe our experience with a rare case of a KIT-negative GIST of the stomach that was diagnosed by positive immunohistochemical staining for DOG1 in a patient who presented with severe anemia. Our findings suggest that immunohistochemical staining for DOG1, in addition to gene analysis, is useful for the diagnosis of KIT-negative tumors that are suspected to be GISTs.
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Rusu MC, Poalelungi CV, Vrapciu AD, Păduraru L, Didilescu AC, Stan CI. Anoctamin 1 Positive Esophageal Interstitial Cajal Cells in Late Stage Human Embryos. Anat Rec (Hoboken) 2013; 297:301-7. [DOI: 10.1002/ar.22837] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 09/21/2013] [Accepted: 10/18/2013] [Indexed: 12/14/2022]
Affiliation(s)
- Mugurel Constantin Rusu
- Division of Anatomy; Faculty of Dental Medicine; “Carol Davila” University of Medicine and Pharmacy; Bucharest Romania
- MEDCENTER - Center of Excellence in Laboratory Medicine and Pathology
| | - Cristian Viorel Poalelungi
- Department of Obstetrics and Gynaecology; "Dr.I.Cantacuzino" Hospital, "Carol Davila" University of Medicine and Pharmacy; Bucharest Romania
| | - Alexandra Diana Vrapciu
- Division of Anatomy; Faculty of Dental Medicine; “Carol Davila” University of Medicine and Pharmacy; Bucharest Romania
| | - Luminiţa Păduraru
- Division of Neonatology; “Mother and Child” Department; “Gr.T.Popa” University of Medicine and Pharmacy; Iasi Romania
| | - Andreea Cristiana Didilescu
- Division of Embryology; Faculty of Dental Medicine; “Carol Davila” University of Medicine and Pharmacy; Bucharest Romania
| | - Cristinel Ionel Stan
- Division of Anatomy; Faculty of Medicine; Gr.T.Popa” University of Medicine and Pharmacy; Iasi Romania
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Wang C, Jin MS, Zou YB, Gao JN, Li XB, Peng F, Wang HY, Wu ZD, Wang YP, Duan XM. Diagnostic significance of DOG-1 and PKC-θ expression and c-Kit/PDGFRA mutations in gastrointestinal stromal tumours. Scand J Gastroenterol 2013; 48:1055-65. [PMID: 23862765 DOI: 10.3109/00365521.2013.816770] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To investigate discovered on gastrointestinal stromal tumor (GIST)-1 (DOG-1) and protein kinase C-θ (PKC-θ) expression in a series of GISTs and determine the sensitivity, specificity, and diagnostic value of these two antigens. METHODS Immnunohistochemistry (IHC) was used to detect CD117, DOG-1, PKC-θ, CD34, Ki-67, α-smooth muscle actin (SMA), S100, and Desmin expression in 147 GISTs and 51 non-GISTs. c-Kit gene (exons 9, 11, 13, and 17) and platelet-derived growth factor receptor-alpha (PDGFRA) gene (exons 12 and 18) mutations were also detected. RESULTS About 94.5% GISTs were CD117 positive, 96% were DOG-1 positive, and 90.5% were PKC-θ positive. DOG-1 had a specificity of 100%, while CD117 and PKC-θ had a specificity of 90% and 80%, respectively. There was no significant difference between DOG-1 and PKC-θ expressions when compared to CD117 expression. In 30 out of 42 (71.5%) GISTs, a c-Kit gene mutation was found, and in 3 out of 42 cases (7%), PDGFRA was mutated. Wild-type c-Kit/PDGFRA genes accounted for 21.5% (9/42). Most c-Kit gene mutations were found to be located at exon 11, mainly as in-frame deletions. Mutations in exon 9 were all missense mutations. Most PDGFRA gene mutations were found in exon 18, codon 842. c-Kit gene mutations in exons 13 and 17, and the PDGFRA gene mutation in exon 12 were not detected. CONCLUSIONS Compared to CD117, DOG-1 is a biomarker with higher sensitivity and specificity. The combination of CD117 and DOG-1 can be used to improve the diagnosis of GIST. Although PKC-θ has a lower specificity than DOG-1, it can be a useful biomarker, especially in CD117(-) and/or DOG-1(-) cases.
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Affiliation(s)
- Chao Wang
- Pathological Diagnosis Center, First Hospital of Jilin University, Changchun 130021, China
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Kara T, Serinsoz E, Arpaci RB, Gubur O, Orekici G, Ata A, Colak T, Arican A. Contribution of DOG1 expression to the diagnosis of gastrointestinal stromal tumors. Pathol Res Pract 2013; 209:413-7. [PMID: 23722018 DOI: 10.1016/j.prp.2013.04.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Revised: 03/11/2013] [Accepted: 04/16/2013] [Indexed: 12/25/2022]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, and the majority contain KIT or PDGFRA-activating mutations. However, up to 10% of GISTs are c-kit-negative. Antibodies with increased sensitivity and specificity for the detection of c-kit-negative GIST cases may be of value, especially because some of these cases may also benefit from tyrosine kinase inhibitor therapy. Hematoxylin and Eosin sections of 33 GISTs were re-examined in order to define histopathological criteria used in risk assessment of these tumors. Immunohistochemistry with a panel of antibodies [c-kit, DOG1 (discovered on GIST 1), CD34, smooth muscle actin (SMA), Desmin, S100 and Ki67] was performed on 5μm-thick paraffin sections of all tumors. Statistical analysis of immunohistochemical studies showed that DOG1 and CD117 were the most sensitive and specific antibodies in the diagnosis of GISTs. Other antibodies were unhelpful in confirming a diagnosis of GIST, but were particularly useful in the differential diagnosis. Reactivity for DOG1 may aid in the diagnosis of GISTs, which fail to express c-kit antigen, and lead to appropriate treatment with imatinib mesylate, an inhibitor of the KIT tyrosine kinase.
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Affiliation(s)
- Tuba Kara
- Mersin University, Medical School, Department of Pathology, Turkey.
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Agaimy A, Wang LM, Eck M, Haller F, Chetty R. Loss of DOG-1 expression associated with shift from spindled to epithelioid morphology in gastric gastrointestinal stromal tumors with KIT and platelet-derived growth factor receptor α mutations. Ann Diagn Pathol 2013; 17:187-91. [DOI: 10.1016/j.anndiagpath.2012.10.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 10/27/2012] [Indexed: 12/13/2022]
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Epstein MG, Pasquetti AF, Costa SV, Favaro MDL, Contrucci Filho O, Ribeiro Junior MAF. Hemoperitoneum secondary to gastric GIST negative for c-KIT and positive for antibody anti-DOG1. EINSTEIN-SAO PAULO 2013; 10:377-9. [PMID: 23386022 DOI: 10.1590/s1679-45082012000300022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Accepted: 01/17/2012] [Indexed: 11/22/2022] Open
Abstract
Although relatively rare, the gastrointestinal stromal tumors comprise most mesenchymal tumors of the digestive tract and account for 5% of all sarcomas. The most common symptoms are pain, gastrointestinal bleeding and palpable mass. This study reported the case of a young patient who developed hemoperitoneum due to gastric neoplasm rupture and required urgent surgical treatment. Pathology and immunohistochemistry analysis showed an epidemiologically rare case: epithelioid and c-KIT negative tumor.
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Chênevert J, Duvvuri U, Chiosea S, Dacic S, Cieply K, Kim J, Shiwarski D, Seethala RR. DOG1: a novel marker of salivary acinar and intercalated duct differentiation. Mod Pathol 2012; 25:919-29. [PMID: 22460810 DOI: 10.1038/modpathol.2012.57] [Citation(s) in RCA: 163] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Anoctamin-1 (ANO1) (DOG1, TMEM16a) is a calcium-activated chloride channel initially described in gastrointestinal stromal tumors, but now known to be expressed in a variety of normal and tumor tissues including salivary tissue in murine models. We herein perform a comprehensive survey of DOG1 expression in 156 cases containing non-neoplastic human salivary tissues and tumors. ANO1 mRNA levels were significantly higher (8-fold increase, P<0.0001) in normal parotid tissue (n=6) as compared with squamous mucosa (n=15). By immunohistochemistry, DOG1 showed a diffuse moderate (2+) apical membranous staining pattern in normal serous acini, 1+ apical membranous pattern in mucous acini, and variable 1-2+ apical staining of distal intercalated ducts. Myoepithelial cells, striated and excretory ducts were invariably negative. All acinic cell carcinomas (n=28) were DOG1 positive demonstrating a complex mixture of intense (3+) apical membranous, cytoplasmic and complete membranous staining. Most ductal tumor types were negative or only showed a subset of positive cases. Within the biphasic tumor category, adenoid cystic carcinomas (18/24 cases) and epithelial-myoepithelial carcinomas (8/15 cases) were frequently positive, often showing a distinctive combined apical ductal and membranous/cytoplasmic myoepithelial staining profile. Thus, DOG1 staining is a marker of salivary acinar and to a lesser extent intercalated duct differentiation. Strong staining can be used to support the diagnosis of acinic cell carcinoma. DOG1 may also be a marker of a 'transformed' myoepithelial phenotype in a subset of biphasic salivary gland malignancies.
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Affiliation(s)
- Jacinthe Chênevert
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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Hemminger J, Iwenofu OH. Discovered on gastrointestinal stromal tumours 1 (DOG1) expression in non-gastrointestinal stromal tumour (GIST) neoplasms. Histopathology 2012; 61:170-7. [DOI: 10.1111/j.1365-2559.2011.04150.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Chandrasekhara V, Ginsberg GG. Endoscopic management of gastrointestinal stromal tumors. Curr Gastroenterol Rep 2012; 13:532-9. [PMID: 21931997 DOI: 10.1007/s11894-011-0224-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Subepithelial lesions are increasingly being identified with improved endoscopic imaging technologies. Many of these lesions are now recognized as gastrointestinal stromal tumors (GISTs). Recent advances in immunohistochemistry have allowed for reliable differentiation of GISTs from other subepithelial tumors, thereby significantly improving our understanding of these lesions. The wealth of recent information and continual evolution in our understanding of GISTs has exposed some knowledge gaps pertaining to the optimal management of these lesions. In this article, we review the endoscopic management of GISTs as it relates to the identification, diagnosis and management of these lesions based on the best available literature and our own clinical experience to date.
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Affiliation(s)
- Vinay Chandrasekhara
- Hospital of the University of Pennsylvania, GI Division, 3 Ravdin, 3400 Spruce Street, Philadelphia, PA 19104, USA.
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Abstract
Gastrointestinal stromal tumor (GIST), generally driven by oncogenic KIT or PDGFRA mutations, is the most common mesenchymal tumor of the gastrointestinal (GI) tract. GIST is most common in the stomach (60%) and small intestine (30%), but can occur anywhere in the GI-tract and the intra-abdominal soft tissues. GIST can show spindle cell or epithelioid morphology, and mitotic count and tumor size are most important prognostic parameters. GISTs in NF1 patients and children are distinctive clinicopathologic groups. Immunohistochemical testing for KIT and sometimes for DOG1/Ano 1 is essential in confirming the diagnosis.
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Affiliation(s)
- Markku Miettinen
- National Cancer Institute, Laboratory of Pathology, Bethesda, Maryland 20892, USA.
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