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Mazurek M, Jaros M, Gliwa AM, Sitarz MZ, Dudzińska E, Zinkiewicz K, Sitarz R. Epstein-Barr Virus (EBV) and Human Papilloma Virus (HPV) in Gastric Cancers, with Special Reference to Gastric Cancer at a Young Age-A Pilot Study in Poland. Int J Mol Sci 2025; 26:711. [PMID: 39859425 PMCID: PMC11765604 DOI: 10.3390/ijms26020711] [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: 11/21/2024] [Revised: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world. It is a multi-factorial disease influenced by both genetic and environmental factors such as diet, obesity, radiation exposure, and infectious agents. Viral infections usually lead to chronic inflammation, which can initiate the development of cancers. To date, only a few studies have been published about Epstein-Barr virus (EBV) and human papillomavirus (HPV) infections in the context of the development of GC. In particular, research on the development of cancer among people under 45 years of age, including the impacts of EBV and HPV, is rare, and clear results have not been obtained. The aim of this study was to analyze the frequency of occurrence of EBV and HPV in GC, particularly in early-onset gastric cancer (EOGC). Tissue material from 135 patients with GC, including 84 men and 51 women, was examined. RT-PCR was performed to detect EBV, and PCR was performed to detect HPV. There were no significant impacts of EBV and HPV infections on any subtype of GC. There was also no statistically significant dependence of gender and location of the tumor on any subtype of GC. Further research on the impacts of infectious agents such as EBV and HPV on GC should be conducted using larger populations.
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Affiliation(s)
- Marek Mazurek
- Department of Surgical Oncology, Masovian Cancer Hospital, 05-135 Wieliszew, Poland;
- Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-950 Lublin, Poland; (M.J.); (A.M.G.)
| | - Małgorzata Jaros
- Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-950 Lublin, Poland; (M.J.); (A.M.G.)
| | - Anna M. Gliwa
- Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-950 Lublin, Poland; (M.J.); (A.M.G.)
| | - Monika Z. Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Ewa Dudzińska
- Department of Dietetics and Nutrition Education, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Krzysztof Zinkiewicz
- Independent Laboratory of Diagnostic, Interventional Endoscopy of the Department of Oncology, Medical University of Lublin, 20-081 Lublin, Poland;
| | - Robert Sitarz
- Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-950 Lublin, Poland; (M.J.); (A.M.G.)
- Department of Surgical Oncology, St. John’s Cancer Center, 20-090 Lublin, Poland
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Zong R, Ma X, Shi Y, Geng L. Can Machine Learning Models Based on Computed Tomography Radiomics and Clinical Characteristics Provide Diagnostic Value for Epstein-Barr Virus-Associated Gastric Cancer? J Comput Assist Tomogr 2024; 48:859-867. [PMID: 38924393 DOI: 10.1097/rct.0000000000001636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2024]
Abstract
OBJECTIVE The aim of this study was to explore whether machine learning model based on computed tomography (CT) radiomics and clinical characteristics can differentiate Epstein-Barr virus-associated gastric cancer (EBVaGC) from non-EBVaGC. METHODS Contrast-enhanced CT images were collected from 158 patients with GC (46 EBV-positive, 112 EBV-negative) between April 2018 and February 2023. Radiomics features were extracted from the volumes of interest. A radiomics signature was built based on radiomics features by the least absolute shrinkage and selection operator logistic regression algorithm. Multivariate analyses were used to identify significant clinicoradiological variables. We developed 6 ML models for EBVaGC, including logistic regression, Extreme Gradient Boosting, random forest (RF), support vector machine, Gaussian Naive Bayes, and K-nearest neighbor algorithm. The area under the receiver operating characteristic curve (AUC), the area under the precision-recall curves (AP), calibration plots, and decision curve analysis were applied to assess the effectiveness of each model. RESULTS Six ML models achieved AUC of 0.706-0.854 and AP of 0.480-0.793 for predicting EBV status in GC. With an AUC of 0.854 and an AP of 0.793, the RF model performed the best. The forest plot of the AUC score revealed that the RF model had the most stable performance, with a standard deviation of 0.003 for AUC score. RF also performed well in the testing dataset, with an AUC of 0.832 (95% confidence interval: 0.679-0.951), accuracy of 0.833, sensitivity of 0.857, and specificity of 0.824, respectively. CONCLUSIONS The RF model based on clinical variables and Rad_score can serve as a noninvasive tool to evaluate the EBV status of gastric cancer.
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Affiliation(s)
- Ruilong Zong
- From the Department of Radiology, Xuzhou Central Hospital, Xuzhou, China
| | - Xijuan Ma
- From the Department of Radiology, Xuzhou Central Hospital, Xuzhou, China
| | - Yibing Shi
- From the Department of Radiology, Xuzhou Central Hospital, Xuzhou, China
| | - Li Geng
- Department of Radiology, The Affiliated Hospital of Xuzhou Medical University
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Li LL, Yu AY, Zhu M, Ma LY, Cao MH, Liu WL, Qin XB, Gao C, Han ZX, Wang HM. Clinicopathological characteristics and prognosis of Epstein-Barr virus-associated gastric cancer. Arch Virol 2024; 169:114. [PMID: 38700535 DOI: 10.1007/s00705-024-06033-3] [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: 04/12/2023] [Accepted: 02/22/2024] [Indexed: 05/24/2024]
Abstract
OBJECTIVE Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct molecular subtype of gastric cancer (GC). At present, the clinical characteristics and prognostic implications of EBV infection and the potential clinical benefits of immune checkpoint blockade in GC remain to be clarified. Hence, this study was designed to analyze the clinical and pathological characteristics of GC patients with varying EBV infection states and compare their overall survival (OS). METHODS A retrospective study was performed on 1031 consecutive GC patients who underwent gastrectomy at the Affiliated Hospital of Xuzhou Medical University from February 2018 to November 2022. EBV-encoded RNA (EBER) in situ hybridization (ISH) was used for EBV assessment, and immunohistochemical staining was used for evaluation of human epidermal growth factor receptor 2 (HER2), programmed death ligand 1 (PD-L1), and Ki67 expression. EBVaGC was defined as tumors with EBV positivity. In addition, EBV-negative GC (EBVnGC) patients were matched with EBVaGC patients based on seven clinicopathological parameters (age, gender, anatomic subsite, tumor size, Lauren classification, degree of differentiation, and tumor-node-metastasis [TNM] stage). The correlations of clinical features with HER2, PD-L1, and Ki67 expression were evaluated statistically. The survival of patients was assessed through medical records, telephone, or WeChat communication, and prognostic analysis was performed using the logrank test as well as univariable and multivariable regression analysis. RESULTS Out of 1031 GC patients tested, 35 (3.4%) were diagnosed with EBVaGC. Notably, the EBVaGC group exhibited a distinct predominance of males and younger patients, significantly higher Ki67 and PD-L1 expression levels, and a lower prevalence of pericancerous nerve invasion than the EBVnGC group (P < 0.01). In the 35 EBVaGC cases, Ki67 expression was negatively correlated with age (P < 0.05), suggesting that a younger onset age was associated with higher Ki67 expression. In addition, PD-L1 expression was correlated with the degree of differentiation, T-stage, and clinical stage of the patient. Furthermore, PD-L1 expression was elevated in tumors with lower differentiation or at later stages (P < 0.05). Using univariate analysis, Ki67, PD-L1, and clinical stage were identified as significant factors influencing the overall survival (OS) of EBVaGC patients (P < 0.05). Moreover, multivariate survival analysis revealed that clinical stage and Ki67 expression were independent risk factors for the OS of the patients (P < 0.05), and the three-year OS rate of EBVaGC patients was 64.2%. CONCLUSION EBV-ISH is a practical and valuable method to identify EBVaGC. Owing to its unique etiological, pathological, and clinical characteristics, patients with EBVaGC might benefit from immune checkpoint blockade therapy.
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Affiliation(s)
- Lin-Lin Li
- Department of Pathology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Ao-Yang Yu
- Graduate School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Mei Zhu
- Department of Oncology, Xuzhou Cancer Hospital, Xuzhou, 221005, Jiangsu, China
| | - Lu-Yao Ma
- Graduate School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Meng-Han Cao
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Wen-Lou Liu
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Xiao-Bing Qin
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Chao Gao
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Zheng-Xiang Han
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China.
| | - Hong-Mei Wang
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China.
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Salnikov MY, MacNeil KM, Mymryk JS. The viral etiology of EBV-associated gastric cancers contributes to their unique pathology, clinical outcomes, treatment responses and immune landscape. Front Immunol 2024; 15:1358511. [PMID: 38596668 PMCID: PMC11002251 DOI: 10.3389/fimmu.2024.1358511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/14/2024] [Indexed: 04/11/2024] Open
Abstract
Epstein-Barr virus (EBV) is a pathogen known to cause a number of malignancies, often taking years for them to develop after primary infection. EBV-associated gastric cancer (EBVaGC) is one such malignancy, and is an immunologically, molecularly and pathologically distinct entity from EBV-negative gastric cancer (EBVnGC). In comparison with EBVnGCs, EBVaGCs overexpress a number of immune regulatory genes to help form an immunosuppressive tumor microenvironment (TME), have improved prognosis, and overall have an "immune-hot" phenotype. This review provides an overview of the histopathology, clinical features and clinical outcomes of EBVaGCs. We also summarize the differences between the TMEs of EBVaGCs and EBVnGCs, which includes significant differences in cell composition and immune infiltration. A list of available EBVaGC and EBVnGC gene expression datasets and computational tools are also provided within this review. Finally, an overview is provided of the various chemo- and immuno-therapeutics available in treating gastric cancers (GCs), with a focus on EBVaGCs.
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Affiliation(s)
- Mikhail Y. Salnikov
- Department of Microbiology and Immunology, Western University, London, ON, Canada
| | - Katelyn M. MacNeil
- Department of Microbiology and Immunology, Western University, London, ON, Canada
| | - Joe S. Mymryk
- Department of Microbiology and Immunology, Western University, London, ON, Canada
- Department of Oncology, Western University, London, ON, Canada
- Department of Otolaryngology, Western University, London, ON, Canada
- Lawson Health Research Institute, London, ON, Canada
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Kim JH, Kim N, Song DH, Choi Y, Jeon EB, Kim S, Jun YK, Yoon H, Shin CM, Park YS, Lee DH, Oh HJ, Lee HS, Park YS, Ahn SH, Suh YS, Park DJ, Kim HH, Kim JW, Kim JW, Lee KW, Chang W, Park JH, Lee YJ, Lee KH, Kim YH, Ahn S. Sex-dependent different clinicopathological characterization of Epstein-Barr virus-associated gastric carcinoma: a large-scale study. Gastric Cancer 2024; 27:221-234. [PMID: 38212543 PMCID: PMC10896815 DOI: 10.1007/s10120-023-01460-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 12/16/2023] [Indexed: 01/13/2024]
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5-16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated the clinicopathological characteristics of EBVaGC including survival rate in South Korea. METHODS A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV-ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed. RESULTS A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (P < 0.001), a predominant presence in the proximal stomach (P < 0.001), a higher proportion of undifferentiated cancer (P < 0.001), and a lower cancer stage (P = 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio [HR] = 1.025, P < 0.001), tumor size (HR = 1.109, P < 0.001), and cancer stage (stage2 HR = 4.761, P < 0.001; stage3 HR = 13.286, P < 0.001; stage4 HR = 42.528, P < 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620, P = 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (P = 0.021) and GC-specific survival (P = 0.007) on the Kaplan-Meier survival curve. However, this effect was evident only in males. CONCLUSIONS EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females.
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Affiliation(s)
- Ji-Hyun Kim
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Nayoung Kim
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea.
- Departments of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
| | - Du Hyun Song
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Yonghoon Choi
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Eun-Bi Jeon
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Sihyun Kim
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Yu Kyung Jun
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Hyuk Yoon
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Cheol Min Shin
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Young Soo Park
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Dong Ho Lee
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
- Departments of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyeon Jeong Oh
- Departments of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hye Seung Lee
- Departments of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Young Suk Park
- Departments of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Sang-Hoon Ahn
- Departments of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Yun-Suhk Suh
- Departments of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Do Joong Park
- Departments of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
- Departments of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyung Ho Kim
- Departments of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
- Departments of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Ji-Won Kim
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Jin Won Kim
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
| | - Keun-Wook Lee
- Departments of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, Gyeonggi-Do, 13620, South Korea
- Departments of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Won Chang
- Departments of Radiology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Ji Hoon Park
- Departments of Radiology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Yoon Jin Lee
- Departments of Radiology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Kyoung Ho Lee
- Departments of Radiology, Seoul National University Bundang Hospital, Seongnam, South Korea
- Departments of Radiology, Seoul National University College of Medicine, Seoul, South Korea
| | - Young Hoon Kim
- Departments of Radiology, Seoul National University Bundang Hospital, Seongnam, South Korea
- Departments of Radiology, Seoul National University College of Medicine, Seoul, South Korea
| | - Soyeon Ahn
- Division of Statistics, Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, South Korea
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Kim JY, Park CK, Noh S, Cheong JH, Noh SH, Kim H. Prognostic Significance of ARID1A Expression Patterns Varies with Molecular Subtype in Advanced Gastric Cancer. Gut Liver 2023; 17:753-765. [PMID: 36789575 PMCID: PMC10502505 DOI: 10.5009/gnl220342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 11/23/2022] [Accepted: 11/23/2022] [Indexed: 02/16/2023] Open
Abstract
Background/Aims AT-rich interactive domain 1A (ARID1A) is frequently mutated in gastric cancer (GC), especially Epstein-Barr virus (EBV)-associated and microsatellite instability high GC. The loss of ARID1A expression has been reported as a poor prognostic marker in GC. However, the relationships between ARID1A alteration and EBV-associated and microsatellite instability high GC, which are known to have a favorable prognosis, has hampered proper evaluation of the prognostic significance of ARID1A expression in GC. We aimed to analyze the true prognostic significance of ARID1A expression by correcting confounding variables. Methods We evaluated the ARID1A expression in a large series (n=1,032) of advanced GC and analyzed the relationships between expression pattern and variable parameters, including clinicopathologic factors, key molecular features such as EBV-positivity, mismatch repair protein deficiency, and expression of p53 and several receptor tyrosine kinases including human epidermal growth factor receptor 2, epidermal growth factor receptor, and mesenchymal-epithelial transition factor. Survival analysis of the molecular subtypes was done according to the ARID1A expression patterns. Results Loss of ARID1A expression was found in 52.5% (53/101) of mutL homolog 1 (MLH1)-deficient and 35.8% (24/67) of EBV-positive GCs, compared with only 9.6% (82/864) of the MLH1-proficient and EBV-negative group (p<0.001). The loss of ARID1A expression was associated only with MLH1 deficiency and EBV positivity. On survival analysis, the loss of ARID1A expression was associated with worse prognosis only in MLH1-proficient and EBV-negative GC. Multivariate analysis revealed that both loss of ARID1A and decreased ARID1A expression were independent worse prognostic factors in patients with advanced GC. Conclusions Only in MLH1-proficient and EBV-negative GC, the loss of ARID1A expression is related to poorer prognosis.
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Affiliation(s)
- Jun Yong Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Cheol Keun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Songmi Noh
- Department of Pathology, CHA Gangnam Medical Center, CHA University, Seoul, Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
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Park YS, Kook MC, Kim BH, Lee HS, Kang DW, Gu MJ, Shin OR, Choi Y, Lee W, Kim H, Song IH, Kim KM, Kim HS, Kang G, Park DY, Jin SY, Kim JM, Choi YJ, Chang HK, Ahn S, Chang MS, Han SH, Kwak Y, Seo AN, Lee SH, Cho MY. A Standardized Pathology Report for Gastric Cancer: 2nd Edition. J Gastric Cancer 2023; 23:107-145. [PMID: 36750994 PMCID: PMC9911618 DOI: 10.5230/jgc.2023.23.e7] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 01/27/2023] Open
Abstract
The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.
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Affiliation(s)
- Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Baek-Hui Kim
- Department of Pathology, Korea University Guro Hospital, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Dong-Wook Kang
- Department of Pathology, Chungnam National University Sejong Hospital, Chungnam National University School of Medicine, Sejong, Korea
| | - Mi-Jin Gu
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea
| | - Ok Ran Shin
- Department of Hospital Pathology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
| | - Younghee Choi
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
| | - Wonae Lee
- Department of Pathology, Dankook University College of Medicine, Cheonan, Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - In Hye Song
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Sung Kim
- Department of Pathology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea
| | - Guhyun Kang
- LabGenomics Clinical Laboratories, Seongnam, Korea
| | | | - So-Young Jin
- Department of Pathology, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Joon Mee Kim
- Department of Pathology, Inha University School of Medicine, Incheon, Korea
| | - Yoon Jung Choi
- Department of Pathology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Hee Kyung Chang
- Department of Pathology, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Song-Hee Han
- Department of Pathology, Dong-A University College of Medicine, Busan, Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - Sung Hak Lee
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
| | - Mee-Yon Cho
- Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.
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8
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Park YS, Kook MC, Kim BH, Lee HS, Kang DW, Gu MJ, Shin OR, Choi Y, Lee W, Kim H, Song IH, Kim KM, Kim HS, Kang G, Park DY, Jin SY, Kim JM, Choi YJ, Chang HK, Ahn S, Chang MS, Han SH, Kwak Y, Seo AN, Lee SH, Cho MY. A standardized pathology report for gastric cancer: 2nd edition. J Pathol Transl Med 2023; 57:1-27. [PMID: 36647283 PMCID: PMC9846007 DOI: 10.4132/jptm.2022.12.23] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 01/18/2023] Open
Abstract
The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.
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Affiliation(s)
- Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Baek-hui Kim
- Department of Pathology, Korea University Guro Hospital, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Dong-Wook Kang
- Department of Pathology, Chungnam National University Sejong Hospital, Chungnam National University School of Medicine, Sejong, Korea
| | - Mi-Jin Gu
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea
| | - Ok Ran Shin
- Department of Hospital Pathology, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
| | - Younghee Choi
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
| | - Wonae Lee
- Department of Pathology, Dankook University College of Medicine, Cheonan, Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - In Hye Song
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Sung Kim
- Department of Pathology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea
| | - Guhyun Kang
- LabGenomics Clinical Laboratories, Seongnam, Korea
| | | | - So-Young Jin
- Department of Pathology, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Joon Mee Kim
- Department of Pathology, Inha University School of Medicine, Incheon, Korea
| | - Yoon Jung Choi
- Department of Pathology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Hee Kyung Chang
- Department of Pathology, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Song-Hee Han
- Department of Pathology, Dong-A University College of Medicine, Busan, Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - Sung Hak Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mee-Yon Cho
- Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - The Gastrointestinal Pathology Study Group of the Korean Society of Pathologists
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Center for Gastric Cancer, National Cancer Center, Goyang, Korea
- Department of Pathology, Korea University Guro Hospital, Seoul, Korea
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Chungnam National University Sejong Hospital, Chungnam National University School of Medicine, Sejong, Korea
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea
- Department of Hospital Pathology, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
- Department of Pathology, Dankook University College of Medicine, Cheonan, Korea
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Pathology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea
- LabGenomics Clinical Laboratories, Seongnam, Korea
- St. Maria Pathology Laboratory, Busan, Korea
- Department of Pathology, Soonchunhyang University Seoul Hospital, Seoul, Korea
- Department of Pathology, Inha University School of Medicine, Incheon, Korea
- Department of Pathology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
- Department of Pathology, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Dong-A University College of Medicine, Busan, Korea
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
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9
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Deep learning model to predict Epstein-Barr virus associated gastric cancer in histology. Sci Rep 2022; 12:18466. [PMID: 36323712 PMCID: PMC9630260 DOI: 10.1038/s41598-022-22731-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 10/18/2022] [Indexed: 11/20/2022] Open
Abstract
The detection of Epstein-Barr virus (EBV) in gastric cancer patients is crucial for clinical decision making, as it is related with specific treatment responses and prognoses. Despite its importance, the limited medical resources preclude universal EBV testing. Herein, we propose a deep learning-based EBV prediction method from H&E-stained whole-slide images (WSI). Our model was developed using 319 H&E stained WSI (26 EBV positive; TCGA dataset) from the Cancer Genome Atlas, and 108 WSI (8 EBV positive; ISH dataset) from an independent institution. Our deep learning model, EBVNet consists of two sequential components: a tumor classifier and an EBV classifier. We visualized the learned representation by the classifiers using UMAP. We externally validated the model using 60 additional WSI (7 being EBV positive; HGH dataset). We compared the model's performance with those of four pathologists. EBVNet achieved an AUPRC of 0.65, whereas the four pathologists yielded a mean AUPRC of 0.41. Moreover, EBVNet achieved an negative predictive value, sensitivity, specificity, precision, and F1-score of 0.98, 0.86, 0.92, 0.60, and 0.71, respectively. Our proposed model is expected to contribute to prescreen patients for confirmatory testing, potentially to save test-related cost and labor.
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10
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Zhang Y, Zhang Q, Xu L, Wang W, Xiao H, Luo B. Analysis of the relationship between the expression of EBV-related antibodies and ET-1 axis in gastric cancer. Cancer Biomark 2022; 35:321-329. [DOI: 10.3233/cbm-220001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND AND OBJECTIVE: EBV-associated gastric cancer (EBVaGC) is a distinct subtype of GC, and EBV plays an important role in tumor progress. The standard method to identify EBV-positive tumor is determined by in situ hybridization for EBV-encoded EBERs in tumor tissues. The present study aims to detect the serological expression of EBV-related antibodies and ET-1 axis to provide a noninvasive method for diagnosis of EBVaGC. METHODS: The content of EBV-related antibodies and ET-1 axis in preoperative peripheral blood of GC was performed by Chemiluminescence and ELISA assay. The EBV DNA copy number was measured by qRT-PCR. RESULTS: The results showed that the levels of anti-EBV early antigen (EA) IgG, viral capsid antigen (VCA) IgA, nuclear antigen (NA) IgG, and EBV DNA copy number were significantly higher in EBVaGC. The ET-1 axis level was much lower in EBVaGC than EBVnGC. CONCLUSIONS: The combined detection of specific anti-EBV antibodies and ET-1 axis might provide new molecular markers for the identification of EBVaGC.
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Affiliation(s)
- Yan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Laboratory, Zibo Central Hospital, Zibo, Shandong, China
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Qianqian Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Lin Xu
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong, China
| | - Weiwen Wang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Hua Xiao
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
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11
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Vuong TTL, Song B, Kwak JT, Kim K. Prediction of Epstein-Barr Virus Status in Gastric Cancer Biopsy Specimens Using a Deep Learning Algorithm. JAMA Netw Open 2022; 5:e2236408. [PMID: 36205993 PMCID: PMC9547324 DOI: 10.1001/jamanetworkopen.2022.36408] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
IMPORTANCE Epstein-Barr virus (EBV)-associated gastric cancer (EBV-GC) is 1 of 4 molecular subtypes of GC and is confirmed by an expensive molecular test, EBV-encoded small RNA in situ hybridization. EBV-GC has 2 histologic characteristics, lymphoid stroma and lace-like tumor pattern, but projecting EBV-GC at biopsy is difficult even for experienced pathologists. OBJECTIVE To develop and validate a deep learning algorithm to predict EBV status from pathology images of GC biopsy. DESIGN, SETTING, AND PARTICIPANTS This diagnostic study developed a deep learning classifier to predict EBV-GC using image patches of tissue microarray (TMA) and whole slide images (WSIs) of GC and applied it to GC biopsy specimens from GCs diagnosed at Kangbuk Samsung Hospital between 2011 and 2020. For a quantitative evaluation and EBV-GC prediction on biopsy specimens, the area of each class and the fraction in total tissue or tumor area were calculated. Data were analyzed from March 5, 2021, to February 10, 2022. MAIN OUTCOMES AND MEASURES Evaluation metrics of predictive model performance were assessed on accuracy, recall, precision, F1 score, area under the receiver operating characteristic curve (AUC), and κ coefficient. RESULTS This study included 137 184 image patches from 16 TMAs (708 tissue cores), 24 WSIs, and 286 biopsy images of GC. The classifier was able to classify EBV-GC image patches from TMAs and WSIs with 94.70% accuracy, 0.936 recall, 0.938 precision, 0.937 F1 score, and 0.909 κ coefficient. The classifier was used for predicting and measuring the area and fraction of EBV-GC on biopsy tissue specimens. A 10% cutoff value for the predicted fraction of EBV-GC to tissue (EBV-GC/tissue area) produced the best prediction results in EBV-GC biopsy specimens and showed the highest AUC value (0.8723; 95% CI, 0.7560-0.9501). That cutoff also obtained high sensitivity (0.895) and moderate specificity (0.745) compared with experienced pathologist sensitivity (0.842) and specificity (0.854) when using the presence of lymphoid stroma and a lace-like pattern as diagnostic criteria. On prediction maps, EBV-GCs with lace-like pattern and lymphoid stroma showed the same prediction results as EBV-GC, but cases lacking these histologic features revealed heterogeneous prediction results of EBV-GC and non-EBV-GC areas. CONCLUSIONS AND RELEVANCE This study showed the feasibility of EBV-GC prediction using a deep learning algorithm, even in biopsy samples. Use of such an image-based classifier before a confirmatory molecular test will reduce costs and tissue waste.
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Affiliation(s)
- Trinh Thi Le Vuong
- School of Electrical Engineering, Korea University, Seoul, Republic of Korea
| | - Boram Song
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin T. Kwak
- School of Electrical Engineering, Korea University, Seoul, Republic of Korea
| | - Kyungeun Kim
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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12
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Abstract
Gastric cancer (GC) is one of the most common lethal malignant neoplasms worldwide, with limited treatment options for both locally advanced and/or metastatic conditions, resulting in a dismal prognosis. Although the widely used morphological classifications may be helpful for endoscopic or surgical treatment choices, they are still insufficient to guide precise and/or personalized therapy for individual patients. Recent advances in genomic technology and high-throughput analysis may improve the understanding of molecular pathways associated with GC pathogenesis and aid in the classification of GC at the molecular level. Advances in next-generation sequencing have enabled the identification of several genetic alterations through single experiments. Thus, understanding the driver alterations involved in gastric carcinogenesis has become increasingly important because it can aid in the discovery of potential biomarkers and therapeutic targets. In this article, we review the molecular classifications of GC, focusing on The Cancer Genome Atlas (TCGA) classification. We further describe the currently available biomarker-targeted therapies and potential biomarker-guided therapies. This review will help clinicians by providing an inclusive understanding of the molecular pathology of GC and may assist in selecting the best treatment approaches for patients with GC.
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Affiliation(s)
- Moonsik Kim
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea.
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13
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Cheng R, Xu Y, Yue B. Short-term outcomes of three rare cases of intramucosal Epstein-Barr virus-associated gastric cancer treated with endoscopic submucosal dissection. J Int Med Res 2022; 50:3000605221115162. [PMID: 35915584 PMCID: PMC9350515 DOI: 10.1177/03000605221115162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Epstein-Barr virus-associated gastric cancer (EBVaGC) is a subtype of gastric cancer morphologically characterized by massive lymphocyte infiltration. We herein report the short-term outcomes of three rare cases of intramucosal EBVaGC treated with endoscopic submucosal dissection (ESD). Histologically, the lesions exhibited poorly to moderately differentiated tubular adenocarcinoma without lymphovascular invasion, and in situ hybridization revealed EBV-encoded small RNA. Helicobacter pylori infection was not found in any of the lesions. During the 3 to 12 months of follow-up following ESD, none of the ESD-treated patients showed evidence of local recurrence or distant metastases. Essential characteristics of intramucosal EBVaGC may include lymphocyte infiltration into the mucosal stroma or cancer nests as well as the presence of a lace pattern. We believe that ESD might be a safe and suitable treatment method for intramucosal EBVaGC that avoids needless surgery, particularly in patients with severe comorbidities or a high operational risk.
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Affiliation(s)
- Rui Cheng
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yao Xu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bing Yue
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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14
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Zhao MH, Liu W, Zhang Y, Liu JJ, Song H, Luo B. Epstein-Barr virus miR-BART4-3p regulates cell proliferation, apoptosis, and migration by targeting AXL in gastric carcinoma. Virus Genes 2022; 58:23-34. [PMID: 35083633 DOI: 10.1007/s11262-021-01882-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 12/10/2021] [Indexed: 12/29/2022]
Abstract
To investigate the role of miR-BART4-3p in EBV-associated gastric cancer (EBVaGC) and its regulation of cell proliferation, apoptosis, and migration by targeting AXL in GC. Quantitative real-time PCR and western blot were used to detect the expression of AXL. The methylation status of AXL gene promoter region was determined by bisulfite sequencing PCR. Luciferase reporter assay was used to detect whether miR-BART4-3p targets AXL. The key molecules of EMT and PI3K/AKT pathway were used to examine by western blot. CCK8, Transwell, and flow cytometry were used to detect the phenotypic gastric cancer cells after interference with AXL and miR-BART4-3p. EBV infection inhibited the expression of AXL in GC cells and the inhibition was not caused by the change of promoter methylation status. MiR-BART4-3p directly targeted AXL. Moreover, both inhibition of miR-BART4-3p and AXL inhibited cell proliferation and migration and promoted cell apoptosis. In addition, E-cadherin, Vimentin, ZEB1, and p-AKT were found to be the downstream molecules of the miR-BART4-3p/AXL pathway. The change of promoter methylation status was not the reason for the downregulation of AXL expression in EBV-positive cells. MiR-BART4-3p may inhibit the proliferation and migration and promote apoptosis of GC cells by directly targeting AXL.
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Affiliation(s)
- Meng-He Zhao
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, People's Republic of China
| | - Wen Liu
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, People's Republic of China
| | - Yan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, People's Republic of China.,Department of Clinical Laboratory, Central Hospital of Zibo, 19 Gongqingtuan Road, Zibo, 255036, People's Republic of China
| | - Juan-Juan Liu
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, People's Republic of China
| | - Hui Song
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, People's Republic of China
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, People's Republic of China.
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15
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Manuel Lopes de Sousa H, Patrícia Costa Ribeiro J, Basílio Timóteo M. Epstein-Barr Virus-Associated Gastric Cancer: Old Entity with New Relevance. Infect Dis (Lond) 2021. [DOI: 10.5772/intechopen.93649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Gastric cancer (GC) represents a major public health issue worldwide, being the fifth most common cancer and one of the leading causes of death by cancer. In 2014, The Cancer Genome Atlas (TCGA) established that tumors positive for Epstein-Barr virus (EBV) are considered a specific subtype of GC (EBVaGC). Several meta-analyses have shown that EBVaGC represents almost 10% of all gastric cancer worldwide, with small differences in the geographic distribution. This tumor subtype has a high potential of being clinically relevant and studies have shown that it has specific features, a better prognosis, and increased overall survival. In this review, we summarize some of the most frequent aspects of EBVaGC, including the specific features of this GC subtype, data regarding the potential steps of EBVaGC carcinogenesis, and perspectives on treatment opportunities.
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16
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de Fátima Aquino Moreira-Nunes C, de Souza Almeida Titan Martins CN, Feio D, Lima IK, Lamarão LM, de Souza CRT, Costa IB, da Silva Maués JH, Soares PC, de Assumpção PP, Burbano RMR. PD-L1 Expression Associated with Epstein-Barr Virus Status and Patients' Survival in a Large Cohort of Gastric Cancer Patients in Northern Brazil. Cancers (Basel) 2021; 13:3107. [PMID: 34206307 PMCID: PMC8268941 DOI: 10.3390/cancers13133107] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 05/31/2021] [Accepted: 06/03/2021] [Indexed: 12/15/2022] Open
Abstract
Gastric cancer (GC) is a worldwide health problem, making it one of the most common types of cancer, in fifth place of all tumor types, and the third highest cause of cancer deaths in the world. There is a subgroup of GC that consists of tumors infected with the Epstein-Barr virus (EBV) and is characterized mainly by the overexpression of programmed cell death protein-ligand-1 (PD-L1). In the present study, we present histopathological and survival data of a thousand GC patients, associated with EBV status and PD-L1 expression. Of the thousand tumors analyzed, 190 were EBV-positive and the vast majority (86.8%) had a high relative expression of mRNA and PD-L1 protein (p < 0.0001) in relation to non-neoplastic control. On the other hand, in EBV-negative samples, the majority had a low PD-L1 expression of RNA and protein (p < 0.0001). In the Kaplan-Meier analysis, the probability of survival and increased overall survival of EBV-positive GC patients was impacted by the PD-L1 overexpression (p < 0.0001 and p = 0.004, respectively). However, the PD-L1 low expression was correlated with low overall survival in those patients. Patients with GC positive for EBV, presenting PD-L1 overexpression can benefit from immunotherapy treatments and performing the quantification of PD-L1 in gastric neoplasms should be adopted as routine.
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Affiliation(s)
- Caroline de Fátima Aquino Moreira-Nunes
- Laboratory of Molecular Biology, Department of Clinical Medicine, Ophir Loyola Hospital, Belém, 66063-240 PA, Brazil; (C.N.d.S.A.T.M.); (D.F.); (I.K.L.); (P.C.S.)
- Laboratory of Pharmacogenetics, Department of Medicine, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, 60430-275 CE, Brazil
| | | | - Danielle Feio
- Laboratory of Molecular Biology, Department of Clinical Medicine, Ophir Loyola Hospital, Belém, 66063-240 PA, Brazil; (C.N.d.S.A.T.M.); (D.F.); (I.K.L.); (P.C.S.)
| | - Isamu Komatsu Lima
- Laboratory of Molecular Biology, Department of Clinical Medicine, Ophir Loyola Hospital, Belém, 66063-240 PA, Brazil; (C.N.d.S.A.T.M.); (D.F.); (I.K.L.); (P.C.S.)
| | - Leticia Martins Lamarão
- Foundation Center for Hemotherapy and Hematology of Pará (HEMOPA), Department of Sorology, Belém, 66033-000 PA, Brazil;
| | | | - Igor Brasil Costa
- Department of Virology, Evandro Chagas Institute, Ananindeua, 67030-000 PA, Brazil;
| | - Jersey Heitor da Silva Maués
- Hematology and Transfusion Medicine Center, Laboratory of Molecular and Cell Biology, Department of Medicine, University of Campinas, Campinas, 13083-970 SP, Brazil;
| | - Paulo Cardoso Soares
- Laboratory of Molecular Biology, Department of Clinical Medicine, Ophir Loyola Hospital, Belém, 66063-240 PA, Brazil; (C.N.d.S.A.T.M.); (D.F.); (I.K.L.); (P.C.S.)
| | - Paulo Pimentel de Assumpção
- Oncology Research Center, Department of Biological Sciences, Federal University of Pará, Belém, 66073-005 PA, Brazil;
| | - Rommel Mário Rodríguez Burbano
- Laboratory of Molecular Biology, Department of Clinical Medicine, Ophir Loyola Hospital, Belém, 66063-240 PA, Brazil; (C.N.d.S.A.T.M.); (D.F.); (I.K.L.); (P.C.S.)
- Oncology Research Center, Department of Biological Sciences, Federal University of Pará, Belém, 66073-005 PA, Brazil;
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17
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Tsuji Y, Ushiku T, Shinozaki T, Yamashita H, Seto Y, Fukayama M, Fujishiro M, Oda I, Katai H, Taniguchi H, Hasatani K, Kaizaki Y, Oga A, Nishikawa J, Akasaka R, Endo M, Sugai T, Matsumoto T, Koike K. Risk for lymph node metastasis in Epstein-Barr virus-associated gastric carcinoma with submucosal invasion. Dig Endosc 2021; 33:592-597. [PMID: 32852875 DOI: 10.1111/den.13823] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 08/09/2020] [Accepted: 08/19/2020] [Indexed: 12/29/2022]
Abstract
OBJECTIVES Epstein-Barr virus-associated gastric cancer (EBVGC) has been reported to be associated with a low risk for lymph node metastasis (LNM). However, the curative criteria for endoscopic submucosal dissection (ESD) for submucosal EBVGC (pT1b-EBVGC) remain unclear. Our study aimed to investigate the risk factors for LNM in pT1b-EBVGC. METHODS This was a retrospective multicenter study at five institutes in Japan. We reviewed medical records and extracted all pT1b-EBVGC cases that met the following criteria: (i) histologically proven submucosal gastric cancer; (ii) surgical or endoscopic resection between January 2000 and December 2016; and (iii) presence of Epstein-Barr virus (EBV) in tumor cells verified by EBV-encoded small RNA in situ hybridization (EBER-ISH). The association between clinicopathological factors and LNM were assessed using multivariable logistic regression analysis. RESULTS A total of 185 pT1b-EBVGC cases were included in the analysis. LNM was found in nine cases (4.9%). Multivariable logistic regression analysis demonstrated that lymphatic invasion (OR 9.1; 95% CI 2.1-46.1) and submucosal invasion ≥4000 μm (OR 9.2; 95% CI 1.3-110.3) were significant risk factors for LNM. When we focused on pT1b-EBVGC without lymphatic invasion and with submucosal invasion <2000 μm, the rate of LNM was 0% (0/96, 95% CI 0-3.8%). CONCLUSIONS Our findings indicated that lymphatic invasion and submucosal invasion ≥4000 μm were significant risk factors for LNM. ESD could be an appropriate option for pT1b-EBVGC without lymphatic invasion and with submucosal invasion <2000 μm.
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Affiliation(s)
- Yosuke Tsuji
- Departments of, Department of, Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomohiro Shinozaki
- Department of Information and Computer Technology, Faculty of Engineering, Tokyo University of Science, Tokyo, Japan
| | - Hiroharu Yamashita
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masashi Fukayama
- Asahi TelePathology Center, Asahi General Hospital, Chiba, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Ichiro Oda
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Hitoshi Katai
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Hirokazu Taniguchi
- Department of Clinical Laboratory, JR Tokyo General Hospital, Tokyo, Japan
| | - Kenkei Hasatani
- Departments of, Department of, Gastroenterology, Fukui Prefectural Hospital, Fukui, Japan
| | - Yasuharu Kaizaki
- Department of, Pathology, Fukui Prefectural Hospital, Fukui, Japan
| | - Atsunori Oga
- Department of Molecular Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Jun Nishikawa
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Risaburo Akasaka
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Masaki Endo
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Iwate, Japan
- Kaiunbashi Endoscopy Clinic, Iwate, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Kazuhiko Koike
- Departments of, Department of, Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Yanai H, Chihara D, Harano M, Sakaguchi E, Murakami T, Nishikawa J. Endoscopic and pathologic motifs for the clinical diagnosis of Epstein–Barr virus‐associated gastric cancer. DEN OPEN 2021; 1:e7. [PMID: 35310151 PMCID: PMC8828195 DOI: 10.1002/deo2.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/25/2021] [Accepted: 02/27/2021] [Indexed: 12/04/2022]
Abstract
Objectives Based on the recent therapeutic trends for gastric cancer (GC), the clinical impact of the diagnosis of Epstein–Barr virus (EBV)‐associated GC (EBVaGC) appears to be important. We retrospectively analyzed endoscopic and pathologic motifs of GC lesions to narrow the number of candidates for EBV testing. Methods We performed EBV tests for 32 upper gastrointestinal lesions of 32 patients in the clinical setting. These tests were ordered by endoscopists or by pathologists without an endoscopist's order. EBV‐encoded small RNA1 (EBER1) in situ hybridization was used for the EBV tests. The endoscopic motif for the EBV test was the location in the upper part of the stomach or remnant stomach, mainly the depressed type with a submucosal tumor‐like protrusion of the lesion. The pathologic motif was carcinoma with lymphoid stroma (CLS) or CLS‐like histology of the lesion. We retrospectively analyzed the results of EBV tests for the endoscopic and pathologic motifs. Results The final pathological diagnoses of the 32 subjects were 26 GCs including CLS, gastric endocrine cell carcinoma, gastric hepatoid carcinoma, gastric T‐cell lymphoma, gastritis of the remnant stomach, esophageal adenocarcinoma, and esophageal squamous cell carcinoma. When nontypical lesions were excluded, the EBER1‐positive rate was 42.3% (11/26) in GCs. Of the 14 GC lesions ordered examined by endoscopists, three (21.4%) were EBVaGC. Eight of the 12 (66.7%) GCs ordered examined by pathologists were EBVaGC. Conclusions The pathologic motif is expected to be useful and the endoscopic motif may be helpful for EBVaGC diagnosis.
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Affiliation(s)
- Hideo Yanai
- Department of Clinical Research National Hospital Organization Kanmon Medical Center Yamaguchi Japan
| | - Daisuke Chihara
- Department of Gastroenterology & Hepatology National Hospital Organization Kanmon Medical Center Yamaguchi Japan
| | - Megumi Harano
- Department of Gastroenterology & Hepatology National Hospital Organization Kanmon Medical Center Yamaguchi Japan
| | - Eiki Sakaguchi
- Department of Gastroenterology & Hepatology National Hospital Organization Kanmon Medical Center Yamaguchi Japan
| | - Tomoyuki Murakami
- Department of Pathology National Hospital Organization Kanmon Medical Center Yamaguchi Japan
| | - Jun Nishikawa
- Department of Laboratory Science Graduate School of Medicine, Yamaguchi University Yamaguchi Japan
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19
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Wei J, Zhang Y, Liu Y, Wang A, Fan B, Fu T, Jia Z, He L, Ji K, Ji X, Wu X, Zhang J, Li Z, Zhang L, Bu Z, Ji J. Construction and Validation of a Risk-Scoring Model that Preoperatively Predicts Lymph Node Metastasis in Early Gastric Cancer Patients. Ann Surg Oncol 2021; 28:6665-6672. [PMID: 33783640 DOI: 10.1245/s10434-021-09867-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/04/2021] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The aim of this study was to create a risk-scoring model to preoperatively predict the incidence of lymph node metastasis (LNM) in early gastric cancer (EGC) patients to guide treatment. METHODS To construct the risk-scoring model, we retrospectively analyzed a primary cohort of 548 EGC patients. Univariate analysis and logistic regression were performed. A risk-scoring model for predicting LNM in EGC patients was developed based on preoperative factors, and another cohort of 73 patients was then analyzed to validate the model. RESULTS In the primary cohort, LNM was pathologically confirmed in 72 (13.1%) patients. In the multivariate analysis, the presence of ulceration and tumor size on gastroscopy, undifferentiated histological type, and presence of enlarged lymph nodes on computed tomography or endoscopic ultrasonography were independent risk factors for LNM. A 17-point risk-scoring model was developed to predict LNM risk. The cut-off score of the model was 8, and the area under the receiver operating characteristic curve (AUC) of the model was 0.835 [95% confidence interval (CI) 0.784-0.886]. In the validation cohort, the AUC of the model was 0.829 (95% CI 0.699-0.959). CONCLUSIONS We developed and validated an effective 17-point risk-scoring model that could preoperatively predict LNM for EGC patients.
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Affiliation(s)
- Jingtao Wei
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yinan Zhang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yiqiang Liu
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Anqiang Wang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Biao Fan
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Tao Fu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ziyu Jia
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Liu He
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ke Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xin Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xiaojiang Wu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ji Zhang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ziyu Li
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Lianhai Zhang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Zhaode Bu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
| | - Jiafu Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
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20
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Lee BE. Epstein-Barr Virus-associated Gastric Carcinoma. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2021. [DOI: 10.7704/kjhugr.2020.0063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Epstein-Barr virus-associated gastric carcinoma (EBVaGC) comprises approximately 10% of all gastric cancers and is now defined as one of the four subtypes of gastric cancer according to the molecular classification proposed by the Cancer Genome Atlas project. EBVaGC has characteristic genetic profiles that harbor a DNA methylation phenotype, frequent mutations in PIK3CA and ARID1A, and amplification of JAK2 and programmed death-ligand (PD-L)1/PD-L2. Therefore, EBVaGC shows several distinct clinicopathological features, including a male predominance, proximal stomach location, gastric carcinoma with lymphoid stroma histology, low risk of lymph node metastasis, and favorable prognosis. In clinical practice, patients with early EBVaGC might be good candidates for endoscopic resection or minimally invasive surgery since the rate of lymph node metastasis is very low, even with deep submucosal invasion. Furthermore, in the case of advanced EBVaGC, the applicability of immunotherapy has been investigated based on its increased expression of PD-L1 and high immunogenicity. In conclusion, EBV can serve as a biomarker in gastric cancer, and further identification of other molecular characteristics of EBVaGC is essential for new potential therapeutic targets.
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21
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Chen J, Wu L, Zhang Z, Zheng S, Lin Y, Ding N, Sun J, Shi L, Xue M. A clinical model to predict distant metastasis in patients with superficial gastric cancer with negative lymph node metastasis and a survival analysis for patients with metastasis. Cancer Med 2020; 10:944-955. [PMID: 33350173 PMCID: PMC7897959 DOI: 10.1002/cam4.3680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Distant metastasis (DM) is relatively rare in superficial gastric cancer (SGC), especially in patients without lymph node metastasis. This study aimed to explore the main clinical risk factors for DM in patients with superficial gastric cancer-no lymph node metastasis (SGC-NLNM) and the prognostic factors for patients with DM. METHODS Records of patients with SGC-NLNM between 2004 and 2015 were collected from the public Surveillance, Epidemiology, and End Results (SEER) database. Both univariate and multivariate logistic regressions were performed to analyze the clinical risk factors for DM. The Kaplan-Meier method and Cox regression model were used to identify prognostic factors for patients with DM. A nomogram was built based on multivariate logistic regression and evaluated by the C-index, the calibration, and the area under the receiver operating characteristic curve (AUC). RESULTS We developed and validated a nomogram to predict DM in patients with SGC-NLNM, showing that race, age, primary site, depth, size, and grade were independent risk factors. The built nomogram had a good discriminatory performance, with a C-index of 0.836 (95% confidence interval [CI]: 0.813-0.859). Calibration plots showed that the predicted DM probability was identical to the actual observations in both the training and validation sets. AUC was 0.846 (95% CI: 0.820-0.871) and 0.801 (95% CI: 0.751-0.850) in the training and validation sets, respectively. The results of the survival analysis revealed that surgery (hazard ratio [HR] = 0.249; 95% CI, 0.125-0.495), chemotherapy (HR = 0.473; 95% CI, 0.353-0.633), and grade (HR = 1.374; 95% CI, 1.018-1.854) were independent prognostic factors associated with cancer-specific survival (CSS), but radiotherapy was not (log-rank test, p = 0.676). CONCLUSIONS We constructed a sensitive and discriminative nomogram to identify high-risk patients with SGC-NLNM who may harbor dissemination at initial diagnosis. The tumor size and primary site were the largest contributors to DM prediction. Compared with radiotherapy, aggressive surgery, and chemotherapy may be better options for patients with DM.
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Affiliation(s)
- Jingyu Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Lunpo Wu
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Zizhen Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Sheng Zheng
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Yifeng Lin
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Ning Ding
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Jiawei Sun
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Liuhong Shi
- Department of Ultrasound, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Meng Xue
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, China
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22
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Ignatova E, Seriak D, Fedyanin M, Tryakin A, Pokataev I, Menshikova S, Vakhabova Y, Smirnova K, Tjulandin S, Ajani JA. Epstein-Barr virus-associated gastric cancer: disease that requires special approach. Gastric Cancer 2020; 23:951-960. [PMID: 32514646 DOI: 10.1007/s10120-020-01095-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
Epstein-Barr virus-associated gastric cancer [EBV-associated GC, EBV( +) GC] is a distinct molecular subtype of gastrointestinal (GI) cancers. It accounts for up to 10% of all molecular subtypes of gastric cancer (GC). It has unique genetic and epigenetic features, which determine its definitive phenotype with male and younger age predominance, proximal stomach localization, and diffuse adenocarcinoma histology. EBV( +) GC also has a unique epigenetic profile and mutational status with frequent mutations of PIK3CA, ARID1A and BCOR, and PD-L1 and PD-L2 amplifications, as well. The aim of this review is to highlight clinical significance of EBV( +) GC and prognostic role of EBV infection, and to determine potentially appropriate drug therapy for this disease.
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Affiliation(s)
- Ekaterina Ignatova
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation.
| | - Daria Seriak
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation
| | - Mikhail Fedyanin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Alexey Tryakin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Ilya Pokataev
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Sofia Menshikova
- Department of Anticancer Drug Treatment, AO K31 City, Moscow, Russian Federation
| | - Yuliya Vakhabova
- Chemotherapy Department of Tumors Drug Treatment, Moscow Scientific Research Oncological Institution N.a. P.A. Herzen, Branch of Federal State Budgetary Institution "National Medical Research Center of Radiology" of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
| | - Ksenia Smirnova
- Laboratory of Viral Carcinogenesis, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
| | - Sergey Tjulandin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
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23
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Zheng D, Chen B, Shen Z, Gu L, Wang X, Ma X, Chen P, Mao F, Wang Z. Prognostic factors in stage I gastric cancer: A retrospective analysis. Open Med (Wars) 2020; 15:754-762. [PMID: 33336033 PMCID: PMC7712043 DOI: 10.1515/med-2020-0164] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/27/2020] [Accepted: 07/14/2020] [Indexed: 01/15/2023] Open
Abstract
Purpose The purpose of this research is to investigate the prognostic factors of patients with stage I gastric cancer (GC) and to determine whether adjuvant chemotherapy improves the prognosis for high-risk patients. Methods We performed a retrospective analysis at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, and HwaMei Hospital, University of Chinese Academy of Sciences from January 2001 to December 2015. Cox regression and Kaplan-Meier were used to evaluate the relationship between the patients’ clinicopathologic characteristics and prognosis. Results A total of 1,550 patients were eligible for the study. The 5-year disease-free survival (DFS) rate of all enrolled patients was 96.5%. The pT and pN stages were significantly associated with the prognosis. The 5-year DFS rates of the three subgroups (T1N0, T2N0, and T1N1) were 97.8%, 95.7%, and 90.5%, respectively (p < 0.001). In the T1N1 subgroup, patients not undergoing chemotherapy showed a lower 5-year DFS rate compared to those undergoing chemotherapy, although the difference was not statistically significant. Conclusions Both the pT and pN stages were closely associated with the prognosis of patients with stage I GC. We also found that the danger coefficient of the pN stage was higher than that of the pT stage, and that postoperative adjuvant chemotherapy might be a reasonable approach to improve outcomes of high-risk patients, particularly in the T1N1 group.
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Affiliation(s)
- Dingcheng Zheng
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China.,Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, Zhejiang, China.,Ningbo Clinical Research Center for Digestive System Tumors, Ningbo, Zhejiang, China
| | - Bangsheng Chen
- Emergency Medical Center, Ningbo Yinzhou No. 2 Hospital, Ningbo, Zhejiang, China
| | - Zefeng Shen
- Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China
| | - Lihu Gu
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Xianfa Wang
- Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China
| | - Xueqiang Ma
- Department of General Surgery, Zhuji People's Hospital, Shaoxing, Zhejiang, China
| | - Ping Chen
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Feiyan Mao
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Zhiyan Wang
- Department of General Surgery, Ningbo Yinzhou No. 2 Hospital, 998 North Qianhe Road, Ningbo, Yinzhou District, Zhejiang, China
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24
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Osumi H, Kawachi H, Yoshio T, Fujisaki J. Clinical impact of Epstein-Barr virus status on the incidence of lymph node metastasis in early gastric cancer. Dig Endosc 2020; 32:316-322. [PMID: 31762090 DOI: 10.1111/den.13584] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 11/20/2019] [Indexed: 02/08/2023]
Abstract
Epstein-Barr virus-positive gastric cancer (EBVGC) comprises approximately 9% of all gastric cancers and is associated with a low prevalence of lymph node metastasis (LNM). Given that limited data concerning LNM in EBV-related early GC are available, EBV status is not considered an indicator for endoscopic submucosal dissection (ESD). In this review, we focused on pT1 EBVGC and on gastric carcinoma with lymphoid stroma (GCLS), and discuss expanded ESD indications and curative resection criteria. In pT1b EBVGC, the incidence of LNM was low (6/180 patients, 3.3%; 95% confidence interval [CI] 1.2-7.1), especially in lymphovascular invasion-negative EBVGC (1/109 patients, 0.9%). No patients with pT1a EBVGC had LNM (0/38 patients, 0%; 95% CI 0-7.6), even those who did not meet the current curative ESD criteria. Although the frequency of LNM in GCLS was low (5.0-10.6%), the incidence of LNM in non-EBV GCLS was relatively high (10.0-20.0%); therefore, EBV status can be considered a more important factor than GCLS. In summary, the clinicopathological characteristics of EBVGC differ from those of conventional GC, and EBV negativity is a risk factor for LNM in early GC. Therefore, patients in this group are likely to be promising candidates for ESD, and we recommend that EBV status evaluation be included in early GC treatment guidelines.
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Affiliation(s)
- Hiroki Osumi
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
| | - Hiroshi Kawachi
- Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
| | - Toshiyuki Yoshio
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
| | - Junko Fujisaki
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
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Nishikawa J, Shuto T, Yanagi A, Takagi T, Ogawa R, Sasaki S, Goto A, Hamabe K, Hashimoto S, Okamoto T, Sakaida I. Epstein-Barr virus-associated gastric carcinomas developed after successful eradication of Helicobacter pylori. Clin J Gastroenterol 2020; 13:506-511. [PMID: 31970662 DOI: 10.1007/s12328-020-01094-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 01/09/2020] [Indexed: 12/28/2022]
Abstract
Epstein-Barr virus-associated gastric carcinoma (EBVaGC) can develop in gastric mucosa affected by Helicobacter pylori (H. pylori)-induced atrophic gastritis. However, it is unclear whether EBVaGC can develop in gastric mucosa after successful eradication of H. pylori. We report 3 cases of EBVaGC discovered more than 5 years after successful eradication of H. pylori. All 3 cases are men with a history of smoking. The periods from successful eradication to development of EBVaGC were 18, 8, and 9 years, respectively. Their tumors were mainly depressed lesions located in the gastric corpus. Two patients had intramucosal cancer and the other had advanced gastric cancer. Mucosal atrophy was present in the background gastric mucosa of all of three, and the anti-H. pylori antibody titer in each patient had fallen to < 3 U/mL. These cases indicate that EBVaGC can occur after successful eradication of H. pylori.
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Affiliation(s)
- Jun Nishikawa
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
| | - Takuya Shuto
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Ayaka Yanagi
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Tatsuya Takagi
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Ryo Ogawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Sho Sasaki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Atsushi Goto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Kouichi Hamabe
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Shinichi Hashimoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Takeshi Okamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
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26
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Thirty years of Epstein-Barr virus-associated gastric carcinoma. Virchows Arch 2019; 476:353-365. [PMID: 31836926 DOI: 10.1007/s00428-019-02724-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/18/2019] [Accepted: 11/25/2019] [Indexed: 12/13/2022]
Abstract
Thirty years have passed since a possible association of Epstein-Barr virus (EBV) with gastric carcinoma was reported. We now know EBV-associated gastric carcinoma to be a specific subtype of gastric carcinoma. Global epigenetic methylation and counteraction of the antitumour microenvironment are two major characteristics of this subtype of gastric carcinoma. Recent development of therapeutic modalities for gastric carcinoma, such as endoscopic mucosal dissection and immune checkpoint inhibitor therapy, has made the presence of EBV infection a biomarker for the treatment of gastric carcinoma. This review presents a portrait of EBV-associated gastric carcinoma from initiation to maturity that we define as the 'gastritis-infection-cancer sequence', followed by its molecular abnormalities and interactions with immune checkpoint molecules and the microenvironment. EBV non-coding RNAs (microRNA and circular RNA) and exosomes derived from EBV-infected cells that were previously behind the scenes are now recognized for their roles in EBV-associated gastric carcinoma. The virus utilizes cellular machinery skilfully to control infected cells and their microenvironment. We should thus strive to understand virus-host interactions more fully in the following years to overcome this virus-driven subtype of gastric carcinoma.
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27
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Kim DG, An JY, Kim H, Shin SJ, Choi S, Seo WJ, Roh CK, Cho M, Son T, Kim HI, Cheong JH, Hyung WJ, Noh SH, Choi YY. Clinical Implications of Microsatellite Instability in Early Gastric Cancer. J Gastric Cancer 2019; 19:427-437. [PMID: 31897345 PMCID: PMC6928080 DOI: 10.5230/jgc.2019.19.e38] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 08/31/2019] [Accepted: 10/07/2019] [Indexed: 12/17/2022] Open
Abstract
Purpose We aimed to evaluate the clinical characteristics of microsatellite instability in early gastric cancer. Materials and Methods The microsatellite instability status of resected early gastric tumors was evaluated using two mononucleotide repeat markers (BAT25 and BAT26) and three dinucleotide repeat markers (D5S346, D2S123, and D17S250). Tumors with instability in two or more markers were defined as microsatellite instability-high (MSI-H) and others were classified as microsatellite stable (MSS). Results Overall, 1,156 tumors were included in the analysis, with 85 (7.4%) classified as MSI-H compared with MSS tumors. For MSI-H tumors, there was a significant correlation with the female sex, older age, tumor location in the lower gastric body, intestinal histology, lymphovascular invasion (LVI), and submucosal invasion (P<0.05). There was also a trend toward an association with lymph node (LN) metastasis (P=0.056). In mucosal gastric cancer, there was no significant difference in MSI status in tumors with LN metastasis or tumors with LVI. In submucosal gastric cancer, LVI was more frequently observed in MSI-H than in MSS tumors (38.9% vs. 25.0%, P=0.027), but there was no difference in the presence of LN metastases. The prognosis of MSI-H tumors was similar to that of MSS tumors (log-rank test, P=0.797, the hazard ratio for MSI-H was adjusted by age, sex, pT stage, and the number of metastatic LNs, 0.932; 95% confidence interval, 0.423–2.054; P=0.861). Conclusions MSI status was not useful in predicting prognosis in early gastric cancer. However, the frequent presence of LVI in early MSI-H gastric cancer may help guide the appropriate treatment for patients, such as endoscopic treatment or limited LN surgical dissection.
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Affiliation(s)
- Dong Gyu Kim
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Yeong An
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Su-Jin Shin
- Department of Pathology, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Seohee Choi
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Won Jun Seo
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Chul Kyu Roh
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Minah Cho
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Taeil Son
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Hyoung-Il Kim
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Woo Jin Hyung
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Young Choi
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
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Risk stratification for lymph node metastasis using Epstein-Barr virus status in submucosal invasive (pT1) gastric cancer without lymphovascular invasion: a multicenter observational study. Gastric Cancer 2019; 22:1176-1182. [PMID: 31062195 DOI: 10.1007/s10120-019-00963-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 04/03/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Lymphovascular invasion (LVI) is a strong predictive factor for lymph node metastasis (LNM) in early gastric cancer (GC). This study investigated the risk for LNM in pT1b GC without LVI based on Epstein-Barr virus (EBV) status in addition to conventional clinicopathological parameters. METHODS In total, 847 consecutive patients of pT1b GC without LVI who underwent surgery at three high-volume centers between 2005 and 2014 were retrospectively analyzed. Clinicopathological parameters and EBV status were evaluated, and univariate and multivariate analyses were performed to estimate LNM risk. With regard to the presence of those three parameters, risk stratification for LNM was performed and compared with a previously proposed risk classification that included low-risk (LNM < 3.0%), intermediate-risk (LNM ≥ 3.0 and < 19.6%), and high-risk (LNM ≥ 19.6%) groups. RESULTS EBV-positive GC (EBVGC) accounted for 11.3% (96 of 847) of cases; LNM was lower in EBVGC than in non-EBVGC (1 of 96, 1.0% vs. 71/751, 9.5%). In the multivariate analysis, non-EBVGC [odds ratio (OR) 10.8, 95% confidence interval (CI) 1.48-78.9], age < 65 years (OR 2.13, 95% CI 1.30-3.48), and tumor diameter > 3 cm (OR 2.26, 95% CI 1.36-3.74) were independent risk factors for LNM. Patients with EBVGC were at low risk for LNM whereas those with all of three independent risk factors were at high risk (36 of 168, 21.4%, 95% CI 15.5-28.4). CONCLUSION LNM risk stratification that includes EBV status is useful for clinical decision-making in pT1b GC cases without LVI.
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Kobayashi Y, Kunogi T, Tanabe H, Murakami Y, Iwama T, Sasaki T, Takahashi K, Ando K, Nomura Y, Ueno N, Kashima S, Moriichi K, Takei H, Fujiya M, Okumura T. Gastric submucosa-invasive carcinoma associated with Epstein-Barr virus and endoscopic submucosal dissection: A case report. World J Gastrointest Oncol 2019; 11:925-932. [PMID: 31662830 PMCID: PMC6815925 DOI: 10.4251/wjgo.v11.i10.925] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 07/24/2019] [Accepted: 08/26/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated carcinoma is a gastric cancer subtype with a morphology characterized by gastric carcinoma with lymphoid stroma (GCLS). Clinicopathological studies have indicated a better prognosis for GCLS than for common gastric carcinomas. Some previous cases of early gastric cancer associated with EBV had been diagnosed by endoscopic resection. CASE SUMMARY We present two GCLS cases subjected to endoscopic submucosal dissection (ESD) for a definitive diagnosis. A protruded gastric lesion was identified by routine endoscopic examination, but forceps biopsy showed no atypical cells before ESD. The resected specimen showed a poorly differentiated adenocarcinoma with lymphoid cells involving the mucosa and submucosa. The final diagnosis was submucosa-invasive poorly differentiated gastric adenocarcinoma. Accordingly, additional gastrectomy was recommended to obtain a complete cure. One patient underwent additional distal gastrectomy with lymph node dissection, but the other was refused because of cardiovascular complications. Both patients remained in remission for more than half a year. EBV positivity was determined by EBV-encoded RNA in situ hybridization. We also conducted a literature review of cases of early gastric cancer associated with EBV that had been diagnosed by ESD. CONCLUSION Submucosa-invasive GCLS could be dissected using ESD, and EBV positivity should be subsequently assessed to determine whether or not any additional curative surgery is required. Further prospective investigations on the prevalence of lymph node metastasis in EBV-associated carcinoma should be performed to expand the indications for endoscopic resection.
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Affiliation(s)
- Yu Kobayashi
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Takehito Kunogi
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Hiroki Tanabe
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Yuki Murakami
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Takuya Iwama
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Takahiro Sasaki
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Keitaro Takahashi
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Katsuyoshi Ando
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Yoshiki Nomura
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Nobuhiro Ueno
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Shin Kashima
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Kentaro Moriichi
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Hidehiro Takei
- Pathological Department of Asahikawa Medical University Hospital, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Mikihiro Fujiya
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
| | - Toshikatsu Okumura
- Division of Gastroenterology and Hematology/Oncology Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
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Wang F, Wu J, Wang Y, Jin Y, Jiang X, Qiu Z, Qin Y, Liu Y, Qi X, Ge X, Mao Y, Cheng Y, Hua D. Gut Microbiota Functional Biomolecules With Immune-Lipid Metabolism for a Prognostic Compound Score in Epstein-Barr Virus-Associated Gastric Adenocarcinoma: A Pilot Study. Clin Transl Gastroenterol 2019; 10:e00074. [PMID: 31609743 PMCID: PMC6884346 DOI: 10.14309/ctg.0000000000000074] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 07/15/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Increasing evidence has indicated an association between gut microbiota in gastrointestinal cancer and clinical outcome. Herein, we aim to develop a prognosis-prediction tool based on an immune-lipid metabolism signature, tumor cell-associated immune microenvironment, and lipid metabolism proteins inferred from the function of gut microbiota. METHODS 16S gene ribosomal RNA sequencing was performed on 10 fecal samples obtained after tumor resection but before chemotherapy (EBVaGC = 4 and EBVnGC = 6). Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to screening for highly accurate marker proteins. A compound score based on the fraction of screened markers was then constructed using a LASSO logistic regression model. RESULTS The Tax4Fun analysis based on Kyoto Encyclopedia of Genes and Genomes data indicated differentially expressed tumor pathway between EBVnGC and EBVaGC. Using the LASSO logistic model, a compound score was established consisting of 14 types of immune microenvironment and lipid metabolism proteins. In the training set (378 patients), significant differences were found between high- and low-compound score groups in overall survival across and within subpopulations with an identical EBV. Multivariable analysis revealed that the compound score was an independent prognostic factor (hazard ratio, 2.26; 95% confidence interval = 2.28-3.36). The prognostic value ;of the compound score was also confirmed in the validation (162 patients) and entire (540 patients) sets. DISCUSSION The proposed compound score is a promising signature for estimating overall survival in patients with gastric cancer having EBVaGCs or EBVnGCs.
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Affiliation(s)
- Fang Wang
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Jingyi Wu
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yan Wang
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
- Key Laboratory of Carbohydrate Chemistry & Biotechnology (Jiangnan University), Ministry of Education, Wuxi, China
| | - Yufen Jin
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xin Jiang
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Zhichao Qiu
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
- Key Laboratory of Carbohydrate Chemistry & Biotechnology (Jiangnan University), Ministry of Education, Wuxi, China
| | - Yan Qin
- Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yankui Liu
- Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xiaowei Qi
- Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xiaosong Ge
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yong Mao
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yang Cheng
- Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Dong Hua
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
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Yanagi A, Nishikawa J, Shimokuri K, Shuto T, Takagi T, Takagi F, Kobayashi Y, Yamamoto M, Miura O, Yanai H, Suehiro Y, Yamasaki T, Yoshiyama H, Sakaida I. Clinicopathologic Characteristics of Epstein-Barr Virus-Associated Gastric Cancer Over the Past Decade in Japan. Microorganisms 2019; 7:microorganisms7090305. [PMID: 31480554 PMCID: PMC6780774 DOI: 10.3390/microorganisms7090305] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/22/2019] [Accepted: 08/30/2019] [Indexed: 12/24/2022] Open
Abstract
: Epstein-Barr virus (EBV) is a ubiquitous human herpes virus, but related with several types of malignancies. Among EBV-related malignancies, EBV-associated gastric carcinoma (EBVaGC) has the largest patient's number. We screened for EBV infection in 1067 GC lesions of 1132 patients who underwent surgical resection from 2007 to 2017 in Japan and examined clinicopathological features of EBVaGC. EBV infection was detected by in situ hybridization with EBV-encoded small RNA 1(EBER-1 ISH). EBV was infected in 80 GC lesions (7.1%). Mean age was significantly lower in patients with EBVaGC than with EBV-negative GC. EBVaGC was more frequent in men than in women. EBVaGC was found twice as frequent in the upper or middle stomach as in the lower stomach. Early EBVaGC was more frequent, and submucosally invaded cases were dominant. The presence of lymphatic vessel invasion was less in EBVaGC, but frequency of lymph node metastasis was similar. Carcinoma with lymphoid stroma (CLS) was found in 3.8% (43/1132) of all lesions with 60.5% of EBV positivity. The synchronous or metachronous multiple GC was frequent in EBVaGC. We clarified clinicopathologic characteristics of EBVaGC over the past decade in Japan. EBV infection should be examined in gastric cancer cases showing these characteristics.
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Affiliation(s)
- Ayaka Yanagi
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
| | - Jun Nishikawa
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
| | - Kanami Shimokuri
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
| | - Takuya Shuto
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
| | - Tatsuya Takagi
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
| | - Fumiya Takagi
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
| | - Yuki Kobayashi
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
| | - Misa Yamamoto
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
| | - Osamu Miura
- Hofu Institute of Gastroenterology, Hofu 747-0801, Japan
| | - Hideo Yanai
- Department of Clinical Research, National Hospital Organization Kanmon Medical Center, 1-1 Sotoura, Chofu, Shimonoseki, Yamaguchi 752-8510, Japan
| | - Yutaka Suehiro
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
| | - Takahiro Yamasaki
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University School of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
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Osumi H, Kawachi H, Yoshio T, Ida S, Yamamoto N, Horiuchi Y, Ishiyama A, Hirasawa T, Tsuchida T, Hiki N, Takeuchi K, Fujisaki J. Epstein-Barr virus status is a promising biomarker for endoscopic resection in early gastric cancer: proposal of a novel therapeutic strategy. J Gastroenterol 2019; 54:774-783. [PMID: 30826866 DOI: 10.1007/s00535-019-01562-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 02/19/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Epstein-Barr virus-positive gastric cancer (EBVGC) is associated with a low prevalence of lymph node metastasis (LNM); however, EBV status is not considered in the indication of endoscopic resection (ER). We aimed to clarify the implication of EBV status for ER of pT1b GC. METHODS Consecutive cases of pT1b GCs treated with surgery between 2005 and 2014 were retrospectively analyzed. Clinicopathological factors and LNM status were compared between EBVGC and non-EBVGC groups. RESULTS EBVGC accounted for 7.9% (71 of 898) cases. Compared to non-EBVGC, EBVGC was more frequent in males (p = 0.0055), the upper third region (p < 0.0001), showed elevated growth features (p = 0.0059), and was associated with a lower frequency of accompanying ulceration (p = 0.002), greater depth of submucosal invasion (p = 0.017), and lower frequency of lymphatic invasion (p < 0.0001). Frequency of LNM was significantly lower in EBVGC than in non-EBVGC (4.2% vs. 21.9%, p < 0.0001). In EBVGC, tumors without lymphovascular invasion showed significantly lower frequency of LNM than those with lymphovascular invasion (0 of 50, 0%; vs 3 of 21, 14.3%; p = 0.023). Histologically, 84.5% (60 of 71) of EBVGC included carcinomas with lymphoid stroma and/or lace pattern components. CONCLUSIONS pT1b EBVGC is a convincing candidate for ER, regardless of risk factors other than lymphovascular invasion.
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Affiliation(s)
- Hiroki Osumi
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Hiroshi Kawachi
- Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Toshiyuki Yoshio
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
| | - Satoshi Ida
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Noriko Yamamoto
- Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Yusuke Horiuchi
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Akiyoshi Ishiyama
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Toshiaki Hirasawa
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Tomohiro Tsuchida
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Naoki Hiki
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Kengo Takeuchi
- Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Junko Fujisaki
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
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Martinez-Ciarpaglini C, Fleitas-Kanonnikoff T, Gambardella V, Llorca M, Mongort C, Mengual R, Nieto G, Navarro L, Huerta M, Rosello S, Roda D, Tarazona N, Navarro S, Ribas G, Cervantes A. Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications. ESMO Open 2019; 4:e000470. [PMID: 31231566 PMCID: PMC6555614 DOI: 10.1136/esmoopen-2018-000470] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 02/07/2019] [Accepted: 02/13/2019] [Indexed: 02/06/2023] Open
Abstract
Background The molecular classification of gastric cancer recognises two subtypes prone to immune checkpoint blockade: the microsatellite unstable and the Epstein-Barr virus (EBV)-related tumours. We aim to assess the concordance between immunohistochemistry and PCR for microsatellite status evaluation, and explore the value of microsatellite instability (MSI) and EBV as predictive survival factors. Material and methods We collected 246 consecutively diagnosed gastric cancer cases in all stages and evaluated the microsatellite status using immunohistochemistry for mismatched repair (MMR) proteins and PCR. EBV expression was studied through in situ hybridisation. Results Forty-five (18%) cases presented MSI and 13 (6%) were positive for EBV. MSI was associated with female sex, older age, distal location and distal non-diffuse type of the modified Lauren classification. EBV expression was most frequent in proximal location and proximal non-diffuse type. The sensitivity, specificity, positive predictive value and negative predictive value of immunohistochemistry for the microsatellite study were 91%, 98%, 91% and 98%, respectively. In the multivariate analysis, MSI was an independent predictor of favourable tumour-specific survival (TSS) in stages I–III (MSI: HR: 0.37, 95% CI 0.12 to 0.95, p=0.04). Conclusions The MSI status and the EBV expression should be incorporated in routine pathological report for two reasons. First, MSI defines a different pathological entity with a better outcome. Second, MSI and EBV may be useful biomarkers to identify patients who will respond to immune checkpoint blockade inhibitors. For this purpose, immunohistochemical study for MMR proteins and in situ hybridisation study for EBV evaluation are feasible and cost-effective methods.
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Affiliation(s)
- Carolina Martinez-Ciarpaglini
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Tania Fleitas-Kanonnikoff
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Valentina Gambardella
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Marta Llorca
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Cristina Mongort
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Regina Mengual
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Gema Nieto
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Lara Navarro
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Marisol Huerta
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Susana Rosello
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Desamparados Roda
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Noelia Tarazona
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Samuel Navarro
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Gloria Ribas
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Andrés Cervantes
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
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Roh CK, Choi YY, Choi S, Seo WJ, Cho M, Jang E, Son T, Kim HI, Kim H, Hyung WJ, Huh YM, Noh SH, Cheong JH. Single Patient Classifier Assay, Microsatellite Instability, and Epstein-Barr Virus Status Predict Clinical Outcomes in Stage II/III Gastric Cancer: Results from CLASSIC Trial. Yonsei Med J 2019; 60:132-139. [PMID: 30666834 PMCID: PMC6342711 DOI: 10.3349/ymj.2019.60.2.132] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 12/26/2018] [Accepted: 12/27/2018] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Clinical implications of single patient classifier (SPC) and microsatellite instability (MSI) in stage II/III gastric cancer have been reported. We investigated SPC and the status of MSI and Epstein-Barr virus (EBV) as combinatory biomarkers to predict the prognosis and responsiveness of adjuvant chemotherapy for stage II/III gastric cancer. MATERIALS AND METHODS Tumor specimens and clinical information were collected from patients enrolled in CLASSIC trial, a randomized controlled study of capecitabine plus oxaliplatin-based adjuvant chemotherapy. The results of nine-gene based SPC assay were classified as prognostication (SPC-prognosis) and prediction of chemotherapy benefit (SPC-prediction). Five quasimonomorphic mononucleotide markers were used to assess tumor MSI status. EBV-encoded small RNA in situ hybridization was performed to define EBV status. RESULTS There were positive associations among SPC, MSI, and EBV statuses among 586 patients. In multivariate analysis of disease-free survival, SPC-prognosis [hazard ratio (HR): 1.879 (1.101-3.205), 2.399 (1.415-4.067), p=0.003] and MSI status (HR: 0.363, 95% confidence interval: 0.161-0.820, p=0.015) were independent prognostic factors along with age, Lauren classification, TNM stage, and chemotherapy. Patient survival of SPC-prognosis was well stratified regardless of EBV status and in microsatellite stable (MSS) group, but not in MSI-high group. Significant survival benefit from adjuvant chemotherapy was observed by SPC-Prediction in MSS and EBV-negative gastric cancer. CONCLUSION SPC, MSI, and EBV statuses could be used in combination to predict the prognosis and responsiveness of adjuvant chemotherapy for stage II/III gastric cancer.
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Affiliation(s)
- Chul Kyu Roh
- Department of Surgery, Yonsei University Health System, Seoul, Korea
| | - Yoon Young Choi
- Department of Surgery, Yonsei University Health System, Seoul, Korea
- Yonsei Biomedical Research Institute, Yonsei University Health System, Seoul, Korea
| | - Seohee Choi
- Department of Surgery, Yonsei University Health System, Seoul, Korea
| | - Won Jun Seo
- Department of Surgery, Yonsei University Health System, Seoul, Korea
| | - Minah Cho
- Department of Surgery, Yonsei University Health System, Seoul, Korea
| | - Eunji Jang
- MediBio-Informatics Research Center, Novomics Co., Ltd., Seoul, Korea
| | - Taeil Son
- Department of Surgery, Yonsei University Health System, Seoul, Korea
| | - Hyoung Il Kim
- Department of Surgery, Yonsei University Health System, Seoul, Korea
| | - Hyeseon Kim
- MediBio-Informatics Research Center, Novomics Co., Ltd., Seoul, Korea
| | - Woo Jin Hyung
- Department of Surgery, Yonsei University Health System, Seoul, Korea
| | - Yong Min Huh
- Yonsei Biomedical Research Institute, Yonsei University Health System, Seoul, Korea
- MediBio-Informatics Research Center, Novomics Co., Ltd., Seoul, Korea
- Department of Radiology, Yonsei University Health System, Seoul, Korea
- Department of Biochemistry & Molecular Biology, Yonsei University Health System, Seoul, Korea
- YUHS-KRIBB Medical Convergence Research Institute, Seoul, Korea
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University Health System, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Ho Cheong
- Department of Surgery, Yonsei University Health System, Seoul, Korea
- Yonsei Biomedical Research Institute, Yonsei University Health System, Seoul, Korea
- Department of Biochemistry & Molecular Biology, Yonsei University Health System, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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35
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Yanai H, Chihara D, Harano M, Sakaguchi E, Murakami T, Nishikawa J. Epstein-Barr Virus-associated Early Gastric Cancer Treated with Endoscopic Submucosal Dissection: A Possible Candidate for Extended Criteria of Endoscopic Submucosal Dissection. Intern Med 2019; 58:3247-3250. [PMID: 31735737 PMCID: PMC6911759 DOI: 10.2169/internalmedicine.3055-19] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
A 73-year-old man visited our hospital for the treatment of an early gastric cancer (GC) lesion. We performed en bloc resection using endoscopic submucosal dissection (ESD) for his GC lesion. The present GC lesion was Epstein-Barr virus (EBV)-associated poorly differentiated-type adenocarcinoma invading into the submucosal layer. Recently, accumulating data has shown that the risk of lymph node metastasis from early EBV GC without local lymphovascular infiltration is low. The present patient has been in good health for over three years since ESD. Some cases of early EBV GC with invasion into the submucosal layer may be candidates for further extension of the ESD criteria.
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Affiliation(s)
- Hideo Yanai
- Department of Clinical Research, Department of Gastroenterology & Hepatology, National Hospital Organization Kanmon Medical Center, Japan
| | - Daisuke Chihara
- Department of Clinical Research, Department of Gastroenterology & Hepatology, National Hospital Organization Kanmon Medical Center, Japan
| | - Megumi Harano
- Department of Clinical Research, Department of Gastroenterology & Hepatology, National Hospital Organization Kanmon Medical Center, Japan
| | - Eiki Sakaguchi
- Department of Clinical Research, Department of Gastroenterology & Hepatology, National Hospital Organization Kanmon Medical Center, Japan
| | - Tomoyuki Murakami
- Department of Pathology, National Hospital Organization Kanmon Medical Center, Japan
| | - Jun Nishikawa
- Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, Japan
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36
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Murai K, Kakushima N, Sugino T, Yoshida M, Kawata N, Tanaka M, Takizawa K, Muramatu K, Kusafuka K, Bando E, Ono H. Epstein-Barr virus positivity among surgically resected intramucosal gastric cancer. Dig Endosc 2018; 30:667-671. [PMID: 29729036 DOI: 10.1111/den.13181] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 04/22/2018] [Indexed: 12/29/2022]
Abstract
Epstein-Barr virus-associated gastric cancer (EBV-GC) accounts for approximately 8% of gastric cancers. However, little is known regarding intramucosal EBV-GC. The present study aimed to evaluate endoscopic and clinicopathological characteristics of intramucosal EBV-GC. Pathological data of 172 patients with 173 intramucosal gastric cancers who received gastrectomy with lymph node dissection were obtained for review. EBV-encoded small RNA in situ hybridization (EBER-ISH) was carried out using a tissue microarray block. Eight intramucosal early gastric cancers (4.6%) were EBER-ISH positive in which no cases had any lymph node metastasis. Macroscopic types were either depressed or flat, dominant histology was mixed type of moderate and poorly differentiated adenocarcinoma. In detail, histological features of "lace pattern" or "lymphocyte infiltration into the stroma or cancer nests" were observed.
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Affiliation(s)
- Katsuyuki Murai
- Division of Endoscopy, Shizuoka Cancer Center, Suntogun, Japan.,Division of Pathology, Shizuoka Cancer Center, Suntogun, Japan
| | - Naomi Kakushima
- Division of Endoscopy, Shizuoka Cancer Center, Suntogun, Japan
| | - Takashi Sugino
- Division of Pathology, Shizuoka Cancer Center, Suntogun, Japan
| | - Masao Yoshida
- Division of Endoscopy, Shizuoka Cancer Center, Suntogun, Japan
| | - Noboru Kawata
- Division of Endoscopy, Shizuoka Cancer Center, Suntogun, Japan
| | - Masaki Tanaka
- Division of Endoscopy, Shizuoka Cancer Center, Suntogun, Japan
| | - Kohei Takizawa
- Division of Endoscopy, Shizuoka Cancer Center, Suntogun, Japan
| | - Koji Muramatu
- Division of Pathology, Shizuoka Cancer Center, Suntogun, Japan
| | | | - Etsuro Bando
- Division of Gastric Surgery, Shizuoka Cancer Center, Suntogun, Japan
| | - Hiroyuki Ono
- Division of Endoscopy, Shizuoka Cancer Center, Suntogun, Japan
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37
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Nishikawa J, Iizasa H, Yoshiyama H, Shimokuri K, Kobayashi Y, Sasaki S, Nakamura M, Yanai H, Sakai K, Suehiro Y, Yamasaki T, Sakaida I. Clinical Importance of Epstein⁻Barr Virus-Associated Gastric Cancer. Cancers (Basel) 2018; 10:cancers10060167. [PMID: 29843478 PMCID: PMC6024931 DOI: 10.3390/cancers10060167] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 05/13/2018] [Accepted: 05/24/2018] [Indexed: 12/17/2022] Open
Abstract
Epstein⁻Barr virus-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. EBVaGC has definite histological characteristics similar to gastric carcinoma with lymphoid stroma. Clinically, EBVaGC has a significantly low frequency of lymph node metastasis compared with EBV-negative gastric cancer, resulting in a better prognosis. The Cancer Genome Atlas of gastric adenocarcinomas proposed a molecular classification divided into four molecular subtypes: (1) EBVaGC; (2) microsatellite instability; (3) chromosomal instability; and (4) genomically stable tumors. EBVaGC harbors a DNA methylation phenotype, PD-L1 and PD-L2 overexpression, and frequent alterations in the PIK3CA gene. We review clinical importance of EBVaGC and discuss novel therapeutic applications for EBVaGC.
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Affiliation(s)
- Jun Nishikawa
- Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
| | - Hisashi Iizasa
- Department of Microbiology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan.
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan.
| | - Kanami Shimokuri
- Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
| | - Yuki Kobayashi
- Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
| | - Sho Sasaki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
| | - Munetaka Nakamura
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
| | - Hideo Yanai
- Department of Clinical Research, National Hospital Organization Kanmon Medical Center, 1-1 Sotoura, Chofu, Shimonoseki, Yamaguchi 752-8510, Japan.
| | - Kohei Sakai
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
| | - Yutaka Suehiro
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
| | - Takahiro Yamasaki
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
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38
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Kato M, Hayashi Y, Fukumoto K, Nagai K, Tsujii Y, Shinzaki S, Iijima H, Takehara T. Early gastric cancer with lymphoid stroma presenting as a subepithelial lesion diagnosed by endoscopic submucosal dissection. Clin J Gastroenterol 2018; 11:382-385. [PMID: 29637432 DOI: 10.1007/s12328-018-0855-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 03/21/2018] [Indexed: 12/19/2022]
Abstract
A 53-year-old man underwent an esophagogastroduodenoscopy that showed a 20-mm subepithelial lesion in the middle gastric body. Endoscopic ultrasound revealed a hypoechoic mass located in the submucosa. Biopsy specimens revealed a benign gastric mucosa with severe lymphocytic infiltration in the submucosa. Malignant lymphoma or gastric cancer with lymphoid stroma was suspected. We performed endoscopic submucosal dissection for definitive diagnosis. Histological examination showed undifferentiated adenocarcinoma, which showed positive Epstein-Barr virus-encoded RNA in situ hybridization results, invading the submucosa mixed with dense lymphocytic infiltration. Thus, Epstein-Barr virus-positive gastric cancer with lymphoid stroma was diagnosed. Gastric cancer with lymphoid stroma is a rare subtype of gastric cancer, which is associated with Epstein-Barr virus infection; it sometimes appears as a subepithelial lesion, which makes it difficult to diagnose using standard biopsy. Endoscopic submucosal dissection was useful in obtaining a sufficient tissue for full histological assessment, including immunostaining.
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Affiliation(s)
- Minoru Kato
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Yoshito Hayashi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Kenji Fukumoto
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Kengo Nagai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Yoshiki Tsujii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Shinichiro Shinzaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Hideki Iijima
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan.
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39
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Naseem M, Barzi A, Brezden-Masley C, Puccini A, Berger MD, Tokunaga R, Battaglin F, Soni S, McSkane M, Zhang W, Lenz HJ. Outlooks on Epstein-Barr virus associated gastric cancer. Cancer Treat Rev 2018; 66:15-22. [PMID: 29631196 DOI: 10.1016/j.ctrv.2018.03.006] [Citation(s) in RCA: 139] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 03/28/2018] [Accepted: 03/29/2018] [Indexed: 12/11/2022]
Abstract
Epstein-Barr virus associated gastric cancer (EBVaGC) comprises approximately 10% of gastric carcinomas. Multiple factors contribute to tumorigenesis, including EBV driven hypermethylation of tumor suppressor genes, inflammatory changes in gastric mucosa, host immune evasion by EBV and changes in cell cycle pathways. The unique molecular characteristics of EBVaGC, such as programmed death ligand 1 (PD-L1) overexpression, highlight the potential for using EBV as a biomarker for response to immunotherapy. Few studies have reported benefit from immunotherapy in EBV positive cancers, and clinical trials investigating the impact of checkpoint inhibitors in EBVaGC are currently underway. This review provides the most recent updates on molecular pathophysiology, epidemiology, clinical features and treatment advances pertaining to EBVaGC.
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Affiliation(s)
- Madiha Naseem
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA
| | - Afsaneh Barzi
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA
| | - Christine Brezden-Masley
- Division of Hematology/Oncology, Department of Medicine, St. Michael's Hospital, University of Toronto, Canada
| | - Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA
| | - Martin D Berger
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA
| | - Ryuma Tokunaga
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA; Clinical and Experimental Oncology Department, Medical Oncology Unit 1, Veneto Institute of Oncology IRCCS, Padua, Italy
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA
| | - Michelle McSkane
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA.
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40
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Park CK, Park JS, Kim HS, Rha SY, Hyung WJ, Cheong JH, Noh SH, Lee SK, Lee YC, Huh YM, Kim H. Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm. Oncotarget 2018; 7:72099-72112. [PMID: 27765925 PMCID: PMC5342148 DOI: 10.18632/oncotarget.12291] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 09/17/2016] [Indexed: 12/12/2022] Open
Abstract
Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8%) 61, (6.15%), and 85 (8.56%) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2% (49/157), 80.3% (49/61), and 30.6% (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age (P < 0.001), differentiated histology (P = 0.001), intestinal or mixed type by Lauren classification (P < 0.001), lymphovascular invasion (P = 0.026), and mutant-pattern of p53 (P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification, based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification. In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy.
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Affiliation(s)
- Cheol Keun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ji Soo Park
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyo Song Kim
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sun Young Rha
- Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Woo Jin Hyung
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Min Huh
- YUMS-KRIBB Medical Convergence Research Institute, Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
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41
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Polom K, Marano L, Marrelli D, De Luca R, Roviello G, Savelli V, Tan P, Roviello F. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br J Surg 2018; 105:159-167. [PMID: 29091259 DOI: 10.1002/bjs.10663] [Citation(s) in RCA: 191] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 02/03/2017] [Accepted: 07/06/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Several associations between microsatellite instability (MSI) and other clinicopathological factors have been reported in gastric cancer, but the results have been ambiguous. This systematic review and meta-analysis investigated the relationship between MSI and overall survival and clinicopathological characteristics of patients with gastric cancer. METHODS A systematic literature search of the PubMed, Cochrane and Ovid databases until 31 January 2016 was performed in accordance with the PRISMA statement. The articles were screened independently according to PICO (population, intervention, comparator, outcome) eligibility criteria. All eligible articles were evaluated independently by two reviewers for risk of bias according to the Quality In Prognosis Study tool. RESULTS Overall, 48 studies with a total of 18 612 patients were included. MSI was found in 9·2 per cent of patients (1718 of 18 612), and was associated with female sex (odds ratio (OR) 1·57, 95 per cent c.i. 1·31 to 1·89; P < 0·001), older age (OR 1·58, 2·20 to 1·13; P < 0·001), intestinal Laurén histological type (OR 2·23, 1·94 to 2·57; P < 0·001), mid/lower gastric location (OR 0·38, 0·32 to 0·44; P < 0·001), lack of lymph node metastases (OR 0·70, 0·57 to 0·86, P < 0·001) and TNM stage I-II (OR 1·77, 1·47 to 2·13; P < 0·001). The pooled hazard ratio for overall survival of patients with MSI versus those with non-MSI gastric cancer from 21 studies was 0·69 (95 per cent c.i. 0·56 to 0·86; P < 0·001). CONCLUSION MSI in gastric cancer was associated with good overall survival, reflected in several favourable clinicopathological tumour characteristics.
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Affiliation(s)
- K Polom
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
- Department of Surgical Oncology, Medical University of Gdansk, Gdansk, Poland
| | - L Marano
- General, Minimally Invasive and Robotic Surgery, Department of Surgery, San Matteo degli Infermi Hospital, Spoleto, Italy
| | - D Marrelli
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - R De Luca
- Department of Surgical Oncology, National Cancer Research Centre-Istituto Tumori G. Paolo II, Bari, Italy
| | - G Roviello
- Department of Oncology, Medical Oncology Unit, San Donato Hospital, Arezzo, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - V Savelli
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - P Tan
- Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Genome Institute of Singapore, Cancer Science Institute of Singapore, National University of Singapore, and Cellular and Molecular Research, National Cancer Centre, Singapore
| | - F Roviello
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
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42
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Kim HS, Shin SJ, Beom SH, Jung M, Choi YY, Son T, Kim HI, Cheong JH, Hyung WJ, Noh SH, Chung H, Park JC, Shin SK, Lee SK, Lee YC, Koom WS, Lim JS, Chung HC, Rha SY, Kim H. Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy. Oncotarget 2018; 7:44608-44620. [PMID: 27331626 PMCID: PMC5190122 DOI: 10.18632/oncotarget.10115] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 05/29/2016] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer (GC) is a leading cause of death. We aim to establish a clinically relevant assay that encompasses recent molecular classifications and provides useful clinical information in a large cohort of GC patients. A consecutive series of 438 GC patients that underwent palliative chemotherapy between 2014 and 2015 were assessed using 10 GC panels: EBER in-situ hybridization, immunohistochemistry for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), receptor tyrosine kinases (RTKs; HER2, EGFR, and MET), PTEN, and p53 protein. With a median of one aberration, 3.3 % of samples analyzed were Epstein-Barr virus (EBV)-positive; 4.8%, MMR-deficient. RTKs were overexpressed in 218 patients; EGFR was most commonly overexpressed (39.9%), followed by HER2 (13.5%) and MET (12.1%). Furthermore, 2.5 % and 10.7 % of cases had simultaneous overexpression of three and two RTKs, respectively. p53 overexpression/null tumors were identified in 259 patients (59.1%), and PTEN loss was identified in 89 patients (20.3%). EBV-positivity was mutually exclusive with MMR-deficiency, predominantly identified in male patients, and these tumors were undifferentiated with proximal location. p53 mutant type was significantly found predominantly in the EBV-negative (60.6% vs 14.3%, P=0.001) and HER2-positive (78.0% vs 56.2%, P=0.002) groups. We described a molecular spectrum of distinct GC subtypes using clinically applicable assay. This assay will provide a convenient screening tool and facilitate the development of targeted agents in clinical trials.
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Affiliation(s)
- Hyo Song Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Su-Jin Shin
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung-Hoon Beom
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Minkyu Jung
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoon Young Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Taeil Son
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyoung-Il Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Woo Jin Hyung
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunsoo Chung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Chul Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Kwan Shin
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Woong Sub Koom
- Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Joon Seok Lim
- Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyun Cheol Chung
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sun Young Rha
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
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Acquisition of histologic diversity contributes to not only invasiveness but also lymph node metastasis in early gastric cancer. Pathol Res Pract 2017; 213:1023-1028. [PMID: 28864348 DOI: 10.1016/j.prp.2017.08.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 07/26/2017] [Accepted: 08/20/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND As more endoscopic resections are performed in early gastric cancer, the pretreatment prediction of lymph node metastasis (LNM) becomes more important. Some tumor characteristics including histologic type, invasion depth, ulceration, size, and lymphovascular invasion have been used to determine the endoscopic resectability of early gastric cancer; however, a more detailed analysis between clinicopathologic factors and lymph node metastasis is needed. METHODS We analyzed the correlation between the clinicopathological findings and LNM with 310 cases of early gastric cancer by dividing invasion depths in detail. RESULTS LNM occurred in 3.2% and 16.2% of the T1a and T1b tumors, respectively. LNM was associated with invasion depth (p=0.002) and lymphatic (p<0.001) and perineural (p=0.013) invasion. Among them, lymphatic invasion was the most powerful factor associated with LNM and significantly constant in T1a and T1b. The rate of LNM increased gradually as the tumor invaded deeper, and invasion of the muscularis mucosae layer was associated with an increased mixed adenocarcinoma incidence, suggesting that histologic diversity was associated with tumor invasiveness. CONCLUSIONS We demonstrated that lymphatic invasion was the most important and powerful parameter for LNM in early gastric cancers. In addition, tumor invasiveness into the muscularis mucosae was accompanied by tumor histologic diversity.
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Kim YH, Park JH, Park CK, Kim JH, Lee SK, Lee YC, Noh SH, Kim H. Histologic purity of signet ring cell carcinoma is a favorable risk factor for lymph node metastasis in poorly cohesive, submucosa-invasive early gastric carcinoma. Gastric Cancer 2017; 20:583-590. [PMID: 27663439 DOI: 10.1007/s10120-016-0645-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 09/12/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND The prediction of biologic behavior of poorly cohesive early gastric carcinoma (EGC) is an important issue in the selection of the treatment modality. To elucidate the risk factors for lymph node metastasis (LNM) of poorly cohesive EGC, we focused on the histologic purity of the poorly cohesive component and evaluated the impact of this factor on LNM. METHODS We divided poorly cohesive EGC into (1) pure signet ring cell (SRC) carcinoma, which was defined as composed only of signet ring cells or poorly cohesive cells and (2) mixed SRC carcinoma, defined as poorly cohesive carcinoma with minor tubular components. We reviewed the clinicopathologic features, including age, sex, location, size, depth, lymphovascular invasion (LVI), LNM, ulceration, and intestinal metaplasia between the two groups in a large series of poorly cohesive, submucosa-invasive EGC (n = 317). RESULTS LNM was found in 58 cases (18.3 %). Mixed SRC carcinoma histologic type (p < 0.001), larger tumor size (more than 2 cm) (p = 0.012), and the presence of LVI (p < 0.001) were associated with LNM. Pure SRC carcinomas accounted for 56.2 % (178/317) of the cases. Fourteen pure SRC carcinomas (7.8 %) showed LNM, whereas 44 mixed SRC carcinomas (31.9 %) exhibited LNM (p < 0.001). On multivariate logistic regression, the presence of LVI (odds ratio 6.737; 95 % confidence interval 2.714-16.720; p < 0.001) and mixed SRC carcinoma histologic type (odds ratio 4.674; 95 % confidence interval 2.370-9.216; p < 0.001) were independent predictors of LNM in poorly cohesive, submucosa-invasive EGC. CONCLUSIONS The presence of a tubular component in SRC carcinoma was a risk factor for LNM in poorly cohesive, submucosa-invasive EGC. On the basis of this finding, we propose that the presence of a minor tubular component or the purity of the poorly cohesive/SRC carcinoma component should be reported in daily pathologic practice.
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Affiliation(s)
- Yon Hee Kim
- Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Ji Hye Park
- Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Cheol Keun Park
- Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Jie-Hyun Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
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Lai JF, Xu WN, Noh SH, Lu WQ. Effect of World Health Organization (WHO) Histological Classification on Predicting Lymph Node Metastasis and Recurrence in Early Gastric Cancer. Med Sci Monit 2016; 22:3147-53. [PMID: 27595490 PMCID: PMC5021020 DOI: 10.12659/msm.897311] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background The World Health Organization (WHO) histological classification for gastric cancer is widely accepted and used. However, its impact on predicting lymph node metastasis and recurrence in early gastric cancer (EGC) is not well studied. Material/Methods From 1987 to 2005, 2873 EGC patients with known WHO histological type who had undergone curative resection were enrolled in this study. In all, 637 well-differentiated adenocarcinomas (WD), 802 moderately-differentiated adenocarcinomas (MD), 689 poorly-differentiated adenocarcinomas (PD), and 745 signet-ring cell adenocarcinomas (SRC) were identified. Results The distribution of demographic and clinical features in early gastric cancer among WD, MD, PD, and SRC were significantly different. Lymph node metastasis was observed in 317 patients (11.0%), with the lymph node metastasis rate being 5.3%, 14.8%, 17.0%, and 6.3% in WD, MD, PD, and SRC, respectively. Univariate and multivariate analyses indicated that gender, tumor size, gross appearance, depth of invasion, and WHO classification were significantly associated with lymph node metastasis. Recurrence was observed in 83 patients (2.9%), with the recurrence rate being 2.2%, 4.5%, 3.0%, and 1.6% in WD, MD, PD, and SRC, respectively. Multivariate analysis confirmed that MD, elevated gross type, and lymph node metastasis were independent risk factors for recurrence in EGC. MD patients showed worse disease-free survival than non-MD patients (P=0.001). Conclusions WHO classification is useful and necessary to evaluate during the perioperative management of EGC. Treatment strategies for EGC should be made prudently according to WHO classification, especially for MD patients.
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Affiliation(s)
- Ji Fu Lai
- Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China (mainland)
| | - Wen Na Xu
- Department of Surgery, Zhejiang University Hospital, Hangzhou, Zhejiang, China (mainland)
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University, College of Medicine, Seoul, Korea, Democratic People's Republic of
| | - Wei Qin Lu
- Department of Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China (mainland)
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