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Mi SY, Liao YJ, Kang D, Tang X, Chen G, Pan ZZ, Zhan J, Zhang RX. Decreasing Use of CT in Favor of Colonoscopy: A Retrospective Analysis of Post-Operative Imaging in Nonmetastatic dMMR/MSI-H Sporadic Colorectal Cancer. Ann Surg Oncol 2025; 32:3814-3827. [PMID: 39948309 DOI: 10.1245/s10434-025-16989-4] [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: 10/17/2024] [Accepted: 01/23/2025] [Indexed: 04/24/2025]
Abstract
BACKGROUND There is no significant difference in postoperative follow-up imaging examinations for varying mismatch repair (MMR)/microsatellite instability (MSI) statuses for sporadic colorectal cancer while facing different prognoses. METHODS We conducted a retrospective study, using Kaplan-Meier curve to compare survival/progression status by varying imaging examination and frequency, using Cox regression to analyze tumor characteristic impact on survival, and monitoring polyp detection time in each colonoscopy screening. RESULTS A total of 282 deficient MMR (dMMR)/MSI-high (MSI-H) patients were included. After a 7 year follow-up, all patients-including 143 examined by CT and colonoscopy, 86 singularly examined (CT/colonoscopy/ultrasound), and 53 received no imaging examination-demonstrated a favorable overall survival (87.97%, 95% CI 75.99-89.19) and disease-free survival (81.92%, 95% CI 70.38-89.30), which had no significant difference between imaging methods. Cox regression proved that different imaging methods had no influence on the prognosis. Stage III patients experienced a deterioration in disease-free survival but not differed between varying imaging methods. Different CT follow-up interval exhibited no difference in survival and progression. Polyps were detected in 39.75% (64/161) of patients during follow-up; 32.81% (21/64) were detected in colonoscopy conducted 0-6 months after surgery, reaching the highest. For multiple polyps, the median of detection interval was 13-24 months (first and second polyps), 7-12 months (second and third polyps). CONCLUSIONS For nonmetastatic dMMR/MSI-H sporadic colorectal cancer patients, less CT scans (interval > 1 year) are tolerable because of good prognosis, whereas more colonoscopy screenings (0-6 months after surgery first year; 13-24 months after first polyps detection; 7-12 months after second polyps detection) is considerable.
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Affiliation(s)
- Si-Yuan Mi
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yi-Jun Liao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Da Kang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Xin Tang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Gong Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Zhi-Zhong Pan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jianhua Zhan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
| | - Rong-Xin Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
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Chen J, Wang G, Ding Y, Zhang Z, Xia K, Xu L, Xu X. Development of an AI-Assisted System for Automatic Recognition and Localization Marking of Colonic Polyps (With Video). J Gastroenterol Hepatol 2025. [PMID: 40229187 DOI: 10.1111/jgh.16980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 03/08/2025] [Accepted: 04/07/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND Localizing colorectal polyps identified during the initial colonoscopy in minimally invasive endoscopic surgery presents significant challenges. These challenges include imprecise location descriptions, unclear images, a high number of polyps, and polyp characteristics such as flat shapes and low color contrast. To address these issues, we developed an AI-assisted system for the automatic detection and localization of colorectal polyps. METHODS Colonic images and videos from three medical centers, collected between January 2018 and August 2024, were categorized based on pathology results into normal, adenomatous polyp, and serrated lesion groups. Transfer learning and fine-tuning were conducted on five pretrained CNN models, with performance evaluated using metrics such as accuracy, precision, sensitivity, and AUC. The best-performing model was selected for interpretability analysis and developed into an AI-assisted system capable of both polyp recognition and location marking. RESULTS Among the five models, EfficientNetV2 performed the best, achieving accuracy, precision, sensitivity, and F1 scores of 0.933, 0.917, 0.916, and 0.917, respectively, on the validation set. On the test set, the model's overall weighted average precision, specificity, and AUC were 0.903, 0.946, and 0.983, respectively. Two representative colonoscopy case videos predicted by the model further demonstrated the feasibility of this AI system in clinical practice. CONCLUSIONS The AI system we developed for the automatic recognition and localization marking of colonic polyps in colonoscopy aids in the rapid localization of polyps during minimally invasive endoscopic surgery.
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Affiliation(s)
- Jian Chen
- Department of Gastroenterology, Changshu Hospital Affiliated to Soochow University, Suzhou, China
- Changshu Key Laboratory of Medical Artificial Intelligence and Big Data, Suzhou, China
| | - Ganhong Wang
- Department of Gastroenterology, Changshu Traditional Chinese Medicine Hospital (Changshu Hospital Affiliated to Nanjing University of Chinese Medicine), Suzhou, China
| | - Yu Ding
- Department of Gastroenterology, Changshu Hospital Affiliated to Soochow University, Suzhou, China
| | - Zihao Zhang
- Shanghai Haoxiong Education Technology Co, Ltd, Shanghai, China
| | - Kaijian Xia
- Changshu Key Laboratory of Medical Artificial Intelligence and Big Data, Suzhou, China
- Center of Intelligent Medical Technology Research, Changshu Hospital Affiliated to Soochow University, Suzhou, China
| | - Lu Xu
- Department of Gastroenterology, Changshu Traditional Chinese Medicine Hospital (Changshu Hospital Affiliated to Nanjing University of Chinese Medicine), Suzhou, China
| | - Xiaodan Xu
- Department of Gastroenterology, Changshu Hospital Affiliated to Soochow University, Suzhou, China
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Zwetkoff BHF, Alberti LR, Rodrigues FG, Junior NC, Ardengh JC, Neto OM, Guzman FR, Dias MMF, de Oliveira Canejo GC, dos Santos CEO. The impact of linked color imaging on adenoma detection rate in colonoscopy: a systematic review and meta-analysis. Clin Endosc 2025; 58:225-239. [PMID: 39443083 PMCID: PMC11982820 DOI: 10.5946/ce.2024.072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/07/2024] [Accepted: 05/16/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND/AIMS Colorectal cancer prevention relies on surveillance colonoscopy, with the adenoma detection rate as a key factor in examination quality. Linked color imaging (LCI) enhances lesion contrast and improves the examination performance. This systematic review and meta-analysis aimed to evaluate the effect of LCI on adenoma detection rate in adults who underwent colonoscopy. METHODS We searched the Medline, PubMed, BIREME, LILACS, and Scientific Electronic Library Online databases for randomized controlled trials comparing the use of LCI versus white light imaging (WLI), published up to March 2023. The outcomes included lesion characteristics, number of adenomas per patient, and the additional polyp detection rate. RESULTS Sixteen studies were included in the analysis, which showed that LCI was more accurate than WLI in detecting adenomas, with an increased number of adenomas detected per patient. Although LCI performed well in terms of lesion size, morphology, and location, the subgroup analyses did not reveal any statistically significant differences between LCI and WLI. The addition of LCI did not result in significant improvements in the detection of serrated lesions, and there were no differences in the withdrawal time between groups. CONCLUSIONS LCI has been shown to be effective in detecting colonic lesions, improving the number of adenomas detected per patient and improving polyp detection rate without negatively affecting other quality criteria in colonoscopy.
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Zhang QQ, Wu JD, Li XY, Fang FF, Li GP, Bai T, Song J. Clinical and endoscopic characteristics of colorectal sessile serrated lesions with or without dysplasia/carcinoma: A systematic review and meta-analysis. J Dig Dis 2024; 25:424-435. [PMID: 39104049 DOI: 10.1111/1751-2980.13302] [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: 02/09/2024] [Revised: 06/05/2024] [Accepted: 06/29/2024] [Indexed: 08/07/2024]
Abstract
OBJECTIVE We aimed to compare the clinical and endoscopic characteristics of sessile serrated lesions (SSLs) with dysplasia/carcinoma (SSLD/Cs) and SSLs without dysplasia in this systematic review and meta-analysis. METHODS MEDLINE, EMBASE, and Cochrane Library databases and Clinicaltrials.gov were searched for relevant studies published up to August 28, 2023. The primary outcome was lesion size in SSLD/Cs and SSLs without dysplasia. The secondary outcomes included risk of dysplasia/carcinoma, morphology (classified based on the Paris classification), and lesion features such as mucus cap and nodules/protrusions in the two groups. RESULTS Thirteen studies with 14 381 patients were included. The proportion of SSLD/Cs ≥10 mm was significantly higher than that of SSLs without dysplasia (odds ratio [OR] 3.82, 95% confidence interval [CI] 1.21-12.02, p = 0.02). There was no significant difference in the risk of dysplasia/carcinoma between the proximal (OR 0.80, 95% CI 0.57-1.14) and distal colon (OR 1.25, 95% CI 0.88-1.77, p = 0.21). The 0-Ip (OR 2.47, 95% CI 1.50-4.09) and 0-IIa + Is (OR 10.38, 95% CI 3.08-34.98) morphologies were more prevalent among SSLD/Cs, whereas the 0-IIa morphology (OR 0.38, 95% CI 0.22-0.65) was more prevalent among SSLs without dysplasia (all p < 0.001). Furthermore, mucus cap (OR 0.61, 95% CI 0.42-0.89, p = 0.01) was more common among SSLs without dysplasia, whereas nodules/protrusions (OR 7.80, 95% CI 3.07-19.85, p < 0.001) were more common in SSLD/Cs. CONCLUSION SSLs >10 mm, 0-Ip or 0-IIa + Is morphologies, and those with nodules/protrusions are significantly associated with dysplasia/carcinoma.
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Affiliation(s)
- Qing Qing Zhang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Jian Di Wu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xue Yan Li
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Fei Fei Fang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Gang Ping Li
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Tao Bai
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Jun Song
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Hajjafari A, Sadr S, Rahdar A, Bayat M, Lotfalizadeh N, Dianaty S, Rezaei A, Moghaddam SP, Hajjafari K, Simab PA, Kharaba Z, Borji H, Pandey S. Exploring the integration of nanotechnology in the development and application of biosensors for enhanced detection and monitoring of colorectal cancer. INORG CHEM COMMUN 2024; 164:112409. [DOI: 10.1016/j.inoche.2024.112409] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/19/2024]
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Sugai T, Uesugi N, Osakabe M, Yao T, Yanagawa N, Ajioka Y. Characterization of sessile serrated adenomas with dysplasia including intramucosal adenocarcinoma and colorectal carcinoma with a microsatellite instability phenotype. Hum Pathol 2024; 145:9-15. [PMID: 38218351 DOI: 10.1016/j.humpath.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/03/2023] [Accepted: 12/19/2023] [Indexed: 01/15/2024]
Abstract
Recent studies have shown that sessile serrated lesions (SSLs) lead to the development of colorectal cancer (CRC) with a microsatellite instability (MSI) phenotype via a dysplasia-carcinoma sequence. However, the pathological and molecular mechanisms of SSL with dysplasia (SSLD) are unclear. Here, we aimed to examine the clinicopathological and molecular alterations in SSLD and to evaluate the significance of such alterations with regard to lesion progression. Fifty-four SSLDs (20 serrated dysplasia cases and 17 intestinal dysplasia cases, including 30 low-grade dysplasia [LGD] cases, 7 high-grade dysplasia [HGD] cases, and 17 intramucosal adenocarcinomas [IMAs]) were evaluated. Molecular alterations, including immunohistochemical expression of various markers, DNA methylation status, and multiple genetic mutations (using next-generation sequencing), were assessed. Additionally, such alterations were also investigated in 41 CRCs with an MSI phenotype (invasion beyond submucosa). The frequency of mismatch repair (MMR) deficiency in SSLD was 12 of 39 cases (32.4 %), whereas the MMR proficient type was observed in 17 of 39 SSLD cases. SSLD with serrated dysplasia showed a significantly higher frequency of loss of MMR protein expression and methylation status. Moreover, loss of MMR protein expression differed significantly between LGD and IMA. Furthermore, the frequency of TP53 mutation was significantly higher in IMA than in LGD. The current findings demonstrated that SSL with serrated dysplasia may be associated with an increased risk of malignant transformation compared with intestinal dysplasia. Loss of MMR proteins and mutation of TP53 may play important roles in tumor progression from dysplasia to carcinomatous lesions.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun'yahabachou, 028-3695, Japan; Diagnostic Pathology Center, Southern Tohoku General Hospital, 7-115, Yatsuyamada, Kooriyama City, Fukushima, 963-8563, Japan.
| | - Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun'yahabachou, 028-3695, Japan; Diagnostic Pathology Center, Southern Tohoku General Hospital, 7-115, Yatsuyamada, Kooriyama City, Fukushima, 963-8563, Japan
| | - Mistumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun'yahabachou, 028-3695, Japan
| | - Takashi Yao
- Department of Diagnostic Pathology, Juntendo University, Tokyo, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun'yahabachou, 028-3695, Japan
| | - Yoichi Ajioka
- Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, 757, Cyuo-Asahi, 951-8510, Niigata, Japan
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Vu NTH, Le HM, Vo DTN, Vu HA, Le NQ, Ho DDQ, Quach DT. Prevalence, risk factors, and BRAF mutation of colorectal sessile serrated lesions among Vietnamese patients. World J Clin Oncol 2024; 15:290-301. [PMID: 38455129 PMCID: PMC10915949 DOI: 10.5306/wjco.v15.i2.290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 12/25/2023] [Accepted: 01/12/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Sessile serrated lesions (SSLs) are considered precancerous colorectal lesions that should be detected and removed to prevent colorectal cancer. Previous studies in Vietnam mainly investigated the adenoma pathway, with limited data on the serrated pathway. AIM To evaluate the prevalence, risk factors, and BRAF mutations of SSLs in the Vietnamese population. METHODS This is a cross-sectional study conducted on patients with lower gastrointestinal symptoms who underwent colonoscopy at a tertiary hospital in Vietnam. SSLs were diagnosed on histopathology according to the 2019 World Health Organization classification. BRAF mutation analysis was performed using the Sanger DNA sequencing method. The multivariate logistic regression model was used to determine SSL-associated factors. RESULTS There were 2489 patients, with a mean age of 52.1 ± 13.1 and a female-to-male ratio of 1:1.1. The prevalence of SSLs was 4.2% [95% confidence interval (CI): 3.5-5.1]. In the multivariate analysis, factors significantly associated with SSLs were age ≥ 40 [odds ratio (OR): 3.303; 95%CI: 1.607-6.790], male sex (OR: 2.032; 95%CI: 1.204-3.429), diabetes mellitus (OR: 2.721; 95%CI: 1.551-4.772), and hypertension (OR: 1.650, 95%CI: 1.045-2.605). The rate of BRAF mutations in SSLs was 35.5%. CONCLUSION The prevalence of SSLs was 4.2%. BRAF mutations were present in one-third of SSLs. Significant risk factors for SSLs included age ≥ 40, male sex, diabetes mellitus, and hypertension.
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Affiliation(s)
- Nhu Thi Hanh Vu
- Department of Internal Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
- GI Endoscopy Department, University Medical Center at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
| | - Huy Minh Le
- GI Endoscopy Department, University Medical Center at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
- Department of Histology-Embryology and Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
| | - Diem Thi-Ngoc Vo
- Department of Histology-Embryology and Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
| | - Hoang Anh Vu
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
| | - Nhan Quang Le
- GI Endoscopy Department, University Medical Center at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
| | - Dung Dang Quy Ho
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh 700000, Viet Nam
| | - Duc Trong Quach
- Department of Internal Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
- GI Endoscopy Department, University Medical Center at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
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Waters KM, Singhi AD, Montgomery EA. Exploring the spectrum of serrated epithelium encountered in inflammatory bowel disease. Hum Pathol 2023; 132:126-134. [PMID: 35753410 PMCID: PMC11186602 DOI: 10.1016/j.humpath.2022.06.018] [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: 06/06/2022] [Accepted: 06/17/2022] [Indexed: 02/07/2023]
Abstract
Patients with inflammatory bowel disease (IBD) are at an increased risk for colorectal cancer. Currently, dysplasia is the best marker of CRC risk. Assessing dysplasia is a challenging task for pathologists as the longstanding inflammation causes marked reactive cytologic changes and architectural distortion. Recent descriptions of nonconventional types of dysplasia in IBD have added to the complexity. In this review, we focus on the clinical, endoscopic, histologic, and molecular findings in lesions with serrated epithelium. Serrated epithelial change (SEC), sessile serrated lesion (SSL)-like, serrated lesion-not otherwise specified (SL-NOS), and traditional serrated adenoma (TSA)-like lesions all typically occur in patients with longstanding IBD with mean ages in the fifth-sixth decade. SEC is often encountered in nontargeted biopsies while the others form visible polyps. While serrated lesions have significant histologic overlap, subtle differences can help pathologists separate them. SEC has markedly distorted architecture with crypts losing perpendicular orientation to the muscularis mucosae. The crypts are goblet cell-rich and have irregular serrations that involve the full length of the crypt. SSL-like lesions are goblet cell poor and have microvesicular cytoplasm. Like their sporadic counterpart in non-IBD patients, these lesions have lateral growth at the crypt bases. TSA-like lesions are characterized by their villous architecture, ectopic crypts, pink cytoplasm, and hyperchromatic elongated nuclei. We also explore molecular findings that help in distinguishing these lesions, current knowledge on the association of each of these lesions with dysplasia and CRC, and future research needed to better characterize these entities.
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Affiliation(s)
- Kevin M Waters
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Elizabeth A Montgomery
- Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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Murakami T, Kurosawa T, Fukushima H, Shibuya T, Yao T, Nagahara A. Sessile serrated lesions: Clinicopathological characteristics, endoscopic diagnosis, and management. Dig Endosc 2022; 34:1096-1109. [PMID: 35352394 DOI: 10.1111/den.14273] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/30/2022] [Accepted: 02/13/2022] [Indexed: 02/08/2023]
Abstract
The 2019 World Health Organization (WHO) Classification of Tumours of the Digestive System (5th edition) introduced the term "sessile serrated lesion" (SSL) to replace the term "sessile serrated adenoma/polyp" (SSA/P). SSLs are early precursor lesions in the serrated neoplasia pathway that result in colorectal carcinomas with BRAF mutations, methylation for DNA repair genes, a CpG island methylator phenotype, and high levels of microsatellite instability. Some of these lesions can rapidly become dysplastic or invasive carcinomas that exhibit high lymphatic invasion and lymph node metastasis potential. The 2019 WHO classification noted that dysplasia arising in an SSL most likely is an advanced polyp, regardless of the morphologic grade of the dysplasia. Detecting SSLs with or without dysplasia is critical; however, detection of SSLs is challenging, and their identification by endoscopists and pathologists is inconsistent. Furthermore, indications for their endoscopic treatment have not been established. Moreover, SSLs are considered to contribute to the development of post-colonoscopy colorectal cancers. Herein, the clinicopathological and endoscopic characteristics of SSLs, including features determined using white light and image-enhanced endoscopy, therapeutic indications, therapeutic methods, and surveillance are reviewed based on the literature. This information may lead to more intensive research to improve detection, diagnosis, and rates of complete resection of these lesions and reduce post-colonoscopy colorectal cancer rates.
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Affiliation(s)
- Takashi Murakami
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Taro Kurosawa
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
- Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hirofumi Fukushima
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tomoyoshi Shibuya
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takashi Yao
- Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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Parmar S, Easwaran H. Genetic and epigenetic dependencies in colorectal cancer development. Gastroenterol Rep (Oxf) 2022; 10:goac035. [PMID: 35975243 PMCID: PMC9373935 DOI: 10.1093/gastro/goac035] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/24/2022] [Accepted: 05/22/2022] [Indexed: 11/12/2022] Open
Abstract
Recent studies have mapped key genetic changes in colorectal cancer (CRC) that impact important pathways contributing to the multistep models for CRC initiation and development. In parallel with genetic changes, normal and cancer tissues harbor epigenetic alterations impacting regulation of critical genes that have been shown to play profound roles in the tumor initiation. Cumulatively, these molecular changes are only loosely associated with heterogenous transcriptional programs, reflecting the heterogeneity in the various CRC molecular subtypes and the paths to CRC development. Studies from mapping molecular alterations in early CRC lesions and use of experimental models suggest that the intricate dependencies of various genetic and epigenetic hits shape the early development of CRC via different pathways and its manifestation into various CRC subtypes. We highlight the dependency of epigenetic and genetic changes in driving CRC development and discuss factors affecting epigenetic alterations over time and, by extension, risk for cancer.
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Affiliation(s)
- Sehej Parmar
- Cancer Genetics and Epigenetics, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hariharan Easwaran
- Cancer Genetics and Epigenetics, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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11
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Forouzesh F, Kia FS, Nazemalhosseini-Mojarad E. BidSi6 and BidEL isoforms as a potential marker for predicting colorectal adenomatous polyps. BMC Med Genomics 2022; 15:129. [PMID: 35668495 PMCID: PMC9172139 DOI: 10.1186/s12920-022-01282-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 06/02/2022] [Indexed: 11/26/2022] Open
Abstract
Background As a well-known protein, Bid links the extrinsic and intrinsic apoptotic pathways and plays important roles in cell proliferation. In this study, we evaluated the expression of two isoforms of the Bid gene (BidSi6 and BidEL) in colorectal adenomatous polyps as a biomarker and investigated the relationship between their expression levels with clinicopathological factors. Methods The expression of BidSi6 and BidEL isoforms in 22 pairs of Adenomatous polyps and adjust non-polyp tissues was measured by qReal-Time PCR and compared with 10 normal colon tissues. ROC curve was performed to examine the diagnostic capacity. Also, sequencing was performed for molecular identification of BidSi6 isoform in adenomatous polyp. Results Our results showed that BidSi6 and BidEL isoforms were significantly overexpressed in Adenomatous polyps and non-polyp adjacent tissues from the same patients compared to that in normal colon tissues, but there was no significant expression between polyps and adjust non-polyp tissues. There were no significant correlations between the expression of two isoforms and other features of clinicopathology. The area under the curve of BidSi6 and BidEL isoforms indicated powerful diagnostic capability. The phylogenetic tree was constructed based on the sequence of idSi6 isoform, and the results showed that adenomatous polyp tissue and adjust non-polyp tissue were separated from healthy colorectal tissue and reference sequence (EU678292). Conclusions These findings suggest that BidSi6 and BidEL isoforms can be used as new potential biomarkers in adenomatous polyps. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-022-01282-0.
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Affiliation(s)
- Flora Forouzesh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, P.O. Box: 193951495, Tehran, Iran.
| | - Fatemeh Sadat Kia
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, P.O. Box: 193951495, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Department of Cancer, Gastroenterology and Liver Disease Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Miller Q, Saeed O, Mesa H. Clinical, Pathologic, and Molecular-Genetic Aspects of Colorectal Polyps. Gastrointest Endosc Clin N Am 2022; 32:313-328. [PMID: 35361338 DOI: 10.1016/j.giec.2021.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Most colorectal cancer arises from epithelial polyps. Polyps can be the result of acquired, germline, or inflammation-associated mutations in colonic stem cells (CSC). Their incidence and risk of progression are determined by factors that modify the baseline rate of spontaneous mutations occurring in CSC. In sporadic polyps, factors are primarily environmental; in individuals with germline mutations, it is the specific mutation, and in inflammation-associated polyps, it correlates with the extent, duration, and severity of the process. The different clinicopathologic and molecular genetic abnormalities underlying the different types of polyps are discussed.
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Affiliation(s)
- Quinn Miller
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, IU Health Pathology Laboratory, 350 West 11th Street, Indianapolis, IN 46202, USA
| | - Omer Saeed
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, IU Health Pathology Laboratory, 350 West 11th Street, Indianapolis, IN 46202, USA
| | - Hector Mesa
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, IU Health Pathology Laboratory, 350 West 11th Street, Indianapolis, IN 46202, USA.
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13
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Kuo YC, Yu LY, Wang HY, Chen MJ, Wu MS, Liu CJ, Lin YC, Shih SC, Hu KC. Effects of Helicobacter pylori infection in gastrointestinal tract malignant diseases: From the oral cavity to rectum. World J Gastrointest Oncol 2022; 14:55-74. [PMID: 35116103 PMCID: PMC8790410 DOI: 10.4251/wjgo.v14.i1.55] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 05/03/2021] [Accepted: 12/09/2021] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) has infected approximately fifty percent of humans for a long period of time. However, improvements in the public health environment have led to a decreased chance of H. pylori infection. However, a high infection rate is noted in populations with a high incidence rate of gastric cancer (GC). The worldwide fraction of GC attributable to H. pylori is greater than 85%, and a high H. pylori prevalence is noted in gastric mucosa-associated lymphoid tissue lymphoma patients. These results indicate that the majority of GC cases can be prevented if H. pylori infection is eliminated. Because H. pylori exhibits oral-oral or fecal-oral transmission, the relationship between this microorganism and other digestive tract malignant diseases has also attracted attention. This review article provides an overview of H. pylori and the condition of the whole gastrointestinal tract environment to further understand the correlation between the pathogen and the host, thus allowing improved realization of disease presentation.
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Affiliation(s)
- Yang-Che Kuo
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Lo-Yip Yu
- Department of Internal Medicine, Healthy Evaluation Center, Mackay Memorial Hospital, Taipei 10449, Taiwan
| | - Horng-Yuan Wang
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Ming-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10051, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan
| | - Ying-Chun Lin
- Department of Anesthesia, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Shou-Chuan Shih
- Division of Gastroenterology, Department of Internal Medicine, Health Evaluate Center, Mackay Memorial Hospital, Taipei 10449, Taiwan
| | - Kuang-Chun Hu
- Department of Internal Medicine, Healthy Evaluation Center, Mackay Memorial Hospital, MacKay Junior College of Medicine, Nursing, and Management, Taipei 10038, Taiwan
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14
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Uesugi N, Ajioka Y, Arai T, Tanaka Y, Sugai T. Clinicopathological and molecular analyses of hyperplastic lesions including microvesicular variant and goblet cell rich variant hyperplastic polyps and hyperplastic nodules-Hyperplastic nodule is an independent histological entity. Pathol Int 2021; 72:128-137. [PMID: 34818448 PMCID: PMC9299182 DOI: 10.1111/pin.13187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/03/2021] [Indexed: 01/23/2023]
Abstract
Hyperplastic nodules (HNs) have been considered to be hyperplastic lesions among Japanese pathologists, although they have not been recognized worldwide. Here, we examined clinicopathological and molecular differences between goblet cell-rich variant hyperplastic polyp (GCHPs), microvesicular variant HPs (MVHPs), and HNs. Patients with hyperplastic lesions including 61 GCHPs, 62 MVHPs, and 19 HNs were enrolled in the present study. The clinicopathological and molecular features examined included the mucin phenotype expression, p53 overexpression, annexin A10, genetic mutations (BRAF and KRAS), and DNA methylation status (low, intermediate, and high methylation epigenotype). In addition, hierarchical cluster analysis was also performed to identify patterns among the histological features. The lesions were stratified into three subgroups and each lesion was assigned into a subgroup. While GCHP was associated with KRAS mutation, MVHP was closely associated with BRAF mutation; no mutation was found in HN. We list specific histological findings that corresponded to each lesion. Finally, there were no significant differences in the methylation status among lesions. The current result shows that both MVHPs and GCHPs have a neoplastic nature whereas HN is non-neoplastic. We suggest that HNs should be distinguished from HPs, in particular GCHPs, in terms of pathological and genetic features.
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Affiliation(s)
- Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Yoichi Ajioka
- Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Tomio Arai
- Department of Diagnostic Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Itabashiku, Japan
| | - Yoshihito Tanaka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
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15
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Murakami T, Sakamoto N, Fukushima H, Shibuya T, Yao T, Nagahara A. Usefulness of the Japan narrow-band imaging expert team classification system for the diagnosis of sessile serrated lesion with dysplasia/carcinoma. Surg Endosc 2021; 35:4528-4538. [PMID: 32909209 DOI: 10.1007/s00464-020-07967-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 08/27/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Sessile serrated lesion (SSL) is a colorectal polyp that has malignant potential. However, the dysplastic components within an SSL can be difficult to diagnose with conventional endoscopy, because most SSLs with dysplasia/carcinoma have subtle mucosal features. Many studies have indicated that narrow-band imaging (NBI) observations of colorectal polyps are very useful, accurate predictors of histology. We aimed to verify the usefulness of the Japan NBI Expert Team (JNET) classification system for the diagnosis of SSLs with dysplasia/carcinoma. METHODS We examined 709 endoscopically or surgically resected lesions that were pathologically diagnosed as SSL, including 647 with no dysplasia, 37 with low-grade dysplasia, 15 with high-grade dysplasia, and 10 with submucosal invasive carcinoma. We retrospectively evaluated their clinicopathologic characteristics and conventional endoscopic and magnifying NBI endoscopic findings using the JNET system. RESULTS Cases in all groups were more frequently located in the proximal colon. Submucosal invasive carcinomas were significantly larger than no dysplasia and low-grade dysplasia lesions. Almost all studied lesions (96.3%) were covered with a mucus cap. Five hundred and eighty (81.8%) lesions exhibited dark spots inside the crypts, which are NBI findings' characteristic of SSL. As for the JNET classification of magnifying NBI endoscopic findings, all 709 lesions showed Type 1. Six hundred and eighteen (95.5%) SSLs with no dysplasia lesions exhibited Type 1 only, whereas 52 (83.9%) SSLs with dysplasia/carcinoma had a combination of Type 1 and Type 2A, 2B, or 3, corresponding to SSL and dysplasia/carcinoma, respectively. The JNET classification had high sensitivity (83.9%), specificity (95.5%), and overall diagnostic accuracy (94.5%) for diagnosing SSLs with dysplasia/carcinoma. CONCLUSIONS Use of magnifying NBI endoscopy with the JNET classification might be useful for diagnosing SSLs with dysplasia/carcinoma. This increased awareness may also improve the recognition of SSLs with dysplasia/carcinoma.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hirofumi Fukushima
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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16
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Kang B, Lee HS, Jeon SW, Park SY, Choi GS, Lee WK, Heo S, Lee DH, Kim DS. Progressive alteration of DNA methylation of Alu, MGMT, MINT2, and TFPI2 genes in colonic mucosa during colorectal cancer development. Cancer Biomark 2021; 32:231-236. [PMID: 34092617 DOI: 10.3233/cbm-203259] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is characterized by different pathways of carcinogenesis and is a heterogeneous disease with diverse molecular landscapes that reflect histopathological and clinical information. Changes in the DNA methylation status of colon epithelial cells have been identified as critical components in CRC development and appear to be emerging biomarkers for the early detection and prognosis of CRC. OBJECTIVE To explore the underlying disease mechanisms and identify more effective biomarkers of CRC. METHODS We compared the levels and frequencies of DNA methylation in 11 genes (Alu, APC, DAPK, MGMT, MLH1, MINT1, MINT2, MINT3, p16, RGS6, and TFPI2) in colorectal cancer and its precursor adenomatous polyp with normal tissue of healthy subjects using pyrosequencing and then evaluated the clinical value of these genes. RESULTS Aberrant methylation of Alu, MGMT, MINT2, and TFPI2 genes was progressively accumulated during the normal-adenoma-carcinoma progression. Additionally, CGI methylation occurred either as an adenoma-associated event for APC, MLH1, MINT1, MINT31, p16, and RGS6 or a tumor-associated event for DAPK. Moreover, relatively high levels and frequencies of DAPK, MGMT, and TFPI2 methylation were detected in the peritumoral nonmalignant mucosa of cancer patients in a field-cancerization manner, as compared to normal mucosa from healthy subjects. CONCLUSION This study identified several biomarkers associated with the initiation and progression of CRC. As novel findings, they may have important clinical implications for CRC diagnostic and prognostic applications. Further large-scale studies are needed to confirm these findings.
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Affiliation(s)
- Ben Kang
- Department of Pediatrics and Bio-medical Research Institute, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Hyun Seok Lee
- Department of Internal Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Seong Woo Jeon
- Department of Internal Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Soo Yeun Park
- Department of General Surgery, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Gyu Seog Choi
- Department of General Surgery, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Won Kee Lee
- Department of Preventive Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Somi Heo
- Department of Preventive Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Duk Hee Lee
- Department of Preventive Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
| | - Dong Sun Kim
- Department of Anatomy, School of Medicine, Kyungpook National University, Dongin-dong, Jung-gu, Daegu, Korea
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17
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Satorres C, García-Campos M, Bustamante-Balén M. Molecular Features of the Serrated Pathway to Colorectal Cancer: Current Knowledge and Future Directions. Gut Liver 2021; 15:31-43. [PMID: 32340435 PMCID: PMC7817929 DOI: 10.5009/gnl19402] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 02/18/2020] [Accepted: 03/04/2020] [Indexed: 02/05/2023] Open
Abstract
Serrated lesions are the precursor lesions of a new model of colorectal carcinogenesis. From a molecular standpoint, the serrated pathway is thought to be responsible for up to 30% of all colorectal cancer cases. The three major processes of this molecular mechanism are alterations in the mitogen-activated protein kinase pathway, production of the CpG island methylation phenotype, and generation of microsatellite instability. Other contributing processes are activation of WNT, alterations in the regulation of tumor suppressor genes, and alterations in microRNAs or in MUC5AC hypomethylation. Although alterations in the serrated pathway also contribute, their precise roles remain obscure because of the various methodologies and definitions used by different research groups. This knowledge gap affects clinical assessment of precursor lesions for their carcinogenic risk. The present review describes the current literature reporting the molecular mechanisms underlying each type of serrated lesion and each phenotype of serrated pathway colorectal cancer, identifying those areas that merit additional research. We also propose a unified serrated carcinogenesis pathway combining molecular alterations and types of serrated lesions, which ends in different serrated pathway colorectal cancer phenotypes depending on the route followed. Finally, we describe some key issues that need to be addressed in order to incorporate the newest technologies in serrated pathway research and to improve overall knowledge for developing specific prevention strategies and new therapeutic targets.
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Affiliation(s)
- Carla Satorres
- Gastrointestinal Endoscopy Research Group, La Fe Health Research Institute, Valencia, Spain
- Gastrointestinal Endoscopy Unit, Digestive Diseases Department, La Fe Polytechnic University Hospital, Valencia, Spain
| | - María García-Campos
- Gastrointestinal Endoscopy Unit, Digestive Diseases Department, La Fe Polytechnic University Hospital, Valencia, Spain
| | - Marco Bustamante-Balén
- Gastrointestinal Endoscopy Research Group, La Fe Health Research Institute, Valencia, Spain
- Gastrointestinal Endoscopy Unit, Digestive Diseases Department, La Fe Polytechnic University Hospital, Valencia, Spain
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18
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Risk factors including night shift work of colorectal polyp. Ann Occup Environ Med 2020; 32:e26. [PMID: 32802342 PMCID: PMC7406667 DOI: 10.35371/aoem.2020.32.e26] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 06/26/2020] [Indexed: 12/15/2022] Open
Abstract
Background The destruction of circadian rhythms by night shift work affects major circadian genes, which are known to play a role in advancing or killing the cell cycle through tumor suppressor genes. To find out whether night shift work affects the incidence of colorectal cancer, which was found to be associated with long-term night shift work in previous studies, we surveyed effect of night shift work on colorectal polyps that have a higher incidence than colorectal cancer and can progress to colorectal cancer. Methods To examine the correlation between rotating night shifts and colorectal polyps, a survey was conducted with 299 men aged 40–60 years from two university hospitals. We examined lifestyle, work history, work patterns, and colonoscopy results. The differences in prevalence among the groups was compared, and prevalence ratio (PR) was calculated via generalized linear modeling. Results The prevalence of colorectal polyps in night shift and non-shift workers were 53.0% and 33.5%, respectively. After adjusting for age, smoking status, dietary habits, family history of colorectal cancer, obesity, job type, night shift work (PR: 1.13, 95% CI: 1.02–1.25) was a risk factor of colorectal polyps. Conclusions The risk of colorectal polyps was greater in night shift workers than non-shift workers. Also risk of colorectal polyp was higher in older group. Our study investigated colorectal polyp instead of colorectal cancer and lacks information about types and gene mutations of colorectal polyps. Further study is needed to clarify effect of night shift work on development of colorectal cancer.
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19
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Kim JH, Kang GH. Evolving pathologic concepts of serrated lesions of the colorectum. J Pathol Transl Med 2020; 54:276-289. [PMID: 32580537 PMCID: PMC7385269 DOI: 10.4132/jptm.2020.04.15] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/13/2020] [Accepted: 04/15/2020] [Indexed: 12/12/2022] Open
Abstract
Here, we provide an up-to-date review of the histopathology and molecular pathology of serrated colorectal lesions. First, we introduce the updated contents of the 2019 World Health Organization classification for serrated lesions. The sessile serrated lesion (SSL) is a new diagnostic terminology that replaces sessile serrated adenoma and sessile serrated polyp. The diagnostic criteria for SSL were revised to require only one unequivocal distorted serrated crypt, which is sufficient for diagnosis. Unclassified serrated adenomas have been included as a new category of serrated lesions. Second, we review ongoing issues concerning the morphology of serrated lesions. Minor morphologic variants with distinct molecular features were recently defined, including serrated tubulovillous adenoma, mucin-rich variant of traditional serrated adenoma (TSA), and superficially serrated adenoma. In addition to intestinal dysplasia and serrated dysplasia, minimal deviation dysplasia and not otherwise specified dysplasia were newly suggested as dysplasia subtypes of SSLs. Third, we summarize the molecular features of serrated lesions. The critical determinant of CpG island methylation development in SSLs is patient age. Interestingly, there may be ethnic differences in BRAF/KRAS mutation frequencies in SSLs. The molecular pathogenesis of TSAs is divided into KRAS and BRAF mutation pathways. SSLs with MLH1 methylation can progress into favorable prognostic microsatellite instability-positive (MSI+)/CpG island methylator phenotype-positive (CIMP+) carcinomas, whereas MLH1-unmethylated SSLs and BRAF-mutated TSAs can be precursors of poor-prognostic MSI-/CIMP+ carcinomas. Finally, based on our recent data, we propose an algorithm for stratifying risk subgroups of non-dysplastic SSLs.
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Affiliation(s)
- Jung Ho Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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20
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Sano W, Hirata D, Teramoto A, Iwatate M, Hattori S, Fujita M, Sano Y. Serrated polyps of the colon and rectum: Remove or not? World J Gastroenterol 2020; 26:2276-2285. [PMID: 32476792 PMCID: PMC7243646 DOI: 10.3748/wjg.v26.i19.2276] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 04/01/2020] [Accepted: 04/29/2020] [Indexed: 02/06/2023] Open
Abstract
In recent years, the serrated neoplasia pathway where serrated polyps arise as a colorectal cancer has gained considerable attention as a new carcinogenic pathway. Colorectal serrated polyps are histopathologically classified into hyperplastic polyps (HPs), sessile serrated lesions, and traditional serrated adenomas; in the serrated neoplasia pathway, the latter two are considered to be premalignant. In western countries, all colorectal polyps, including serrated polyps, apart from diminutive rectosigmoid HPs are removed. However, in Asian countries, the treatment strategy for colorectal serrated polyps has remained unestablished. Therefore, in this review, we described the clinicopathological features of colorectal serrated polyps and proposed to remove HPs and sessile serrated lesions ≥ 6 mm in size, and traditional serrated adenomas of any size.
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Affiliation(s)
- Wataru Sano
- Gastrointestinal Center, Sano Hospital, Hyogo 655-0031, Japan
| | - Daizen Hirata
- Gastrointestinal Center, Sano Hospital, Hyogo 655-0031, Japan
| | - Akira Teramoto
- Gastrointestinal Center, Sano Hospital, Hyogo 655-0031, Japan
| | - Mineo Iwatate
- Gastrointestinal Center, Sano Hospital, Hyogo 655-0031, Japan
| | - Santa Hattori
- Gastrointestinal Center, Sano Hospital, Hyogo 655-0031, Japan
| | - Mikio Fujita
- Gastrointestinal Center, Sano Hospital, Hyogo 655-0031, Japan
| | - Yasushi Sano
- Gastrointestinal Center, Sano Hospital, Hyogo 655-0031, Japan
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21
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Chan AWH, Pan Y, Tong JHM, Lung RWM, Kwan JSH, Chow C, Tin EKY, Chung LY, Li H, Wong SSY, Chau SL, Chan YY, Mak TWC, Ng SSM, To KF. Receptor tyrosine kinase fusions act as a significant alternative driver of the serrated pathway in colorectal cancer development. J Pathol 2020; 251:74-86. [PMID: 32162306 DOI: 10.1002/path.5418] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 02/18/2020] [Accepted: 03/02/2020] [Indexed: 02/06/2023]
Abstract
Serrated polyps are a clinically and molecularly heterogeneous group of lesions that can contribute to the development of colorectal cancers (CRCs). However, the molecular mechanism underlying the development of serrated lesions is still not well understood. Here, we combined multiple approaches to analyze the genetic alterations in 86 colorectal adenomas (including 35 sessile serrated lesions, 15 traditional adenomas, and 36 conventional adenomatous polyps). We also investigated the in vitro and in vivo oncogenic properties of a novel variant of the NCOA4-RET fusion gene. Molecular profiling revealed that sessile serrated lesions and traditional serrated adenomas have distinct clinicopathological and molecular features. Moreover, we identified receptor tyrosine kinase translocations exclusively in sessile serrated lesions (17%), and the observation was validated in a separate cohort of 34 sessile serrated lesions (15%). The kinase fusions as well as the BRAF and KRAS mutations were mutually exclusive to each other. Ectopic expression of a novel variant of the NCOA4-RET fusion gene promoted cell proliferation in vitro and in vivo, and the proliferation was significantly suppressed by RET kinase inhibitors. All of these underscored the importance of mitogen-activated protein kinase (MAPK) pathway activation in the serrated pathway of colorectal tumorigenesis. In addition, we demonstrated that the kinase fusion may occur early in the precursor lesion and subsequent loss of TP53 may drives the transformation to carcinoma during serrated tumorigenesis. In conclusion, we identified kinase fusions as a significant alternative driver of the serrated pathway in colorectal cancer development, and detecting their presence may serve as a biomarker for the diagnosis of sessile serrated lesions. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Anthony W-H Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Yi Pan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Joanna H-M Tong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Raymond W-M Lung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Johnny S-H Kwan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Chit Chow
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Edith K-Y Tin
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Lau-Ying Chung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Hui Li
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Shela S-Y Wong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Shuk-Ling Chau
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Yuk Yu Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Tony W-C Mak
- Division of Colorectal Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Simon Siu-Man Ng
- Division of Colorectal Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China
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22
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Segev L, Kalady MF, Plesec T, Mor E, Schtrechman G, Nissan A, Church JM. The location of premalignant colorectal polyps under age 50: a further rationale for screening sigmoidoscopy. Int J Colorectal Dis 2020; 35:529-535. [PMID: 31930456 DOI: 10.1007/s00384-020-03504-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/08/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE The incidence of colorectal cancer (CRC) among young adults has been dramatically rising, with guidelines for screening recently adjusted to start at age 45. However, knowledge of the precursor lesions is limited. We recently reported that 83% of CRC diagnosed under age 50 are left sided. Our aim was to analyze the location and histology of benign colorectal lesions found in a cohort of patients younger than 50, documenting the presence of advanced histology. METHODS We used the database in the Department of Pathology to retrospectively review the location and histology of all benign colorectal neoplasms in patients under age 50 submitted to pathology examination during 2006-2016. RESULTS A total of 8364 lesions were examined from 4773 patients, and 3534 (65.5%) of the patients had only one polyp and the rest had multiple. Mean age was 41.9 years (range 16-49) while 3843 (72.8%) of the patients were between the ages of 40 and 49. In total, 4570/8364 lesions (54.6%) were distal to the splenic flexure. The most common pathology was tubular adenoma (63.7%), then hyperplastic polyps (16.6%), sessile serrated lesions (SSLs) (13.1%), and tubulovillous adenomas (6.3%). Tubulovillous adenomas, villous lesions, advanced adenomas, and adenomas with high-grade dysplasia were all predominantly left sided (left colon and rectum = 77.6%, 85%, 78.3%, and 87.6% respectively). Of the SSLs, 71.5% were in the right colon while 16.6% of hyperplastic lesions were right sided. CONCLUSIONS High-risk advanced adenomas are predominantly left sided. This focuses attention on the rectum and left colon where carcinogenesis is strong in the young.
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Affiliation(s)
- Lior Segev
- Department of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, OH, USA. .,Department of Surgery C, Sheba Medical Center, 5265601, Tel HaShomer, Israel. .,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
| | - Matthew F Kalady
- Department of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Thomas Plesec
- Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Eyal Mor
- Department of Surgery C, Sheba Medical Center, 5265601, Tel HaShomer, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Gal Schtrechman
- Department of Surgery C, Sheba Medical Center, 5265601, Tel HaShomer, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Aviram Nissan
- Department of Surgery C, Sheba Medical Center, 5265601, Tel HaShomer, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - James M Church
- Department of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, OH, USA
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Abstract
BACKGROUND Colorectal sessile serrated lesion (SSL) with synchronous neoplasm or large size are linked to higher risk of cancer, but their characteristics are unclear. METHODS We prospectively included consecutive colorectal hyperplasic polyp and SSL collected at our institution from August 2011 to August 2012. The following data were collected and analyzed: age, gender, polyp site, aggregated polyp size, history of polyp, and synchronous neoplasm. RESULTS We collected 437 specimens including 353 (80.8%) hyperplasic polyp and 84 (19.2%) SSL. Compared with hyperplasic polyp, SSL was independently associated with proximal colon [odds ratio (OR) 3.61, P< 0.001], larger size (OR 3.98, P< 0.001), but not history of polyp, age or gender. Large SSL (≥1 vs <1 cm) was associated with polyp site (P= 0.035) and synchronous advanced adenoma and cancer (P< 0.001). SSL with synchronous adenoma and cancer were more likely found in males (OR 1.91, P= 0.001), elderly (OR 1.02, P= 0.033), and patients with the index polyp in proximal colon (OR 1.32, P= 0.022), but not related to history of adenoma and cancer. Moreover, synchronous adenoma, SSL and cancer were independently associated with male gender (OR 1.90, P< 0.001), but surprisingly not older age, histology of index polyp (SSL vs hyperplasic polyp), index-polyp site or history of adenoma and cancer. CONCLUSIONS This prospective study shows male gender is associated with both synchronous adenoma and cancer, and synchronous adenoma, SSL and cancer, while index polyp site is associated with synchronous adenoma and cancer.
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24
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Park SK, Kim HS, Yang HJ, Jung YS, Park JH, Sohn CI, Park SH, Sohn JH, Lee MY, Park DI. Coexistent adenoma and serrated polyps on index colonoscopy and the risk of metachronous advanced colorectal neoplasia. Endosc Int Open 2019; 7:E1748-E1754. [PMID: 31828212 PMCID: PMC6904238 DOI: 10.1055/a-1019-2976] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 08/23/2019] [Indexed: 12/20/2022] Open
Abstract
Background and aims The family of serrated polyps (SP) includes hyperplastic polyps (HP), sessile serrated adenomas/polyps, and traditional serrated adenoma. We investigated whether SP synchronous with adenoma at index colonoscopy is associated with metachronous advanced colorectal neoplasia (CRN). Methods Patients with ≥ 1 adenoma on index colonoscopy and who had undergone a follow-up colonoscopy were included. The patients were divided into four groups according to the presence of SP and advanced adenoma (AA) on index colonoscopy (non-AA, non-AA + SP, AA, AA + SP). The cumulative incidence of metachronous advanced CRN at surveillance colonoscopy was compared between groups. Results Among a total of 2209 patients, the numbers of patients in the non-AA, non-AA + SP, AA, and AA + SP groups were 922, 441, 625, and 221, respectively. The cumulative incidence of metachronous advanced CRN was higher in patients in the AA + SP group than that in the AA group ( P <0.001), and there was no significant difference between the non-AA + SP group and the non-AA group ( P = 0.06). The cumulative incidence of metachronous advanced CRN at 3 years was 17.9 % [95 % confidence interval (CI) 8.0-27.6], 10.7 % [95 %CI 7.7-3.6], 3.5 % [95 %CI 1.3-5.6], and 3.4 % [95 %CI 2.0-4.7] in the AA + SP, AA, non-AA + SP, and non-AA group, respectively. In a multivariate analysis, overall SP [hazard ratio (HR) 2.24; 95 %CI 1.38-3.64, P = 0.001], proximal SP (HR 2.31; 95 %CI 1.32-4.08), and HP (HR 2.19; 95 %CI 1.35-3.57) were risk factors for metachronous advanced CRN in patients with AA on index colonoscopy. Conclusions Coexistent AA and SP on index colonoscopy significantly increased the risk of metachronous advanced CRN compared with AA alone. Further large prospective studies are needed to confirm whether more intensive follow-up improves outcomes in these high risk patients.
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Affiliation(s)
- Soo-Kyung Park
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hak-Soo Kim
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hyo-Joon Yang
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yoon Suk Jung
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jung Ho Park
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Chong Il Sohn
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang Hyun Park
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin Hee Sohn
- Division of Pathology, Department of R&D Management, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Mi Yeon Lee
- Division of Biostatistics, Department of R&D Management, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Il Park
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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25
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Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol 2019; 16:713-732. [PMID: 31455888 DOI: 10.1038/s41575-019-0189-8] [Citation(s) in RCA: 1522] [Impact Index Per Article: 253.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/11/2019] [Indexed: 02/06/2023]
Abstract
Globally, colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death. Arising through three major pathways, including adenoma-carcinoma sequence, serrated pathway and inflammatory pathway, CRC represents an aetiologically heterogeneous disease according to subtyping by tumour anatomical location or global molecular alterations. Genetic factors such as germline MLH1 and APC mutations have an aetiologic role, predisposing individuals to CRC. Yet, the majority of CRC is sporadic and largely attributable to the constellation of modifiable environmental risk factors characterizing westernization (for example, obesity, physical inactivity, poor diets, alcohol drinking and smoking). As such, the burden of CRC is shifting towards low-income and middle-income countries as they become westernized. Furthermore, the rising incidence of CRC at younger ages (before age 50 years) is an emerging trend. This Review provides a comprehensive summary of CRC epidemiology, with emphasis on modifiable lifestyle and nutritional factors, chemoprevention and screening. Overall, the optimal reduction of CRC incidence and mortality will require concerted efforts to reduce modifiable risk factors, to leverage chemoprevention research and to promote population-wide and targeted screening.
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Affiliation(s)
- NaNa Keum
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Food Science and Biotechnology, Dongguk University, Goyang, South Korea
| | - Edward Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. .,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. .,Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA.
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26
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Murakami T, Sakamoto N, Nagahara A. Clinicopathological features, diagnosis, and treatment of sessile serrated adenoma/polyp with dysplasia/carcinoma. J Gastroenterol Hepatol 2019; 34:1685-1695. [PMID: 31158302 DOI: 10.1111/jgh.14752] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/22/2019] [Accepted: 05/28/2019] [Indexed: 12/17/2022]
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in BRAF-mutated colorectal carcinomas with not only high levels of microsatellite instability but also microsatellite stable. SSA/Ps with advanced histology, including cytological dysplasia or minimally invasive carcinomas, are important lesions because SSA/Ps are considered major contributors to "interval cancers" and these lesions can rapidly become dysplastic or invasive carcinomas. Clinicopathologically, SSA/Ps with dysplasia or invasive carcinoma were associated with advanced age, female sex, and proximal colon. Although SSA/Ps with submucosal invasive carcinoma were smaller and invaded less deeply into the submucosal layer than conventional tubular adenomas with submucosal invasive carcinoma, SSA/Ps with submucosal invasive carcinoma frequently had a mucinous component and exhibited a higher potential for lymphatic invasion and lymph node metastasis. In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, may help accurately diagnose SSA/Ps with advanced histology. Removal of SSA/Ps with dysplasia or invasive carcinoma was recommended. Endoscopic treatment such as endoscopic mucosal resection or endoscopic submucosal dissection is useful for those lesions. However, surgical resection with lymph node dissection might be indicated when SSA/Ps with invasive carcinoma are endoscopically suspected, because these have the high risk of lymph node metastasis. Greater awareness may promote further research into improving the detection, recognition, and complete resection rates of SSA/Ps with dysplasia or invasive carcinoma and reduce the interval cancer rates.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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27
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Hissong E, Fernandes H, Jessurun J. Colonic Mucosa With Polypoid Hyperplasia. Am J Clin Pathol 2019; 152:423-430. [PMID: 31152544 DOI: 10.1093/ajcp/aqz053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Define the morphologic and molecular features of colonic polyps with subtle histologic features. METHODS Two hundred specimens were obtained of surveillance colonoscopies. Endoscopic findings were reviewed. Histologic features of the polyps were compared with the flat mucosa. Next-generation sequencing was performed on 30 study polyps and 20 control samples. RESULTS Polyps with subtle changes comprised 12% of all polyps. All polyps were sessile and small (<0.5 cm) and were located predominantly in the distal colon (60%). Synchronous hyperplastic, sessile serrated, and dysplastic polyps were found in 30%, 7%, and 51% of patients, respectively. A total of 169 (84.5%) polyps showed wide, nonserrated crypts, increased intraluminal mucus, and patent openings. KRAS alterations were present in 30% of polyps. CONCLUSIONS Most polyps with subtle histologic features have recognizable morphologic changes. About one-third harbored KRAS alterations. These polyps should not be regarded as variants of hyperplastic polyps.
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Affiliation(s)
- Erika Hissong
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Helen Fernandes
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY
| | - Jose Jessurun
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
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28
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Rezasoltani S, Khatibi S, Pezeshkiyan Z, Nazemalhosseini-Mojarad E, Sharafkhah M, Sadeghi A, Asadzadeh Aghdaei H, Zali MR. Investigating the TLR9 mRNA Expression Level in Different Histological Types of Colorectal Polyps. Asian Pac J Cancer Prev 2019; 20:2299-2302. [PMID: 31450898 PMCID: PMC6852833 DOI: 10.31557/apjcp.2019.20.8.2299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Indexed: 01/14/2023] Open
Abstract
Toll-like receptor 9 (TLR9) is a cellular DNA receptor of the innate immune system which plays a pivotal role in inflammatory response. Recently, changing expression levels of TLR9 has been observed in a wide range of cancer cells; however, there is little information about colorectal polyps. Herein, we assessed the mRNA expression of TLR9 in different colorectal polyp types compared to normal group in order to investigate its expression level during CRC initiation. Fifty-four biopsy samples from colorectal polyp patients and from 20 healthy subjects were collected. The mucosal mRNA expression level of TLR9 gene was identified by real time PCR. Fold change of gene expression was evaluated by 2-ΔΔct method. There was a significant relationship between the lower expression of TLR9 gene in the polyp cases compared to normal individuals (P value = 0.0005), Also, decreased TLR9 mRNA expression was obtained in adenomas in contrast to hyperplastic and normal groups (P value = 0.0008). Based on the current results, we hypothesized that aberrant surface expression of TLR9 on tumor cells may promote the growth and invasion of colorectal polyps. Further, TLR9 modulation may have an important impact on the development of novel therapeutic strategies.
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Affiliation(s)
- Sama Rezasoltani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Khatibi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Pezeshkiyan
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maryam Sharafkhah
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Sadeghi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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29
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Travaglino A, D'Armiento FP, Cassese G, Campanino MR, Borrelli G, Pignatiello S, Luglio G, Maione F, De Palma GD, D'Armiento M. Clinicopathological factors associated with BRAF-V600E mutation in colorectal serrated adenomas. Histopathology 2019; 75:160-173. [PMID: 30815911 DOI: 10.1111/his.13846] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Serrated adenomas are genetically heterogeneous, and the histological classification into sessile serrated (SSA) adenoma and traditional serrated adenoma (TSA) does not reflect the molecular landscape. The objective of this study was to assess clinical or pathological factors associated with BRAF-V600E mutation in serrated adenomas. Systematic review and meta-analysis was performed by searching electronic databases from January 2011 to January 2019 for studies assessing the association of BRAF-V600E mutation with clinical or pathological features of serrated adenomas. Odds ratio (OR) was calculated for each factor; a P-value <0.05 was considered significant. Forty studies assessing 3511 serrated adenomas (2375 SSAs and 1136 TSAs) were included. BRAF-V600E mutation was significantly associated with proximal localisation (OR = 2.71; P < 0.00001) and CIMP-H status (OR = 4.81; P < 0.0001) in both SSA and TSA, with polyp size <10 mm (OR = 0.41; P = 0.02) in TSA, and with endoscopic pit pattern II-O (OR = 13.11; P < 0.00001) and expression of MUC5A5 (OR = 4.43; P = 0.003) and MUC6 (OR = 2.28; P < 0.05) in SSA. Conversely, BRAF mutation was not associated with age <70 years (OR = 1.63; P = 0.34), age <60 years (OR = 0.86; P = 0.79), female sex (OR = 0.77; P = 0.12), flat morphology (OR = 1.52; P = 0.16), presence of any dysplasia (OR = 1.01; P = 0.59), serrated dysplasia (OR = 1.23; P = 0.72) and invasive cancer (OR = 0.67; P = 0.32), nuclear β-catenin expression (OR = 0.73; P = 0.21) and p53 overexpression (OR = 1.24; P = 0.82). In conclusion, BRAF-V600E mutation is associated with proximal localisation and CIMP-H status in both SSA and TSA, with size <10 mm only in TSA, and with expression of MUC5A5 and MUC6 and endoscopic pit pattern II-O at least in SSA. In serrated adenomas, BRAF-V600E mutation does not seem to be associated with age and sex, with the prevalence of dysplasia and cancer and with the morphology of the dysplastic component.
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Affiliation(s)
- Antonio Travaglino
- Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Francesco P D'Armiento
- Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Gianluca Cassese
- Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Maria R Campanino
- Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giorgio Borrelli
- Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Sara Pignatiello
- Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Gaetano Luglio
- Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Francesco Maione
- Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giovanni D De Palma
- Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Maria D'Armiento
- Department of Public Health, School of Medicine, University of Naples Federico II, Naples, Italy
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30
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Liu C, Fennell LJ, Bettington ML, Walker NI, Dwine J, Leggett BA, Whitehall VLJ. DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas. Clin Epigenetics 2019; 11:90. [PMID: 31200767 PMCID: PMC6570920 DOI: 10.1186/s13148-019-0691-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 06/04/2019] [Indexed: 12/31/2022] Open
Abstract
Background Sessile serrated adenomas (SSAs) are common polyps which give rise to 20–30% of colorectal cancer (CRC). SSAs display clinicopathologic features which present challenges in surveillance, including overrepresentation in young patients, proclivity for the proximal colon and rarity of histologic dysplasia (referred to then as SSAs with dysplasia, SSADs). Once dysplasia develops, there is rapid progression to CRC, even at a small size. There is therefore a clinical need to separate the “advanced” SSAs at high risk of progression to SSAD and cancer from ordinary SSAs. Since SSAs are known to accumulate methylation over time prior to the development of dysplasia, SSAD backgrounds (the remnant SSA present within an SSAD) likely harbour additional methylation events compared with ordinary SSAs. We therefore performed MethyLight and comprehensive methylation array (Illumina MethylationEPIC) on 40 SSAD backgrounds and 40 matched ordinary SSAs, and compared the methylation results with CRC methylation, CRC expression and immunohistochemical data. Results SSAD backgrounds demonstrated significant hypermethylation of CpG islands compared with ordinary SSAs, and the proportion of hypermethylated probes decreased progressively in the shore, shelf and open sea regions. Hypomethylation occurred in concert with hypermethylation, which showed a reverse pattern, increasing progressively away from the island regions. These methylation changes were also identified in BRAF-mutant hypermethylated CRCs. When compared with CRC expression data, SV2B, MLH1/EPM2AIP1, C16orf62, RCOR3, BAIAP3, OGDHL, HDHD3 and ATP1B2 demonstrated both promoter hypermethylation and decreased expression. Although SSAD backgrounds were histologically indistinguishable from ordinary SSAs, MLH1 methylation was detectable via MethyLight in 62.9% of SSAD backgrounds, and focal immunohistochemical MLH1 loss was seen in 52.5% of SSAD backgrounds. Conclusions Significant hyper- and hypomethylation events occur during SSA progression well before the development of histologically identifiable changes. Methylation is a heterogeneous process within individual SSAs, as typified by MLH1, where both MLH1 methylation and focal immunohistochemical MLH1 loss can be seen in the absence of dysplasia. This heterogeneity is likely a generalised phenomenon and should be taken into account in future methylation-based studies and the development of clinical methylation panels. Electronic supplementary material The online version of this article (10.1186/s13148-019-0691-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Cheng Liu
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia. .,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. .,Envoi Specialist Pathologists, Brisbane, QLD, Australia.
| | - Lochlan J Fennell
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Mark L Bettington
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Neal I Walker
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Joel Dwine
- Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Barbara A Leggett
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Vicki L J Whitehall
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Department of Chemical Pathology, Pathology Queensland, Brisbane, QLD, Australia
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31
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Kim KH, Kim KO, Jung Y, Lee J, Kim SW, Kim JH, Kim TJ, Cho YS, Joo YE. Clinical and endoscopic characteristics of sessile serrated adenomas/polyps with dysplasia/adenocarcinoma in a Korean population: A Korean Association for the Study of Intestinal Diseases (KASID) multicenter study. Sci Rep 2019; 9:3946. [PMID: 30850671 PMCID: PMC6408487 DOI: 10.1038/s41598-019-40559-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 02/19/2019] [Indexed: 12/27/2022] Open
Abstract
Sessile serrated adenomas/polyps (SSA/Ps) are precancerous lesions that account for one-third of colorectal cancers. The endoscopic and pathologic differentiation between SSA/Ps without dysplasia (SSA/POs) and SSA/Ps with dysplasia or adenocarcinoma (SSA/PDAs) can be difficult. This study aimed to assess the clinical characteristics of SSA/PDs. This multicenter retrospective cohort study included 532 patients who underwent endoscopic resection and were pathologically diagnosed with SSA/POs and SSA/PDAs. Initially, medical, endoscopic, and histopathological records of patients who underwent endoscopic resection of SSA/POs and SSA/PDAs at eight university hospitals in Korea between January 2005 and December 2015 were reviewed. A total of 307 (57.7%) patients were detected in men and 319 (60.0%) were located in the proximal colon. Most SSA/Ps had a flat, slightly elevated, or sessile morphology. The most prevalent endoscopic findings of SSA/Ps were nodular surface (244, 45.9%), disrupted vascular pattern (232, 43.6%), altered fold contour (141, 26.5%), dome-shaped morphology (135, 25.4%), and pale color (115, 21.6%). SSA/POs were more commonly found in the proximal colon, compared to SSA/PDAs. SSA/PDAs displayed 0-Ip, Isp, IIb or IIa + IIc morphologies more frequently, while SSA/POs displayed 0-Is or IIa morphology more frequently. The frequency of a rim of debris/bubbles was significantly higher in SSA/POs, while nodular surface and disrupted vascular pattern were significantly higher in SSA/PDAs. In the univariate analysis of endoscopic features, SSA/PDAs were significantly associated with the distal colon location, 0-Isp and IIb morphologies, nodular surface, and disrupted vascular pattern. In the multivariate analysis, 0-IIb, nodular surface, and disrupted vascular pattern were significantly associated with SSA/PDAs. SSA/Ps with 0-IIb morphology, nodular surface and disrupted vascular pattern are associated with an increased risk of dysplasia or adenocarcinoma.
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Affiliation(s)
- Ki-Hyun Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Kyeong-Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Yunho Jung
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea
| | - Jun Lee
- Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Republic of Korea
| | - Sang-Wook Kim
- Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Jae-Hyun Kim
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Republic of Korea
| | - Tae-Jun Kim
- Department of Internal Medicine, Sungkyunkwan University College of Medicine, Seoul, Republic of Korea
| | - Young-Seok Cho
- Department of Internal Medicine, Catholic University College of Medicine, Seoul, Republic of Korea
| | - Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
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Kim KO, Huh KC, Hong SP, Kim WH, Yoon H, Kim SW, Kim YS, Park JH, Lee J, Lee BJ, Park YS. Frequency and Characteristics of Interval Colorectal Cancer in Actual Clinical Practice: A KASID Multicenter Study. Gut Liver 2019; 12:537-543. [PMID: 29938454 PMCID: PMC6143441 DOI: 10.5009/gnl17485] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 01/16/2018] [Accepted: 03/03/2018] [Indexed: 12/13/2022] Open
Abstract
Background/Aims The aims of the present study were to determine the frequency of interval colorectal cancers (CRCs) after surveillance colonoscopy and to compare the clinicopathologic features and survival outcomes with those of non-interval CRCs. Methods From January 2003 to December 2013, 66,016 follow-up colonoscopies for 38,412 patients performed within recommended time were reviewed retrospectively based on data from 11 tertiary hospitals in South Korea. To compare clinicopathologic features and survival rates for interval CRC, 106 patients with non-interval CRC matched in age and gender were included. Results Among the 66,016 colonoscopies performed within the surveillance period, 63 cases (63/66,016) of interval CRC were detected, and 53 were finally included in the analysis. The mean age was 69.9±8.8 years, and the male to female ratio was 1.94:1. Although the occurrence rate of cancer in the right side colon was higher than that of non-interval CRC, interval CRCs were predominantly left sided. Other clinicopathologic features and overall survival were not significantly different between the two groups. Missed lesion was suspected to be the most common cause (29 cases, 54.7%). Conclusions The frequency of interval CRC among patients who had undergone a surveillance colonoscopy was 0.095%. While sharing some similar clinical features and survival outcomes, interval CRCs in Korea developed more often in males and on the left side in contrast to results from Western studies.
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Affiliation(s)
- Kyeong Ok Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Kyu Chan Huh
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Sung Pil Hong
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Won Hee Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sang Wook Kim
- Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea
| | - Yeon Soo Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Jong Ha Park
- Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea
| | - Jun Lee
- Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Korea
| | - Bum Jae Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Young Sook Park
- Department of Internal Medicine, Eulji Hospital, Eulji University College of Medicine, Seoul, Korea
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Bläker H, Alwers E, Arnold A, Herpel E, Tagscherer KE, Roth W, Jansen L, Walter V, Kloor M, Chang-Claude J, Brenner H, Hoffmeister M. The Association Between Mutations in BRAF and Colorectal Cancer-Specific Survival Depends on Microsatellite Status and Tumor Stage. Clin Gastroenterol Hepatol 2019; 17:455-462.e6. [PMID: 29660527 DOI: 10.1016/j.cgh.2018.04.015] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 03/29/2018] [Accepted: 04/08/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Colorectal tumors with mutations in BRAF and microsatellite stability (MSS) have been associated with adverse outcomes of patients. Combined tests for microsatellite instability-high (MSI-H) and BRAF mutations might therefore be used in risk assessment, particularly for patients with stage II tumors. We investigate the stage-specific prognostic value of combined testing for MSI-H and BRAF for patients with colorectal cancer. METHODS We performed a retrospective analysis of colorectal tumor samples collected from 1995 patients at 22 hospitals in Germany, between 2003 and 2010. Samples were analyzed for MSI-H using an established mononucleotide marker panel; BRAF mutations (BRAFV600E) were detected by Sanger sequencing or in tissue microarray blocks using immunohistochemistry. Cancers were assigned to categories of having MSS without mutations in BRAF, MSS with mutant BRAF, MSI-H without mutations in BRAF, and MSI-H with mutant BRAF. We investigated the association between tumor categories with clinical and pathologic features and patient's overall, disease-specific, and recurrence-free survival (median follow-up time, 5.1 y). RESULTS Tumors were stage I in 364 (18%), stage II in 678 (34%), stage III in 673 (34%), and stage IV (14%) in 280 patients. Sixty-three percent of tumors were located in the colon and 37% in the rectum. Most tumors (85%) had MSS without mutations in BRAF, 3% had MSS with mutant BRAF, 7% had MSI-H without mutations in BRAF, and 5% had MSI-H with mutant BRAF. In patients whose tumors were MSI-H, mutation of BRAF did not significantly affect survival time. Patients whose tumors had MSS with mutant BRAF had significantly reduced overall survival (hazard ratio [HR], 2.16; 95% CI, 1.54-3.04; P < .001), disease-specific survival (HR, 2.59; 95% CI, 1.77-3.79; P < .001), and recurrence-free survival (HR, 2.45; 95% CI, 1.70-3.52; P < .001) than patients whose tumors had MSS without BRAF mutation. Although BRAF mutations in tumors with MSS were associated with disease-specific survival of patients with stage III or IV tumors (P < .001), these features did not affect survival of patients with stage II tumors (P = .639). CONCLUSIONS In an analysis of almost 2000 patients with colorectal cancer, we found BRAF mutations to reduce survival of patients in stage III or IV (but not stage II) tumors with MSS. These findings do not support testing stage I or II colorectal tumors for BRAF mutations, although additional large studies are needed.
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Affiliation(s)
- Hendrik Bläker
- Department of General Pathology, Institute of Pathology, Charité University Medicine Hospital, Berlin, Germany.
| | - Elizabeth Alwers
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Alexander Arnold
- Department of General Pathology, Institute of Pathology, Charité University Medicine Hospital, Berlin, Germany
| | - Esther Herpel
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Tissue Bank, National Center for Tumor Diseases, Heidelberg, Germany
| | - Katrin E Tagscherer
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Medical Center Mainz, Mainz, Germany
| | - Wilfried Roth
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Medical Center Mainz, Mainz, Germany
| | - Lina Jansen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Viola Walter
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Genetic Tumor Epidemiology Group, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Tissue Bank, National Center for Tumor Diseases, Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (Deutschen Konsortium für Translationale Krebsforschung), German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Murakami T, Akazawa Y, Yatagai N, Hiromoto T, Sasahara N, Saito T, Sakamoto N, Nagahara A, Yao T. Molecular characterization of sessile serrated adenoma/polyps with dysplasia/carcinoma based on immunohistochemistry, next-generation sequencing, and microsatellite instability testing: a case series study. Diagn Pathol 2018; 13:88. [PMID: 30458818 PMCID: PMC6247685 DOI: 10.1186/s13000-018-0771-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 11/08/2018] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway. METHODS We performed immunostaining for β-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma. RESULTS Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear β-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation. CONCLUSIONS SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/β-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yoichi Akazawa
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Noboru Yatagai
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takafumi Hiromoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Noriko Sasahara
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
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Rahadiani N, Handjari DR, Stephanie M, Krisnuhoni E. The low prevalence of colonic serrated adenocarcinoma with high KRAS mutational status at Cipto Mangunkusumo Hospital, Indonesia. MEDICAL JOURNAL OF INDONESIA 2018. [DOI: 10.13181/mji.v27i3.1719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background: Serrated adenocarcinoma (SA), a subtype of colorectal carcinoma, and the KRAS mutation, a strong marker for the patient’s response to anti-epidermal growth factor receptor therapy, have a clinical importance because of its progressive nature and tendency for chemoresistance. The purposes of this study were to (1) determine the prevalence of SA, (2) evaluate the histomorphological characteristics of SA and classical adenocarcinoma based on its prognostic factors, (3) determine the prevalence of the KRAS mutation in SA cases, and (4) identify the main characteristics of SA cases and classical adenocarcinoma with a KRAS mutation.Methods: This study was conducted by reviewing hematoxylin-eosin-stained slides of colorectal carcinoma (CRC) cases from January 2013 to July 2015 at the Department of Anatomical Pathology Cipto Mangunkusumo General Hospital. The final diagnosis of SA was based on the Tuppurainen et al criteria and the KRAS mutation was evaluated using real-time polymerase chain reaction.Results: Among the 117 adenocarcinoma cases, there were 41 unequivocal SA, 11 equivocal SA, and 65 classical adenocarcinoma. The prevalence rates of unequivocal and equivocal SA among all CRC cases were 7.7% and 2.1%, respectively. There were 11 (28.2%) cases of wild-type KRAS and 28 (71.7%) cases of mutated KRAS among all unequivocal SA cases. Tumor budding (TB) was the predominant prognostic factor.Conclusion: The prevalence of SA among all CRC cases was 7.7%. The KRAS mutation was found in almost three-quarters of all SA cases.
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Murakami T, Sakamoto N, Nagahara A. Endoscopic diagnosis of sessile serrated adenoma/polyp with and without dysplasia/carcinoma. World J Gastroenterol 2018; 24:3250-3259. [PMID: 30090005 PMCID: PMC6079289 DOI: 10.3748/wjg.v24.i29.3250] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 06/27/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in colorectal carcinomas with BRAF mutations, methylation for DNA repair genes, a CpG island methylator phenotype, and high levels of microsatellite instability. Some of these lesions can rapidly become dysplastic or invasive carcinomas that exhibit high lymphatic invasion and lymph node metastasis potentials. Detecting serrated lesions, including SSA/Ps with and without dysplasia/carcinoma, is critical, but SSA/Ps can be difficult to detect, are inconsistently identified by endoscopists and pathologists, and are often incompletely resected. Therefore, SSA/Ps are considered to be major contributors to "interval cancers". If colonoscopists can identify the specific endoscopic characteristics of SSA/Ps, their detection and the effectiveness of colonoscopy may improve. Here, the endoscopic features of SSA/Ps with and without dysplasia/carcinoma, including the characteristics determined using magnifying endoscopy, are reviewed in the context of previous reports. Endoscopically, these subtle polyps are like hyperplastic polyps, because they are slightly elevated and pale. Unlike hyperplastic polyps, SSA/Ps are usually larger than 5 mm, frequently covered by a thin layer called the ''mucus cap'', and are more commonly located in the proximal colon. Magnifying narrow-band imaging findings, which include dark spots inside the crypts and varicose microvascular vessels, in addition to the type II-open pit patterns detected using magnifying chromoendoscopy, effectively differentiate SSA/Ps from hyperplastic polyps. The lesions' endoscopic characteristics, which include their (semi)pedunculated morphologies, double elevations, central depressions, and reddishness, and the use of magnifying endoscopy, might help to detect dysplasia/carcinoma within SSA/Ps. Greater awareness may promote further research into improving the detection, identification, and complete resection rates of SSA/Ps with and without dysplasia/carcinoma and reduce the interval cancer rates.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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Cho H, Hashimoto T, Yoshida H, Taniguchi H, Ogawa R, Mori T, Hiraoka N, Saito Y, Sekine S. Reappraisal of the genetic heterogeneity of sessile serrated adenoma/polyp. Histopathology 2018; 73:672-680. [DOI: 10.1111/his.13688] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 06/16/2018] [Indexed: 01/16/2023]
Affiliation(s)
- Hourin Cho
- Division of Pathology and Clinical Laboratories; National Cancer Center Hospital; Tokyo Japan
- Endoscopy Division; National Cancer Center Hospital; Tokyo Japan
| | - Taiki Hashimoto
- Division of Pathology and Clinical Laboratories; National Cancer Center Hospital; Tokyo Japan
| | - Hiroshi Yoshida
- Division of Pathology and Clinical Laboratories; National Cancer Center Hospital; Tokyo Japan
| | - Hirokazu Taniguchi
- Division of Pathology and Clinical Laboratories; National Cancer Center Hospital; Tokyo Japan
| | - Reiko Ogawa
- Molecular Pathology Division; National Cancer Center Research Institute; Tokyo Japan
| | - Taisuke Mori
- Division of Pathology and Clinical Laboratories; National Cancer Center Hospital; Tokyo Japan
- Molecular Pathology Division; National Cancer Center Research Institute; Tokyo Japan
| | - Nobuyoshi Hiraoka
- Division of Pathology and Clinical Laboratories; National Cancer Center Hospital; Tokyo Japan
- Molecular Pathology Division; National Cancer Center Research Institute; Tokyo Japan
| | - Yutaka Saito
- Endoscopy Division; National Cancer Center Hospital; Tokyo Japan
| | - Shigeki Sekine
- Division of Pathology and Clinical Laboratories; National Cancer Center Hospital; Tokyo Japan
- Molecular Pathology Division; National Cancer Center Research Institute; Tokyo Japan
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Moy BT, Forouhar F, Kuo CL, Devers TJ. Endoscopic Features of Mucous Cap Polyps: A Way to Predict Serrated Polyps. Clin Endosc 2018; 51:368-374. [PMID: 29699379 PMCID: PMC6078921 DOI: 10.5946/ce.2017.155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 11/20/2017] [Indexed: 12/19/2022] Open
Abstract
Background/Aims The aims of the study were to identify whether a mucous-cap predicts the presence of serrated polyps, and to determine whether additional endoscopic findings predict the presence of a sessile serrated adenomas/polyp (SSA/P).
Methods We analyzed 147 mucous-capped polyps with corresponding histology, during 2011–2014. Eight endoscopic features (presence of borders, elevation, rim of debris, location in the colon, size ≥10 mm, varicose vessels, nodularity, and alteration in mucosal folds) of mucous-capped polyps were examined to see if they can predict SSA/Ps.
Results A total of 86% (n=126) of mucous-capped polyps were from the right sided serrated pathway (right-sided hyperplastic [n=83], SSA/Ps [n=43], traditional serrated adenoma [n=1]), 10% (n=15) were left-sided hyperplastic polyps, and 3% (n=5) were from the adenoma-carcinoma sequence. The presence of a mucous cap combined with varicose vessels was the only significant predictor for SSA/Ps. The other seven characteristics were not found to be statistically significant for SSA/Ps, although location in the colon and the presence of nodularity trended towards significance.
Conclusions Our study suggests that mucous-capped polyps have high predictability for being a part of the serrated pathway. Gastroenterologists should be alert for a mucous-capped polyp with varicose veins, as these lesions have a higher risk of SSA/P.
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Affiliation(s)
- Brian T Moy
- Division of Gastroenterology and Hepatology, UConn Health, Farmington, CT, USA
| | | | - Chia-Ling Kuo
- Connecticut Institute for Clinical & Translational Science, UConn Health, Farmington, CT, USA
| | - Thomas J Devers
- Division of Gastroenterology and Hepatology, UConn Health, Farmington, CT, USA
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Clinicopathologic and outcome study of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia. Mod Pathol 2018; 31:633-642. [PMID: 29271414 DOI: 10.1038/modpathol.2017.169] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 10/15/2017] [Accepted: 10/16/2017] [Indexed: 01/12/2023]
Abstract
It is believed that sessile serrated adenomas/polyps lead to the development of microsatellite unstable cancer via a dysplasia-carcinoma sequence. Little is known regarding the morphologic and biologic features, and outcome of sessile serrated adenomas/polyps with dysplasia, or of its specific dysplasia subtypes (intestinal versus serrated). The aims of this study were to analyze and compare the clinical, pathologic, and outcome characteristics of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia. The study included 86 patients with sessile serrated adenomas/polyps with dysplasia (50 serrated dysplasia, 22 intestinal dysplasia, 14 mixed serrated and intestinal dysplasia). The clinical and pathologic features, and the prevalence rate of prior, concurrent, and future neoplastic lesions, were compared between sessile serrated adenomas/polyps with intestinal versus serrated dysplasia and with matched control patients with ≥1 conventional adenoma. The mean age of the patients, polyp size, and prevalence of adenocarcinoma within the polyps were significantly higher in sessile serrated adenomas/polyps with high versus low-grade dysplasia. Sessile serrated adenomas/polyps with intestinal dysplasia showed a significantly higher rate of adenocarcinoma (23%) compared with those with serrated dysplasia (6%, P=0.05), and the high-grade lesions occurred at a significantly younger age in the former compared with the latter (65 versus 76 years, P=0.05). Compared with patients with conventional adenomas, patients with sessile serrated adenomas/polyps with dysplasia showed a significantly higher rate of invasive carcinoma within the polyps (12 versus 0%, P=0.01) and a significantly lower association with prior or future conventional adenomas. Sessile serrated adenomas/polyps with dysplasia should be considered high-risk neoplastic precursor lesions, particularly those with intestinal dysplasia. Cancer may develop from sessile serrated adenomas/polyps with either type of dysplasia.
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Murakami T, Mitomi H, Yao T, Saito T, Shibuya T, Sakamoto N, Osada T, Watanabe S. Distinct histopathological characteristics in colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp and conventional tubular adenoma. Virchows Arch 2018; 472:383-393. [PMID: 28929387 DOI: 10.1007/s00428-017-2234-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 08/27/2017] [Accepted: 09/13/2017] [Indexed: 12/31/2022]
Abstract
The histopathological characteristics of colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp (SSA/P), a rare malignant tumour, have not yet been fully elucidated. To investigate the features of such, we retrospectively analysed 40 submucosal invasive carcinomas with SSA/P (CA-SSA/P) and compared them to 129 cases of submucosal invasive carcinoma with conventional tubular adenoma (CA-AD). We additionally performed hMLH1 immunostaining. CA-SSA/Ps were significantly smaller than CA-ADs (P < 0.001). Histologically, well to moderately differentiated adenocarcinoma was predominant in both CA-SSA/Ps and CA-ADs. No significant differences in depth of invasion were found between the two groups. However, lymphatic invasion was more often found in CA-SSA/Ps (30%) than in CA-ADs (13%; P = 0.028), as was lymph node metastasis (CA-SSA/Ps, 28%; CA-ADs, 7%; P = 0.011). Furthermore, mucinous component and serrated architecture were significantly more frequent in CA-SSA/Ps (30 and 63%) than in CA-ADs (5 and 18%; P < 0.001, respectively). Tumour-infiltrating lymphocytes and Crohn-like inflammatory reaction were also more frequently found in CA-SSA/Ps (70 and 30%) than in CA-ADs (31 and 9%; P ≤ 0.001, respectively), whereas the opposite was true of desmoplastic reaction (CA-SSA/Ps, 35%; CA-ADs, 67%; P < 0.001). Loss of hMLH1 expression was more frequent in CA-SSA/P cases (93%) than in CA-AD cases (5%; P < 0.001). In conclusion, CA-SSA/P lesions exhibit a higher potential for lymphatic invasion and lymph node metastasis and have distinct histopathological features, including mucinous component, serrated architecture, tumour-infiltrating lymphocytes, Crohn-like inflammatory reaction, and absence of desmoplastic reaction, compared to their conventional counterparts.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
- Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Hiroyuki Mitomi
- Department of Diagnostic Pathology and Laboratory Medicine, Odawara Municipal Hospital, Odawara, Kanagawa, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Taro Osada
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Sumio Watanabe
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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Liu JC, Hao WR, Hsu YP, Sung LC, Kao PF, Lin CF, Wu ATH, Yuan KSP, Wu SY. Statins dose-dependently exert a significant chemopreventive effect on colon cancer in patients with chronic obstructive pulmonary disease: A population-based cohort study. Oncotarget 2018; 7:65270-65283. [PMID: 27542242 PMCID: PMC5323154 DOI: 10.18632/oncotarget.11263] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/27/2016] [Indexed: 12/21/2022] Open
Abstract
Purpose We evaluated the chemopreventive effect of statins on colon cancer in patients with chronic obstructive pulmonary disease (COPD) and identified the statin exerting the strongest chemopreventive effect. Methods Using the National Health Insurance Research Database, we identified patients who received a COPD diagnosis in Taiwan between January 1, 2001, and December 31, 2012, and included them in the study cohort. Each patient was followed to assess the colon cancer risk and protective factors. A propensity score was derived using a logistic regression model to estimate the effect of statins by accounting for covariates predicted during the intervention (statins). To examine the dose–response relationship, we categorized statin doses into four groups in each cohort [<28, 28–90, 91–365, and >365 cumulative defined daily dose]. Results Compared with the statin nonusers, the adjusted hazard ratio (aHR) for colon cancer decreased in the statin users (aHR = 0.52, 95% confidence interval = 0.44, 0.62). Hydrophilic statins exerted a stronger preventive effect against colon cancer. Regarding the statin type, lovastatin, pravastatin, and fluvastatin nonsignificantly reduced the colon cancer risk in the patients with COPD. Compared with the statin nonusers, the aHRs for colon cancer decreased in the individual statin users (rosuvastatin, simvastatin, and atorvastatin: aHRs = 0.28, 0.64, and 0.65, respectively). In the sensitivity analysis, statins dose-dependently reduced the colon cancer risk. Conclusions Statins dose-dependently exert significant chemopreventive effects on colon cancer in patients with COPD, with rosuvastatin exerting the largest chemopreventive effect.
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Affiliation(s)
- Ju-Chi Liu
- Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wen-Rui Hao
- Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Yi-Ping Hsu
- Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Li-Chin Sung
- Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Pai-Feng Kao
- Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chao-Feng Lin
- Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Alexander T H Wu
- Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kevin Sheng-Po Yuan
- Department of Otorhinolaryngology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Szu-Yuan Wu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biotechnology, Hungkuang University, Taichung, Taiwan
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Colorectal Cancer Subtypes - The Current Portrait. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1110:1-6. [PMID: 30623362 DOI: 10.1007/978-3-030-02771-1_1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one prominent example for how chemotherapy has been changing by moving from the use of general cytotoxic agents to more tumour-specific drugs. For example, antibody-based drugs neutralize a growth factor receptor protein on the surface of tumour cells. The development of such new therapeutic opportunities requires a more thorough and systematic subclassification of CRC because tumour cells can exploit several alternative genetic pathways for their survival. This chapter gives an overview on CRC subtypes as an introduction to the following book chapters that will describe aspects of specific subtypes, and how these may lead to the development of novel pathway-specific drugs for a more precise therapeutic intervention.
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Evaluating the expression level of co-stimulatory molecules CD 80 and CD 86 in different types of colon polyps. Curr Res Transl Med 2017; 66:19-25. [PMID: 29277562 DOI: 10.1016/j.retram.2017.11.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 10/14/2017] [Accepted: 11/02/2017] [Indexed: 01/08/2023]
Abstract
PURPOSE OF THE STUDY Co-stimulatory molecules CD80 and CD86 are the members of B7 family, which stimulate the T lymphocytes in response to the malignant colon polyps. However, the expression of these molecules is depressed in cancers. In the present study, the transcription levels of CD80 and CD86 genes in the colon polyps (Precancerous lesions) and its association with the clinical features were examined. PATIENTS AND METHODS Forty-nine biopsies samples from patients with the colorectal polyps and 10 healthy subjects were collected by the colonoscopy. Questionnaires including clinical and demographic data were filled for all cases. Using Real-time PCR, the mucosal mRNA expression levels of CD80 and CD86 genes were quantified. RESULTS Adenoma and hyperplastic polyps were reported in 69.3 and 30.7 percent of 49 patients, respectively. Unlike hyperplastic polyps, the expression of CD86 was increased in adenoma polyps compared to controls (RQ=2.75 vs. 0.837, respectively). The data from CD80 showed noticeable reduction about 0.31 and 0.11 in adenoma and hyperplastic polyps, respectively, in response to control group (RQ=0.729). Also, analyzing colon and rectum polyps depicted a marked increment in CD86 level, in contrast to CD80. CONCLUSION Examining the mRNA expression levels of CD80 and CD86 genes between colon polyps with the rectal polyps shows that the enhanced level of CD86 in adenoma samples could be considered as a valuable biomarker for distinguishing the adenoma from hyperplastic polyps and the masses located in the colon from the rectum.
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Clinicopathologic distribution of KRAS and BRAF mutations in a Chinese population with colorectal cancer precursor lesions. Oncotarget 2017; 7:17265-74. [PMID: 26910894 PMCID: PMC4941386 DOI: 10.18632/oncotarget.7504] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 01/13/2016] [Indexed: 12/21/2022] Open
Abstract
Investigating the clinical features and corresponding histomorphologic and molecular profiles of precursor lesions of colorectal cancer in a natural population provides new insights into the nature of colorectal cancer, uncovers new screening markers and establishes new prevention strategies for colorectal cancer. In this study, 4302 patients with at least one colorectal polyp from a large colorectal cancer screening program were evaluated and genetic mutations in either KRAS or BRAF were detected in 495 patients. The population-based mutation rates of KRAS and BRAF genes in colorectal polyps within this Chinese patient population were 21.8% and 12.1% respectively. Interestingly, considerable variability in the KRAS and BRAF mutations rates were found among different types of polyps. In a multivariate analysis, presence of villous histology and high-grade dysplasia was associated with KRAS mutations (OR, 3.0; 95% CI, 1.7-5.4 and OR, 3.5; 95% CI 1.9-6.5, respectively), while serrated adenomas and hyperplastic polyps were associated with BRAF V600E mutations (OR, 20.6; 95% CI, 8.2–51.8 and OR, 11.9; 95% CI 4.9–29.0, respectively). KRAS mutations may, in part, drive the histologic progression of adenomas toward a villous histology and higher grades of dysplasia. Mutant BRAF may, in part, drive the histologic progression of adenomas toward serrated histology. Dysplasia may arise from hyperplastic polyps, resulting in the formation of serrated adenomas and potentially the development of colorectal carcinoma.
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Abstract
BACKGROUND In the past decade, there have been significant changes in the classification and nomenclature of colorectal polyps. Previously, only two groups of lesions were widely recognized, the adenoma and the hyperplastic polyp. Adenomas were considered the only precursor of colorectal cancer, and hyperplastic polyps were considered innocent with no malignant potential. However, recent discoveries about molecular pathways of colorectal cancers have significantly changed our understanding of these neoplasms. Serrated polyps-previously uniformly called hyperplastic polyps-are now known to comprise a heterogeneous family of neoplasms united by their characteristic saw tooth morphology but differing in many important ways, including their malignant potential and molecular profile. This group of neoplasms includes both hyperplastic polyps and the more recently recognized serrated adenomas. Serrated adenomas can be subdivided into the traditional serrated adenoma and the sessile serrated adenoma/polyp. Both of these lesions show characteristic molecular changes, which differ from traditional colorectal adenomatous polyps. OBJECTIVES In this review, we will discuss the morphologic features of serrated colorectal lesions, the molecular alterations that characterize them, and their role in colorectal cancer development. MATERIAL AND METHODS The English literature regarding the new nomenclature will be reviewed and the key diagnostic points will be recorded. RESULTS AND DISCUSSION This large group of polyps has recently been better classified which needs specific attention by pathologists, gastroenterologists and even surgeons.
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Affiliation(s)
- Bita Geramizadeh
- Department of Pathology, Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Scott Robertson
- Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA
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46
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Sessile serrated adenomas with dysplasia: morphological patterns and correlations with MLH1 immunohistochemistry. Mod Pathol 2017; 30:1728-1738. [PMID: 28752838 PMCID: PMC5719122 DOI: 10.1038/modpathol.2017.92] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 05/30/2017] [Accepted: 06/02/2017] [Indexed: 12/30/2022]
Abstract
Sessile serrated adenomas are the precursor polyp of approximately 20% of colorectal carcinomas. Sessile serrated adenomas with dysplasia are rarely encountered and represent an intermediate step to malignant progression, frequently associated with loss of MLH1 expression. Accurate diagnosis of these lesions is important to facilitate appropriate surveillance, particularly because progression from dysplasia to carcinoma can be rapid. The current World Health Organization classification describes two main patterns of dysplasia occurring in sessile serrated adenomas, namely, serrated and conventional. However, this may not adequately reflect the spectrum of changes seen by pathologists in routine practice. Furthermore, subtle patterns of dysplasia that are nevertheless associated with loss of MLH1 expression are not encompassed in this classification. We performed a morphological analysis of 266 sessile serrated adenomas with dysplasia with concurrent MLH1 immunohistochemistry with the aims of better defining the spectrum of dysplasia occurring in these lesions and correlating dysplasia patterns with MLH1 expression. We found that dysplasia can be divided morphologically into four major patterns, comprising minimal deviation (19%), serrated (12%), adenomatous (8%) and not otherwise specified (79%) groups. Minimal deviation dysplasia is defined by minor architectural and cytological changes that typically requires loss of MLH1 immunohistochemical expression to support the diagnosis. Serrated dysplasia and adenomatous dysplasia have distinctive histological features and are less frequently associated with loss of MLH1 expression (13 and 5%, respectively). Finally, dysplasia not otherwise specified encompasses most cases and shows a diverse range of morphological changes that do not fall into the other subgroups and are frequently associated with loss of MLH1 expression (83%). This morphological classification of sessile serrated adenomas with dysplasia may represent an improvement on the current description as it correlates with the underlying mismatch repair protein status of the polyps and better highlights the range of morphologies seen by pathologists.
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Horpaopan S, Kirfel J, Peters S, Kloth M, Hüneburg R, Altmüller J, Drichel D, Odenthal M, Kristiansen G, Strassburg C, Nattermann J, Hoffmann P, Nürnberg P, Büttner R, Thiele H, Kahl P, Spier I, Aretz S. Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS). Hered Cancer Clin Pract 2017; 15:22. [PMID: 29213343 PMCID: PMC5707812 DOI: 10.1186/s13053-017-0082-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 11/21/2017] [Indexed: 01/01/2023] Open
Abstract
Background Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia (BRAF, KRAS, RNF43 mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified. Methods To identify somatic point mutations in potential novel candidate genes of SPS-associated lesions and the involved pathways we performed exome sequencing of eleven early serrated polyps obtained from a 41 year-old female patient with clinically confirmed SPS. For data filtering and analysis, standard pipelines were used. Somatic mutations were identified by comparison with leukocyte DNA and were validated by Sanger sequencing. Results The BRAF p.V600E or KRAS p.G12D mutation was identified in six polyps (~50%) and not found in polyps from the distal colon. In addition, we found seven unique rare somatic alterations of seven different genes in four serrated tumours, all of which are missense variants. The variant in ABI3BP and CATSPERB are predicted to be deleterious. No established cancer gene or candidate genes related to serrated tumorigenesis were affected. Conclusions Somatic mutations seem to be rare events in early hyperplastic and serrated lesions of SPS patients. Neither frequently affected genes nor enrichment of specific pathways were observed. Thus, other alterations such as non-coding variants or epigenetic changes might be the major driving force of tumour progression in SPS. Electronic supplementary material The online version of this article (10.1186/s13053-017-0082-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sukanya Horpaopan
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.,Center of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok, Thailand
| | - Jutta Kirfel
- Institute of Pathology, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Sophia Peters
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Michael Kloth
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Robert Hüneburg
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Janine Altmüller
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Dmitriy Drichel
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | | | - Glen Kristiansen
- Institute of Pathology, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Christian Strassburg
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Jacob Nattermann
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Per Hoffmann
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.,Institute of Medical Genetics and Pathology, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Peter Nürnberg
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | | | - Holger Thiele
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | - Philip Kahl
- Heinz-Werner-Seifert-Institut für Dermatopathologie Bonn, Bonn, Germany
| | - Isabel Spier
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Stefan Aretz
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Institute of Human Genetics, Center for Hereditary Tumor Syndromes, University of Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany
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Hashimoto T, Yamashita S, Yoshida H, Taniguchi H, Ushijima T, Yamada T, Saito Y, Ochiai A, Sekine S, Hiraoka N. WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps. Am J Surg Pathol 2017; 41:1188-1197. [PMID: 28614199 DOI: 10.1097/pas.0000000000000877] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are believed to be the major precursor of serrated pathway-derived colorectal carcinomas. To better characterize the process of progression from SSA/Ps to carcinomas, we analyzed 46 SSA/Ps with dysplasia and 45 SSA/Ps without dysplasia using targeted next-generation sequencing and immunohistochemistry. Among the WNT pathway genes analyzed, protein-truncating mutations of RNF43, APC, and ZNRF3 were identified in 23 (50%), 4 (9%), and 3 (7%) SSA/Ps with dysplasia, respectively. In contrast, SSA/Ps without dysplasia rarely had WNT pathway gene mutations, except for 3 lesions with RNF43 mutations (7%). None of the SSA/Ps had CTNNB1 mutations or RSPO fusions. Thus, WNT pathway gene mutations were more common in SSA/Ps with dysplasia than in SSA/Ps without dysplasia (P=3.0×10). Consistently, nuclear β-catenin accumulation and MYC overexpression, indicative of active WNT signaling, were present in most of the SSA/Ps with dysplasia, but were rare in those without dysplasia. BRAF (86%) or KRAS mutations (7%) were identified in the majority of SSA/Ps, regardless of the presence or absence of dysplasia. MLH1 expression was lost in 14 SSA/Ps with dysplasia (30%). The majority of MLH1-deficient SSA/Ps with dysplasia had RNF43 mutations (86%), most of which were frameshift mutations involving mononucleotide repeats. In contrast, MLH1-retained lesions had less frequent RNF43 mutations with no hot spots (34%), and 4 had APC mutations (13%). These results suggest that WNT pathway gene mutations are involved in the development of dysplasia in SSA/Ps and that MLH1-deficient and MLH1-retained SSA/Ps with dysplasia exhibit distinct mutation profiles of WNT pathway genes.
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Affiliation(s)
- Taiki Hashimoto
- *Division of Pathology and Clinical Laboratories ∥Endoscopy Division, National Cancer Center Hospital †Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine ‡Division of Epigenomics §Division of Chemotherapy and Clinical Research #Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo ¶Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Chiba, Japan
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Kang G, Kang Y, Kim KH, Ha SY, Kim JY, Shim YM, Heinrich MC, Kim KM, Corless CL. Gastrointestinal stromal tumours of the oesophagus: a clinicopathological and molecular analysis of 27 cases. Histopathology 2017. [PMID: 28644569 DOI: 10.1111/his.13292] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AIMS Gastrointestinal stromal tumours (GISTs) may arise anywhere in the gastrointestinal tract, but are rare in the oesophagus. We describe the clinical, pathological and molecular characteristics of 27 primary oesophageal GISTs, the largest series to date. METHODS AND RESULTS DNA was extracted and exons 9, 11, 13 and 17 of KIT, exons 12, 14 and 18 of PDGFRA and exon 15 of BRAF were amplified and sequenced. Oesophageal GISTs occurred in 14 men and 13 women aged between 22 and 80 years (mean: 56 years). All 27 cases were immunohistochemically positive for KIT, and 92 and 47% co-expressed CD34 or smooth muscle actin, respectively. Fifteen (71% of analysed cases) harboured KIT exon 11 mutations and one case each had a mutation in KIT exon 13 (K642E) or BRAF exon 15 (V600E). Long-term follow-up data (median, 96.5 months) were obtained for 20 cases; two patients had metastases at presentation and seven had developed local recurrence and/or metastasis after surgery. A large tumour size (≥ 10 cm), high mitotic rate (> 5/5 mm2 ), presence of a deletion mutation in KIT exon 11 involving codons 557-558 and a positive microscopic margin were associated with recurrence and metastasis. The KIT mutations identified in oesophageal GISTs are similar to those observed in gastric GISTs. CONCLUSIONS Complete surgical resection with clear margins is recommended, if technically feasible, and genotyping can help to improve diagnosis and further patient management in oesophageal GIST.
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Affiliation(s)
- Guhyun Kang
- Department of Pathology, Sanggye Paik Hospital, Inje University, Seoul, Korea
| | - Yuna Kang
- Department of Pathology, Dongsan Medical Center, Keimyung University, Daegu, Korea
| | - Kyung-Hee Kim
- Department of Pathology, Chungnam National University School of Medicine, Daejeon, Korea
| | - Sang Yun Ha
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea
| | - Jung Yeon Kim
- Department of Pathology, Sanggye Paik Hospital, Inje University, Seoul, Korea
| | - Young Mog Shim
- Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Michael C Heinrich
- Division of Hematology and Medical Oncology, VA Portland Health Care System and Oregon Health and Science University, Portland, OR, USA
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea
| | - Christopher L Corless
- Department of Pathology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
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Patai ÁV, Barták BK, Péterfia B, Micsik T, Horváth R, Sumánszki C, Péter Z, Patai Á, Valcz G, Kalmár A, Tóth K, Krenács T, Tulassay Z, Molnár B. Comprehensive DNA Methylation and Mutation Analyses Reveal a Methylation Signature in Colorectal Sessile Serrated Adenomas. Pathol Oncol Res 2017; 23:589-594. [PMID: 27896617 DOI: 10.1007/s12253-016-0154-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 11/22/2016] [Indexed: 01/07/2023]
Abstract
Colorectal sessile serrated adenomas (SSA) are hypothesized to be precursor lesions of an alternative, serrated pathway of colorectal cancer, abundant in genes with aberrant promoter DNA hypermethylation. In our present pilot study, we explored DNA methylation profiles and examined selected gene mutations in SSA. Biopsy samples from patients undergoing screening colonoscopy were obtained during endoscopic examination. After DNA isolation and quality analysis, SSAs (n = 4) and healthy controls (n = 5) were chosen for further analysis. DNA methylation status of 96 candidate genes was screened by q(RT)PCR using Methyl-Profiler PCR array system. Amplicons for 12 gene mutations were sequenced by GS Junior Instrument using ligated and barcoded adaptors. Analysis of DNA methylation revealed 9 hypermethylated genes in both normal and SSA samples. 12 genes (CALCA, DKK2, GALR2, OPCML, PCDH10, SFRP1, SFRP2, SLIT3, SST, TAC1, VIM, WIF1) were hypermethylated in all SSAs and 2 additional genes (BNC1 and PDLIM4) were hypermethylated in 3 out of 4 SSAs, but in none of the normal samples. 2 SSAs exhibited BRAF mutation and synchronous MLH1 hypermethylation and were microsatellite instable by immunohistochemical analysis. Our combined mutation and DNA methylation analysis revealed that there is a common DNA methylation signature present in pre-neoplastic SSAs. This study advocates for the use of DNA methylation as a potential biomarker for the detection of SSA; however, further investigation is needed to better characterize the molecular background of these newly recognized colorectal lesions.
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Affiliation(s)
- Árpád V Patai
- 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary.
| | - Barbara Kinga Barták
- 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary
| | - Bálint Péterfia
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Roosevelt tér 9, Budapest, 1051, Hungary
| | - Tamás Micsik
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary
| | - Réka Horváth
- 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary
| | - Csaba Sumánszki
- 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary
| | - Zoltán Péter
- 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary
| | - Árpád Patai
- Department of Gastroenterology and Internal Medicine, Markusovszky University Teaching Hospital, Markusovszky Lajos utca 5, Szombathely, 9700, Hungary
| | - Gábor Valcz
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Roosevelt tér 9, Budapest, 1051, Hungary
| | - Alexandra Kalmár
- 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary
| | - Kinga Tóth
- 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary
| | - Tibor Krenács
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085, Hungary
| | - Zsolt Tulassay
- 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Roosevelt tér 9, Budapest, 1051, Hungary
| | - Béla Molnár
- 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Roosevelt tér 9, Budapest, 1051, Hungary
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