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Hagen R, Srivastava A, Anderson JC. The serrated pathway and colorectal cancer: what the gastroenterologist should know. Expert Rev Gastroenterol Hepatol 2025:1-14. [PMID: 40409278 DOI: 10.1080/17474124.2025.2509797] [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: 03/20/2025] [Revised: 04/28/2025] [Accepted: 05/19/2025] [Indexed: 05/25/2025]
Abstract
INTRODUCTION Serrated polyps can progress to colorectal cancer (CRC), through a pathway that is distinct from the conventional adenoma-carcinoma sequence. This pathway includes hyperplastic polyps (HPs), sessile serrated polyps (SSPs), and traditional serrated adenomas (TSAs). AREAS COVERED Our review includes the histology and pathological challenges, carcinogenesis, risk factors, detection, emerging technologies, resection, and surveillance. EXPERT OPINION Serrated polyp management presents many detection, diagnosis, resection, and surveillance challenges. Missed serrated polyps contribute to preventable CRCs. A new SSP detection rate benchmark will guide endoscopists with a goal when improving detection. Furthermore, new SSP-specific surveillance strategies may also aid in reducing CRC burden. Histologic differentiation remains a challenge, underscoring the need for standardized pathology practices and exploring novel ways to stratify risk independent of histology, given interobserver variation. Moreover, the clinical significance of proximal HPs requires further clarification. Which HPs < 1 cm require closer surveillance intervals? Molecular profiling may help identify markers that separate proximal low risk from high-risk HP. The best approach for resection of serrated polyps also needs to be clarified. There is also a lack of robust longitudinal outcome data to guide surveillance recommendations since current guidelines are based on low quality of evidence.
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Affiliation(s)
- Rachael Hagen
- Department of Medicine, University of Connecticut, Farmington, CT, USA
| | - Amitabh Srivastava
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joseph C Anderson
- Department of Medicine, University of Connecticut, Farmington, CT, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, White River Junction VAMC, White River Junction, VT, USA
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Kamba E, Murakami T, Tsugawa N, Otsuki Y, Nomura K, Kadomatsu Y, Fukushima H, Saito T, Shibuya T, Yao T, Nagahara A. Endoscopic and Clinicopathological Features of a Colorectal Mucin-Rich Variant of Traditional Serrated Adenoma. Digestion 2025:1-13. [PMID: 39987910 DOI: 10.1159/000543700] [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: 10/29/2024] [Accepted: 01/19/2025] [Indexed: 02/25/2025]
Abstract
INTRODUCTION The mucin-rich variant of traditional serrated adenoma (MR-TSA), pathologically defined by the presence of goblet cells comprising over 50% of the lesion compared to the absorptive epithelial eosinophilic cytoplasm, was recently introduced as one morphological variants of traditional serrated adenoma (TSA). This study aimed to characterize the endoscopic and clinicopathological characteristics of MR-TSAs. METHODS Lesions pathologically diagnosed as TSAs at our hospital between 2011 and 2023 were reviewed. We analyzed the endoscopic and clinicopathological features of 49 MR-TSAs and 236 conventional TSAs (C-TSAs). Furthermore, immunohistochemical and genetic analyses were performed to ensure that there were no discrepancies with our previous study. RESULTS MR-TSAs, like C-TSAs, were often located in the sigmoid colon and rectum, with no significant difference in lesion size. Macroscopically, MR-TSAs frequently appeared as type 0-Is with a weak reddish color and had a mucous cap, less often exhibiting a pinecone-like or coral-shaped appearance compared to C-TSAs (p < 0.001). Magnifying endoscopy showed expanded crypt openings in 80% of MR-TSAs (p < 0.001). Both groups had similar IIIH and IVH pit patterns. Immunohistochemical analysis revealed that MUC5AC was expressed more frequently in MR-TSAs than in C-TSAs. Additionally, genetic analysis showed that MR-TSAs more frequently harbored the BRAF mutation than C-TSAs (p < 0.001), whereas MR-TSAs less frequently harbored the KRAS mutation than C-TSAs (p = 0.047). CONCLUSION MR-TSAs, frequently harboring the BRAF but not KRAS mutation, exhibited several distinct endoscopic findings, including a sessile morphology, lack of pinecone-like or coral-like appearance, weak reddish color, and mucous cap.
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Affiliation(s)
- Eiji Kamba
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan,
| | - Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoki Tsugawa
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yudai Otsuki
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kei Nomura
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yuichiro Kadomatsu
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hirofumi Fukushima
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
- Department of Pathophysiological Research and Therapeutics for Gastrointestinal Disease, Juntendo University School of Medicine, Tokyo, Japan
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Andrea MK, Jepsen RK, Klein MF, Gögenur I, Kuhlmann TP. Predictors for dMMR colorectal cancer in patients with serrated lesions and polyps - A register-based cohort study. Cancer Epidemiol 2024; 91:102601. [PMID: 38905781 DOI: 10.1016/j.canep.2024.102601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND Serrated lesions and polyps (SP) are precursors of up to 30 % of colorectal cancers (CRC) through the serrated pathway. This often entails early BRAF mutations and MLH1 hypermethylation leading to mismatch repair deficient (dMMR) CRC. We investigated predictors of dMMR CRC among patients with co-occurrence of CRC and SP to increase our knowledge on the serrated pathway. METHODS We used data from The Danish Pathology Registry and Danish Colorectal Cancer Groups Database from the period 2010-2021 to investigate risk factors for development of dMMR CRC. We used logistic regression models to identify difference in risk factors of developing dMMR CRC in comparison to CRC with proficient MMR (pMMR). RESULTS We included 3273 patients with a median age of 70.7 years [64.3,76.4] of which 1850 (56.5 %) were male. dMMR CRC was present in 592 patients (18.1 %), with loss of MLH1/PMS2 being most common. The risk of dMMR CRC was significantly higher in females OR 3.47 [2.87;4.20]. When adjusting for age, SP subtype, conventional adenomas (CA), anatomical location and lifestyle factors, female sex remained the strongest predictor OR 2.84 [2.27;3.56]. The presence of sessile serrated lesions with or without dysplasia was related to higher risk OR 1.60 [1.11;2.31] and OR 1.42 [1.11;1.82] respectively, while conventional adenomas constituted a lower risk OR 0.68 [0.55;0.84]. CONCLUSION In conclusion we found several predictors of whom female sex had the strongest correlation with dMMR CRC in patients with SP.
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Affiliation(s)
- Mille Kyhn Andrea
- Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.
| | - Rikke Karlin Jepsen
- Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Mads Falk Klein
- Department of Surgery, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ismail Gögenur
- Department of Surgery, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Center for Surgical Sciences, University Hospital Zealand, Køge, Denmark; Department of Surgery, University Hospital Zealand, Køge, Denmark
| | - Tine Plato Kuhlmann
- Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Sullivan BA, Lieberman DA. Colon Polyp Surveillance: Separating the Wheat From the Chaff. Gastroenterology 2024; 166:743-757. [PMID: 38224860 DOI: 10.1053/j.gastro.2023.11.305] [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: 01/30/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 01/17/2024]
Abstract
One goal of colorectal cancer (CRC) screening is to prevent CRC incidence by removing precancerous colonic polyps, which are detected in up to 50% of screening examinations. Yet, the lifetime risk of CRC is 3.9%-4.3%, so it is clear that most of these individuals with polyps would not develop CRC in their lifetime. It is, therefore, a challenge to determine which individuals with polyps will benefit from follow-up, and at what intervals. There is some evidence that individuals with advanced polyps, based on size and histology, benefit from intensive surveillance. However, a large proportion of individuals will have small polyps without advanced histologic features (ie, "nonadvanced"), where the benefits of surveillance are uncertain and controversial. Demand for surveillance will further increase as more polyps are detected due to increased screening uptake, recent United States recommendations to expand screening to younger individuals, and emergence of polyp detection technology. We review the current understanding and clinical implications of the natural history, biology, and outcomes associated with various categories of colon polyps based on size, histology, and number. Our aims are to highlight key knowledge gaps, specifically focusing on certain categories of polyps that may not be associated with future CRC risk, and to provide insights to inform research priorities and potential management strategies. Optimization of CRC prevention programs based on updated knowledge about the future risks associated with various colon polyps is essential to ensure cost-effective screening and surveillance, wise use of resources, and inform efforts to personalize recommendations.
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Affiliation(s)
- Brian A Sullivan
- Cooperative Studies Program Epidemiology Center-Durham, Durham VA Health Care System, Durham, North Carolina; Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
| | - David A Lieberman
- Portland Veteran Affairs Medical Center, Portland, Oregon; Division of Gastroenterology and Hepatology, School of Medicine, Oregon Health and Science University, Portland, Oregon
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Wang JD, Xu GS, Hu XL, Li WQ, Yao N, Han FZ, Zhang Y, Qu J. The histologic features, molecular features, detection and management of serrated polyps: a review. Front Oncol 2024; 14:1356250. [PMID: 38515581 PMCID: PMC10955069 DOI: 10.3389/fonc.2024.1356250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/21/2024] [Indexed: 03/23/2024] Open
Abstract
The serrated pathway to colorectal cancers (CRCs) is a significant pathway encompassing five distinct types of lesions, namely hyperplastic polyps (HPs), sessile serrated lesions (SSLs), sessile serrated lesions with dysplasia (SSL-Ds), traditional serrated adenomas (TSAs), and serrated adenoma unclassified. In contrast to the conventional adenoma-carcinoma pathway, the serrated pathway primarily involves two mechanisms: BRAF/KRAS mutations and CpG island methylator phenotype (CIMP). HPs are the most prevalent non-malignant lesions, while SSLs play a crucial role as precursors to CRCs, On the other hand, traditional serrated adenomas (TSAs) are the least frequently encountered subtype, also serving as precursors to CRCs. It is crucial to differentiate these lesions based on their unique morphological characteristics observed in histology and colonoscopy, as the identification and management of these serrated lesions significantly impact colorectal cancer screening programs. The management of these lesions necessitates the crucial steps of removing premalignant lesions and implementing regular surveillance. This article provides a comprehensive summary of the epidemiology, histologic features, molecular features, and detection methods for various serrated polyps, along with recommendations for their management and surveillance.
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Affiliation(s)
- Jin-Dong Wang
- Department of General Surgery, Peking University Aerospace School of Clinical Medicine, Beijing, China
| | - Guo-Shuai Xu
- Department of General Surgery, Aerospace Center Hospital, Beijing, China
| | - Xin-Long Hu
- Department of General Surgery, Aerospace Center Hospital, Beijing, China
| | - Wen-Qiang Li
- Department of General Surgery, Aerospace Center Hospital, Beijing, China
| | - Nan Yao
- Department of General Surgery, Aerospace Center Hospital, Beijing, China
| | - Fu-Zhou Han
- Department of General Surgery, Aerospace Center Hospital, Beijing, China
| | - Yin Zhang
- Department of General Surgery, Aerospace Center Hospital, Beijing, China
| | - Jun Qu
- Department of General Surgery, Aerospace Center Hospital, Beijing, China
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Fusco S, Bauer ME, Schempf U, Stüker D, Blumenstock G, Malek NP, Werner CR, Wichmann D. Analysis of Predictors and Risk Factors of Postpolypectomy Syndrome. Diagnostics (Basel) 2024; 14:127. [PMID: 38248004 PMCID: PMC10814321 DOI: 10.3390/diagnostics14020127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 12/26/2023] [Accepted: 01/03/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND AND AIMS Postpolypectomy syndrome (PPS) is a relevant adverse event that can appear after polypectomy. Several publications mention postpolypectomy syndrome using different criteria to define it. The aim of this study is to detect potential risk factors and predictors for developing PPS and to define the main criteria of PPS. METHODS In this retrospective monocentric study, 475 out of 966 patients who underwent colonoscopy with polypectomy from October 2015 to June 2020 were included. The main criterion of PPS is defined as the development of postinterventional abdominal pain lasting more than six hours. RESULTS A total of 9.7% of the patients developed PPS, which was defined as local abdominal pain around the polypectomy area after six hours. A total of 8.6% of the study population had abdominal pain within six hours postintervention. A total of 3.7% had an isolated triad of fever, leukocytosis, and increased CRP in the absence of abdominal pain. Increased CRP combined with an elevated temperature over 37.5 °C seems to be a positive predictor for developing PPS. Four independent risk factors could be detected: serrated polyp morphology, polypoid configurated adenomas, polyp localization in the cecum, and the absence of intraepithelial neoplasia. CONCLUSIONS Four independent risk factors for developing PPS were detected. The combination of increased CRP levels with elevated temperature seems to be a predictor for this pathology. As expected, the increasing use of cold snare polypectomies will reduce the incidence of this syndrome. Key summary: Our monocentric study on 966 patients detected four independent risk factors for developing PPS: pedunculated polyp, resected polyps in the cecum, absence of IEN, and serrated polyp morphology. The combination of increased CRP levels with elevated temperature seems to be a predictor for this pathology.
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Affiliation(s)
- Stefano Fusco
- Department of Internal Medicine I, Section of Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectiology and Geriatrics, University Hospital of Tübingen, 72076 Tübingen, Germany (U.S.); (N.P.M.); (C.R.W.); (D.W.)
| | - Michelle E. Bauer
- Department of Internal Medicine I, Section of Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectiology and Geriatrics, University Hospital of Tübingen, 72076 Tübingen, Germany (U.S.); (N.P.M.); (C.R.W.); (D.W.)
| | - Ulrike Schempf
- Department of Internal Medicine I, Section of Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectiology and Geriatrics, University Hospital of Tübingen, 72076 Tübingen, Germany (U.S.); (N.P.M.); (C.R.W.); (D.W.)
| | - Dietmar Stüker
- Department of Internal Medicine I, Section of Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectiology and Geriatrics, University Hospital of Tübingen, 72076 Tübingen, Germany (U.S.); (N.P.M.); (C.R.W.); (D.W.)
| | - Gunnar Blumenstock
- Department of Clinical Epidemiology, Eberhard-Karls-University, 72076 Tübingen, Germany
| | - Nisar P. Malek
- Department of Internal Medicine I, Section of Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectiology and Geriatrics, University Hospital of Tübingen, 72076 Tübingen, Germany (U.S.); (N.P.M.); (C.R.W.); (D.W.)
| | - Christoph R. Werner
- Department of Internal Medicine I, Section of Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectiology and Geriatrics, University Hospital of Tübingen, 72076 Tübingen, Germany (U.S.); (N.P.M.); (C.R.W.); (D.W.)
| | - Dörte Wichmann
- Department of Internal Medicine I, Section of Gastroenterology, Gastrointestinal Oncology, Hepatology, Infectiology and Geriatrics, University Hospital of Tübingen, 72076 Tübingen, Germany (U.S.); (N.P.M.); (C.R.W.); (D.W.)
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Watson MM, Watson DC, Maddern GJ, Wichmann MW. Colorectal adenomatous and serrated polyps in rural South Australia: who, why, what and where? ANZ J Surg 2023; 93:2939-2945. [PMID: 37684707 DOI: 10.1111/ans.18662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/20/2023] [Accepted: 08/07/2023] [Indexed: 09/10/2023]
Abstract
BACKGROUNDS The adenoma-carcinoma and serrated pathways offer a window of opportunity for the removal of pre-malignant polyps and prevention of colorectal cancer (CRC) through the use of colonoscopy. The aim of this study was to investigate variation in polyp incidence in different age groups, gender and indications for undertaking colonoscopy. We also address histological types of polyps found and where in the bowel they are located. METHODS This study is based on the colonoscopy data collected prospectively over a one-year period in multiple South Australian rural centres, 24 general surgeons contributed to this study. All histopathology results were subsequently entered into the dataset. RESULTS A total of 3497 colonoscopies were performed, with a total of 2221 adenomatous and serrated polyps removed. Both serrated and adenomatous polyps were more common in the distal colon. Patients of male gender, aged 70 years and over and with an indication of polyp surveillance had higher adenoma and serrated polyp detection rates (ADR and SPDR). Patients aged 40-49 years old who underwent colonoscopy for positive faecal occult blood had an ADR and SPDR of 25.0% and 6.3%, respectively. CONCLUSIONS This study has shown variation in ADR and SPDR depending on age, gender and indication for colonoscopy. This variation will help further develop key performance indicators in colonoscopy. The high ADR and SPDR in patients aged 40-49 years old whom underwent colonoscopy for positive faecal occult blood may support lowering the age of commencement of CRC screening in Australia.
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Affiliation(s)
- Matthew M Watson
- Department of General Surgery, Mount Gambier and Districts Health Service, Mount Gambier, South Australia, Australia
- Discipline of Surgery, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, South Australia, Australia
| | - Dianne C Watson
- Discipline of Surgery, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, South Australia, Australia
| | - Guy J Maddern
- Discipline of Surgery, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, South Australia, Australia
| | - Matthias W Wichmann
- Department of General Surgery, Mount Gambier and Districts Health Service, Mount Gambier, South Australia, Australia
- Discipline of Surgery, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, South Australia, Australia
- Flinders University Rural Health South Australia, Flinders University, Adelaide, South Australia, Australia
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Utsumi T, Yamada Y, Diaz-Meco MT, Moscat J, Nakanishi Y. Sessile serrated lesions with dysplasia: is it possible to nip them in the bud? J Gastroenterol 2023; 58:705-717. [PMID: 37219625 PMCID: PMC10366009 DOI: 10.1007/s00535-023-02003-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 05/14/2023] [Indexed: 05/24/2023]
Abstract
The serrated neoplasia pathway constitutes an "alternative route" to colorectal cancer (CRC), and sessile serrated lesions with dysplasia (SSLDs) are an intermediate step between sessile serrated lesions (SSLs) and invasive CRC in this pathway. While SSLs show indolent growth before becoming dysplastic (> 10-15 years), SSLDs are considered to rapidly progress to either immunogenic microsatellite instable-high (MSI-H) CRC (presumably 75% of cases) or mesenchymal microsatellite stable (MSS) CRC. Their flat shapes and the relatively short window of this intermediate state make it difficult to detect and diagnose SSLDs; thus, these lesions are potent precursors of post-colonoscopy/interval cancers. Confusing terminology and the lack of longitudinal observation data of serrated polyps have hampered the accumulation of knowledge about SSLDs; however, a growing body of evidence has started to clarify their characteristics and biology. Together with recent efforts to incorporate terminology, histological studies of SSLDs have identified distinct dysplastic patterns and revealed alterations in the tumor microenvironment (TME). Molecular studies at the single-cell level have identified distinct gene alterations in both the epithelium and the TME. Mouse serrated tumor models have demonstrated the importance of TME in disease progression. Advances in colonoscopy provide clues to distinguish pre-malignant from non-malignant-SSLs. Recent progress in all aspects of the field has enhanced our understanding of the biology of SSLDs. The aim of this review article was to assess the current knowledge of SSLDs and highlight their clinical implications.
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Affiliation(s)
- Takahiro Utsumi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
| | - Yosuke Yamada
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Maria Teresa Diaz-Meco
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, NY, USA
| | - Jorge Moscat
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, NY, USA
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan.
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Turner MA, Cox KE, Liu S, Neel N, Amirfakhri S, Nishino H, Hosseini M, Alcantara JA, Abd El-Hafeez AA, Lwin TM, Mallya K, Pisegna JR, Singh SK, Ghosh P, Hoffman RM, Batra SK, Bouvet M. Specific Targeting and Labeling of Colonic Polyps in CPC-APC Mice with Mucin 5AC Fluorescent Antibodies: A Model for Detection of Early Colon Cancer. Curr Issues Mol Biol 2023; 45:3347-3358. [PMID: 37185743 PMCID: PMC10136452 DOI: 10.3390/cimb45040219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/03/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023] Open
Abstract
Poor visualization of polyps can limit colorectal cancer screening. Fluorescent antibodies to mucin5AC (MUC5AC), a glycoprotein upregulated in adenomas and colorectal cancer, could improve screening colonoscopy polyp detection rate. Adenomatous polyposis coli flox mice with a Cdx2-Cre transgene (CPC-APC) develop colonic polyps that contain both dysplastic and malignant tissue. Mice received MUC5AC-IR800 or IRdye800 as a control IV and were sacrificed after 48 h for near-infrared imaging of their colons. A polyp-to-background ratio (PBR) was calculated for each polyp by dividing the mean fluorescence intensity of the polyp by the mean fluorescence intensity of the background tissue. The mean 25 μg PBR was 1.70 (±0.56); the mean 50 μg PBR was 2.64 (±0.97); the mean 100 μg PBR was 3.32 (±1.33); and the mean 150 μg PBR was 3.38 (±0.87). The mean PBR of the dye-only control was 2.22 (±1.02), significantly less than the 150 μg arm (p-value 0.008). The present study demonstrates the ability of fluorescent anti-MUC5AC antibodies to specifically target and label colonic polyps containing high-grade dysplasia and intramucosal adenocarcinoma in CPC-APC mice. This technology can potentially improve the detection rate and decrease the miss rate of advanced colonic neoplasia and early cancer at colonoscopy.
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Affiliation(s)
- Michael A. Turner
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- Department of Surgery, VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Kristin E. Cox
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- Department of Surgery, VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Shanglei Liu
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
| | - Nicholas Neel
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- Department of Surgery, VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Siamak Amirfakhri
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- Department of Surgery, VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Hiroto Nishino
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- Department of Surgery, VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Mojgan Hosseini
- Department of Pathology, University of California San Diego, La Jolla, CA 92037, USA
| | - Joshua A. Alcantara
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92037, USA
| | - Amer Ali Abd El-Hafeez
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92037, USA
| | - Thinzar M. Lwin
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Kavita Mallya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Joseph R. Pisegna
- Department of Gastroenterology, VA Los Angeles Healthcare System, Los Angeles, CA 90073, USA
| | - Satish K. Singh
- Medical Service, Section of Gastroenterology, VA Boston Healthcare System, Boston, MA 02130, USA
- Department of Medicine, Section of Gastroenterology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Pradipta Ghosh
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92037, USA
- Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA
| | - Robert M. Hoffman
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- Department of Surgery, VA San Diego Healthcare System, La Jolla, CA 92161, USA
- AntiCancer, Inc., San Diego, CA 92111, USA
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Michael Bouvet
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- Department of Surgery, VA San Diego Healthcare System, La Jolla, CA 92161, USA
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Bateman AC, Booth AL, Gonzalez RS, Shepherd NA. Microvesicular hyperplastic polyp and sessile serrated lesion of the large intestine: a biological continuum or separate entities? J Clin Pathol 2023:jcp-2023-208783. [PMID: 36927607 DOI: 10.1136/jcp-2023-208783] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 03/07/2023] [Indexed: 03/18/2023]
Abstract
The range of lesions with a serrated appearance within the large intestine has expanded and become more complex over the last 30 years. The majority of these were previously known as metaplastic polyps but are today called hyperplastic polyps (HPs). HPs show two main growth patterns: microvesicular and goblet cell-rich. The former type shows morphological and molecular similarities (eg, BRAF mutations) to the more recently described sessile serrated lesion (SSL). In this review, we debate whether these lesions represent a biological spectrum or separate entities. Whichever view is held, microvesicular HPs and SSLs are distinct from the goblet cell-rich HP and the traditional serrated adenoma (TSA), which may themselves share molecular changes (eg, KRAS mutations), with the goblet cell-rich HP representing a precursor to the TSA. Both SSLs and the goblet cell-rich HP-TSA pathway are routes to colorectal cancer within the serrated pathway and overlaps between them can occur, for example, a (BRAF-mutated) TSA may arise from an SSL.
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Affiliation(s)
- Adrian C Bateman
- Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Adam L Booth
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Raul S Gonzalez
- Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Neil A Shepherd
- Gloucestershire Cellular Pathology Laboratory, Cheltenham, UK
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11
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Vithayathil M, Smith S, Song M. Epidemiology of overall and early-onset serrated polyps versus conventional adenomas in a colonoscopy screening cohort. Int J Cancer 2023; 152:1085-1094. [PMID: 36178673 DOI: 10.1002/ijc.34306] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/12/2022] [Accepted: 09/23/2022] [Indexed: 01/21/2023]
Abstract
Serrated polyps (SPs) are precursors to one-third of colorectal cancers (CRCs), with histological subtypes: hyperplastic polyps (HPs), sessile serrated lesions (SSLs) and traditional serrated adenomas (TSAs). The incidence of early-onset CRC before the age of 50 is increasing, with limited understanding of SPs in younger cohorts. Using a large colonoscopy-based cohort, we characterized epidemiologic profiles of SP subtypes, compared to conventional adenomas, with secondary analysis on early-onset polyps. Ninety-four thousand four hundred and twenty-seven patients underwent screening colonoscopies between 2010 and 2018. Demographic, endoscopic and histopathologic characteristics of each polyp subtype were described. High-risk polyps included SSLs ≥10 mm/with dysplasia and conventional adenomas ≥10 mm/with tubulovillous/villous histology/high-grade dysplasia. We examined polyp prevalence with age and compared early- (age < 50) and late-onset polyps (age ≥ 50). Eighteen thousand one hundred and twenty-five patients had SPs (4357 SSLs, 15 415 HPs, 120 TSAs) and 26 699 had conventional adenomas. High-risk SSLs were enriched in the ascending colon (44.1% vs 2.6-35.8% for other locations; P < .003). Early- and late-onset SPs had similar subsite distribution. Early-onset conventional adenomas were more enriched in the distal colon/rectum (51.8% vs 43.4%, P < .001). Multiple conventional adenomas were more represented in late-onset groups (40.8% vs 33.8%, P < .001), with no difference in SSLs. The prevalence of conventional adenomas/high-risk conventional adenomas increased continuously with age, whereas the prevalence of SSLs/high-risk SSLs was stable from age 40 years onwards. A higher proportion of women were diagnosed with early-onset than late-onset SSLs (62.9% vs 57.6%, P = .03). Conventional adenomas, SSLs, early- and late-onset polyps have distinct epidemiology. The findings have implications for improved colonoscopy screening and surveillance and understanding the etiologic heterogeneity of CRC.
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Affiliation(s)
- Mathew Vithayathil
- Department of Epidemiology and Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Scott Smith
- Department of Epidemiology and Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Mingyang Song
- Department of Epidemiology and Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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12
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Oh SJ, Kim JW, Oh CH. Sessile serrated lesion presenting as large pedunculated polyp in the rectum: A case report. Medicine (Baltimore) 2022; 101:e32287. [PMID: 36595848 PMCID: PMC9794319 DOI: 10.1097/md.0000000000032287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
RATIONALE Sessile serrated lesions (SSLs) are serrated polyps (SP) with the typical serrated architecture of the crypt lining epithelium. SSL has an important clinical implication because they are recognized as precursor lesion of sporadic colorectal cancer (CRC) through "serrated pathway." SSLs usually appear flat to sessile, and are located in the right colon. PATIENT CONCERNS A 69-year-old man was referred to a tertiary medical center because of intermittent hematochezia for 2 years. DIAGNOSIS Colonoscopy revealed a large, pedunculated polyp in the rectum. The polyp surface was slightly reddish in color and the elongated stalk was covered with almost normal mucosa. Histopathological examination of the resected specimens revealed the typical features of SSL with low-grade dysplasia. INTERVENTION Endoscopic mucosal resection using a detachable snare was performed on the tumor for definite diagnosis and treatment. OUTCOMES There was no evidence of immediate or delayed bleeding after endoscopic mucosal resection, and the hemoglobin level normalized after a 1-year follow-up. LESSONS We report a rare case of a large pedunculated polyp with typical histological features of SSLs in the rectum. Endoscopists should always consider SSLs at any location even with unusual morphological findings.
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Affiliation(s)
- Shin Ju Oh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea
| | - Jung-Wook Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea
| | - Chi Hyuk Oh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea
- *Correspondence: Chi Hyuk Oh, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyung Hee University College of Medicine, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea (e-mail: )
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13
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Hidaka M, Iwaizumi M, Taniguchi T, Baba S, Osawa S, Sugimoto K, Maekawa M. Pure somatic pathogenic variation profiles for patients with serrated polyposis syndrome: a case series. BMC Res Notes 2022; 15:350. [PMID: 36419139 PMCID: PMC9682711 DOI: 10.1186/s13104-022-06245-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 11/08/2022] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE The serrated pathway is a distinct genetic/epigenetic mechanism of the adenoma-carcinoma sequence in colorectal carcinogenesis. Although many groups have reported the genetic-phenotypic correlation of serrated lesions (SLs), previous studies regarding the serrated pathway were conducted on patients with SLs that have different germline and environmental genetic backgrounds. We aimed to compare pure somatic genetic profiles among SLs within identical patient with SPS. RESULTS We analyzed SLs from one patient with SPS (Case #1) and compared DNA variant profiles using targeted DNA multigene panels via NGS among the patient's hyperplastic polyp (HP), three sessile serrated lesions (SSLs), and one traditional serrated adenoma (TSA), and separately analyzed three SSLs and one tubular adenoma (TA) within another patient with SPS (Case #2). In two patients, known pathogenic variant of BRAF (c.1799 T > A, p.Val600Glu) was observed in one TSA and one SSL in Case #1, and in three SSLs within Case #2. The pure somatic pathogenic variant BRAF (c.1799 T > A, p.Val600Glu) among SLs with identical germline genetic background supports its importance as a strong contributor for SLs.
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Affiliation(s)
- Misaki Hidaka
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Moriya Iwaizumi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.
| | - Terumi Taniguchi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Satoshi Baba
- Department of Diagnostic Pathology, Hamamatsu University Hospital, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University of School of Medicine, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masato Maekawa
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
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14
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Soons E, Rath T, Hazewinkel Y, van Dop WA, Esposito D, Testoni PA, Siersema PD. Real-time colorectal polyp detection using a novel computer-aided detection system (CADe): a feasibility study. Int J Colorectal Dis 2022; 37:2219-2228. [PMID: 36163514 PMCID: PMC9560918 DOI: 10.1007/s00384-022-04258-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/18/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Colonoscopy aims to early detect and remove precancerous colorectal polyps, thereby preventing development of colorectal cancer (CRC). Recently, computer-aided detection (CADe) systems have been developed to assist endoscopists in polyp detection during colonoscopy. The aim of this study was to investigate feasibility and safety of a novel CADe system during real-time colonoscopy in three European tertiary referral centers. METHODS Ninety patients undergoing colonoscopy assisted by a real-time CADe system (DISCOVERY; Pentax Medical, Tokyo, Japan) were prospectively included. The CADe system was turned on only at withdrawal, and its output was displayed on secondary monitor. To study feasibility, inspection time, polyp detection rate (PDR), adenoma detection rate (ADR), sessile serrated lesion (SSL) detection rate (SDR), and the number of false positives were recorded. To study safety, (severe) adverse events ((S)AEs) were collected. Additionally, user friendliness was rated from 1 (worst) to 10 (best) by endoscopists. RESULTS Mean inspection time was 10.8 ± 4.3 min, while PDR was 55.6%, ADR 28.9%, and SDR 11.1%. The CADe system users estimated that < 20 false positives occurred in 81 colonoscopy procedures (90%). No (S)AEs related to the CADe system were observed during the 30-day follow-up period. User friendliness was rated as good, with a median score of 8/10. CONCLUSION Colonoscopy with this novel CADe system in a real-time setting was feasible and safe. Although PDR and SDR were high compared to previous studies with other CADe systems, future randomized controlled trials are needed to confirm these detection rates. The high SDR is of particular interest since interval CRC has been suggested to develop frequently through the serrated neoplasia pathway. CLINICAL TRIAL REGISTRATION The study was registered in the Dutch Trial Register (reference number: NL8788).
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Affiliation(s)
- E Soons
- Department of Gastroenterology and Hepatology, Radboud Institute for Health Sciences, Radboud University Medical Center, 9101, 6500 HB, Nijmegen, the Netherlands.
| | - T Rath
- Department of Internal Medicine 1, Division of Gastroenterology, Friedrich-Alexander-University, Ludwig Demling Endoscopy Center of Excellence, Erlangen Nuernberg, Germany
| | - Y Hazewinkel
- Department of Gastroenterology and Hepatology, Radboud Institute for Health Sciences, Radboud University Medical Center, 9101, 6500 HB, Nijmegen, the Netherlands
| | - W A van Dop
- Department of Gastroenterology and Hepatology, Radboud Institute for Health Sciences, Radboud University Medical Center, 9101, 6500 HB, Nijmegen, the Netherlands
| | - D Esposito
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, Scientific Institute San Raffaele, Milan, Italy
| | - P A Testoni
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, Scientific Institute San Raffaele, Milan, Italy
| | - P D Siersema
- Department of Gastroenterology and Hepatology, Radboud Institute for Health Sciences, Radboud University Medical Center, 9101, 6500 HB, Nijmegen, the Netherlands
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15
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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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16
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Fennell L, Kane A, Liu C, McKeone D, Hartel G, Su C, Bond C, Bettington M, Leggett B, Whitehall V. Braf mutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium. Gut 2022; 71:1127-1140. [PMID: 34230216 PMCID: PMC9120393 DOI: 10.1136/gutjnl-2020-322166] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 06/30/2021] [Indexed: 12/08/2022]
Abstract
OBJECTIVE Sessile serrated lesions (SSLs) are common across the age spectrum, but the BRAF mutant cancers arising occur predominantly in the elderly. Aberrant DNA methylation is uncommon in SSL from young patients. Here, we interrogate the role of ageing and DNA methylation in SSL initiation and progression. DESIGN We used an inducible model of Braf mutation to direct recombination of the oncogenic Braf V637E allele to the murine intestine. BRAF mutation was activated after periods of ageing, and tissue was assessed for histological, DNA methylation and gene expression changes thereafter. We also investigated DNA methylation alterations in human SSLs. RESULTS Inducing Braf mutation in aged mice was associated with a 10-fold relative risk of serrated lesions compared with young mice. There were extensive differences in age-associated DNA methylation between animals induced at 9 months versus wean, with relatively little differential Braf-specific methylation. DNA methylation at WNT pathway genes scales with age and Braf mutation accelerated age-associated DNA methylation. In human SSLs, increased epigenetic age was associated with high-risk serrated colorectal neoplasia. CONCLUSIONS SSLs arising in the aged intestine are at a significantly higher risk of spontaneous neoplastic progression. These findings provide support for a new conceptual model for serrated colorectal carcinogenesis, whereby risk of Braf-induced neoplastic transformation is dependent on age and may be related to age-associated molecular alterations that accumulate in the ageing intestine, including DNA methylation. This may have implications for surveillance and chemopreventive strategies targeting the epigenome.
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Affiliation(s)
- Lochlan Fennell
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Saint Lucia, Queensland, Australia
| | - Alexandra Kane
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Saint Lucia, Queensland, Australia
- Conjoint Internal Medical Laboratory, Chemical Pathology, Health Support Queensland Pathology Queensland, Herston, Queensland, Australia
| | - Cheng Liu
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Saint Lucia, Queensland, Australia
| | - Diane McKeone
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Gunter Hartel
- Statistics Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Chang Su
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Saint Lucia, Queensland, Australia
| | - Catherine Bond
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Saint Lucia, Queensland, Australia
| | - Mark Bettington
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Barbara Leggett
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Saint Lucia, Queensland, Australia
- Department of Gastroenterology and Hepatology, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Vicki Whitehall
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Saint Lucia, Queensland, Australia
- Conjoint Internal Medical Laboratory, Chemical Pathology, Health Support Queensland Pathology Queensland, Herston, Queensland, Australia
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Mezzapesa M, Losurdo G, Celiberto F, Rizzi S, d’Amati A, Piscitelli D, Ierardi E, Di Leo A. Serrated Colorectal Lesions: An Up-to-Date Review from Histological Pattern to Molecular Pathogenesis. Int J Mol Sci 2022; 23:4461. [PMID: 35457279 PMCID: PMC9032676 DOI: 10.3390/ijms23084461] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/16/2022] [Accepted: 04/17/2022] [Indexed: 12/10/2022] Open
Abstract
Until 2010, colorectal serrated lesions were generally considered as harmless lesions and reported as hyperplastic polyps (HPs) by pathologists and gastroenterologists. However, recent evidence showed that they may bear the potential to develop into colorectal carcinoma (CRC). Therefore, the World Health Organization (WHO) classification has identified four categories of serrated lesions: hyperplastic polyps (HPs), sessile serrated lesions (SSLs), traditional serrated adenoma (TSAs) and unclassified serrated adenomas. SSLs with dysplasia and TSAs are the most common precursors of CRC. CRCs arising from serrated lesions originate via two different molecular pathways, namely sporadic microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP), the latter being considered as the major mechanism that drives the serrated pathway towards CRC. Unlike CRCs arising through the adenoma-carcinoma pathway, APC-inactivating mutations are rarely shown in the serrated neoplasia pathway.
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Affiliation(s)
- Martino Mezzapesa
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (M.M.); (G.L.); (F.C.); (S.R.); (A.D.L.)
| | - Giuseppe Losurdo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (M.M.); (G.L.); (F.C.); (S.R.); (A.D.L.)
- PhD Course in Organs and Tissues Transplantation and Cellular Therapies, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy
| | - Francesca Celiberto
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (M.M.); (G.L.); (F.C.); (S.R.); (A.D.L.)
- PhD Course in Organs and Tissues Transplantation and Cellular Therapies, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy
| | - Salvatore Rizzi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (M.M.); (G.L.); (F.C.); (S.R.); (A.D.L.)
| | - Antonio d’Amati
- Section of Pathology, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (A.d.); (D.P.)
| | - Domenico Piscitelli
- Section of Pathology, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (A.d.); (D.P.)
| | - Enzo Ierardi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (M.M.); (G.L.); (F.C.); (S.R.); (A.D.L.)
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (M.M.); (G.L.); (F.C.); (S.R.); (A.D.L.)
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Abstract
Colorectal cancer is the second leading cause of cancer-associated mortality, with a lifetime risk of approximately 4% to 5%. Colorectal cancer develops from the sequential acquisition of defined genetic mutations in the colonic epithelium. Tumorigenesis from normal tissue to cancer occurs largely through 3 pathways: the chromosomal instability pathway, the microsatellite instability pathway, and the sessile serrated pathway. Colorectal cancer incidence and mortality have decreased by approximately 35% since the beginning of screening programs in the 1990s, although other factors such as use of aspirin for coronary disease prevention and decreased smoking rates may also be important. In this review, we discuss the etiology, epidemiology, and histology of colorectal polyps and cancer.
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19
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Vithayathil M, Smith S, Goryachev S, Nayor J, Song M. Development of a Large Colonoscopy-Based Longitudinal Cohort for Integrated Research of Colorectal Cancer: Partners Colonoscopy Cohort. Dig Dis Sci 2022; 67:473-480. [PMID: 33590405 DOI: 10.1007/s10620-021-06882-x] [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: 09/16/2020] [Accepted: 01/27/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIMS Conventional adenomas (CAs) and serrated polyps (SPs) are precursors to colorectal cancer (CRC). Understanding metachronous cancer risk is poor due to lack of accurate large-volume datasets. We outline the use of natural language processing (NLP) in forming the Partners Colonoscopy Cohort, an integrated longitudinal cohort of patients undergoing colonoscopies. METHODS We identified endoscopy quality data from endoscopy reports for colonoscopies performed from 2007 to 2018 in a large integrated healthcare system, Mass General Brigham). Through modification of an established NLP pipeline, we extracted histopathological data (polyp location, histology and dysplasia) from corresponding pathology reports. Pathology and endoscopy data were merged by polyp location using a four-stage algorithm. NLP and merging procedures were validated by manual review of 500 pathology reports. RESULTS 305,656 colonoscopies in 213,924 patients were identified. After merging, 76,137 patients had matched polyp data for 334,750 polyps. CAs and SPs were present in 86,707 (28.5%) and 55,373 (18.2%) colonoscopies. Among patients with polyps at index screening colonoscopy, 14,931 (33.4%) had follow-up colonoscopy (median 46.4, interquartile range 33.8-62.4 months); 91 (0.2%) and 1127 (2.5%) patients developed metachronous CRC and high-risk polyps (polyps ≥ 10 mm or CAs having high-grade dysplasia/villous/tublovillous histology or SPs with dysplasia). Genetic data were available for 23,787 (31.7%) patients with polyps from the Partners Biobank. The validation study showed a positive predictive value of 100% for polyp histology and locations. CONCLUSION We created the Partners Colonoscopy Cohort providing essential infrastructure for future studies to better understand the natural history of CRC and improve screening and post-polypectomy strategies.
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Affiliation(s)
- Mathew Vithayathil
- Departments of Epidemiology and Nutrition, Harvard T. H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA
| | - Scott Smith
- Departments of Epidemiology and Nutrition, Harvard T. H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA
| | - Sergey Goryachev
- Research Information Science and Computing (RISC), Partners Healthcare, Boston, MA, USA
| | - Jennifer Nayor
- Division of Gastroenterology, Emerson Hospital, Concord, MA, USA
| | - Mingyang Song
- Departments of Epidemiology and Nutrition, Harvard T. H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA. .,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. .,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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20
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Lall V, Ismail AGM, Ayonrinde OT. Disparate age and sex distribution of sessile serrated lesions and conventional adenomas in an outpatient colonoscopy population-implications for colorectal cancer screening? Int J Colorectal Dis 2022; 37:1569-1579. [PMID: 35660947 PMCID: PMC9262786 DOI: 10.1007/s00384-022-04191-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/21/2022] [Indexed: 02/06/2023]
Abstract
PURPOSE Colorectal cancer (CRC) is increasingly diagnosed in individuals aged < 50 years, resulting in advocacy of screening from age 45 years. Despite existing knowledge associating CRC with conventional adenomas, the significance of sessile serrated lesions (SSLs) on the burden of CRC is less detailed. We aimed to provide contemporary estimates for SSL prevalence and examine patient and procedure factors associated with SSL detection. METHODS Retrospective observational study examining associations between SSL and conventional adenoma detection, polyp histopathology, patient, and procedure characteristics in an outpatient colonoscopy unit over 12 months. RESULTS From 2097 colonoscopies, SSL detection was 13.8% overall and 12.5% in patients < 50 years. SSLs were mostly proximal in location (64%), and SSL detection was significantly higher in females compared with males (16.2% vs. 11.7%, p = 0.003), particularly in those < 50 years (16.8% vs. 8.6%, p < 0.001). In multivariable analysis, SSL detection was associated with female sex (adjusted odds ratio [aOR] 1.48, 95% confidence interval [CI] 1.15-1.91), synchronous conventional adenoma detection (aOR 1.36, 95% CI 1.04-1.78) and BMI ≥ 25 kg/m2 (aOR 1.34, 95% CI 1.02-1.77). Conventional adenoma detection was 33.6% and associated with age ≥ 50 years (aOR 3.57, 95% CI 2.84-4.47) and synchronous SSL detection (aOR 1.36, 95% CI 1.03-1.79). CONCLUSIONS We observed age and sex disparities in polyp types and prevalence in this outpatient colonoscopy population. SSLs were most prevalent in females aged < 50 years, suggesting a potential increased susceptibility of young females to SSLs and CRC. Our findings may have implications for the design of CRC screening programs.
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Affiliation(s)
- Vidit Lall
- Sir Charles Gairdner Hospital, Nedlands, Australia ,Medical School, The University of Western Australia, Nedlands, Australia
| | - Ali Galalah Mostafa Ismail
- Royal Perth Hospital, Perth, Australia ,Medical School, The University of Western Australia, Nedlands, Australia
| | - Oyekoya Taiwo Ayonrinde
- Medical School, The University of Western Australia, Nedlands, Australia ,Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch, Australia ,Faculty of Health Sciences, Curtin University, Bentley, Australia
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21
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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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22
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Bonert M, Collins A, Xenodemetropoulos T, Dmetrichuk JM, Al-Haddad S, Major P, Naqvi A. Application of Next Generation Quality/Statistical Process Control and Expert-Led Case Review to Increase the Consistency of Diagnostic Rates in Precancerous Colorectal Polyps. Qual Manag Health Care 2021; 30:176-183. [PMID: 33405466 PMCID: PMC8219089 DOI: 10.1097/qmh.0000000000000299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Prior work suggests high interrater variability in the pathologist diagnostic rate (PDR) of the precancerous polyp sessile serrated adenoma (SSA). OBJECTIVES To improve the diagnostic consistency in the pathological evaluation of colorectal polyp specimens with diagnostic rate awareness, using funnel plots (FPs)/control charts (CCs), and a focused group case review. METHODS All colorectal polyp specimen (CRPS) reports September 2015 to August 2017 were analyzed at one institution. PDRs were extracted using a hierarchical free-text string matching algorithm and visualized using FPs, showing pathologist specimen volume versus PDR, and CCs, showing pathologist versus normed PDR. The FPs/CCs were centered on the group median diagnostic rate (GMDR). Pathologists were shown their baseline SSA diagnostic rate in relation to the practice, and in January 2017, there was a focused group case review/open discussion of approximately 40 sequential cases signed as SSA with a gastrointestinal pathology expert. RESULTS Nine pathologists interpreted more than 250 CRPSs per year. FPs/CCs for the first and second years showed 6/4 and 3/1 P < .05/P < .001 pathologist outliers, respectively, in relation to the GMDR for SSA and 0/0 and 0/0 P < .05/P < .001 pathologist outliers, respectively, in relation to the GMDR for tubular adenoma (TA). An in silico kappa (ISK) for SSA improved from 0.52 to 0.62. CONCLUSION Diagnostic rate awareness facilitated by FPs/CCs coupled with focused expert-led reviews may help calibrate PDR. Variation in SSA PDRs still remains high in relation to TA. ISK represents an intuitive, useful metric and Next Generation Quality/Statistical Process Control a promising approach for objectively increasing diagnostic consistency.
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Affiliation(s)
- Michael Bonert
- Departments of Pathology and Molecular Medicine (Drs Bonert, Dmetrichuk, Al-Haddad, and Naqvi), Medicine (Dr Collins), and Oncology (Dr Major), McMaster University, Hamilton, Ontario, Canada; St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada (Drs Bonert and Naqvi); Farncombe Family Digestive Health Research Institute/Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (Dr Xenodemetropoulos); and Juravinski Hospital/Hamilton Health Sciences Centre/Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (Ms Al-Haddad and Dr Major)
| | - Andrew Collins
- Departments of Pathology and Molecular Medicine (Drs Bonert, Dmetrichuk, Al-Haddad, and Naqvi), Medicine (Dr Collins), and Oncology (Dr Major), McMaster University, Hamilton, Ontario, Canada; St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada (Drs Bonert and Naqvi); Farncombe Family Digestive Health Research Institute/Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (Dr Xenodemetropoulos); and Juravinski Hospital/Hamilton Health Sciences Centre/Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (Ms Al-Haddad and Dr Major)
| | - Ted Xenodemetropoulos
- Departments of Pathology and Molecular Medicine (Drs Bonert, Dmetrichuk, Al-Haddad, and Naqvi), Medicine (Dr Collins), and Oncology (Dr Major), McMaster University, Hamilton, Ontario, Canada; St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada (Drs Bonert and Naqvi); Farncombe Family Digestive Health Research Institute/Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (Dr Xenodemetropoulos); and Juravinski Hospital/Hamilton Health Sciences Centre/Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (Ms Al-Haddad and Dr Major)
| | - Jennifer M. Dmetrichuk
- Departments of Pathology and Molecular Medicine (Drs Bonert, Dmetrichuk, Al-Haddad, and Naqvi), Medicine (Dr Collins), and Oncology (Dr Major), McMaster University, Hamilton, Ontario, Canada; St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada (Drs Bonert and Naqvi); Farncombe Family Digestive Health Research Institute/Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (Dr Xenodemetropoulos); and Juravinski Hospital/Hamilton Health Sciences Centre/Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (Ms Al-Haddad and Dr Major)
| | - Sahar Al-Haddad
- Departments of Pathology and Molecular Medicine (Drs Bonert, Dmetrichuk, Al-Haddad, and Naqvi), Medicine (Dr Collins), and Oncology (Dr Major), McMaster University, Hamilton, Ontario, Canada; St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada (Drs Bonert and Naqvi); Farncombe Family Digestive Health Research Institute/Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (Dr Xenodemetropoulos); and Juravinski Hospital/Hamilton Health Sciences Centre/Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (Ms Al-Haddad and Dr Major)
| | - Pierre Major
- Departments of Pathology and Molecular Medicine (Drs Bonert, Dmetrichuk, Al-Haddad, and Naqvi), Medicine (Dr Collins), and Oncology (Dr Major), McMaster University, Hamilton, Ontario, Canada; St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada (Drs Bonert and Naqvi); Farncombe Family Digestive Health Research Institute/Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (Dr Xenodemetropoulos); and Juravinski Hospital/Hamilton Health Sciences Centre/Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (Ms Al-Haddad and Dr Major)
| | - Asghar Naqvi
- Departments of Pathology and Molecular Medicine (Drs Bonert, Dmetrichuk, Al-Haddad, and Naqvi), Medicine (Dr Collins), and Oncology (Dr Major), McMaster University, Hamilton, Ontario, Canada; St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada (Drs Bonert and Naqvi); Farncombe Family Digestive Health Research Institute/Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (Dr Xenodemetropoulos); and Juravinski Hospital/Hamilton Health Sciences Centre/Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada (Ms Al-Haddad and Dr Major)
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23
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Munari G, Businello G, Mattiolo P, Pennelli G, Sbaraglia M, Borga C, Pucciarelli S, Spolverato G, Mescoli C, Galuppini F, Sommariva A, Bellan E, Lonardi S, Loupakis F, Luchini C, Dei Tos AP, Fassan M. Molecular profiling of appendiceal serrated lesions, polyps and mucinous neoplasms: a single-centre experience. J Cancer Res Clin Oncol 2021; 147:1897-1904. [PMID: 33712927 PMCID: PMC8164605 DOI: 10.1007/s00432-021-03589-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/07/2021] [Indexed: 12/17/2022]
Abstract
PURPOSE Non-neuroendocrine neoplasms of the appendix are a phenotypically heterogeneous group of lesions; a comprehensive molecular characterization of these tumors is still lacking. METHODS A total of 52 samples taken from 49 patients was evaluated: 18 sessile serrated lesions (SSL; 3 with dysplasia), 2 high-grade tubular adenomas, 1 tubulo-villous adenoma,1 hyperplastic polyp, 18 low-grade appendiceal mucinous neoplasms (LAMN), 3 high-grade appendiceal mucinous neoplasms (HAMN) and 9 mucinous adenocarcinomas. Hotspot mutational profiling of the RNF43, SMAD4, KRAS, NRAS, BRAF and PIK3CA genes was performed. Expression of p53, MLH1, PMS2, MSH2, and MSH6 was evaluated by immunohistochemistry. RESULTS KRAS was the most frequently mutated gene (53.9% of cases), followed by RNF43 (15.4%), and BRAF (13.5%). In particular: KRAS was mutated in 44.4% of adenocarcinomas, 66.7% of HAMNs, 61.1% of LAMNs, 53.3% of SSL without dysplasia and in 66.7% of SSL with dysplasia; RNF43 was mutated in 33.3% of adenocarcinomas, 66.7% of HAMNs, 11.1% of LAMNs and in 6.7% of SSL without dysplasia; BRAF was mutated in 11.1% of adenocarcinomas, 26.7% of SSL without dysplasia and in 5.6% of LAMNs. Only a case of high-grade tubular adenoma showed mismatch repair deficiency, while immunohistochemical expression of p53 was altered in 21.1% of cases. CONCLUSIONS The histological phenotypic similarities between appendicular mucinous lesions and serrated colon lesions do not reflect a similar genetic landscape. Mismatch repair deficiency is a rare event during appendiceal mucinous carcinogenesis.
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Affiliation(s)
- Giada Munari
- Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Gianluca Businello
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Via Gabelli 61, 35121, Padua, Italy
| | - Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Gianmaria Pennelli
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Via Gabelli 61, 35121, Padua, Italy
| | - Marta Sbaraglia
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Via Gabelli 61, 35121, Padua, Italy
| | - Chiara Borga
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Via Gabelli 61, 35121, Padua, Italy
| | - Salvatore Pucciarelli
- Department of Surgical, Oncological, and Gastroenterological Sciences, Section of Surgery, University of Padua, Padua, Italy
| | - Gaya Spolverato
- Department of Surgical, Oncological, and Gastroenterological Sciences, Section of Surgery, University of Padua, Padua, Italy
| | - Claudia Mescoli
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Via Gabelli 61, 35121, Padua, Italy
| | - Francesca Galuppini
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Via Gabelli 61, 35121, Padua, Italy
| | - Antonio Sommariva
- Advanced Surgical Oncology Unit, Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Elena Bellan
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Via Gabelli 61, 35121, Padua, Italy
| | - Sara Lonardi
- First Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Fotios Loupakis
- First Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Angelo Paolo Dei Tos
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Via Gabelli 61, 35121, Padua, Italy
| | - Matteo Fassan
- Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy.
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Via Gabelli 61, 35121, Padua, Italy.
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24
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Mikaeel RR, Young JP, Tapia Rico G, Hewett PJ, Hardingham JE, Uylaki W, Horsnell M, Price TJ. Immunohistochemistry features and molecular pathology of appendiceal neoplasms. Crit Rev Clin Lab Sci 2021; 58:369-384. [PMID: 33569997 DOI: 10.1080/10408363.2021.1881756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Primary appendiceal neoplasms (ANs) comprise a heterogeneous group of tumors. The pathology and classification of ANs have been controversial, and thus, a new classification of these neoplasms was published in the World Health Organization (WHO) classification of tumors (5th edition, 2019). However, immunohistochemistry (IHC) features of epithelial ANs are not explained in this edition and the limited data on the molecular pathology of these tumors shows inconsistent findings in various studies. It would be useful to identify biomarkers appropriate for each subtype to better aid in treatment selection. Therefore, we reviewed the literature to investigate what is known of the molecular pathology and IHC features of the most frequently diagnosed pathological subtypes of epithelial ANs based on the recent classification. The inconsistencies in research findings regarding the IHC features and molecular pathology of ANs could be due to differences in the number of samples and their collection and preparation as well as to the lack of a universally accepted classification system for these neoplasms. However, the literature shows that epithelial ANs typically stain positive for MUC2, CK20, and CDX2 and that the expression of SATB2 protein could be used as a biomarker for appendix tumor origin. Low-grade appendiceal mucinous neoplasms tend to have mutations in KRAS and GNAS but are usually wild-type for BRAF, APC, and P53. Conversely, appendiceal adenocarcinomas are frequently found with mutations in KRAS, GNAS, P53, PIK3CA, and APC, and have significant nuclear expression of β-catenin, loss of nuclear or nuclear and cytoplasmic expression of SMAD4, and loss of cytoplasmic membranous expression of E-cadherin. Goblet cell carcinomas (GCCs) typically stain positive for keratin and mucin markers and are frequently mutated in P53 and chromatin-modifier genes, but they tend to be wild-type for KRAS, GNAS, APC, and PIK3CA. The expression of CK7 and SATB2 proteins is usually negative in appendiceal neuroendocrine neoplasms and they lack the mutations in common cancer-associated genes including APC, BRAF, SMAD4, and PIK3C. The available data suggest that GCCs have distinct molecular and immunohistochemical features and that they have characteristics more in common with adenocarcinoma than classical neuroendocrine tumors. In addition, MSI does not seem to have a role in the pathogenesis of epithelial ANs because they are rarely detected in these tumors. Finally, hereditary predisposition may have a role in the development of ANs because heterozygous CTNNβ1, NOTCH1, and NOTCH4 germline mutations have recently been identified in low and high grades ANs.
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Affiliation(s)
- Reger R Mikaeel
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Adelaide, Australia.,SAHMRI Colorectal Node, Basil Hetzel Institute, Woodville South, Australia.,Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.,Department of Biology, College of Science, University of Duhok, Duhok, Kurdistan
| | - Joanne P Young
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Adelaide, Australia.,SAHMRI Colorectal Node, Basil Hetzel Institute, Woodville South, Australia.,Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
| | - Gonzalo Tapia Rico
- Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, Australia
| | - Peter J Hewett
- University of Adelaide Department of Surgery, The Queen Elizabeth Hospital, Adelaide, Australia
| | - Jennifer E Hardingham
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Adelaide, Australia.,SAHMRI Colorectal Node, Basil Hetzel Institute, Woodville South, Australia.,Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
| | - Wendy Uylaki
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Adelaide, Australia
| | - Mehgan Horsnell
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Adelaide, Australia
| | - Timothy J Price
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Adelaide, Australia.,Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
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25
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Bateman AC. The spectrum of serrated colorectal lesions-new entities and unanswered questions. Histopathology 2021; 78:780-790. [PMID: 33332664 DOI: 10.1111/his.14305] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hyperplastic polyps (HPs) of the colon and rectum were historically thought not to be associated with an increased risk of development of colorectal cancer (CRC). The recognition of variants of serrated colorectal lesions that possessed relatively subtle but significant morphological differences from those of HPs and that could be associated with epithelial dysplasia and CRC led to the characterisation of sessile serrated lesions (SSLs) and traditional serrated adenomas (TSAs). These links were supported by the identification of genetic alterations that are commonly found in HPs, SSLs, TSAs, and CRC, e.g. BRAF and KRAS mutations. The 'serrated pathway' to CRC may progress faster than the traditional 'adenoma-carcinoma sequence', underlining the importance of identifying these lesions. The diagnostic histological criteria for SSLs have since been more clearly defined, in parallel with a drive to increase the recognition of these lesions at endoscopy. The existence of lesions showing overlapping morphological and molecular features with those of HPs, SSLs and TSAs has most recently been highlighted-including mucin-rich TSA, serrated tubulovillous adenoma, and those showing mixed histological features, e.g. comprising differing combinations of HP, SSL, and TSA. Morphological and molecular studies of this range of lesions are providing insights into the relationships of serrated colorectal lesions with each other and with CRC. This article provides an overview of the current understanding of serrated colorectal lesions, including a discussion of those with overlapping and mixed features.
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Affiliation(s)
- Adrian C Bateman
- Department of Cellular Pathology, University Hospitals Southampton NHS Foundation Trust, Southampton, UK
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26
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Hang D, He X, Kværner AS, Chan AT, Wu K, Ogino S, Hu Z, Shen H, Giovannucci EL, Song M. Plasma sex hormones and risk of conventional and serrated precursors of colorectal cancer in postmenopausal women. BMC Med 2021; 19:18. [PMID: 33504335 PMCID: PMC7841996 DOI: 10.1186/s12916-020-01895-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/22/2020] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Sex hormones have been suggested to play a role in colorectal cancer (CRC), but their influence on early initiation of CRC remains unknown. METHODS We retrospectively examined the associations with risk of CRC precursors, including conventional adenomas and serrated polyps, for plasma estrone, estradiol, free estradiol, testosterone, free testosterone, sex hormone-binding globulin (SHBG), and the ratio of estradiol to testosterone among 5404 postmenopausal women from the Nurses' Health Study I and II. Multivariable logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI). Given multiple testing, P < 0.005 was considered statistically significant. RESULTS During 20 years of follow-up, we documented 535 conventional adenoma cases and 402 serrated polyp cases. Higher concentrations of SHBG were associated with lower risk of conventional adenomas, particularly advanced adenomas (multivariable OR comparing the highest to the lowest quartile, 0.40, 95% CI 0.24-0.67, P for trend < 0.0001). A nominally significant association was found for SHBG with lower risk of large serrated polyps (≥ 10 mm) (OR, 0.47, 95% CI 0.17-1.35, P for trend = 0.02) as well as free estradiol and free testosterone with higher risk of conventional adenomas (OR, 1.54, 95% CI 1.02-2.31, P for trend = 0.03 and OR, 1.33, 95% CI 0.99-1.78, P for trend = 0.03, respectively). CONCLUSIONS The findings suggest a potential role of sex hormones, particularly SHBG, in early colorectal carcinogenesis.
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Affiliation(s)
- Dong Hang
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA
| | - Xiaosheng He
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Colorectal Surgery, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ane Sørlie Kværner
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA
| | - Shuji Ogino
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Mingyang Song
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA.
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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27
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Variation Over Time and Factors Associated With Detection Rates of Sessile Serrated Lesion Across the United States: Results Form a National Sample Using the GIQuIC Registry. Am J Gastroenterol 2021; 116:95-99. [PMID: 32833735 DOI: 10.14309/ajg.0000000000000824] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 07/01/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Sessile serrated lesions (SSLs) are important precursor lesions for the CpG island-methylated pathway to colorectal cancer. The reported detection rates of SSL are highly variable, and national or population-based estimates are not available. Patient-, provider-, and procedure-level factors associated with the detection rates of SSL have not been well described. The aim of our study was to study the detection rates of SSL, variability of rates over time, and factors associated with detection rates of SSL in a national sample of patients undergoing colonoscopy using the GIQuIC registry. METHODS We used colonoscopies submitted to the GIQuIC registry from 2014 to 2017 on adults, aged 18-89 years. Only the first colonoscopy record per patient was included. Indications for colonoscopy were categorized as screening, diagnostic, and surveillance. We used the hierarchical logistic models to study the factors associated with the detection rates of SSL. The Cochrane-Armitage test was used to study the significance of trend over time. RESULTS There were a total of 5,173,211 colonoscopies performed by 3,934 endoscopists during the study period. Among the 2,101,082 screening colonoscopies over the study period in adults older than or equal to 50 years that were complete to the cecum, the average detection rate per endoscopist for SSL was 6.43% (SD 5.18) and 6.25% standardized for the 2010 US population. There was a significant increase in the detection rates of SSLs from screening colonoscopies over the study period from 4.99% in 2014 to 7.09% in 2017 (P trend <0.001). Clinically significant factors associated with higher detection rates of SSL were longer withdrawal times (>11 minutes vs ≤6 minutes) (odds ratio [OR] 9.61; 9.03-10.24), adequate preparation (OR 1.25; 1.22-1.28), female sex (OR 1.17; 1.16-1.18), and use of a specialized gastrointestinal pathology group (OR 1.12; 95% confidence interval 1.04, 1.19). DISCUSSION Population-based estimates of the detection rates of SSL are 6% and have increased over time.
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28
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Peruhova M, Peshevska-Sekulovska M, Krastev B, Panayotova G, Georgieva V, Konakchieva R, Nikolaev G, Velikova TV. What could microRNA expression tell us more about colorectal serrated pathway carcinogenesis? World J Gastroenterol 2020; 26:6556-6571. [PMID: 33268946 PMCID: PMC7673963 DOI: 10.3748/wjg.v26.i42.6556] [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: 08/29/2020] [Revised: 09/24/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
In the last two decades, the vision of a unique carcinogenesis model for colorectal carcinoma (CRC) has completely changed. In addition to the adenoma to carcinoma transition, colorectal carcinogenesis can also occur via the serrated pathway. Small non-coding RNA, known as microRNAs (miRNAs), were also shown to be involved in progression towards malignancy. Furthermore, increased expression of certain miRNAs in premalignant sessile serrated lesions (SSLs) was found, emphasizing their role in the serrated pathway progression towards colon cancer. Since miRNAs function as post-transcriptional gene regulators, they have enormous potential to be used as useful biomarkers for CRC and screening in patients with SSLs particularly. In this review, we have summarized the most relevant information about the specific role of miRNAs and their relevant signaling pathways among different serrated lesions and polyps as well as in serrated adenocarcinoma. Additional focus is put on the correlation between gut immunity and miRNA expression in the serrated pathway, which remains unstudied.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | | | - Boris Krastev
- Department of Clinical Oncology, MHAT Hospital for Women Health Nadezhda, Sofia 1330, Bulgaria
| | - Gabriela Panayotova
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Viktoriya Georgieva
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
| | | | - Georgi Nikolaev
- Faculty of Biology, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Tsvetelina Veselinova Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- Department of Clinical Immunology, University Hospital Lozenetz, Sofia 1407, Bulgaria
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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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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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Nguyen LH, Goel A, Chung DC. Pathways of Colorectal Carcinogenesis. Gastroenterology 2020; 158:291-302. [PMID: 31622622 PMCID: PMC6981255 DOI: 10.1053/j.gastro.2019.08.059] [Citation(s) in RCA: 294] [Impact Index Per Article: 58.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/13/2019] [Accepted: 08/15/2019] [Indexed: 12/15/2022]
Abstract
Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic changes associated with the development of precancerous colorectal adenomas and their progression to tumors, as well as the effects of defective DNA repair, chromosome instability, microsatellite instability, and alterations in the serrated pathway and DNA methylation. We provide insights into the different molecular subgroups of colorectal tumors that develop via each of these different mechanisms and their associations with patient outcomes.
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Affiliation(s)
- Long H Nguyen
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Dallas, Texas; Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
| | - Daniel C Chung
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Center for Cancer Risk Assessment, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Bozorg SR, Song M, Emilsson L, Ludvigsson JF. Validation of serrated polyps (SPs) in Swedish pathology registers. BMC Gastroenterol 2019; 20:3. [PMID: 31892305 PMCID: PMC6938642 DOI: 10.1186/s12876-019-1134-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 12/04/2019] [Indexed: 12/18/2022] Open
Abstract
Background Little is known about the natural history of serrated polyps (SPs), partly due to the lack of large-scale epidemiologic data. In this study, we examined the validity of SP identification according to SNOMED (Systematised Nomenclature of Medicine) codes and free text from colorectal histopathology reports. Methods Through the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, we retrieved data on SPs from all pathology departments in Sweden in 2015–2017 by using SNOMED codes and free-text search in colorectal histopathology reports. Randomly selected individuals with a histopathology report of SPs were validated against patient charts using a structured, retrospective review. Results SPs were confirmed in 101/106 individuals with a histopathology report of SPs, yielding a positive predictive value (PPV) of 95% (95%CI = 89–98%). By year of diagnosis, the PPV was 89% (95%CI = 69–97%), 96% (95%CI = 81–99%) and 97% (95%CI = 89–99%) for individuals diagnosed before 2001 (n = 19), between 2001 and 2010 (n = 26) and after 2010 (n = 61), respectively. According to search method, the PPV for individuals identified by SNOMED codes was 100% (95%CI = 93–100%), and 93% (95%CI = 86–97%) using free-text search. Recorded location (colon vs. rectum) was correct in 94% of all SP histopathology reports (95%CI = 84–98%) identified by SNOMED codes. Individuals with SPs were classified into hyperplastic polyps (n = 34; 32%), traditional serrated adenomas (n = 3; 3%), sessile serrated adenomas/polyps (SSA/Ps) (n = 70; 66%), unspecified SPs (n = 3, 3%), and false positive SPs (n = 5, 5%). For individuals identified by SNOMED codes, SSA/Ps were confirmed in 49/52 individuals, resulting in a PPV of 94% (95%CI: 84–98%). In total, 57% had ≥2 polyps (1: n = 44, 2–3: n = 33 and ≥ 4: n = 27). Some 46% of SPs (n = 71) originated from the proximal colon and 24% were ≥ 10 mm in size (n = 37). Heredity for colorectal cancer, intestinal polyposis syndromes, or both was reported in seven individuals (7%). Common comorbidities included diverticulosis (n = 45, 42%), colorectal cancer (n = 19, 18%), and inflammatory bowel disease (n = 10, 9%). Conclusion Colorectal histopathology reports are a reliable data source to identify individuals with SPs.
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Affiliation(s)
- Soran R Bozorg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Solna, Sweden.
| | - Mingyang Song
- Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Louise Emilsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Solna, Sweden.,Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Institute of Health and Society, University of Oslo, Oslo, Norway.,Vårdcentralen Värmlands Nysäter and Centre for Clinical Research, County Council of Värmland, Värmland, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Solna, Sweden.,Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.,Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK.,Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
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Crockett SD, Nagtegaal ID. Terminology, Molecular Features, Epidemiology, and Management of Serrated Colorectal Neoplasia. Gastroenterology 2019; 157:949-966.e4. [PMID: 31323292 DOI: 10.1053/j.gastro.2019.06.041] [Citation(s) in RCA: 230] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 06/07/2019] [Accepted: 06/15/2019] [Indexed: 12/11/2022]
Abstract
In addition to the adenoma to carcinoma sequence, colorectal carcinogenesis can occur via the serrated pathway. Studies have focused on clarification of categories and molecular features of serrated polyps, as well as endoscopic detection and risk assessment. Guidelines from the World Health Organization propose assigning serrated polyps to categories of hyperplastic polyps, traditional serrated adenomas, and sessile serrated lesions (SSLs). Traditional serrated adenomas and SSLs are precursors to colorectal cancer. The serrated pathway is characterized by mutations in RAS and RAF, disruptions to the Wnt signaling pathway, and widespread methylation of CpG islands. Epidemiology studies of serrated polyps have been hampered by inconsistencies in terminology and reporting, but the prevalence of serrated class polyps is 20%-40% in average-risk individuals; most serrated polyps detected are hyperplastic. SSLs, the most common premalignant serrated subtype, and are found in up to 15% of average-risk patients by high-detecting endoscopists. Variations in rate of endoscopic detection of serrated polyps indicate the need for careful examination, with adequate bowel preparation and sufficient withdrawal times. Risk factors for SSLs include white race, family history of colorectal cancer, smoking, and alcohol intake. Patients with serrated polyps, particularly SSLs and traditional serrated adenomas, have an increased risk of synchronous and metachronous advanced neoplasia. Surveillance guidelines vary among countries, but SSLs and proximal hyperplastic polyps require special attention in assignment of surveillance interval-especially in light of concerns regarding incomplete detection and resection.
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Affiliation(s)
- Seth D Crockett
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
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Villanacci V, Baronchelli C, Manenti S, Bassotti G, Salviato T. Serrated lesions of the colon A window on a more clear classification. Ann Diagn Pathol 2019; 41:8-13. [PMID: 31112900 DOI: 10.1016/j.anndiagpath.2019.05.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 05/11/2019] [Indexed: 01/26/2023]
Abstract
Serrated polyps evaluation represents a challenge for pathologists for lacking of univocal criteria that leads to different inter -individual interpretation. The aim of our review is to offer an alternative simpler histologic and endoscopic approach to these lesions for a more correct relationship between endoscopists and pathologists.
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Affiliation(s)
| | | | | | - Gabrio Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia, Italy
| | - Tiziana Salviato
- Pathology Institute, Azienda Ospedaliera Universitaria, Ospedali Riuniti di Trieste, Trieste, Italy.
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McCarthy AJ, Serra S, Chetty R. Traditional serrated adenoma: an overview of pathology and emphasis on molecular pathogenesis. BMJ Open Gastroenterol 2019; 6:e000317. [PMID: 31413858 PMCID: PMC6673762 DOI: 10.1136/bmjgast-2019-000317] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/02/2019] [Accepted: 07/08/2019] [Indexed: 12/21/2022] Open
Abstract
Objective To provide an overview of the pathology and molecular pathogenesis of traditional serrated adenomas (TSA). Design Describe the morphology and molecules that play a role in their pathogenesis. Results These exuberant polypoid lesions are typified by tall cells with deeply eosinophilic cytoplasm, elongated nuclei bearing delicate chromatin, ectopic crypt foci, deep clefting of the lining mucosa and an overall resemblance to small bowel mucosa. Broadly, TSAs arise via three mechanisms. They may be BRAF mutated and CpG island methylator phenotype (CIMP)-high: right sided, mediated through a microvesicular hyperplastic polyp or a sessile serrated adenoma, may also have RNF43 mutations and result in microsatellite stable (MSS) colorectal cancers (CRC). The second pathway that is mutually exclusive of the first is mediated through KRAS mutation with CIMP-low TSAs. These are left-sided TSAs, are not associated with another serrated polyp and result in MSS CRC. These TSAs also have RSPO3, RNF43 and p53 mutations together with aberrant nuclear localisation of β-catenin. Third, there is a smaller group of TSAs that are BRAF and KRAS wild type and arise by as yet unknown molecular events. All TSAs show retention of mismatch repair proteins. Conclusion These are characteristic unusual polyps with a complex molecular landscape.
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Affiliation(s)
- Aoife J McCarthy
- Division of Anatomical Pathology, Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Ontario, Canada
| | - Stefano Serra
- Division of Anatomical Pathology, Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Ontario, Canada
| | - Runjan Chetty
- Division of Anatomical Pathology, Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Ontario, Canada
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Abstract
GOALS To provide preliminary evidence that sessile serrated adenomas (SSA) are low-risk polyps in young patients. BACKGROUND SSAs are the dominant polyp of the serrated neoplasia pathway and as such are the precursor of up to 20% of colorectal carcinomas (CRC). Up to 90% of these cancers are expected to harbor a BRAF mutation. SSAs are being diagnosed with increasing frequency in young patients, placing a significant burden on colonoscopic services. Evidence to direct the surveillance intervals for these young patients is not available. STUDY We utilized 2 patient cohorts comprising (1) a consecutive series of patients who underwent outpatient colonoscopy through a tertiary hospital and (2) a consecutive series of resection specimens for CRC processed through a gastrointestinal pathology service. The prevalence of SSAs by age was determined in the patients undergoing colonoscopy and compared with the ages of patients with BRAF mutated CRC in the pathology series. RESULTS The prevalence of SSAs was similar irrespective of age. By comparison, BRAF mutated CRCs were very rare (3.8% of cases) in patients younger than 50 years of age and uncommon (9.3% of cases) in patients younger than 60 years of age, but increased to 39.8% in patients older than 80 years of age. CONCLUSIONS These results suggest that SSAs develop at a young age, but have a prolonged dwell time and are unlikely to develop into cancer in patients younger than 60 years of age. These findings highlight the need for further targeted research to determine the most appropriate surveillance intervals for young patients with sporadic SSAs.
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Wan XB, Wang AQ, Cao J, Dong ZC, Li N, Yang S, Sun MM, Li Z, Luo SX. Relationships among KRAS mutation status, expression of RAS pathway signaling molecules, and clinicopathological features and prognosis of patients with colorectal cancer. World J Gastroenterol 2019; 25:808-823. [PMID: 30809081 PMCID: PMC6385012 DOI: 10.3748/wjg.v25.i7.808] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/17/2019] [Accepted: 01/21/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase (MAPK) signaling pathways, Mutations in any one of the upstream genes (such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer (CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.
AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis
METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF, MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots, and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.
RESULTS Of the 196 patients, 62 (32%) carried mutations in codon 12 (53/62) or codon 13 (9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues, respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis (P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors (P < 0.05), whereas BRAF, MEK, and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence (P < 0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.
CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC. KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.
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Affiliation(s)
- Xiang-Bin Wan
- Department of General Surgery, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, China
| | - Ai-Qin Wang
- Department of Pharmacy, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang 453002, Henan Province, China
| | - Jian Cao
- Department of General Surgery, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, China
| | - Zhi-Chuang Dong
- Department of General Surgery, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, China
| | - Ning Li
- Department of Medical Oncology, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, China
| | - Sen Yang
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China
| | - Miao-Miao Sun
- Department of Pathology, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, China
| | - Zhi Li
- Department of General Surgery, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, China
| | - Su-Xia Luo
- Department of Medical Oncology, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, China
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Colorectal Serrated Neoplasia: An Institutional 12-Year Review Highlights the Impact of a Screening Programme. Gastroenterol Res Pract 2019; 2019:1592306. [PMID: 30881445 PMCID: PMC6381559 DOI: 10.1155/2019/1592306] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/17/2018] [Accepted: 01/06/2019] [Indexed: 01/26/2023] Open
Abstract
Background As the malignant potential of sessile serrated lesions/polyps (SSL/Ps) and traditional serrated adenomas (TSAs) has been clearly demonstrated, it is important that serrated polyps are identified and correctly classified histologically. Aim Our aim was to characterize the clinicopathological features of a series of SSL/Ps & TSAs, to assess the accuracy of the pathological diagnosis, the incidence, and the rate of dysplasia in SSL/Ps & TSAs. Methods We identified all colorectal serrated polyps between 01/01/2004 and 31/05/2016, by searching the laboratory information system for all cases assigned a “serrated adenoma” SNOMED code. All available and suitable slides were reviewed by one pathologist, who was blinded to the original diagnosis and the site of the polyp. Subsequently discordant cases, SSL/Ps with dysplasia, and all TSAs were reviewed by a second pathologist. Results Over a 149-month period, 759 “serrated adenoma” polyps were identified, with 664 (from 523 patients) available for review. 41.1% were reviewed by both pathologists; 15.1% (100/664) were reclassified, with the majority being changed from SSL/P to hyperplastic polyp (HYP) (66/664; 9.9%). 80.3% of these HYPs were located in the left colon, and the majority exhibited prolapse effect. There were 520 SSL/Ps (92.2%) & 40 TSAs (7.1%). The majority of SSL/Ps were in the right colon (86.7%) and were small (64.5% <1 cm), while most TSAs were in the left colon (85.7%) and were large (73.1%≥1 cm). 6.7% of SSL/Ps exhibited dysplasia, the majority of which were large (66.7%≥1 cm). Following consensus review, 13/520 (2.5%) SSL/Ps were downgraded from SSL/P with dysplasia to SSL/P without dysplasia. Detection of SSL/Ps peaked in the most recent years reviewed (87.5% reported between 2013 and 2016, inclusive), coinciding with the introduction of “BowelScreen” (the Irish FIT-based colorectal cancer screening programme). Conclusions Awareness of, and adherence to, diagnostic criteria is essential for accurate classification of colorectal polyps.
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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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Aspects of the Natural History of Sessile Serrated Adenomas/Polyps: Risk Indicators for Carcinogenesis in the Colorectal Mucosa? Dis Colon Rectum 2018; 61:1380-1385. [PMID: 30346367 DOI: 10.1097/dcr.0000000000001208] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Sessile serrated adenomas/polyps are potentially premalignant colorectal lesions that are precursors to colorectal cancer arising via CpG island methylator phenotype. They are caused by the combination of a BRAF mutation and promoter hypermethylation. DNA methylation is an age-dependent phenomenon in the right colon, and we would expect the occurrence and severity of serrated neoplasia to reflect this. OBJECTIVE The purpose of this study was to document the natural history of sessile serrated adenomas/polyps, including the ages at which they appear and the ranges of their number, size, and associated lesions. DESIGN This was a retrospective cohort study. SETTINGS The study was conducted at a tertiary referral center. PATIENTS Consecutive patients with sessile serrated adenomas/polyps removed between 2006 and 2015 were included. Patients with IBD, familial adenomatous polyposis, Lynch syndrome, serrated polyposis, and hereditary nonpolyposis colorectal cancer were excluded. MAIN OUTCOME MEASURES Age at which polyps were first diagnosed, location and size of polyps, demographics, and family history were measured. RESULTS A total of 440 patients had 668 sessile serrated adenomas/polyps, 257 (58%) also had ≥1 adenoma, and 28 (6%) had a history of colorectal cancer. Mean age at diagnosis was 68 ± 11 years, and 45% were men. Two hundred had had ≥1 colonoscopy before the diagnosis of the first sessile serrated adenomas/polyps. A total of 136 patients (31%) had multiple sessile serrated adenomas/polyps, including 24% synchronous and 10% metachronous. The range of total cumulative sessile serrated adenomas/polyps was from 1 to 7. A total of 554 (83%) of 668 sessile serrated adenomas/polyps were right sided; 48% were ≥1 cm diameter and 22% were >2 cm. The size of the first sessile serrated adenomas/polyps in those diagnosed under age 50 years averaged 10 mm, those between 50 and 60 years averaged 12 mm, and those between 60 and 70 years averaged 12 mm. LIMITATIONS No measurement of methylation or BRAF mutations in polyps or normal mucosa and a lack of subclassification of hyperplastic polyps limited this study. CONCLUSIONS The age of onset of sessile serrated adenomas/polyps varies, but the pattern is consistent with increasing methylation in the mucosa. Early negative colonoscopies predict a low risk of methylator cancers. See Video Abstract at http://links.lww.com/DCR/A736.
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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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Kim SY, Kim TI. Serrated neoplasia pathway as an alternative route of colorectal cancer carcinogenesis. Intest Res 2018; 16:358-365. [PMID: 30090034 PMCID: PMC6077295 DOI: 10.5217/ir.2018.16.3.358] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 05/28/2018] [Accepted: 05/29/2018] [Indexed: 01/10/2023] Open
Abstract
In the past two decades, besides conventional adenoma pathway, a subset of colonic lesions, including hyperplastic polyps, sessile serrated adenoma/polyps, and traditional serrated adenomas have been suggested as precancerous lesions via the alternative serrated neoplasia pathway. Major molecular alterations of sessile serrated neoplasia include BRAF mutation, high CpG island methylator phenotype, and escape of cellular senescence and progression via methylation of tumor suppressor genes or mismatch repair genes. With increasing information of the morphologic and molecular features of serrated lesions, one major challenge is how to reflect this knowledge in clinical practice, such as pathologic and endoscopic diagnosis, and guidelines for treatment and surveillance.
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Affiliation(s)
- Soon Young Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Il Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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Pyo JH, Ha SY, Hong SN, Chang DK, Son HJ, Kim KM, Kim H, Kim K, Kim JE, Choi YH, Kim YH. Identification of risk factors for sessile and traditional serrated adenomas of the colon by using big data analysis. J Gastroenterol Hepatol 2018; 33:1039-1046. [PMID: 29087626 DOI: 10.1111/jgh.14035] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 10/23/2017] [Accepted: 10/24/2017] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM Little is known about the risk factors associated with serrated polyps, because the early studies, which occurred before the new World Health Organization classification was introduced, included mixtures of serrated polyps. This study aimed to evaluate the risk factors associated with the presence of sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs) using big data analytics. METHODS Using a case-control design, we evaluated the risk factors associated with the presence of SSAs and TSAs. Subjects who underwent colonoscopies from 2002 to 2012 as part of the comprehensive health screening programs undertaken at the Samsung Medical Center, Korea, participated in this study. RESULTS Of the 48 677 individuals who underwent colonoscopies, 183 (0.4%) had SSAs and 212 (0.4%) had TSAs. The multivariate analysis determined that being aged ≥ 50 years (odds ratio [OR] 1.91, 95% confidential interval [CI] 1.27-2.90, P = 0.002) and a history of colorectal cancer among first-degree relatives (OR 3.14, 95% CI 1.57-6.27, P = 0.001) were significant risk factors associated with the presence of SSAs and that being aged ≥ 50 years (OR 2.61, 95% CI 1.79-3.80, P < 0.001), obesity (OR 1.63, 95% CI 1.12-2.36, P = 0.010), and a higher triglyceride level (OR 1.63, 95% CI 1.12-2.36, P = 0.010) were independent risk factors associated with the presence of TSAs. CONCLUSIONS We used big data analytics to determine the risk factors associated with the presence of specific polyp subgroups, and individuals who have these risk factors should be carefully scrutinized for the presence of SSAs or TSAs during screening colonoscopies.
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Affiliation(s)
- Jeung Hui Pyo
- Center for Health Promotion, Samsung Medical Center, Seoul, Korea
| | - Sang Yun Ha
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Noh Hong
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Kyung Chang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Jung Son
- Center for Health Promotion, Samsung Medical Center, Seoul, Korea.,Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyeseung Kim
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Kyunga Kim
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Jee Eun Kim
- Center for Health Promotion, Samsung Medical Center, Seoul, Korea
| | - Yoon-Ho Choi
- Center for Health Promotion, Samsung Medical Center, Seoul, Korea.,Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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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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Liu TY, Jin DC, Khan S, Chen X, Shi T, Dong WX, Qi YR, Guo ZX, Wang BM, Cao HL. Clinicopathological features of advanced colorectal serrated lesions: A single-center study in China. J Dig Dis 2018. [PMID: 29542866 DOI: 10.1111/1751-2980.12589] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE A growing body of evidence indicates that patients with colorectal serrated lesions, especially advanced serrated lesions (ASLs), are at risk of subsequent malignancy. This study aimed to analyze the clinicopathological features of ASLs and the association between ASLs and synchronous advanced colorectal neoplasia (sACN) in a single center of China. METHODS A retrospective cross-sectional study of consecutive symptomatic patients and healthy individuals who underwent colonoscopy between January 2010 and March 2016 was performed. Clinicopathological characteritics of the patients with ASLs were documented from the colonoscopy database. RESULTS Colorectal serrated lesions were pathologically confirmed in 277 (N = 38 981, 0.7%) cases. Among them, 156 (56.3%) were found to have ASLs, with a total of 161 lesions including 71 sessile serrated adenoma/polyps (SSA/P) and 90 traditional serrated adenomas (TSAs). There were no differences in age and gender between the ASL and non-ASL patients. Among the 161 ASLs, 29 (18.0%) were ≥10 mm in diameter. Compared with non-ASLs, ASLs appeared more in the proximal colon (P = 0.007). Flat and subpedunculated lesions were more commonly found in the ASL group compared with the non-ASL group. Nearly all ASLs (160/161) had dysplasia. Moreover, 16 sACN lesions were found in 156 ASL patients, and large diameter (≥10 mm) might be a significant risk factor for sACN (odds ratio 4.35, 95% confidence interval 1.467-12.894, P < 0.05). CONCLUSIONS ASLs are more likely to occur in the proximal colon, and mainly present as flat and sub-pedunculated types. Large ASLs are significantly associated with sACN.
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Affiliation(s)
- Tian Yu Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Duo Chen Jin
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Samiullah Khan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Xue Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Tao Shi
- Department of Pathology, Tianjin Medical University General Hospital, Tianjin, China
| | - Wen Xiao Dong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Yan Rong Qi
- Department of Gastroenterology and Hepatology, Tianjin Haibin People's Hospital, Tianjin, China
| | - Zi Xuan Guo
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Bang Mao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Hai Long Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
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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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Tate DJ, Jayanna M, Awadie H, Desomer L, Lee R, Heitman SJ, Sidhu M, Goodrick K, Burgess NG, Mahajan H, McLeod D, Bourke MJ. A standardized imaging protocol for the endoscopic prediction of dysplasia within sessile serrated polyps (with video). Gastrointest Endosc 2018; 87:222-231.e2. [PMID: 28713060 DOI: 10.1016/j.gie.2017.06.031] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Accepted: 06/26/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Dysplasia within sessile serrated polyps (SSPs) is difficult to detect and may be mistaken for an adenoma, risking incomplete resection of the background serrated tissue, and is strongly implicated in interval cancer after colonoscopy. The use of endoscopic imaging to detect dysplasia within SSPs has not been systematically studied. METHODS Consecutively detected SSPs ≥8 mm in size were evaluated by using a standardized imaging protocol at a tertiary-care endoscopy center over 3 years. Lesions suspected as SSPs were analyzed with high-definition white light then narrow-band imaging. A demarcated area with a neoplastic pit pattern (Kudo type III/IV, NICE type II) was sought among the serrated tissue. If this was detected, the lesion was labeled dysplastic (sessile serrated polyp with dysplasia); if not, it was labeled non-dysplastic (sessile serrated polyp without dysplasia). Histopathology was reviewed by 2 blinded specialist GI pathologists. RESULTS A total of 141 SSPs were assessed in 83 patients. Median lesion size was 15.0 mm (interquartile range 10-20), and 54.6% were in the right side of the colon. Endoscopic evidence of dysplasia was detected in 36 of 141 (25.5%) SSPs; of these, 5 of 36 (13.9%) lacked dysplasia at histopathology. Two of 105 (1.9%) endoscopically designated non-dysplastic SSPs had dysplasia at histopathology. Endoscopic imaging, therefore, had an accuracy of 95.0% (95% confidence interval [CI], 90.1%-97.6%) and a negative predictive value of 98.1% (95% CI, 92.6%-99.7%) for detection of dysplasia within SSPs. CONCLUSIONS Dysplasia within SSPs can be detected accurately by using a simple, broadly applicable endoscopic imaging protocol that allows complete resection. Independent validation of this protocol and its dissemination to the wider endoscopic community may have a significant impact on rates of interval cancer. (Clinical trial registration number: NCT03100552.).
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Affiliation(s)
- David J Tate
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia; Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
| | - Mahesh Jayanna
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia
| | - Halim Awadie
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia
| | - Lobke Desomer
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia
| | - Ralph Lee
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia
| | - Steven J Heitman
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia
| | - Mayenaaz Sidhu
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia
| | - Kathleen Goodrick
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia
| | - Nicholas G Burgess
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia; Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
| | - Hema Mahajan
- Institute of Clinical Pathology and Medical Research, Department of Pathology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Duncan McLeod
- Institute of Clinical Pathology and Medical Research, Department of Pathology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Michael J Bourke
- Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia; Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
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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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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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