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Brown I, Bettington M. Sporadic Polyps of the Colorectum. Gastroenterol Clin North Am 2024; 53:155-177. [PMID: 38280746 DOI: 10.1016/j.gtc.2023.10.002] [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] [Indexed: 01/29/2024]
Abstract
Colorectal polyps are common, and their diagnosis and classification represent a major component of gastrointestinal pathology practice. The majority of colorectal polyps represent precursors of either the chromosomal instability or serrated neoplasia pathways to colorectal carcinoma. Accurate reporting of these polyps has major implications for surveillance and thus for cancer prevention. In this review, we discuss the key histologic features of the major colorectal polyps with a particular emphasis on diagnostic pitfalls and areas of contention.
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Affiliation(s)
- Ian Brown
- Envoi Pathology, Brisbane; Pathology Queensland, Royal Brisbane and Women's Hospital Cnr Herston and Bowen Bridge Roads, Herston Qld 4006, Australia; University of Queensland, St Lucia, Qld 4072, Australia.
| | - Mark Bettington
- Envoi Pathology, Brisbane; University of Queensland, St Lucia, Qld 4072, Australia; Queensland Institute of Medical Research, 300 Herston Road, Herston QLD 4006, 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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MORPHOLOGICAL AND MOLECULAR CHARACTERIZATION OF COLORECTAL SESSILE SERRATED LESIONS WITH DYSPLASIA. Pathol Res Pract 2022; 240:154214. [PMID: 36395596 DOI: 10.1016/j.prp.2022.154214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/08/2022] [Accepted: 11/08/2022] [Indexed: 11/10/2022]
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Yılmaz O, Crabbe A, Neyaz A, Pankaj A, Lee SH, Hosseini S, Rickelt S, Cerda S, Zhao G, Leijsen L, Dineaux A, Shroff SG, Crotty R, Zhang ML, Yilmaz OH, Patil DT, Berger D, Deshpande V. Clinical, Pathologic, Genetics and Intratumoral Immune Milieu of Serrated Adenocarcinoma of the Colon. Histopathology 2022; 81:380-388. [PMID: 35789111 DOI: 10.1111/his.14719] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/21/2022] [Accepted: 07/02/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Serrated adenocarcinoma (SAC), a recognized WHO variant of colonic adenocarcinoma, is the purported end-product of serrated neoplasia. Yet, the diagnosis of SAC is infrequently rendered, and little is known about its prognosis, immune microenvironment, and molecular alterations. MATERIALS AND METHODS We assessed 903 consecutive colon carcinomas and recognized tumors with ≥5% (n=77) serrated pattern, and ≥50% serrated pattern (n=13). We assessed precursor polyps and synchronous polyps. We recorded demographic/clinical parameters, histological features, and MMR status. We performed immunohistochemistry and quantification on tissue microarray for HLA class I/II proteins, beta-2-microglobulin (B2MG), CD8, CD163, LAG3, PD-L1, FoxP3, PD-L1and BRAF V600E. RESULTS We identified ≥ 5% epithelial serration prevalence in 8.5% of cases, and ≥50% epithelial serration prevalence in 1.4% of cases. Precursor lesions were present in 21.4% of cases; these were mostly tubular adenomas with two traditional serrated adenoma identified. SAC with ≥ 5% serrations exhibited lower numbers of CD8 positive lymphocytes (p=0.002) and lower B2MG expression (p=0.048), although neither value was significant at ≥50% serration threshold. There was no difference in HLA class I/II, or PD-L1 expression on tumor cells and no difference in PD-L1, LAG3, FOXP3 and CD163 expression on immune cells. There was no association with MMR status, or BRAFV600E relative to conventional adenocarcinoma. There was improved disease-specific survival on univariate (but not multivariate) analysis between carcinomas with serrated pattern and non-mucinous conventional colonic carcinomas at ≥5% epithelial serrations (p=0.04). CONCLUSION SAC category shows a limited impact on survival, and this phenotype may harbor a unique immunologic milieu.
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Affiliation(s)
- Osman Yılmaz
- Department of Pathology, Boston Medical Center, Boston
| | - Andrew Crabbe
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Azfar Neyaz
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Amaya Pankaj
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Soo Hyun Lee
- Department of Pathology, Boston Medical Center, Boston
| | - Sahar Hosseini
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Steffen Rickelt
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Sandra Cerda
- Department of Pathology, Boston Medical Center, Boston
| | - Grace Zhao
- Department of Pathology, Boston Medical Center, Boston
| | - Lieve Leijsen
- Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Anne Dineaux
- Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Stuti G Shroff
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Rory Crotty
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - M Lisa Zhang
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Omer H Yilmaz
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Deepa T Patil
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - David Berger
- Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
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Lamba M, Brown I, Bettington M, Ryan K, Hanigan K, Lasenby K, Dixon A, Grimpen F, Gan C, Tutticci N, Appleyard M, Leggett B. Clinicopathological Correlates of Dysplastic Sessile Serrated Lesion: A Prospective Cohort Study With a High Detection Rate. GASTRO HEP ADVANCES 2022; 1:313-320. [PMID: 39131677 PMCID: PMC11308794 DOI: 10.1016/j.gastha.2021.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/27/2021] [Indexed: 08/13/2024]
Abstract
Background and Aims Sessile serrated lesions (SSLs) develop colorectal cancer (CRC), through a critical intermediary stage of SSL with dysplasia (SSLd). In this prospective observational study, we aimed to assess clinicopathological correlates of SSLd in the setting of a high lesion-detection rate. Methods Patients diagnosed with SSL and SSLd from February 2018 until January 2020 were prospectively recruited, and SSLd specimens were re-evaluated by 2 expert pathologists in a blinded manner. Associations were analyzed using multivariate logistic regression models. Results A total of 6425 patients underwent 7423 colonoscopies, and 2671 SSLs were resected from 1047 patients. The overall SSL detection rate per colonoscopy was 15.9%. The median age of patients with SSL was 54 years (interquartile range, 39-66), and 43.3% were male. After pathologist review, 24 SSLds were confirmed in 20 patients. The median size of SSLd was 8 mm (interquartile range, 5.75-15.25), and 13 of 24 SSLds were <10 mm in size. After multivariate analysis, older age (odds ratio = 1.07, 95% confidence interval = 1.03-1.1) and higher number of synchronous SSLs (odds ratio = 1.12, 95% confidence interval = 1.02-1.23) were associated with the presence of dysplasia. Patient sex and number and size of synchronous adenomas were not associated with the presence of SSLd. Seven of 20 patients with SSLd had synchronous or metachronous SSLd. Six of 20 patients with SSLd met the diagnostic criteria for serrated polyposis syndrome. Conclusion The overall SSL detection rate was 15.9%, and 0.9% of SSLs were dysplastic. Older age and higher number of synchronous SSL were risk factors for the presence of dysplasia in SSLs. Thirty percent of patients with SSLd had serrated polyposis syndrome, and 35% had multiple SSLd.
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Affiliation(s)
- Mehul Lamba
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Ian Brown
- Department of Pathology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- Envoi Specialists Pathologists, Brisbane, Queensland, Australia
| | - Mark Bettington
- Envoi Specialists Pathologists, Brisbane, Queensland, Australia
| | - Kimberley Ryan
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Katherine Hanigan
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Kay Lasenby
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Alicia Dixon
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Florian Grimpen
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Chun Gan
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Nicholas Tutticci
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Mark Appleyard
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Barbara Leggett
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- The School of Medicine, University of Queensland, Brisbane, Australia
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Batts KP, Cinnor B, Kim A, Stickney E, Burgart LJ. Sessile Serrated Adenoma With Dysplasia of the Colon. Am J Clin Pathol 2022; 157:180-195. [PMID: 34542560 DOI: 10.1093/ajcp/aqab112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/01/2021] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Sessile serrated adenomas with dysplasia (SSADs) of the colon are transitional lesions between sessile serrated adenomas (SSAs) and a subset of colorectal adenocarcinomas. We wished to gain insight into the relative percentages and significance of SSAD subtypes. METHODS Retrospective (2007-2012) clinicopathologic review of colorectal polyps initially regarded as having mixed serrated and dysplastic elements. SSADs were subdivided into those with cap-like adenomatous dysplasia (ad1), non-cap-like adenomatous dysplasia (ad2), serrated dysplasia (ser), minimal dysplasia (min), and dysplasia not otherwise specified (nos). MLH1 immunostaining was performed on many. RESULTS SSADser (7.7%) had a greater propensity for right colon, women, and MLH1 loss vs the entire cohort. SSAad1 (11.6%) had the least female preponderance, was least likely to have MLH1 loss, and was most likely to affect the left colorectum. SSAD with MLH1 loss was associated with an increased burden of SSAs in the background colon (P = .0003) but not tubular adenomas or hyperplastic polyps. Most SSADs (ad2 and nos groups, 80% combined) showed difficult-to-classify dysplasia, intermediate MLH1 loss rates, and intermediate clinical features. CONCLUSIONS While some trends exist, morphologically subclassifying SSADs is probably not justified in routine clinical practice. MLH1 loss portends a greater burden of SSAs in the background colon.
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Affiliation(s)
| | | | - Adam Kim
- MNGI Digestive Health, Minneapolis, MN, USA
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Kane AM, Liu C, Akhter DT, McKeone DM, Bell CA, Thurecht KJ, Leggett BA, Whitehall VLJ. Curcumin Chemoprevention Reduces the Incidence of Braf Mutant Colorectal Cancer in a Preclinical Study. Dig Dis Sci 2021; 66:4326-4332. [PMID: 33387125 DOI: 10.1007/s10620-020-06752-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/26/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Colorectal cancer is a leading cause of cancer-related death worldwide and approximately 20% of cases can be attributed to a mutation in the BRAF oncogene. Curcumin is a promising chemopreventive agent with various anti-cancer benefits. Although curcumin has been reported to have poor bioavailability, this limitation has been overcome by the formulation of nano-carriers. In this preclinical study, we investigated the ability of an improved formulation of curcumin to reduce the incidence of Braf mutant carcinoma. AIM To investigate curcumin as a chemopreventive for Braf mutant colorectal cancer in a preclinical study utilizing a murine model of serrated neoplasia. METHODS An intestine-specific Braf mutant murine model (BrafV637E/+/Villin-CreERT2/+) was administered curcumin micelles (240 mg/kg, n = 69) in normal drinking water. Mice in the control group consumed normal drinking water (n = 83). Mice were euthanized at 14 months and the incidence of murine serrated lesions and carcinoma in each cohort were determined by histologic examination. RESULTS At completion of the study (14 months), it was found that curcumin did not reduce the incidence or multiplicity of murine serrated lesions but did significantly reduce the number of invasive carcinomas (RR 0.83, 95% CI 0.69-0.9985, P = 0.0360) compared to control. CONCLUSIONS We have performed the first long-term study assessing curcumin's effect on the development of serrated neoplasia. We found that curcumin significantly reduces the risk of developing Braf mutant colorectal cancer. Our data supports further investigation of curcumin as a chemopreventive to reduce the risk of colorectal cancer arising via the serrated pathway.
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Affiliation(s)
- Alexandra M Kane
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. .,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. .,Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, QLD, Australia.
| | - Cheng Liu
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Dewan T Akhter
- Centre for Advanced Imaging, Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence in Bio-Nano Science and Technology, The University of Queensland, Brisbane, QLD, Australia
| | - Diane M McKeone
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Craig A Bell
- Centre for Advanced Imaging, Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence in Bio-Nano Science and Technology, The University of Queensland, Brisbane, QLD, Australia
| | - Kristofer J Thurecht
- Centre for Advanced Imaging, Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence in Bio-Nano Science and Technology, The University of Queensland, Brisbane, QLD, Australia.,ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Brisbane, QLD, Australia
| | - Barbara A Leggett
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Department of Gastroenterology and Hepatology, The Royal Brisbane and Women's Hospital, Queensland Health, Brisbane, QLD, Australia
| | - Vicki L J Whitehall
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, QLD, Australia
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Tan YY, Tay GSK, Wong YJ, Li JW, Kwek ABE, Ang TL, Wang LM, Tan MTK. Clinical Features and Predictors of Dysplasia in Proximal Sessile Serrated Lesions. Clin Endosc 2021; 54:578-588. [PMID: 33915614 PMCID: PMC8357591 DOI: 10.5946/ce.2020.198] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 12/11/2020] [Indexed: 02/05/2023] Open
Abstract
Background/Aims Proximal colorectal cancers (CRCs) account for up to half of CRCs. Sessile serrated lesions (SSLs) are precursors to CRC. Proximal location and presence of dysplasia in SSLs predict higher risks of progression to cancer. The prevalence of dysplasia in proximal SSLs (pSSLs) and clinical characteristics of dysplastic pSSLs are not well studied.
Methods Endoscopically resected colonic polyps at our center between January 2016 and December 2017 were screened for pSSLs. Data of patients with at least one pSSL were retrieved and clinicopathological features of pSSLs were analysed. pSSLs with and without dysplasia were compared for associations.
Results Ninety pSSLs were identified, 45 of which had dysplasia giving a prevalence of 50.0%. Older age (65.9 years vs. 60.1 years, p=0.034) was associated with the presence of dysplasia. Twelve pSSLs were 10 mm or larger. After adjusting for age, pSSLs ≥10 mm had an adjusted odds ratio of 5.98 (95% confidence interval, 1.21–29.6) of having dysplasia compared with smaller pSSLs.
Conclusions In our cohort of pSSLs, the prevalence of dysplasia is high at 50.0% and is associated with lesion size ≥10 mm. Endoscopic resection for all proximal serrated lesions should be en bloc to facilitate accurate histopathological examination for dysplasia as its presence warrants shorter surveillance intervals.
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Affiliation(s)
- Yi Yuan Tan
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore
| | - Gary Sei Kiat Tay
- Department of Pathology, Changi General Hospital, Singapore, Singapore
| | - Yu Jun Wong
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - James Weiquan Li
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Andrew Boon Eu Kwek
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tiing Leong Ang
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Lai Mun Wang
- Department of Pathology, Changi General Hospital, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Pathology Academic Clinical Programme, SingHealth Duke-NUS Medical School, Singapore, Singapore
| | - Malcolm Teck Kiang Tan
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Booth AL, Taggart MW, Ono Y, Gonzalez RS. From Mixed Hyperplastic/Adenomatous Polyp to Sessile Serrated Lesion: A Long and Winding Road for Long and Winding Crypts. Arch Pathol Lab Med 2020; 145:1289-1296. [PMID: 33351878 DOI: 10.5858/arpa.2020-0591-ra] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— During the past 3 decades, numerous articles in the literature have offered terminology, diagnostic criteria, and consensus recommendations regarding the entity currently referred to by the World Health Organization as sessile serrated lesion. Given the many names and various, variably reproducible diagnostic criteria ascribed to sessile serrated lesion, confusion persists for many pathologists and gastroenterologists regarding the diagnosis. This distinction is important, as sessile serrated lesion can progress to malignancy, unlike its main differential diagnosis, hyperplastic polyp. Research studies have shed light on the characteristic architecture and morphology, immunohistochemical patterns, and molecular alterations of sessile serrated lesion, and multiple consensus meetings around the globe have developed their criteria and nomenclature, often clashing or mixing terms. OBJECTIVE.— To provide a narrative review from the entity's early description to our current understanding. DATA SOURCES.— The existing scientific and clinical literature, published texts, medical society recommendations, and specialty consensus guidelines. CONCLUSIONS.— The current World Health Organization criteria are a distillation of this scientific process, but terminology is still a point of contention worldwide.
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Affiliation(s)
- Adam L Booth
- From the Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Booth, Ono, Gonzalez)
| | - Melissa W Taggart
- The Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston (Taggart)
| | - Yuho Ono
- From the Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Booth, Ono, Gonzalez)
| | - Raul S Gonzalez
- From the Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Booth, Ono, Gonzalez)
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Colonoscopy and Reduction of Colorectal Cancer Risk by Molecular Tumor Subtypes: A Population-Based Case-Control Study. Am J Gastroenterol 2020; 115:2007-2016. [PMID: 32858564 DOI: 10.14309/ajg.0000000000000819] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION In previous studies, the protective effect of colonoscopy was generally stronger for distal colorectal cancer than for proximal colorectal cancer (CRC). This study aimed to investigate whether reduction of CRC risk through colonoscopy varies according to major tumor markers and pathways of CRC. METHODS This is a population-based case-control study from Germany, including 2,132 patients with a first diagnosis of CRC and information on major molecular tumor markers and 2,486 control participants without CRC. Detailed participant characteristics were collected by standardized questionnaires. Information on previous colonoscopy was derived from medical records. Polytomous logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between previous colonoscopy and subtypes of CRC. RESULTS Overall, we observed strong risk reduction of CRC after colonoscopy that was weaker for microsatellite instable (MSI) than for non-MSI CRC (OR 0.70, 95% CI 0.50-0.97 vs OR 0.28, 95% CI 0.24-0.33), for CpG island methylator phenotype high CRC than for CpG island methylator phenotype low/negative CRC (OR 0.45, 95% CI 0.34-0.59 vs OR 0.29, 95% CI 0.25-0.34), for BRAF-mutated than for BRAF nonmutated CRC (OR 0.62, 95% CI 0.42-0.91 vs OR 0.30, 95% CI 0.25-0.35), for KRAS nonmutated than for KRAS-mutated CRC (OR 0.34, 95% CI 0.29-0.40 vs OR 0.26, 95% CI 0.20-0.32), and for CRC classified into the sessile serrated pathway than for CRC of the traditional pathway (OR 0.57, 95% CI 0.36-0.91 vs OR 0.30, 95% CI 0.25-0.37). After colonoscopy with the detection of adenomas or hyperplastic polyps, no risk reduction was found for sessile serrated pathway CRC, MSI, and BRAF-mutated subtypes. DISCUSSION Our study extends the molecular understanding of existing differences in risk reduction of proximal and distal CRCs reported by previous studies and may imply important information for improving strategies for timely detection of relevant precursors.
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Anderson JC, Srivastava A. Colorectal Cancer Screening for the Serrated Pathway. Gastrointest Endosc Clin N Am 2020; 30:457-478. [PMID: 32439082 DOI: 10.1016/j.giec.2020.02.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Serrated polyps are classified into hyperplastic polyps, sessile serrated adenomas/polyps, and traditional serrated adenomas. Although all serrated polyps share characteristic colonic crypts serrations, distinguishing hyperplastic polyps from sessile serrated adenomas/polyps is challenging. Traditional serrated adenomas are cytologically dysplastic lesions; sessile serrated adenomas/polyps develop cytologic dysplasia as they progress to colorectal cancer. A flat and pale appearance of serrated polyps may make detection difficult. Endoscopic mucosal resection has higher rates of complete resection. Close surveillance is recommended for sessile serrated adenomas/polyps, sessile serrated adenomas/polyp with dysplasia, hyperplastic polyps ≥10 mm, and traditional serrated adenomas.
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Affiliation(s)
- Joseph C Anderson
- Department of Veterans Affairs Medical Center, White River Junction, VT, USA; The Geisel School of Medicine at Dartmouth, 1 Rope Ferry Road, Hanover, NH 03755, USA; Division of Gastroenterology and Hepatology, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
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Hua X, Newcomb PA, Chubak J, Malen RC, Ziebell R, Kamineni A, Zhu LC, Upton MP, Wurscher MA, Thomas SS, Newman H, Hardikar S, Burnett-Hartman AN. Associations between molecular characteristics of colorectal serrated polyps and subsequent advanced colorectal neoplasia. Cancer Causes Control 2020; 31:631-640. [PMID: 32358694 DOI: 10.1007/s10552-020-01304-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 04/24/2020] [Indexed: 02/08/2023]
Abstract
PURPOSE BRAF mutation and DNA hypermethylation have linked sessile serrated adenomas/polyps (SSA/Ps) to serrated colorectal cancer (CRC) in cross-sectional studies, but they have not been evaluated in a longitudinal study. We aimed to evaluate the associations between molecular markers of serrated polyps and subsequent advanced colorectal neoplasia. METHODS Study subjects included Kaiser Permanente Washington members aged 20-75 years who received an index colonoscopy between 1/1/1998 and 12/31/2007 and had hyperplastic polyps (HPs) or SSA/Ps according to study pathology review. Polyps from index colonoscopies were removed and assayed for BRAF mutation, CpG island methylator phenotype (CIMP), and MLH1 methylation. Pathology reports and biopsies from the subsequent lower gastrointestinal endoscopy through 1/1/2013 were reviewed for advanced colorectal neoplasia. We identified additional incident CRC cases through linkage to the Seattle-Puget Sound Surveillance Epidemiology and End Results registry. We used generalized estimating equations to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for subsequent advanced colorectal neoplasia, comparing index serrated polyps with different molecular markers. RESULTS We included 553 individuals with index serrated polyps (420 HPs and 133 SSA/Ps) and 795 subsequent endoscopies. The prevalence of BRAF-mutant, CIMP-high, and MLH1-methylated serrated polyps were 51%, 4%, and 2%, respectively. BRAF and CIMP were not associated with subsequent advanced colorectal neoplasia. MLH1-methylated SSP/As were significantly more likely to have subsequent advanced neoplasia (OR = 4.66, 95% CI 1.06-20.51). CONCLUSION Our results suggest that BRAF-mutant and CIMP-high serrated polyps are not associated with subsequent advanced colorectal neoplasia. Among SSA/Ps, MLH1 methylation may be an important marker to identify high-risk CRC precursors.
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Affiliation(s)
- Xinwei Hua
- School of Public Health, University of Washington, Seattle, WA, USA
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Polly A Newcomb
- School of Public Health, University of Washington, Seattle, WA, USA
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Jessica Chubak
- School of Public Health, University of Washington, Seattle, WA, USA
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Rachel C Malen
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Rebecca Ziebell
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Aruna Kamineni
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Lee-Ching Zhu
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Melissa P Upton
- Department of Pathology, University of Washington, Seattle, WA, USA
| | | | | | - Hana Newman
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Sheetal Hardikar
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Andrea N Burnett-Hartman
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Kaiser Permanente Colorado, Institute for Health Research, 2550 S Parker Rd, Suite 200, Waterpark III, 2nd floor, Aurora, CO, 80014, USA.
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13
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Traditional Serrated Pathway-associated Colorectal Carcinoma: Morphologic Reappraisal of Serrated Morphology, Tumor Budding, and Identification of Frequent PTEN Alterations. Am J Surg Pathol 2020; 43:1042-1051. [PMID: 31094930 DOI: 10.1097/pas.0000000000001274] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The phenotypic characteristics of traditional serrated adenoma (TSA)-associated malignancies remain obscure. This study was a morphologic reappraisal of 27 colorectal carcinomas arising from TSA (TSA-CRCs) and 53 BRAF-mutated/microsatellite-stable colorectal carcinomas (BRAF-mut/MSS CRCs). Makinen's criteria for serrated adenocarcinoma were applied to assess the morphologic similarity of the 2 entities. Tumor budding, another histologic feature of serrated adenocarcinoma, was also evaluated. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a commonly mutated gene in the serrated pathway, was assessed with immunohistochemistry. Tumors with aberrant PTEN expression were subjected to molecular analysis using quantitative methylation assay, exon sequencing, and fluorescence in situ hybridization. Most cases (>90%) of TSA-CRCs and BRAF-mut/MSS CRCs exhibited a constellation of serrated morphology, including epithelial serrations, abundant eosinophilic cytoplasm, and discernible/vesicular nuclei. A majority (65%) of them qualified for the diagnosis of serrated adenocarcinoma. High-grade tumor budding was closely associated with serrated morphology and was a significant independent factor for poor patient survival in multivariate analysis (P=0.008). Aberrant PTEN expression was detected in nearly half of the cases of both entities (P=0.501). Among the 44 samples with aberrant PTEN expression, 8 harbored PTEN somatic mutations, which were characterized by random distribution without hotspot clustering, 12 had promoter hypermethylation, and 14 had deleted alleles. These findings support a unique model of colorectal carcinogenesis that is similar between TSA-CRCs and BRAF-mut/MSS CRCs. Both entities exhibited common histologic patterns and similar molecular alterations and may well constitute the TSA pathway.
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14
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Dabir PD, Bruggeling CE, van der Post RS, Dutilh BE, Hoogerbrugge N, Ligtenberg MJL, Boleij A, Nagtegaal ID. Microsatellite instability screening in colorectal adenomas to detect Lynch syndrome patients? A systematic review and meta-analysis. Eur J Hum Genet 2019; 28:277-286. [PMID: 31695176 DOI: 10.1038/s41431-019-0538-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 10/01/2019] [Accepted: 10/13/2019] [Indexed: 11/09/2022] Open
Abstract
The colorectal cancer spectrum has changed due to population screening programs, with a shift toward adenomas and early cancers. Whether it would be a feasible option to test these adenomas for detection of Lynch syndrome (LS) patients is unclear. Through meta-analysis and systematic review, risk factors for DNA mismatch repair deficiency (dMMR) and microsatellite instability (MSI) in adenomas were identified in LS and unselected patient cohorts. Data were extracted for patient age and MMR variant together with adenoma type, grade, size, and location. A total of 41 studies were included, and contained more than 519 LS patients and 1698 unselected patients with 1142 and 2213 adenomas respectively. dMMR/MSI was present in 69.5% of conventional adenomas in LS patients, compared with 2.8% in unselected patients. In the LS cohort, dMMR/MSI was more frequently present in patients older than 60 years (82% versus 54%). dMMR/MSI was also more common in villous adenomas (84%), adenomas over 1 cm (81%), and adenomas with high grade dysplasia (88%). No significant differences were observed for dMMR/MSI in relation to MMR variants and location of adenomas. In the context of screening, we conclude that detection of dMMR/MSI in conventional adenomas of unselected patients is uncommon and might be considered as indication for LS testing. Within the LS cohort, 69.5% of LS patients could have been detected through dMMR/MSI screening of their conventional adenomas.
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Affiliation(s)
- Parag D Dabir
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Pathology, Randers Regional Hospital, Randers, Denmark
| | - Carlijn E Bruggeling
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Rachel S van der Post
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bas E Dutilh
- Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands.,Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nicoline Hoogerbrugge
- Department of Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marjolijn J L Ligtenberg
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Annemarie Boleij
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
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15
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Pai RK, Bettington M, Srivastava A, Rosty C. An update on the morphology and molecular pathology of serrated colorectal polyps and associated carcinomas. Mod Pathol 2019; 32:1390-1415. [PMID: 31028362 DOI: 10.1038/s41379-019-0280-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/28/2019] [Accepted: 03/29/2019] [Indexed: 02/08/2023]
Abstract
Our understanding of serrated colorectal polyps has increased dramatically over the past two decades and has led to a modern classification scheme for these lesions. Sessile serrated polyps with dysplasia represent the most clinically significant serrated polyp; however, the morphologic heterogeneity of dysplasia in sessile serrated polyps has only recently been recognized and correlated with MLH1 immunohistochemistry. Detailed morphologic analysis of traditional serrated adenomas has led to the recognition of flat and early forms of this polyp. Robust data on the risk of metachronous lesions in patients with serrated polyps are also beginning to emerge. This review will summarize our current understanding of serrated polyps and associated carcinomas with a focus on diagnostic criteria, morphologic heterogeneity, molecular findings, and natural history. Controversial issues in the diagnosis and classification of these polyps are also discussed.
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Affiliation(s)
- Rish K Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA.
| | - Mark Bettington
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia.,Envoi Specialist Pathologists, Brisbane, QLD, 4059, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Amitabh Srivastava
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Christophe Rosty
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia. .,Envoi Specialist Pathologists, Brisbane, QLD, 4059, Australia. .,Department of Pathology, University of Melbourne, Melbourne, VIC, 3010, Australia.
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16
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Yozu M, Kem M, Cenaj O, Mino-Kenudson M, Odze RD, Misdraji J. Loss of expression of MLH1 in non-dysplastic crypts is a harbinger of neoplastic progression in sessile serrated adenomas/polyps. Histopathology 2019; 75:376-384. [PMID: 30974487 DOI: 10.1111/his.13874] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 04/08/2019] [Indexed: 01/26/2023]
Abstract
AIMS Dysplasia in colonic sessile serrated adenomas (SSAs)/sessile serrated polyps often shows loss of MLH1 expression as determined with immunohistochemistry, but the significance of loss of MLH1 expression in non-dysplastic crypts in these polyps is less well studied. The purpose of this study was to evaluate the prevalence of loss of MLH1 expression in non-dysplastic crypts in SSAs, and to evaluate its significance with regard to progression of these polyps. METHODS AND RESULTS Four hundred SSAs, including 158 SSAs without dysplasia, 219 SSAs with dysplasia (SSAD), and 23 SSAs with invasive adenocarcinoma (SSAC), were evaluated immunohistochemically for loss of MLH1 expression in both non-dysplastic and dysplastic portions of the polyps. Seventy-one of 400 (18%) SSAs showed loss of MLH1 expression in non-dysplastic crypts. The prevalence of MLH1-deficient non-dysplastic crypts was higher in polyps with dysplasia or carcinoma (7%, 22%, and 52% in SSAs, SSADs, and SSACs, respectively; P < 0.0001). When SSAs with MLH1-deficient dysplasia and those with MLH-1-proficient dysplasia were compared, those with MLH1-deficient dysplasia were more likely to have MLH1-deficient non-dysplastic crypts (66% versus 8.1%, P < 0.0001) and a greater number of discrete foci (3.6 foci versus 1.1 foci, P = 0.008). Also, non-dysplastic crypts with loss of MLH1 expression were more likely to be contiguous with the dysplasia when the dysplasia also showed loss of MLH1 expression (26% versus 0%, P = 0.02). CONCLUSIONS Our results suggest that loss of MLH1 expression in non-dysplastic crypts in SSAs precedes the development of MLH1-deficient dysplasia and adenocarcinoma, and may be a biomarker of an advanced serrated polyp even in the absence of dysplasia.
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Affiliation(s)
- Masato Yozu
- Histopathology Department, Middlemore Hospital, Auckland, New Zealand
| | - Marina Kem
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Odise Cenaj
- Department of Pathology, New York University Langone Medical Center and New York University School of Medicine, New York, NY, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Robert D Odze
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Joseph Misdraji
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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17
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Serrated Lesions of the Colon-Rectum: A Focus on New Diagnostic Tools and Current Management. Gastroenterol Res Pract 2019; 2019:9179718. [PMID: 30774654 PMCID: PMC6350577 DOI: 10.1155/2019/9179718] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 12/23/2018] [Indexed: 02/07/2023] Open
Abstract
Prompt diagnosis and correct management of the so called "serrated lesions" (SLs) of the colon-rectum are generally considered of crucial importance in the past years, mainly due to their histological heterogeneity and peculiar clinical and molecular patterns; sometimes, they are missed at conventional endoscopy and are possibly implicated in the genesis of interval cancers. The aim of this review is to focus on the diagnostic challenges of serrated lesions, underlying the role of both conventional endoscopy and novel technologies. We will show how an accurate and precise diagnosis should immediately prompt the most appropriate therapy other than defining a proper follow-up program. It will be emphasized how novel endoscopic techniques may provide better visualization of mucosal microsurface structures other than enhancing the microvascular architecture, in order to better define and characterize specific patterns of mucosal lesions of the gastrointestinal tract. Standard therapy of SLs of the colon-rectum is still very debated, also due to the relatively lack of studies focusing on treatment issues. The high risk of incomplete resection, together with the high rate of postcolonoscopy interval cancers, suggests the need of an extra care when facing this kind of lesions. Given this background, we will outline useful technical tips and tricks in the resection of SLs, taking aspects such as the size and location of the lesions, as well as novel available techniques and technologies, other than future perspectives, including confocal laser endomicroscopy into consideration. Follow-up of SLs is another hot topic, also considering that their clinical impact has been misunderstood for a long time. The incidence of the so called interval colorectal cancer underlines how some weaknesses exist in current screening and follow-up programs. Considering the lack of wide consensus for the management of some SLs, we will try to summarize and clarify the best strategies for their optimal management.
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18
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van Lanschot MCJ, Carvalho B, Rausch C, Snaebjornsson P, van Engeland M, Kuipers EJ, Stoker J, Tutein Nolthenius CJ, Dekker E, Meijer GA. Molecular profiling of longitudinally observed small colorectal polyps: A cohort study. EBioMedicine 2019; 39:292-300. [PMID: 30555044 PMCID: PMC6354708 DOI: 10.1016/j.ebiom.2018.12.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 12/06/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Knowledge of the natural history of colorectal adenomas is limited because these lesions are removed upon detection. The few studies in which small adenomas have been left in situ for a limited period of time, have shown that most lesions remain stable or even completely regress. Specific DNA copy number changes ('cancer associated events' or CAEs) are associated with progression of adenomas to cancer. In this study we evaluated whether molecular features of progression correlated with growth of small polyps. METHODS Small (6-9 mm) colorectal precursor lesions detected on CT-colonography (CTC) were left in situ and re-evaluated with CTC after three years. Based on volumetric change, polyps were classified as either grown, stable or regressed. Surveillance CTC was followed by colonoscopy, during which all lesions were resected. Using DNA isolated from FFPE polyp tissues, low-coverage whole genome sequencing was performed to determine DNA copy number profiles, as well as target enrichment mutation analysis and CpG island methylation phenotype (CIMP) analysis. Expression of DNA mismatch repair (MMR) proteins was determined by immunohistochemistry. Samples were marked as MMR proficient if all MMR proteins were expressed. FINDINGS Out of 68 polyps resected at colonoscopy, for 65 (96%) material was available. Of these, 31 (48%) had grown, 27 (41%) remained stable and 7 (11%) regressed. Polyps with at least one CAE had higher growth rates compared to polyps without CAEs (difference 91% growth (95% CI 13-169), p = .023). CAEs were absent in lesions that had partially regressed. Mutations occurred in 94% of the polyps, with higher growth rates being associated with polyps having ≥2 mutations compared to lesions with only 0-1 mutations (difference 99% growth (95% CI 9-189), p = .032). All samples were MMR proficient. No relation between growth and CIMP was observed. INTERPRETATION Molecular alterations associated with colorectal cancer, correlated with growth of small polyps and were absent in polyps that regressed. Therefore, this longitudinal study provides in vivo support in the human setting for the functional role of these molecular alterations, that have mostly been identified by cross sectional observations in tissue samples of colorectal adenomas and cancers. FUND: Alpe d'Huzes- Dutch Cancer Society (project number NKI2013-6338).
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Affiliation(s)
- M C J van Lanschot
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Centre Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - B Carvalho
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - C Rausch
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - P Snaebjornsson
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - M van Engeland
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - E J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - J Stoker
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - C J Tutein Nolthenius
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - E Dekker
- Cancer Centre Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - G A Meijer
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
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19
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Epigenetically regulated miR-1247 functions as a novel tumour suppressor via MYCBP2 in methylator colon cancers. Br J Cancer 2018; 119:1267-1277. [PMID: 30318507 PMCID: PMC6251029 DOI: 10.1038/s41416-018-0249-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 07/24/2018] [Accepted: 08/03/2018] [Indexed: 01/27/2023] Open
Abstract
Background Colorectal cancer (CRC) is a heterogeneous disease with distinct clinical subsets based on underlying genetic and epigenetic changes. DNA hypermethylation yields a unique CRC subset with a distinct phenotype and clinical behaviour, but this oncogenic pathway is not fully characterised. This study identifies and characterises miR-1247 as a novel tumour suppressor microRNA in methylated human colon cancers. Method Tumour samples from patients with hypermethylated and non-methylated colon cancer and cell lines were evaluated for miR-1247 expression and function. A murine subcutaneous xenograft model was used for in vivo functional studies. Results miR-1247 was methylated and underexpressed in methylator colon cancers. Overexpression of miR-1247 significantly inhibited cell proliferation, decreased tumour cell motility, induced apoptosis, and mitigated tumour formation capacity both in vivo and in vitro. Pharmacologic demethylation increased miR-1247 expression and produced similar anti-tumour activities. Mechanistic investigations revealed that MYCBP2, a member of the c-myc oncogene family, is a direct functional target of miR-1247. Furthermore, in CRC patients, MYCBP2 protein levels are associated with miR-1247 levels and survival. Conclusions miR-1247 acts as a tumour suppressor by inhibiting MYCBP2 in methylator colon cancer. The MYCBP2/c-myc axis may underlie the anti-tumour activities of miR-1247 and is a potential therapeutic target via demethylation agents.
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20
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Hashimoto T, Tanaka Y, Ogawa R, Mori T, Yoshida H, Taniguchi H, Hiraoka N, Kojima M, Oono Y, Saito Y, Sekine S. Superficially serrated adenoma: a proposal for a novel subtype of colorectal serrated lesion. Mod Pathol 2018; 31:1588-1598. [PMID: 29789649 DOI: 10.1038/s41379-018-0069-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 03/30/2018] [Accepted: 03/30/2018] [Indexed: 12/12/2022]
Abstract
We describe a series of colorectal polyps characterized by mixed adenomatous and serrated features, herein referred to as superficially serrated adenomas. Twenty superficially serrated adenomas were obtained from 11 female and 9 male patients aged 62-87 years. Most lesions endoscopically appeared as small sessile polyps, but larger lesions were plaque-like (2-20 mm; median, 5 mm). Eighteen lesions (90%) were located in the sigmoid colon or rectum. They consisted primarily of straight, adenomatous glands but showed serration confined to the superficial layer. Immunohistochemistry revealed CK20 expression in the upper layer. Proliferating cells, determined by their expression of Ki-67, were localized to the middle to bottom layers. Genetic analyses identified KRAS mutations in 19 lesions and a BRAF mutation in one lesion. Furthermore, RSPO fusions and/or overexpression were observed in 18 lesions and truncating APC mutations were observed in the two remaining lesions. Consistent with the presence of WNT pathway gene alterations, all superficially serrated adenomas showed focal or diffuse nuclear β-catenin accumulation. Since concurrent KRAS mutations and RSPO fusions are reportedly common in traditional serrated adenomas, we reviewed 129 traditional serrated adenomas and found 15 lesions (12%) that were associated with superficially serrated adenoma components. Remarkably, all but one superficially serrated adenoma-associated traditional serrated adenoma exhibited concurrent KRAS mutations and RSPO fusions/overexpression. The present study suggests that superficially serrated adenoma is a morphologically and molecularly distinct type of colorectal serrated polyp that is histogenetically related to traditional serrated adenoma.
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Affiliation(s)
- Taiki Hashimoto
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Yusaku Tanaka
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Reiko Ogawa
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Taisuke Mori
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, 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
| | - Nobuyoshi Hiraoka
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Motohiro Kojima
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Chiba, Kashiwa, Japan
| | - Yasuhiro Oono
- Endoscopy Division, National Cancer Center Hospital East, Chiba, Kashiwa, 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. .,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
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21
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22
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Acosta-Gonzalez G, Ouseph M, Lombardo K, Lu S, Glickman J, Resnick MB. Immune environment in serrated lesions of the colon: intraepithelial lymphocyte density, PD-1, and PD-L1 expression correlate with serrated neoplasia pathway progression. Hum Pathol 2018; 83:115-123. [PMID: 30172913 DOI: 10.1016/j.humpath.2018.08.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/17/2018] [Accepted: 08/23/2018] [Indexed: 12/30/2022]
Abstract
The serrated neoplasia pathway accounts for approximately 20% of colorectal carcinomas (CRCs). Sessile serrated adenomas (SSAs), the main precursor lesion of the serrated pathway, are molecularly driven by MLH1 promoter methylation and microsatellite instability (MSI) in their progression to CRC. MSI-high (MSI-H) lesions are highly immunogenic and associated with a high density of tumor-infiltrating lymphocytes. Our study's aim was to determine how the kinetics of this immune environment relates to SSAs in their progression through low-grade (SSA-LD) to high-grade dysplasia (SSA-HD) and CRC. We analyzed 74 cases (16 CRCs, 14 SSAs-HD, and 44 SSAs-LD). Cases of hyperplastic polyp and SSA without dysplasia were analyzed for comparison. MSI status, intraepithelial lymphocyte (IEL) density, and immune checkpoint expression were assessed by immunohistochemistry for mismatch repair proteins, CD3, and PD-1/PD-L1, respectively. Average IEL density was 12, 18.6, 21.6, and 31 for SSA, SSA-LD, SSA-HD, and CRC, respectively, as opposed to 8.1 in normal colon (P < .0001). Average PD-1/PD-L1 lymphocytic expression was 1.1/1.0, 1.2/2.9, 4.8/6.9, and 12.4/15.2 in SSA, SSA-LD, SSA-HD, and CRC, respectively, compared with 0.5/0 in normal crypts (P < .0001). IEL and PD-1/PD-L1 lymphocytic expression values of MSI-H lesions were 22.6, 27.7, and 36.8, and 3/6.5, 6.2/10.6, and 18.3/17.6 in MSI-H SSA-LD, SSA-HD, and CRCs, respectively (P ranged from .0478 to .3529). PD-L1 epithelial expression was positive in 40% of SSAs, 59.1% of SSAs-LD, 100% of SSAs-HD, and 60% of CRCs (P < .0001). Increased IELs and PD-1/PD-L1 expression correlate with sequential progression of SSAs, through development of cytologic dysplasia, to CRC and MSI-H status.
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Affiliation(s)
- Gabriel Acosta-Gonzalez
- Department of Pathology, Brown University Warren Alpert Medical School, Rhode Island Hospital, Providence, RI 02903, USA
| | - Madhu Ouseph
- Department of Pathology, Brown University Warren Alpert Medical School, Rhode Island Hospital, Providence, RI 02903, USA
| | - Kara Lombardo
- Department of Pathology, Brown University Warren Alpert Medical School, Rhode Island Hospital, Providence, RI 02903, USA
| | - Shaolei Lu
- Department of Pathology, Brown University Warren Alpert Medical School, Rhode Island Hospital, Providence, RI 02903, USA
| | - Jonathan Glickman
- Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Murray B Resnick
- Department of Pathology, Brown University Warren Alpert Medical School, Rhode Island Hospital, Providence, RI 02903, USA.
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Choi WT, Wen KW, Rabinovitch PS, Huang D, Mattis AN, Gill RM. DNA content analysis of colorectal serrated lesions detects an aneuploid subset of inflammatory bowel disease-associated serrated epithelial change and traditional serrated adenomas. Histopathology 2018; 73:464-472. [DOI: 10.1111/his.13652] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 05/11/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Won-Tak Choi
- Department of Pathology; University of California at San Francisco; San Francisco CA USA
| | - Kwun Wah Wen
- Department of Pathology; University of California at San Francisco; San Francisco CA USA
| | | | - Danning Huang
- Department of Public Health and Preventive Medicine; SUNY Upstate Medical University; Syracuse NY USA
| | - Aras N Mattis
- Department of Pathology; University of California at San Francisco; San Francisco CA USA
| | - Ryan M Gill
- Department of Pathology; University of California at San Francisco; San Francisco CA USA
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24
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Ma MX, Bourke MJ. Sessile Serrated Adenomas: How to Detect, Characterize and Resect. Gut Liver 2018; 11:747-760. [PMID: 28494577 PMCID: PMC5669590 DOI: 10.5009/gnl16523] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 12/06/2016] [Indexed: 12/13/2022] Open
Abstract
Serrated polyps are important contributors to the burden of colorectal cancers (CRC). These lesions were once considered to have no malignant potential, but currently up to 30% of all CRC are recognized to arise from the serrated neoplasia pathway. The primary premalignant lesions are sessile serrated adenomas/polyps (SSA/Ps), although traditional serrated adenomas are relatively uncommon. Compared to conventional adenomas, SSA/Ps are morphologically subtle with indistinct borders, may be difficult to detect endoscopically, are more prevalent than previously thought, are associated with synchronous and metachronous advanced neoplasia, and have a higher risk of incomplete resection. Although many lesions remain “dormant,” progressive disease is associated with the development of dysplasia and more rapid progression to CRC. As a result, SSA/Ps are strongly implicated in the development of interval cancers. These factors represent unique challenges that require a meticulous approach to their management. In this review, we summarize the contemporary literature on the characterization, detection and resection of SSA/Ps.
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Affiliation(s)
- Michael X Ma
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, Australia
| | - Michael J Bourke
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, Australia.,University of Sydney, Sydney, Australia
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25
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Clinicopathologic and outcome study of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia. Mod Pathol 2018; 31:633-642. [PMID: 29271414 DOI: 10.1038/modpathol.2017.169] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 10/15/2017] [Accepted: 10/16/2017] [Indexed: 01/12/2023]
Abstract
It is believed that sessile serrated adenomas/polyps lead to the development of microsatellite unstable cancer via a dysplasia-carcinoma sequence. Little is known regarding the morphologic and biologic features, and outcome of sessile serrated adenomas/polyps with dysplasia, or of its specific dysplasia subtypes (intestinal versus serrated). The aims of this study were to analyze and compare the clinical, pathologic, and outcome characteristics of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia. The study included 86 patients with sessile serrated adenomas/polyps with dysplasia (50 serrated dysplasia, 22 intestinal dysplasia, 14 mixed serrated and intestinal dysplasia). The clinical and pathologic features, and the prevalence rate of prior, concurrent, and future neoplastic lesions, were compared between sessile serrated adenomas/polyps with intestinal versus serrated dysplasia and with matched control patients with ≥1 conventional adenoma. The mean age of the patients, polyp size, and prevalence of adenocarcinoma within the polyps were significantly higher in sessile serrated adenomas/polyps with high versus low-grade dysplasia. Sessile serrated adenomas/polyps with intestinal dysplasia showed a significantly higher rate of adenocarcinoma (23%) compared with those with serrated dysplasia (6%, P=0.05), and the high-grade lesions occurred at a significantly younger age in the former compared with the latter (65 versus 76 years, P=0.05). Compared with patients with conventional adenomas, patients with sessile serrated adenomas/polyps with dysplasia showed a significantly higher rate of invasive carcinoma within the polyps (12 versus 0%, P=0.01) and a significantly lower association with prior or future conventional adenomas. Sessile serrated adenomas/polyps with dysplasia should be considered high-risk neoplastic precursor lesions, particularly those with intestinal dysplasia. Cancer may develop from sessile serrated adenomas/polyps with either type of dysplasia.
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26
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Lee CT, Huang YC, Hung LY, Chow NH, Su PF, Ho CL, Tsai HW, Chen YL, Lin SC, Lin BW, Lin PC, Lee JC. Serrated adenocarcinoma morphology in colorectal mucinous adenocarcinoma is associated with improved patient survival. Oncotarget 2018; 8:35165-35175. [PMID: 28422723 PMCID: PMC5471043 DOI: 10.18632/oncotarget.16815] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/19/2017] [Indexed: 02/06/2023] Open
Abstract
Colorectal mucinous adenocarcinoma (MAC) and serrated adenocarcinoma (SAC) share many characteristics, including right-side colon location, frequent mucin production, and various molecular features. This study examined the frequency of SAC morphology in MACs. We assessed the correlation of SAC morphology with clinicopathological parameters, molecular characteristics, and patient prognosis. Eighty-eight colorectal MACs were collected and reviewed for SAC morphology according to Makinen's criteria. We sequenced KRAS and BRAF, assessed CpG island methylator phenotype (CIMP) frequency, and analyzed DNA mismatch repair enzyme levels using immunohistochemistry in tumor samples. SAC morphology was observed in 38% of MACs, and was associated with proximal location (P=0.001), BRAF mutation (P=0.042), CIMP-positive status (P=0.023), and contiguous traditional serrated adenoma (P=0.019). Multivariate analysis revealed that MACs without both SAC morphology and CIMP-positive status exhibited 3.955 times greater risk of cancer relapse than MACs having both characteristics or either one (P=0.035). Our results show that two MAC groups with distinct features can be identified using Makinen's criteria, and suggest a favorable prognostic role for the serrated neoplastic pathway in colorectal MAC.
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Affiliation(s)
- Chung-Ta Lee
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Yu-Chuan Huang
- Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan
| | - Liang-Yi Hung
- Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan.,Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan
| | - Nan-Haw Chow
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Pei-Fang Su
- Department of Statistics, College of Management, National Cheng Kung University, Tainan 70101, Taiwan
| | - Chung-Liang Ho
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Yi-Lin Chen
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Shao-Chieh Lin
- Department of Statistics, College of Management, National Cheng Kung University, Tainan 70101, Taiwan
| | - Bo-Wen Lin
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Peng-Chan Lin
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Jenq-Chang Lee
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
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27
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Borowsky J, Dumenil T, Bettington M, Pearson SA, Bond C, Fennell L, Liu C, McKeone D, Rosty C, Brown I, Walker N, Leggett B, Whitehall V. The role of APC in WNT pathway activation in serrated neoplasia. Mod Pathol 2018; 31:495-504. [PMID: 29148535 DOI: 10.1038/modpathol.2017.150] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 09/14/2017] [Accepted: 09/15/2017] [Indexed: 02/07/2023]
Abstract
Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear β-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of β-catenin and truncating APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear β-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P=0.0001). However, unlike the conventional pathway, truncating APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations common in conventional adenomas.
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Affiliation(s)
- Jennifer Borowsky
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Troy Dumenil
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Mark Bettington
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Sally-Ann Pearson
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Catherine Bond
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Lochlan Fennell
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Cheng Liu
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Diane McKeone
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Christophe Rosty
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Ian Brown
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia.,Pathology Queensland, Queensland Health, Brisbane, QLD, Australia
| | - Neal Walker
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Barbara Leggett
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Vicki Whitehall
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Pathology Queensland, Queensland Health, Brisbane, QLD, Australia
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28
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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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29
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Hirano D, Oka S, Tanaka S, Sumimoto K, Ninomiya Y, Tamaru Y, Shigita K, Hayashi N, Urabe Y, Kitadai Y, Shimamoto F, Arihiro K, Chayama K. Clinicopathologic and endoscopic features of early-stage colorectal serrated adenocarcinoma. BMC Gastroenterol 2017; 17:158. [PMID: 29233113 PMCID: PMC5727877 DOI: 10.1186/s12876-017-0702-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 11/22/2017] [Indexed: 01/03/2023] Open
Abstract
Background Serrated adenocarcinoma (SAC) is a distinct colorectal carcinoma variant that accounts for approximately 7.5% of all advanced colorectal carcinomas. While its prognosis is worse than conventional carcinoma, its early-stage clinicopathologic features are unclear. We therefore aimed to clarify the clinicopathologic and endoscopic characteristics of early-stage SACs. Methods Forty consecutive early-stage SAC patients at Hiroshima University Hospital were enrolled; SACs were classified into epithelial serration (Group A, n = 17) and non-epithelial serration (Group B, n = 23) groups. Additionally, we classified serrated adenoma into 4 types: sessile serrated adenoma (SSA), traditional serrated adenoma (TSA), unclassified, and non-serrated adenoma type. Results There were significant differences between Groups A and B in terms of tumor size (27.6 vs. 43.1 mm), incidences of T1 carcinoma (71% vs. 13%), and having the same color as normal mucosa (47% vs. 17%), respectively (p <0.01). In SACs >20 mm, the incidence of T1 carcinoma in Group A (70%) was significantly greater than that in Group B (13%) (p <0.05). There were significant differences in ‘Japan NBI Expert Team’ type 3 and type V pit pattern classifications between the 2 groups. The average TSA-type tumor size (42.6 mm) was significantly larger than that of the SSA (17.2 mm) and non-serrated component types (18.3 mm). The incidences of submucosal invasion in SSA- (80%), unclassified- (100%), and non-serrated-type (100%) tumors were significantly higher than that in the TSA type (11%). Conclusions Epithelial serration in the cancerous area and a non-TSA background indicated aggressive behavior in early-stage SACs.
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Affiliation(s)
- Daiki Hirano
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shiro Oka
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Shinji Tanaka
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Kyoku Sumimoto
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yuki Ninomiya
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yuzuru Tamaru
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kenjiro Shigita
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Nana Hayashi
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Yuji Urabe
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yasuhiko Kitadai
- Department of the Faculty of Human Culture and Science, Prefectural University of Hiroshima, Hiroshima, Japan
| | - Fumio Shimamoto
- The Faculty of Humanities and Human Sciences, Hiroshima Shudo University Hiroshima, Hiroshima, Japan
| | - Koji Arihiro
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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30
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Sessile serrated adenomas with dysplasia: morphological patterns and correlations with MLH1 immunohistochemistry. Mod Pathol 2017; 30:1728-1738. [PMID: 28752838 PMCID: PMC5719122 DOI: 10.1038/modpathol.2017.92] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 05/30/2017] [Accepted: 06/02/2017] [Indexed: 12/30/2022]
Abstract
Sessile serrated adenomas are the precursor polyp of approximately 20% of colorectal carcinomas. Sessile serrated adenomas with dysplasia are rarely encountered and represent an intermediate step to malignant progression, frequently associated with loss of MLH1 expression. Accurate diagnosis of these lesions is important to facilitate appropriate surveillance, particularly because progression from dysplasia to carcinoma can be rapid. The current World Health Organization classification describes two main patterns of dysplasia occurring in sessile serrated adenomas, namely, serrated and conventional. However, this may not adequately reflect the spectrum of changes seen by pathologists in routine practice. Furthermore, subtle patterns of dysplasia that are nevertheless associated with loss of MLH1 expression are not encompassed in this classification. We performed a morphological analysis of 266 sessile serrated adenomas with dysplasia with concurrent MLH1 immunohistochemistry with the aims of better defining the spectrum of dysplasia occurring in these lesions and correlating dysplasia patterns with MLH1 expression. We found that dysplasia can be divided morphologically into four major patterns, comprising minimal deviation (19%), serrated (12%), adenomatous (8%) and not otherwise specified (79%) groups. Minimal deviation dysplasia is defined by minor architectural and cytological changes that typically requires loss of MLH1 immunohistochemical expression to support the diagnosis. Serrated dysplasia and adenomatous dysplasia have distinctive histological features and are less frequently associated with loss of MLH1 expression (13 and 5%, respectively). Finally, dysplasia not otherwise specified encompasses most cases and shows a diverse range of morphological changes that do not fall into the other subgroups and are frequently associated with loss of MLH1 expression (83%). This morphological classification of sessile serrated adenomas with dysplasia may represent an improvement on the current description as it correlates with the underlying mismatch repair protein status of the polyps and better highlights the range of morphologies seen by pathologists.
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31
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Tanaka Y, Yamano HO, Yamamoto E, Matushita HO, Aoki H, Yoshikawa K, Takagi R, Harada E, Nakaoka M, Yoshida Y, Eizuka M, Sugai T, Suzuki H, Nakase H. Endoscopic and molecular characterization of colorectal sessile serrated adenoma/polyps with cytologic dysplasia. Gastrointest Endosc 2017; 86:1131-1138.e4. [PMID: 28501592 DOI: 10.1016/j.gie.2017.05.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 05/01/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Sessile serrated adenoma/polyps (SSA/Ps), which are precursor lesions of colorectal cancer (CRC) with BRAF mutation and the CpG island methylator phenotype (CIMP), develop cytologic dysplasia (CD) during the progression of colorectal tumorigenesis. In the present study we aimed to clarify the endoscopic and molecular signatures of SSA/Ps, with and without CD. METHODS A series of 208 serrated lesions, including 41 hyperplastic polyps, 90 SSA/Ps, 33 SSA/Ps with CD, and 44 traditional serrated adenomas, were observed and resected using magnifying endoscopy. BRAF and KRAS mutations and methylation of CIMP markers (MINT1, MINT2, MINT12, MINT31, and p16) were analyzed through pyrosequencing. Molecular alterations were then compared with endoscopic and pathologic characteristics. RESULTS Among SSA/Ps without CD, the Type II-Open pit pattern (Type II-O), BRAF mutation, and CIMP were tightly associated with a proximal colon location. SSA/Ps in the distal colon infrequently exhibited Type II-O and CIMP. By contrast, most SSA/Ps with CD showed Type II-O plus adenomatous pit patterns (Type III or IV), BRAF mutation, and CIMP, irrespective of their locations. CONCLUSIONS Our results suggest that the Type II-O plus III/IV pit pattern is a common feature of SSA/Ps with CD in both the proximal and distal colon and that this pit pattern is a hallmark of serrated lesions at high risk of developing into CRCs.
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Affiliation(s)
- Yoshihito Tanaka
- Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan
| | - Hiro-O Yamano
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Eiichiro Yamamoto
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiro-O Matushita
- Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan
| | - Hironori Aoki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kenjiro Yoshikawa
- Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan
| | - Ryo Takagi
- Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan
| | - Eiji Harada
- Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan
| | - Michiko Nakaoka
- Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan
| | - Yuko Yoshida
- Department of Digestive Disease Center, Akita Red Cross Hospital, Akita, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
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32
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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 2017; 472:383-393. [PMID: 28929387 DOI: 10.1007/s00428-017-2234-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [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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Hashimoto T, Yamashita S, Yoshida H, Taniguchi H, Ushijima T, Yamada T, Saito Y, Ochiai A, Sekine S, Hiraoka N. WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps. Am J Surg Pathol 2017; 41:1188-1197. [PMID: 28614199 DOI: 10.1097/pas.0000000000000877] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are believed to be the major precursor of serrated pathway-derived colorectal carcinomas. To better characterize the process of progression from SSA/Ps to carcinomas, we analyzed 46 SSA/Ps with dysplasia and 45 SSA/Ps without dysplasia using targeted next-generation sequencing and immunohistochemistry. Among the WNT pathway genes analyzed, protein-truncating mutations of RNF43, APC, and ZNRF3 were identified in 23 (50%), 4 (9%), and 3 (7%) SSA/Ps with dysplasia, respectively. In contrast, SSA/Ps without dysplasia rarely had WNT pathway gene mutations, except for 3 lesions with RNF43 mutations (7%). None of the SSA/Ps had CTNNB1 mutations or RSPO fusions. Thus, WNT pathway gene mutations were more common in SSA/Ps with dysplasia than in SSA/Ps without dysplasia (P=3.0×10). Consistently, nuclear β-catenin accumulation and MYC overexpression, indicative of active WNT signaling, were present in most of the SSA/Ps with dysplasia, but were rare in those without dysplasia. BRAF (86%) or KRAS mutations (7%) were identified in the majority of SSA/Ps, regardless of the presence or absence of dysplasia. MLH1 expression was lost in 14 SSA/Ps with dysplasia (30%). The majority of MLH1-deficient SSA/Ps with dysplasia had RNF43 mutations (86%), most of which were frameshift mutations involving mononucleotide repeats. In contrast, MLH1-retained lesions had less frequent RNF43 mutations with no hot spots (34%), and 4 had APC mutations (13%). These results suggest that WNT pathway gene mutations are involved in the development of dysplasia in SSA/Ps and that MLH1-deficient and MLH1-retained SSA/Ps with dysplasia exhibit distinct mutation profiles of WNT pathway genes.
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Affiliation(s)
- Taiki Hashimoto
- *Division of Pathology and Clinical Laboratories ∥Endoscopy Division, National Cancer Center Hospital †Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine ‡Division of Epigenomics §Division of Chemotherapy and Clinical Research #Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo ¶Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Chiba, Japan
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Haumaier F, Sterlacci W, Vieth M. Histological and molecular classification of gastrointestinal polyps. Best Pract Res Clin Gastroenterol 2017; 31:369-379. [PMID: 28842046 DOI: 10.1016/j.bpg.2017.06.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 06/06/2017] [Accepted: 06/25/2017] [Indexed: 01/31/2023]
Abstract
Endoscopic diagnosis and treatment for gastrointestinal polyps became widely available within the last decades. Exact terminology is important for further therapeutic steps, follow up or treatment. Gastroenterologists, Oncologists, Surgeons and Pathologists need to be aware of the most recent terminology to ensure proper risk assessment and subsequent treatment if necessary. This manuscript aims to list the variety of gastrointestinal polyps and the molecular background where appropriate.
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Affiliation(s)
| | | | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany.
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35
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Rex DK, Hassan C, Bourke MJ. The colonoscopist's guide to the vocabulary of colorectal neoplasia: histology, morphology, and management. Gastrointest Endosc 2017; 86:253-263. [PMID: 28396276 DOI: 10.1016/j.gie.2017.03.1546] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 03/29/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Douglas K Rex
- Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Cesare Hassan
- Digestive Endoscopy Unit, Catholic University, Rome, Italy
| | - Michael J Bourke
- Department of Gastroenterology and Hepatology, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
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36
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Rex DK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA, Kaltenbach T, Levin TR, Lieberman D, Robertson DJ. Colorectal Cancer Screening: Recommendations for Physicians and Patients From the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2017; 153:307-323. [PMID: 28600072 DOI: 10.1053/j.gastro.2017.05.013] [Citation(s) in RCA: 493] [Impact Index Per Article: 61.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This document updates the colorectal cancer (CRC) screening recommendations of the U.S. Multi-Society Task Force of Colorectal Cancer (MSTF), which represents the American College of Gastroenterology, the American Gastroenterological Association, and The American Society for Gastrointestinal Endoscopy. CRC screening tests are ranked in 3 tiers based on performance features, costs, and practical considerations. The first-tier tests are colonoscopy every 10 years and annual fecal immunochemical test (FIT). Colonoscopy and FIT are recommended as the cornerstones of screening regardless of how screening is offered. Thus, in a sequential approach based on colonoscopy offered first, FIT should be offered to patients who decline colonoscopy. Colonoscopy and FIT are recommended as tests of choice when multiple options are presented as alternatives. A risk-stratified approach is also appropriate, with FIT screening in populations with an estimated low prevalence of advanced neoplasia and colonoscopy screening in high prevalence populations. The second-tier tests include CT colonography every 5 years, the FIT-fecal DNA test every 3 years, and flexible sigmoidoscopy every 5 to 10 years. These tests are appropriate screening tests, but each has disadvantages relative to the tier 1 tests. Because of limited evidence and current obstacles to use, capsule colonoscopy every 5 years is a third-tier test. We suggest that the Septin9 serum assay (Epigenomics, Seattle, Wash) not be used for screening. Screening should begin at age 50 years in average-risk persons, except in African Americans in whom limited evidence supports screening at 45 years. CRC incidence is rising in persons under age 50, and thorough diagnostic evaluation of young persons with suspected colorectal bleeding is recommended. Discontinuation of screening should be considered when persons up to date with screening, who have prior negative screening (particularly colonoscopy), reach age 75 or have <10 years of life expectancy. Persons without prior screening should be considered for screening up to age 85, depending on age and comorbidities. Persons with a family history of CRC or a documented advanced adenoma in a first-degree relative age <60 years or 2 first-degree relatives with these findings at any age are recommended to undergo screening by colonoscopy every 5 years, beginning 10 years before the age at diagnosis of the youngest affected relative or age 40, whichever is earlier. Persons with a single first-degree relative diagnosed at ≥60 years with CRC or an advanced adenoma can be offered average-risk screening options beginning at age 40 years.
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Affiliation(s)
- Douglas K Rex
- Indiana University School of Medicine, Indianapolis, Indiana.
| | | | - Jason A Dominitz
- VA Puget Sound Health Care System, University of Washington, Seattle, Washington
| | | | | | - Tonya Kaltenbach
- San Francisco Veterans Affairs Medical Center, San Francisco, California
| | | | | | - Douglas J Robertson
- VA Medical Center, White River Junction, Vermont, and Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
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East JE, Atkin WS, Bateman AC, Clark SK, Dolwani S, Ket SN, Leedham SJ, Phull PS, Rutter MD, Shepherd NA, Tomlinson I, Rees CJ. British Society of Gastroenterology position statement on serrated polyps in the colon and rectum. Gut 2017; 66:1181-1196. [PMID: 28450390 PMCID: PMC5530473 DOI: 10.1136/gutjnl-2017-314005] [Citation(s) in RCA: 196] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 03/31/2017] [Accepted: 04/03/2017] [Indexed: 02/07/2023]
Abstract
Serrated polyps have been recognised in the last decade as important premalignant lesions accounting for between 15% and 30% of colorectal cancers. There is therefore a clinical need for guidance on how to manage these lesions; however, the evidence base is limited. A working group was commission by the British Society of Gastroenterology (BSG) Endoscopy section to review the available evidence and develop a position statement to provide clinical guidance until the evidence becomes available to support a formal guideline. The scope of the position statement was wide-ranging and included: evidence that serrated lesions have premalignant potential; detection and resection of serrated lesions; surveillance strategies after detection of serrated lesions; special situations-serrated polyposis syndrome (including surgery) and serrated lesions in colitis; education, audit and benchmarks and research questions. Statements on these issues were proposed where the evidence was deemed sufficient, and re-evaluated modified via a Delphi process until >80% agreement was reached. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool was used to assess the strength of evidence and strength of recommendation for finalised statements. Key recommendation: we suggest that until further evidence on the efficacy or otherwise of surveillance are published, patients with sessile serrated lesions (SSLs) that appear associated with a higher risk of future neoplasia or colorectal cancer (SSLs ≥10 mm or serrated lesions harbouring dysplasia including traditional serrated adenomas) should be offered a one-off colonoscopic surveillance examination at 3 years (weak recommendation, low quality evidence, 90% agreement).
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Affiliation(s)
- James E East
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Wendy S Atkin
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Adrian C Bateman
- Department of Cellular Pathology, Southampton General Hospital, Southampton, UK
| | - Susan K Clark
- The Polyposis Registry, St. Mark's Hospital, London, UK
| | - Sunil Dolwani
- Cancer Screening, Prevention and Early Diagnosis Group, Division of Population Medicine, Cardiff University, Cardiff, UK
| | - Shara N Ket
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Simon J Leedham
- Gastrointestinal Stem-cell Biology Laboratory, Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Perminder S Phull
- Department of Digestive Disorders, Aberdeen Royal Infirmary, Aberdeen, UK
| | - Matt D Rutter
- Department of Gastroenterology, University Hospital of North Tees, Stockton-on-Tees, Cleveland, UK
- School of Medicine, Durham University, Durham, UK
| | - Neil A Shepherd
- Gloucestershire Cellular Pathology Laboratory, Cheltenham General Hospital, Cheltenham, UK
| | - Ian Tomlinson
- Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Colin J Rees
- School of Medicine, Durham University, Durham, UK
- Department of Gastroenterology, South Tyneside NHS Foundation Trust, South Shields, UK
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38
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Rex DK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA, Kaltenbach T, Levin TR, Lieberman D, Robertson DJ. Colorectal Cancer Screening: Recommendations for Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2017; 112:1016-1030. [PMID: 28555630 DOI: 10.1038/ajg.2017.174] [Citation(s) in RCA: 457] [Impact Index Per Article: 57.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This document updates the colorectal cancer (CRC) screening recommendations of the U.S. Multi-Society Task Force of Colorectal Cancer (MSTF), which represents the American College of Gastroenterology, the American Gastroenterological Association, and The American Society for Gastrointestinal Endoscopy. CRC screening tests are ranked in 3 tiers based on performance features, costs, and practical considerations. The first-tier tests are colonoscopy every 10 years and annual fecal immunochemical test (FIT). Colonoscopy and FIT are recommended as the cornerstones of screening regardless of how screening is offered. Thus, in a sequential approach based on colonoscopy offered first, FIT should be offered to patients who decline colonoscopy. Colonoscopy and FIT are recommended as tests of choice when multiple options are presented as alternatives. A risk-stratified approach is also appropriate, with FIT screening in populations with an estimated low prevalence of advanced neoplasia and colonoscopy screening in high prevalence populations. The second-tier tests include CT colonography every 5 years, the FIT-fecal DNA test every 3 years, and flexible sigmoidoscopy every 5 to 10 years. These tests are appropriate screening tests, but each has disadvantages relative to the tier 1 tests. Because of limited evidence and current obstacles to use, capsule colonoscopy every 5 years is a third-tier test. We suggest that the Septin9 serum assay (Epigenomics, Seattle, Wash) not be used for screening. Screening should begin at age 50 years in average-risk persons, except in African Americans in whom limited evidence supports screening at 45 years. CRC incidence is rising in persons under age 50, and thorough diagnostic evaluation of young persons with suspected colorectal bleeding is recommended. Discontinuation of screening should be considered when persons up to date with screening, who have prior negative screening (particularly colonoscopy), reach age 75 or have <10 years of life expectancy. Persons without prior screening should be considered for screening up to age 85, depending on age and comorbidities. Persons with a family history of CRC or a documented advanced adenoma in a first-degree relative age <60 years or 2 first-degree relatives with these findings at any age are recommended to undergo screening by colonoscopy every 5 years, beginning 10 years before the age at diagnosis of the youngest affected relative or age 40, whichever is earlier. Persons with a single first-degree relative diagnosed at ≥60 years with CRC or an advanced adenoma can be offered average-risk screening options beginning at age 40 years.
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Affiliation(s)
- Douglas K Rex
- Indiana University School of Medicine, Indianapolis, Indiana, USA
| | | | - Jason A Dominitz
- VA Puget Sound Health Care System, University of Washington, Seattle, Washington, USA
| | | | | | - Tonya Kaltenbach
- San Francisco Veterans Affairs Medical Center, San Francisco, California, USA
| | | | | | - Douglas J Robertson
- VA Medical Center, White River Junction, Vermont, and Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
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39
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Rex DK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA, Kaltenbach T, Levin TR, Lieberman D, Robertson DJ. Colorectal cancer screening: Recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc 2017; 86:18-33. [PMID: 28600070 DOI: 10.1016/j.gie.2017.04.003] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 04/06/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Douglas K Rex
- Indiana University School of Medicine, Indianapolis, Indiana, USA.
| | | | - Jason A Dominitz
- VA Puget Sound Health Care System, University of Washington, Seattle, Washington, USA
| | | | | | - Tonya Kaltenbach
- San Francisco Veterans Affairs Medical Center, San Francisco, California, USA
| | | | | | - Douglas J Robertson
- VA Medical Center, White River Junction, Vermont, and Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
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40
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Rashtak S, Rego R, Sweetser SR, Sinicrope FA. Sessile Serrated Polyps and Colon Cancer Prevention. Cancer Prev Res (Phila) 2017; 10:270-278. [PMID: 28325827 DOI: 10.1158/1940-6207.capr-16-0264] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 11/21/2016] [Accepted: 03/15/2017] [Indexed: 11/16/2022]
Abstract
Evidence suggests that up to one fifth of colorectal carcinomas develop from serrated polyps, named for their pattern of colonic crypts, and include the sessile serrated adenoma/polyp (SSA/P) that has malignant potential. SSA/Ps are typically located in the proximal colon and have molecular features of hypermethylation of CpG islands in gene promoters and activating point mutations (V600E) in the BRAF oncogene. Both of these features are seen in sporadic colorectal carcinomas with microsatellite instability (MSI) which is potentially consistent with an origin of these cancers from precursor SSA/Ps. Dysplasia is detected in a subset of SSA/Ps with a high risk of progression to carcinoma. An uncommon serrated polyp is the traditional serrated adenoma that is typically found in the left colon, has a tubulovillous architecture, and frequently harbors mutant KRAS To date, the epidemiology of these serrated lesions is poorly understood, and limited observational data suggest a potential chemopreventive benefit of nonsteroidal anti-inflammatory drugs. The current primary strategy to reduce the risk of colorectal carcinoma from serrated polyps is to enhance their detection at colonoscopy and to ensure their complete removal. This review provides insight into the epidemiologic, clinical, histopathologic, and molecular features of serrated polyps and includes data on their endoscopic detection and chemoprevention. Cancer Prev Res; 10(5); 270-8. ©2017 AACR.
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Affiliation(s)
- Shahrooz Rashtak
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Rafaela Rego
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.,Department of Pathology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Seth R Sweetser
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Frank A Sinicrope
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota. .,Department of Oncology, Mayo Clinic, Rochester, Minnesota
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41
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Abstract
Serrated polyps (SPs) of the colorectum pose a novel challenge to practicing gastroenterologists. Previously thought benign and unimportant, there is now compelling evidence that SPs are responsible for a significant percentage of incident colorectal cancer worldwide. In contrast to conventional adenomas, which tend to be slow growing and polypoid, SPs have unique features that undermine current screening and surveillance practices. For example, sessile serrated polyps (SSPs) are flat, predominately right-sided, and thought to have the potential for rapid growth. Moreover, SSPs are subject to wide variations in endoscopic detection and pathologic interpretation. Unfortunately, little is known about the natural history of SPs, and current guidelines are based largely on expert opinion. In this review, we outline the current taxonomy, epidemiology, and management of SPs with an emphasis on the clinical and public health impact of these lesions.
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Affiliation(s)
| | - Seth D Crockett
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
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Bettington M, Walker N, Rosty C, Brown I, Clouston A, McKeone D, Pearson SA, Leggett B, Whitehall V. Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma. Gut 2017; 66:97-106. [PMID: 26475632 DOI: 10.1136/gutjnl-2015-310456] [Citation(s) in RCA: 147] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 09/15/2015] [Accepted: 09/20/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Sessile serrated adenomas (SSAs) are the precursors of at least 15% of colorectal carcinomas, but their biology is incompletely understood. We performed a clinicopathological and molecular analysis of a large number of the rarely observed SSAs with dysplasia/carcinoma to better define their features and the pathways by which they progress to carcinoma. DESIGN A cross-sectional analysis of 137 SSAs containing regions of dysplasia/carcinoma prospectively collected at a community GI pathology practice was conducted. Samples were examined for BRAF and KRAS mutations, the CpG island methylator phenotype (CIMP) and immunostained for MLH1, p53, p16, β-catenin and 0-6-methylguanine DNA methyltransferase (MGMT). RESULTS The median polyp size was 9 mm and 86.5% were proximal. Most were BRAF mutated (92.7%) and 94.0% showed CIMP. Mismatch repair deficiency, evidenced by loss of MLH1 (74.5%) is associated with older age (76.7 versus 71.0; p<0.0029), female gender (70% versus 36%; p<0.0008), proximal location (91% versus 72%; p<0.02), CIMP (98% versus 80%; p<0.02) and lack of aberrant p53 (7% versus 34%; p<0.001) when compared with the mismatch repair-proficient cases. Loss of p16 (43.1%) and gain of nuclear β-catenin (55.5%) were common in areas of dysplasia/cancer, irrespective of mismatch repair status. CONCLUSIONS SSAs containing dysplasia/carcinoma are predominantly small (<10 mm) and proximal. The mismatch repair status separates these lesions into distinct clinicopathological subgroups, although WNT activation and p16 silencing are common to both. Cases with dysplasia occur at a similar age to cases with carcinoma. This, together with the rarity of these 'caught in the act' lesions, suggests a rapid transition to malignancy following a long dwell time as an SSA without dysplasia.
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Affiliation(s)
- Mark Bettington
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Neal Walker
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Christophe Rosty
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Ian Brown
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Andrew Clouston
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Diane McKeone
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Sally-Ann Pearson
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Barbara Leggett
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Vicki Whitehall
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Department of Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia
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Rau T. [Pathogenetic aspects in precursor lesions of gastrointestinal tumors]. DER PATHOLOGE 2016; 37:186-190. [PMID: 27638535 DOI: 10.1007/s00292-016-0220-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The pathogenesis of precursor lesions of gastrointestinal tumors is manifested in many ways. In the esophagus an aberrant genetic expression of intestinal transcription factors, such as CDX2 is initiated by local environment factors. During the subsequent dysplasia to carcinoma sequence, chromosomal gain and loss of genes occurs. A 4-color fluorescence in situ hybridization (FISH) assay can be applied in dysplasia as well as in Barrett's adenocarcinoma to define prognostic marker combinations. In the gastric carcinogenesis sequence the gene expression of CDX1 is regulatively dependent on an interplay between inflammation and promotor methylation. In the colon sessile serrated adenomas show a sequence with initial BRAF mutation and late onset of MLH1 promotor hypermethylation with consecutive potential cancer progression. This event is accompanied by an increase of intraepithelial lymphocytes, which is an easy to use tool for routine diagnostics using H&E sections. Next generation sequencing (NGS) investigations of germline mutations in colorectal cancer revealed a spectrum of mutations with low penetration in the field of mismatch repair proteins as well as the APC gene. An individual risk stratification for penetration of these germline mutations is necessary. In conclusion, genetics, phenotypes and terminology of gastrointestinal precursor lesions are unified to a mutually influencing concept within medicine.
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Affiliation(s)
- T Rau
- Pathologisches Institut, Universitätsklinikum Erlangen, Erlangen, Deutschland. .,Institut für Pathologie, Universität Bern, Murtenstr. 31, 3010, Bern, Schweiz.
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Sessile Serrated Polyps are Precursors of Colon Carcinomas With Deficient DNA Mismatch Repair. Clin Gastroenterol Hepatol 2016; 14:1056-9. [PMID: 26898652 PMCID: PMC4912894 DOI: 10.1016/j.cgh.2016.01.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 01/22/2016] [Accepted: 01/24/2016] [Indexed: 02/07/2023]
Abstract
We investigated whether sessile serrated adenomas/polyps (SSA/Ps) are direct precursors of colorectal carcinomas. We identified colon carcinomas that arose from SSA/Ps among 2646 colorectal cancers included in the surgical pathology database at the Mayo Clinic (2006-2012). Molecular features of the serrated neoplasia pathway were analyzed in these tumors by immunohistochemical analyses of mutant BRAF (V600E) and MLH1 proteins. Among the 33 identified SSA/P-associated colonic adenocarcinomas (median patient age, 75 y), 24 developed in women (73%), 31 were located in the proximal colon (94%), and 23 (69%) were TNM stage I or II. Thirty-one of the tumors (94%) expressed mutant BRAF; of these, 26 also had loss of MLH1 (79%), indicating deficient DNA mismatch repair of sporadic origin. Twenty-two of the tumors (67%) were interval cancers that were more common in women and did not differ significantly in TNM stage, BRAF mutation, or loss of MLH1. By histopathology, SSA/Ps that were associated with colon carcinomas contained frequent dysplasia (48%). Most cancers that arose from SSA/Ps were located on the right side of the colon and had mutant BRAF and loss of MLH1. These findings indicate that SSA/Ps are precursors of most sporadic colon carcinomas with deficient DNA mismatch repair.
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Gibson JA, Odze RD. Pathology of premalignant colorectal neoplasia. Dig Endosc 2016; 28:312-23. [PMID: 26861656 DOI: 10.1111/den.12633] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 01/29/2016] [Accepted: 02/05/2016] [Indexed: 02/08/2023]
Abstract
Colorectal cancer is a heterogeneous oncological disease that develops through several molecular pathways. Each pathway is associated with specific neoplastic precursor lesions. Classification of colorectal polyps and the molecular features of associated colorectal cancers have undergone significant changes. An understanding of colorectal carcinogenesis and the molecular features of colorectal carcinomas is now regarded as necessary for personalized treatment and management of patients with colon cancer, and even for patients undergoing screening colonoscopy for early detection and prevention of colorectal cancer. In the present review, we describe the pathological and molecular features of epithelial precursor lesions involved in the early phases of colorectal carcinogenesis.
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Affiliation(s)
- Joanna A Gibson
- Department of Pathology, Yale University School of Medicine, New Haven, USA
| | - Robert D Odze
- Department of Pathology, Brigham and Women's Hospital, Boston, USA
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Burgess NG, Pellise M, Nanda KS, Hourigan LF, Zanati SA, Brown GJ, Singh R, Williams SJ, Raftopoulos SC, Ormonde D, Moss A, Byth K, P'Ng H, McLeod D, Bourke MJ. Clinical and endoscopic predictors of cytological dysplasia or cancer in a prospective multicentre study of large sessile serrated adenomas/polyps. Gut 2016; 65:437-46. [PMID: 25731869 DOI: 10.1136/gutjnl-2014-308603] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 02/07/2015] [Indexed: 12/29/2022]
Abstract
OBJECTIVE The serrated neoplasia pathway accounts for up to 30% of all sporadic colorectal cancers (CRCs). Sessile serrated adenomas/polyps (SSA/Ps) with cytological dysplasia (SSA/P-D) are a high-risk serrated CRC precursor with little existing data. We aimed to describe the clinical and endoscopic predictors of SSA/P-D and high grade dysplasia (HGD) or cancer. DESIGN Prospective multicentre data of SSA/Ps ≥20 mm referred for treatment by endoscopic mucosal resection (September 2008-July 2013) were analysed. Imaging and lesion assessment was standardised. Histological findings were correlated with clinical and endoscopic findings. RESULTS 268 SSA/Ps were found in 207/1546 patients (13.4%). SSA/P-D comprised 32.4% of SSA/Ps ≥20 mm. Cancer occurred in 3.9%. On multivariable analysis, SSA/P-D was associated with increasing age (OR=1.69 per decade; 95% CI (1.19 to 2.40), p0.004) and increasing lesion size (OR=1.90 per 10 mm; 95% CI (1.30 to 2.78), p0.001), an 'adenomatous' pit pattern (Kudo III, IV or V) (OR=3.98; 95% CI (1.94 to 8.15), p<0.001) and any 0-Is component within a SSA/P (OR=3.10; 95% CI (1.19 to 8.12) p0.021). Conventional type dysplasia was more likely to exhibit an adenomatous pit pattern than serrated dysplasia. HGD or cancer was present in 7.2% and on multivariable analysis, was associated with increasing age (OR=2.0 per decade; 95% CI 1.13 to 3.56) p0.017) and any Paris 0-Is component (OR=10.2; 95% CI 3.18 to 32.4, p<0.001). CONCLUSIONS Simple assessment tools allow endoscopists to predict SSA/P-D or HGD/cancer in SSA/Ps ≥20 mm. Correct prediction is limited by failure to recognise SSA/P-D which may mimic conventional adenoma. Understanding the concept of SSA/P-D and the pitfalls of SSA/P assessment may improve detection, recognition and resection and potentially reduce interval cancer. TRIAL REGISTRATION NUMBER NCT01368289.
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Affiliation(s)
- Nicholas G Burgess
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
| | - Maria Pellise
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Kavinderjit S Nanda
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Luke F Hourigan
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia Department of Gastroenterology and Hepatology, Greenslopes Private Hospital, Brisbane, Queensland, Australia
| | - Simon A Zanati
- Department of Gastroenterology and Hepatology, The Alfred Hospital, Melbourne, Victoria, Australia Department of Gastroenterology and Hepatology, Western Hospital, Melbourne, Victoria, Australia
| | - Gregor J Brown
- Department of Gastroenterology and Hepatology, The Alfred Hospital, Melbourne, Victoria, Australia Department of Gastroenterology and Hepatology, Epworth Hospital, Melbourne, Victoria, Australia
| | - Rajvinder Singh
- Department of Gastroenterology and Hepatology, Lyell McEwin Hospital, Adelaide, South Australia, Australia
| | - Stephen J Williams
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Spiro C Raftopoulos
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Donald Ormonde
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Alan Moss
- Department of Gastroenterology and Hepatology, Western Hospital, Melbourne, Victoria, Australia
| | - Karen Byth
- University of Sydney NHMRC Clinical Trials Centre, Sydney, New South Wales, Australia
| | - Heok P'Ng
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, Australia
| | - Duncan McLeod
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, Australia
| | - Michael J Bourke
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
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Lee EJ, Chun SM, Kim MJ, Jang SJ, Kim DS, Lee DH, Youk EG. Reappraisal of hMLH1 promoter methylation and protein expression status in the serrated neoplasia pathway. Histopathology 2016; 69:198-210. [PMID: 26713412 DOI: 10.1111/his.12925] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 12/23/2015] [Indexed: 12/12/2022]
Abstract
AIMS The aim of this study was to determine whether human mutL homologue 1 (hMLH1) inactivation precedes the progression of sessile serrated lesion (SSL) into SSL with cytological dysplasia (SSL/D) and to define the histological stage at which promoter methylation and inactivation of hMLH1 occur. METHODS AND RESULTS Using the MassARRAY EpiTYPER assay and immunohistochemistry, we examined methylation levels and the protein expression status of hMLH1 in 33 SSL/Ds with conventional epithelial dysplasia and compared the results with those of control hyperplastic polyps (HPs) and SSLs. The methylation level of hMLH1 was higher in the dysplastic component than in the non-dysplastic component of SSL/Ds (P = 0.005), and differed significantly with regard to the degree of dysplasia (P = 0.002). The methylation levels of hMLH1 in the dysplastic component of SSL/Ds tended to be higher than those of control SSLs and HPs (P = 0.063 and P = 0.017, respectively). The loss of hMLH1 protein expression was identified in only 13 of 33 (39.39%) dysplastic components of SSL/Ds. CONCLUSION Promoter methylation and loss of protein expression of hMLH1 are not parallel processes that occur concurrently. hMLH1 methylation is an early molecular event which occurs even in HP. However, the loss of hMLH1 expression is a much later step, found in approximately 40% of SSL/Ds at various histological stages. Notably, the loss of hMLH1 protein expression does not necessarily precede the development of cytological dysplasia in SSL.
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Affiliation(s)
- Eun-Jung Lee
- Department of Surgery, Daehang Hospital, Seoul, Korea
| | - Sung-Min Chun
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Mi-Jung Kim
- Department of Pathology, Daehang Hospital, Seoul, Korea
| | - Se-Jin Jang
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Do Sun Kim
- Department of Surgery, Daehang Hospital, Seoul, Korea
| | - Doo Han Lee
- Department of Surgery, Daehang Hospital, Seoul, Korea
| | - Eui Gon Youk
- Department of Surgery, Daehang Hospital, Seoul, Korea
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Tsai JH, Cheng CH, Chen CC, Lin YL, Lin LI, Chen ML, Liau JY. Traditional serrated adenoma withBRAFmutation is associated with synchronous/metachronousBRAF-mutated serrated lesions. Histopathology 2015; 68:810-8. [DOI: 10.1111/his.12814] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 08/16/2015] [Indexed: 01/09/2023]
Affiliation(s)
- Jia-Huei Tsai
- Department of Pathology; National Taiwan University; Taipei Taiwan
- Graduate Institute of Pathology; College of Medicine; National Taiwan University; Taipei Taiwan
| | - Chien-Hsuan Cheng
- Department of Internal Medicine; National Taiwan University; Taipei Taiwan
| | - Chien-Chuan Chen
- Department of Internal Medicine; National Taiwan University; Taipei Taiwan
| | - Yu-Lin Lin
- Department of Oncology; National Taiwan University; Taipei Taiwan
- Graduate Institute of Clinical Medicine; College of Medicine; National Taiwan University; Taipei Taiwan
| | - Liang-In Lin
- Department of Laboratory Medicine; National Taiwan University; Taipei Taiwan
- Department of Clinical Laboratory Sciences and Medical Biotechnology; College of Medicine; National Taiwan University; Taipei Taiwan
| | - Mei-Ling Chen
- Department of Pathology; National Taiwan University; Taipei Taiwan
| | - Jau-Yu Liau
- Department of Pathology; National Taiwan University; Taipei Taiwan
- Graduate Institute of Pathology; College of Medicine; National Taiwan University; Taipei Taiwan
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Nosho K, Igarashi H, Ito M, Mitsuhashi K, Kurihara H, Kanno S, Yoshii S, Mikami M, Takahashi H, Kusumi T, Hosokawa M, Sukawa Y, Adachi Y, Hasegawa T, Okita K, Hirata K, Maruyama R, Suzuki H, Imai K, Yamamoto H, Shinomura Y. Clinicopathological and molecular characteristics of serrated lesions in Japanese elderly patients. Digestion 2015; 91:57-63. [PMID: 25632919 DOI: 10.1159/000368820] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The population in Japan is aging more rapidly than in any other country. However, no studies have determined the characteristics of the large population of elderly patients with colorectal tumors. Therefore, we examined the clinicopathological and molecular features of these tumors in elderly patients. METHODS In total, 1,627 colorectal tumors (393 serrated lesions, 277 non-serrated adenomas and 957 colorectal cancers) were acquired from patients. Tumor specimens were analyzed for BRAF and KRAS mutations, CpG island methylator phenotype-specific promoters (CACNA1G, CDKN2A, IGF2 and RUNX3), IGFBP7, MGMT, MLH1 and RASSF2 methylation, microsatellite instability (MSI) and microRNA- 31 (miR-31). RESULTS The frequency of elderly patients (aged ≥75 years) with sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that of those with other serrated lesions and non-serrated adenomas (p < 0.0001). In elderly patients, all SSAs were located in the proximal colon (particularly the cecum to ascending colon). High miR-31 expression, MLH1 methylation and MSI-high status were more frequently detected in SSAs from elderly patients than in those from non-elderly patients. In contrast, no significant differences were found between older age of onset and high-grade dysplasia for traditional serrated adenomas or non-serrated adenomas in any of these molecular alterations. CONCLUSION In elderly patients, all SSAs were located in the proximal colon. Furthermore, cytological dysplasia and molecular alterations were more frequently detected in elderly patients with SSAs than in non-elderly patients. Thus, careful colonoscopic examinations of the proximal colon are necessary for elderly patients because SSAs in those patients may exhibit malignant potential.
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Affiliation(s)
- Katsuhiko Nosho
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Yang HM, Mitchell JM, Sepulveda JL, Sepulveda AR. Molecular and histologic considerations in the assessment of serrated polyps. Arch Pathol Lab Med 2015; 139:730-41. [PMID: 26030242 DOI: 10.5858/arpa.2014-0424-ra] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
UNLABELLED CONTEXT : Colorectal cancer is a heterogeneous disease resulting from different molecular pathways of carcinogenesis. Recent data evaluating the histologic features and molecular basis of the serrated polyp-carcinoma pathway have significantly contributed to more comprehensive classifications of and treatment recommendations for these tumors. OBJECTIVE To integrate the most recent molecular findings in the context of histologic classifications of serrated lesions and their implications in diagnostic pathology and colorectal cancer surveillance. DATA SOURCES Published literature focused on serrated polyps and their association with colorectal cancer. CONCLUSIONS Three types of serrated polyps are currently recognized: hyperplastic polyps, sessile serrated adenomas/polyps, and traditional serrated adenomas. The BRAF V600E mutation is one of the most frequent molecular abnormalities identified in hyperplastic polyps and sessile serrated adenomas. In contrast, in traditional serrated adenomas, either BRAF V600E or KRAS mutations can be frequently identified. CpG methylation has emerged as a critical molecular mechanism in the sessile serrated pathway. CpG methylation of MLH1 often leads to reduced or lost expression in dysplastic foci and carcinomas arising in sessile serrated adenomas/polyps.
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Affiliation(s)
- Hui-Min Yang
- From the Department of Pathology and Cell Biology, Columbia University, New York, New York
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