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Florea MA, Becheanu G, Niculae A, Dobre M, Costache M. Immunohistochemical insights into the pathogenesis of colonic sessile serrated lesions. Arch Clin Cases 2025; 12:22-28. [PMID: 40135194 PMCID: PMC11934239 DOI: 10.22551/2025.46.1201.10307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND Sessile serrated lesions (SSLs) are recognized as precursor lesions in the pathogenesis of colorectal cancer, particularly in the context of microsatellite instability (MSI). This study evaluates the role of immunohistochemical (IHC) markers in understanding the molecular and immunologic characteristics of SSLs. MATERIALS AND METHODS A retrospective analysis was performed on 45 colonic neoplastic lesions diagnosed as SSLs. An IHC staining panel was conducted, including MLH1, p53, CD44, CD3, CD8, MUC2, MUC5AC, MUC6, chromogranin and Ki67 antibodies. RESULTS MLH1 and p53 expressions showed correlations with dysplastic changes. Immunological markers CD3 and CD8 indicated a variable immune response, potentially reflecting the tumor's ability to evade immune surveillance in certain situations. CD44 was overexpressed in all SSLs. The number of neuroendocrine cells was overall reduced. CONCLUSIONS SSLs are heterogeneous lesions, exhibiting a wide range of histological and molecular features. Using IHC might enhance diagnostic accuracy, particularly in lesions with ambiguous histological features, when dysplasia develops. Accurate identification of SSLs and understanding their molecular characteristics are crucial for assessing their malignant potential.
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Affiliation(s)
- Maria-Alexandra Florea
- Victor Babeş National Institute of Pathology, Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Gabriel Becheanu
- Victor Babeş National Institute of Pathology, Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Andrei Niculae
- Victor Babeş National Institute of Pathology, Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Maria Dobre
- Victor Babeş National Institute of Pathology, Bucharest, Romania
| | - Mariana Costache
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Pathology Department, Emergency University Hospital, Bucharest, Romania
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Yilmaz O, Arora K, Lee SH, Hosseini S, Chen F, Padmanabha N, Eng G, Kantekure K, Yilmaz O, Deshpande V. LGR5 as a diagnostic marker for dysplasia in serrated polyps. J Clin Pathol 2025:jcp-2024-209856. [PMID: 39788729 DOI: 10.1136/jcp-2024-209856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
AIMS WNT signalling pathway dysregulation is often a critical early component in colorectal neoplasia, particularly the chromosomal instability pathway. Using two WNT reporters, LGR5 and AXIN2, we sought to assess whether these polyps demonstrate predictable expression patterns and if these patterns show diagnostic value. METHODS We evaluated 23 adenomas (TA), 23 sessile serrated lesions (SSLs), 14 SSL with dysplasia and 38 traditional serrated adenomas (TSA). Chromogenic in situ hybridisation stains (ISH) for LGR5 and AXIN2 were performed. Reactivity was defined as strong, intermediate or weak. Upper third crypt reactivity was defined as full-thickness staining. Accentuation within ectopic crypts (ECF) was recorded. RESULTS TAs (91%) showed strong reactivity and full-thickness staining with LGR5. TSAs showed full-thickness and weak to intermediate LGR5 reactivity (79%) and ECF with LGR5 accentuation was exclusively seen in TSA. SSL showed weak LGR5 reactivity confined to the basal crypt region (100%). SSL with dysplasia also showed weak or intermediate (100%) LGR5 reactivity, but the reactivity pattern was full thickness (88%). AXIN2 expression parallels LGR5 expression (Pearson coefficient=0.63) regarding signal intensity for the examined polyp groups. CONCLUSIONS Qualitative and quantitative differences in AXIN2 and LGR5 expression assist in the diagnosis of SSL with dysplasia.
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Affiliation(s)
- Osman Yilmaz
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Kshtij Arora
- Massachusetts General Hospital, Wuincy, Massachusetts, USA
| | - Soo Hyun Lee
- Boston Medical Center, Boston, Massachusetts, USA
| | | | - Feidi Chen
- Harvard Medical School, Boston, Massachusetts, USA
| | - Nandan Padmanabha
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - George Eng
- Harvard Medical School, Boston, Massachusetts, USA
| | | | - Omer Yilmaz
- Massachusetts General Hospital, Boston, Massachusetts, USA
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Rahmatallah Y, Glazko G. Improving data interpretability with new differential sample variance gene set tests. RESEARCH SQUARE 2024:rs.3.rs-4888767. [PMID: 39315246 PMCID: PMC11419169 DOI: 10.21203/rs.3.rs-4888767/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Background Gene set analysis methods have played a major role in generating biological interpretations from omics data such as gene expression datasets. However, most methods focus on detecting homogenous pattern changes in mean expression and methods detecting pattern changes in variance remain poorly explored. While a few studies attempted to use gene-level variance analysis, such approach remains under-utilized. When comparing two phenotypes, gene sets with distinct changes in subgroups under one phenotype are overlooked by available methods although they reflect meaningful biological differences between two phenotypes. Multivariate sample-level variance analysis methods are needed to detect such pattern changes. Results We use ranking schemes based on minimum spanning tree to generalize the Cramer-Von Mises and Anderson-Darling univariate statistics into multivariate gene set analysis methods to detect differential sample variance or mean. We characterize these methods in addition to two methods developed earlier using simulation results with different parameters. We apply the developed methods to microarray gene expression dataset of prednisolone-resistant and prednisolone-sensitive children diagnosed with B-lineage acute lymphoblastic leukemia and bulk RNA-sequencing gene expression dataset of benign hyperplastic polyps and potentially malignant sessile serrated adenoma/polyps. One or both of the two compared phenotypes in each of these datasets have distinct molecular subtypes that contribute to heterogeneous differences. Our results show that methods designed to detect differential sample variance are able to detect specific hallmark signaling pathways associated with the two compared phenotypes as documented in available literature. Conclusions The results in this study demonstrate the usefulness of methods designed to detect differential sample variance in providing biological interpretations when biologically relevant but heterogeneous changes between two phenotypes are prevalent in specific signaling pathways. Software implementation of the developed methods is available with detailed documentation from Bioconductor package GSAR. The available methods are applicable to gene expression datasets in a normalized matrix form and could be used with other omics datasets in a normalized matrix form with available collection of feature sets.
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Affiliation(s)
- Yasir Rahmatallah
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Galina Glazko
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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Chetty R. Serrated and mucinous appendiceal lesions: a viewpoint. J Clin Pathol 2024; 77:452-456. [PMID: 38772615 DOI: 10.1136/jcp-2024-209554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/01/2024] [Indexed: 05/23/2024]
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Su MC, Hsu CH, Chen KC, Lin JR, Li HY, Fang YT, Huang RYJ, Jeng YM. Identification of Early Events in Serrated Pathway Colorectal Tumorigenesis by Using Digital Spatial Profiling. Pathobiology 2024; 91:393-410. [PMID: 38830348 PMCID: PMC11614314 DOI: 10.1159/000539612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 05/30/2024] [Indexed: 06/05/2024] Open
Abstract
INTRODUCTION The colorectal serrated pathway involves precursor lesions known as sessile serrated lesions (SSL) and traditional serrated adenomas (TSA). Mutations in BRAF or KRAS are crucial early events in this pathway. Additional genetic and epigenetic changes contribute to the progression of these lesions into high-grade lesions and, eventually, invasive carcinoma. METHODS We employed digital spatial profiling to investigate the transcriptional changes associated with SSL and TSA. The genes identified are confirmed by immunohistochemical (IHC) staining. Colorectal cancer (CRC) cell lines with CEACAM6 overexpression and knockdown were established to study the roles of CEACAM6 on tumorigenesis of CRC. RESULTS Ten genes were upregulated in SSL and TSA, and seven were upregulated in both types of lesions. IHC staining confirmed overexpression of CEACAM6, LCN2, KRT19, and lysozyme in SSL and TSA. CEACAM6 expression is an early event in the serrated pathway but a late event in the conventional pathway. Using cell line models, we confirmed that CEACAM6 promotes CRC cells' proliferation, migration, and invasion abilities. CONCLUSION These results highlight that the transcriptional changes in the early stages of tumorigenesis exhibit relative uniformity. Identifying these early events may hold significant promise in elucidating the mechanisms behind tumor initiation.
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Affiliation(s)
- Min-Cheng Su
- Department of Pathology, Min-Sheng General Hospital, Taoyuan, Taiwan
| | - Ching-Hsiang Hsu
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan
| | - Ko-Chen Chen
- School of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Jun-Ru Lin
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan
| | - Huei-Ying Li
- Medical Microbiota Center of the First Core Laboratory, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Ting Fang
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ruby Yun-Ju Huang
- School of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yung-Ming Jeng
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
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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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Matoba H, Iwaya M, Sato Y, Kobayashi N, Takemura H, Kouno Y, Karasawa A, Nakayama J. Increased GS-II lectin binding and SATB2 downregulation are biological features for sessile serrated lesions and microvesicular hyperplastic polyps. Pathol Int 2023; 73:246-254. [PMID: 37036163 PMCID: PMC11551811 DOI: 10.1111/pin.13321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/15/2023] [Indexed: 04/11/2023]
Abstract
Sessile serrated lesions (SSLs) and microvesicular hyperplastic polyps (MVHPs) are colorectal lesions displaying gastric differentiation. Griffonia simplicifolia-II (GS-II) is a lectin specific to terminal α/βGlcNAc residues. Here, we assessed GS-II binding and performed immunostaining for HIK1083 (specific to terminal αGlcNAc residues), MUC5AC, MUC6, and special AT-rich sequence binding protein 2 (SATB2) in SSLs, MVHPs, and tubular adenomas (TAs). We observed MUC5AC positivity in 28 of 30 SSLs, but in only three of 23 TAs. Moreover, 24 of 30 SSLs were MUC6-positive, while none of the 23 TAs were MUC6-positive. None of the 30 SSLs or 23 TAs showed HIK1083 positivity. All 30 SSLs and 26 MVHPs were GS-II-positive, while only seven of 23 were in TAs. GS-II staining was mainly distributed in the Golgi region, but SSLs and MVHPs showed goblet cell distribution, in 20 of 30 and 19 of 26 cases, respectively. All SSLs, MVHPs, and TAs were SATB2-positive, but 21 of 30 SSLs and 12 of 26 MVHPs showed decreased staining intensity relative to adjacent mucosa, a decrease seen in only two of 23 in TAs. These results indicate overall that increased terminal βGlcNAc and decreased SATB2 expression are characteristics of SSLs and MVHPs.
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Affiliation(s)
- Hisanori Matoba
- Department of Molecular PathologyShinshu University School of MedicineMatsumotoJapan
| | - Mai Iwaya
- Department of Laboratory Medicine and PathologyShinshu University HospitalMatsumotoJapan
| | - Yoshiko Sato
- Department of Molecular PathologyShinshu University School of MedicineMatsumotoJapan
| | - Noriyasu Kobayashi
- Department of Laboratory MedicineJA North Alps Medical Center Azumi HospitalOaza‐ikedaKitaazumi‐gunJapan
| | - Haruka Takemura
- Department of Laboratory MedicineJA North Alps Medical Center Azumi HospitalOaza‐ikedaKitaazumi‐gunJapan
| | - Yusuke Kouno
- Department of PathologyIna Central HospitalKoshiroukuboInaJapan
| | - Ayumi Karasawa
- Department of PathologyIna Central HospitalKoshiroukuboInaJapan
| | - Jun Nakayama
- Department of Molecular PathologyShinshu University School of MedicineMatsumotoJapan
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Klorin G, Hayat N, Linder R, Amit A, Reiss A, Sabo E. Fourier transformation based texture analysis for differentiating between hyperplastic polyps and sessile serrated adenomas. Microsc Res Tech 2023; 86:473-480. [PMID: 36625540 DOI: 10.1002/jemt.24288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 11/17/2022] [Accepted: 12/16/2022] [Indexed: 01/11/2023]
Abstract
Colorectal cancer (CRC) is the third most common type of cancer. One major pathway involved in the development of CRC is the serrated pathway. Colorectal polyps can be divided in benign, like small hyperplastic polyps and premalignant polyps, like the sessile serrated adenomas (SSA) that has a significant potential of malignant transformation. The morphological similarity between these types of polyp, not-infrequently raises diagnostic difficulties. This study aimed to morphologically differentiate between hyperplastic polyps (HP) and SSAs by using automated computerized texture analysis of Fourier transformed histological images. Thirty images of HP and 58 images of SSA were analyzed by computerized texture analysis. A fast Fourier transformation was applied to the images. The Fourier frequency plots were further transformed into gray level co-occurrence matrices and four textural variables were extracted: entropy, correlation, contrast, and homogeneity. Our study is the first to combine this type of analysis for automated classification of colonic neoplasia. The results were analyzed using statistical and neural network (NNET) classification models. The predictive values of these classifiers were compared. The statistical regression algorithm presented a sensitivity of 95% to detect the SSA and a specificity of 80% to detect the HP. The NNET analysis was superior to the statistical analysis displaying a classification accuracy of 100%. The results of this study have confirmed the hypothesis that Fourier based texture image analysis is helpful in differentiating between HP and SSA. RESEARCH HIGHLIGHTS: Colorectal polyps can be divided in benign, like hyperplastic polyps (HP) and premalignant, like the sessile serrated adenomas (SSA). There is a high morphologic similarity between these two types of polyp that not-infrequently raises diagnostic difficulties. The results of our morphometric analysis that were used to build a neural network based model of prediction of the polyp types, have a great clinical importance of identifying SSA polyps which have significant potential of malignant progression as compared to HP.
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Affiliation(s)
- Geula Klorin
- Department of Internal Medicine B, Rambam Health Care Campus, Haifa, Israel
- Department of Gyneco-Oncology, Rambam Health Care Campus, Haifa, Israel
- Technion-Israel Institute of Technology, Faculty of Medicine, Haifa, Israel
| | - Noa Hayat
- Technion-Israel Institute of Technology, Faculty of Medicine, Haifa, Israel
| | - Revital Linder
- Department of Gyneco-Oncology, Rambam Health Care Campus, Haifa, Israel
| | - Amnon Amit
- Department of Gyneco-Oncology, Rambam Health Care Campus, Haifa, Israel
- Technion-Israel Institute of Technology, Faculty of Medicine, Haifa, Israel
| | - Ari Reiss
- Department of Gyneco-Oncology, Rambam Health Care Campus, Haifa, Israel
| | - Edmond Sabo
- Technion-Israel Institute of Technology, Faculty of Medicine, Haifa, Israel
- Department of Pathology, Carmel Medical Center, Haifa, Israel
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Bateman AC, Booth AL, Gonzalez RS, Shepherd NA. Microvesicular hyperplastic polyp and sessile serrated lesion of the large intestine: a biological continuum or separate entities? J Clin Pathol 2023:jcp-2023-208783. [PMID: 36927607 DOI: 10.1136/jcp-2023-208783] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 03/07/2023] [Indexed: 03/18/2023]
Abstract
The range of lesions with a serrated appearance within the large intestine has expanded and become more complex over the last 30 years. The majority of these were previously known as metaplastic polyps but are today called hyperplastic polyps (HPs). HPs show two main growth patterns: microvesicular and goblet cell-rich. The former type shows morphological and molecular similarities (eg, BRAF mutations) to the more recently described sessile serrated lesion (SSL). In this review, we debate whether these lesions represent a biological spectrum or separate entities. Whichever view is held, microvesicular HPs and SSLs are distinct from the goblet cell-rich HP and the traditional serrated adenoma (TSA), which may themselves share molecular changes (eg, KRAS mutations), with the goblet cell-rich HP representing a precursor to the TSA. Both SSLs and the goblet cell-rich HP-TSA pathway are routes to colorectal cancer within the serrated pathway and overlaps between them can occur, for example, a (BRAF-mutated) TSA may arise from an SSL.
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Affiliation(s)
- Adrian C Bateman
- Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Adam L Booth
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Raul S Gonzalez
- Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Neil A Shepherd
- Gloucestershire Cellular Pathology Laboratory, Cheltenham, UK
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Vithayathil M, Smith S, Song M. Epidemiology of overall and early-onset serrated polyps versus conventional adenomas in a colonoscopy screening cohort. Int J Cancer 2023; 152:1085-1094. [PMID: 36178673 DOI: 10.1002/ijc.34306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/12/2022] [Accepted: 09/23/2022] [Indexed: 01/21/2023]
Abstract
Serrated polyps (SPs) are precursors to one-third of colorectal cancers (CRCs), with histological subtypes: hyperplastic polyps (HPs), sessile serrated lesions (SSLs) and traditional serrated adenomas (TSAs). The incidence of early-onset CRC before the age of 50 is increasing, with limited understanding of SPs in younger cohorts. Using a large colonoscopy-based cohort, we characterized epidemiologic profiles of SP subtypes, compared to conventional adenomas, with secondary analysis on early-onset polyps. Ninety-four thousand four hundred and twenty-seven patients underwent screening colonoscopies between 2010 and 2018. Demographic, endoscopic and histopathologic characteristics of each polyp subtype were described. High-risk polyps included SSLs ≥10 mm/with dysplasia and conventional adenomas ≥10 mm/with tubulovillous/villous histology/high-grade dysplasia. We examined polyp prevalence with age and compared early- (age < 50) and late-onset polyps (age ≥ 50). Eighteen thousand one hundred and twenty-five patients had SPs (4357 SSLs, 15 415 HPs, 120 TSAs) and 26 699 had conventional adenomas. High-risk SSLs were enriched in the ascending colon (44.1% vs 2.6-35.8% for other locations; P < .003). Early- and late-onset SPs had similar subsite distribution. Early-onset conventional adenomas were more enriched in the distal colon/rectum (51.8% vs 43.4%, P < .001). Multiple conventional adenomas were more represented in late-onset groups (40.8% vs 33.8%, P < .001), with no difference in SSLs. The prevalence of conventional adenomas/high-risk conventional adenomas increased continuously with age, whereas the prevalence of SSLs/high-risk SSLs was stable from age 40 years onwards. A higher proportion of women were diagnosed with early-onset than late-onset SSLs (62.9% vs 57.6%, P = .03). Conventional adenomas, SSLs, early- and late-onset polyps have distinct epidemiology. The findings have implications for improved colonoscopy screening and surveillance and understanding the etiologic heterogeneity of CRC.
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Affiliation(s)
- Mathew Vithayathil
- Department of Epidemiology and Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Scott Smith
- Department of Epidemiology and Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Mingyang Song
- Department of Epidemiology and Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Significance of Micromorphological Characteristics and Expression of Intermediate Filament Proteins CK7 and CK20 in the Differential Diagnosis of Serrated Lesions of the Colorectum. GASTROENTEROLOGY INSIGHTS 2023. [DOI: 10.3390/gastroent14010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/03/2023] Open
Abstract
Serrated lesions in the colorectum include all epithelial neoplastic lesions, which show a sawtooth-like morphology in the epithelial crypts. Classification systems nosologically divide colon serrated polyps into three different categories, primarily emphasizing their micromorphological growth pattern and cytodifferentiation: (1) hyperplastic polyps, (2) sessile serrated adenomas/polyps and (3) traditional serrated adenomas. Overall, 109 patients with serrated lesions of the colon, who underwent endoscopic or surgical polypectomy/tumorectomy during one or multiple endoscopic or surgical interventions, over a four-year period, were analyzed. The average age of patients was 62.8 ± 11.6 years. The frequency of serrated lesions of the colon in male patients was 2.4 times higher than in females (70.6% vs. 29.4%). All sessile serrated lesions without dysplasia were positive for CK7 and statistically significant compared to other serrated lesions, if this positivity was present in the complete crypt (p = 0.005). CK20 positivity, which is limited to the upper half of the crypt, is a special feature of hyperplastic polyps compared to other serrated lesions, which is statistically significant (p = 0.0078). Whereas, CK20 positivity of complete crypts is a statistically significant feature of traditional serrated adenomas (p < 0.01). Differences in the expression pattern of cytokeratin 7 and 20 in different serrated lesions may indicate different pathways of colorectal carcinogenesis, and be diagnostically and prognostically useful.
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Serrated polyps in patients with ulcerative colitis: Unique clinicopathological and biological characteristics. PLoS One 2023; 18:e0282204. [PMID: 36827302 PMCID: PMC9955668 DOI: 10.1371/journal.pone.0282204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 02/10/2023] [Indexed: 02/25/2023] Open
Abstract
BACKGROUND Serrated polyps have recently been reported in patients with ulcerative colitis (UC); however, their prevalence and detailed characteristics remain unclear. METHODS The prevalence and clinicopathological and biological characteristics of serrated polyps in patients with UC were retrospectively examined in a single tertiary inflammatory bowel disease center in Japan from 2000 to 2020. RESULTS Among 2035 patients with UC who underwent total colonoscopy, 252 neoplasms, including 36 serrated polyps (26 in colitis-affected segments, 10 in colitis-unaffected segments), were identified in 187 patients with UC. The proportion of serrated polyps was 1.8% (36/2035). Serrated polyps in colitis-affected segments were common with extensive colitis (88%), history of persistent active colitis (58%), and long UC duration (12.1 years). Serrated polyps in colitis-affected segments were more common in men (88%). Of the 26 serrated polyps in colitis-affected segments, 15, 6, and 5 were categorized as sessile serrated lesion-like dysplasia, traditional serrated adenoma-like dysplasia, and serrated dysplasia not otherwise specified, respectively. Sessile serrated lesion-like dysplasia was common in the proximal colon (67%) and with BRAF mutation (62%), whereas traditional serrated adenoma-like dysplasia and serrated dysplasia not otherwise specified were common in the distal colon (100% and 80%, respectively) and with KRAS mutations (100% and 75%, respectively). CONCLUSIONS Serrated polyps comprised 14% of the neoplasias in patients with UC. Serrated polyps in colitis-affected segments were common in men with extensive and longstanding colitis, suggesting chronic inflammation in the development of serrated polyps in patients with UC.
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Waters KM, Singhi AD, Montgomery EA. Exploring the spectrum of serrated epithelium encountered in inflammatory bowel disease. Hum Pathol 2023; 132:126-134. [PMID: 35753410 PMCID: PMC11186602 DOI: 10.1016/j.humpath.2022.06.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 06/17/2022] [Indexed: 02/07/2023]
Abstract
Patients with inflammatory bowel disease (IBD) are at an increased risk for colorectal cancer. Currently, dysplasia is the best marker of CRC risk. Assessing dysplasia is a challenging task for pathologists as the longstanding inflammation causes marked reactive cytologic changes and architectural distortion. Recent descriptions of nonconventional types of dysplasia in IBD have added to the complexity. In this review, we focus on the clinical, endoscopic, histologic, and molecular findings in lesions with serrated epithelium. Serrated epithelial change (SEC), sessile serrated lesion (SSL)-like, serrated lesion-not otherwise specified (SL-NOS), and traditional serrated adenoma (TSA)-like lesions all typically occur in patients with longstanding IBD with mean ages in the fifth-sixth decade. SEC is often encountered in nontargeted biopsies while the others form visible polyps. While serrated lesions have significant histologic overlap, subtle differences can help pathologists separate them. SEC has markedly distorted architecture with crypts losing perpendicular orientation to the muscularis mucosae. The crypts are goblet cell-rich and have irregular serrations that involve the full length of the crypt. SSL-like lesions are goblet cell poor and have microvesicular cytoplasm. Like their sporadic counterpart in non-IBD patients, these lesions have lateral growth at the crypt bases. TSA-like lesions are characterized by their villous architecture, ectopic crypts, pink cytoplasm, and hyperchromatic elongated nuclei. We also explore molecular findings that help in distinguishing these lesions, current knowledge on the association of each of these lesions with dysplasia and CRC, and future research needed to better characterize these entities.
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Affiliation(s)
- Kevin M Waters
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Elizabeth A Montgomery
- Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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15
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Özsoy Ş, Deniz K, Temiz MZ, Semerciöz A. Traditional Serrated Adenoma of the Urinary Bladder: The First Report. Int J Surg Pathol 2022:10668969221113495. [PMID: 35898180 DOI: 10.1177/10668969221113495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
A 71-year-old woman was hospitalized with hematuria and underwent cystourethroscopy. Cystourethroscopy revealed a polypoid bladder tumor. Histopathologic examination showed complex villiform growth pattern, slit-like serrations, and ectopic crypts lined by epithelium with eosinophilic cytoplasm, pseudostratified elongated nuclei, consistent with traditional serrated adenoma. Nephrogenic and intestinal metaplasia with severe inflammation were present in adjacent bladder mucosa. Molecular study of the polyp revealed mutation (p.G12V) in codon 12 of exon 2 of the KRAS gene. Traditional serrated adenoma is a rare type of colonic serrated polyp, making up less than 1% of the colonic polyps with a predilection to distal colon. In the literature, there is no traditional serrated adenoma reported outside the gastrointestinal tract. Here in we report the first extra-gastrointestinal traditional serrated adenoma within the bladder and bladder diverticulum, arising from intestinal metaplasia. The present study reports an additional information on molecular background of this unusual bladder polyp.
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Affiliation(s)
- Şule Özsoy
- Department of Pathology, University of Health Sciences, Bağcılar Training and Research Hospital, İstanbul, Turkey
| | - Kemal Deniz
- Department of Pathology, Erciyes University, Kayseri, Turkey
| | - Mustafa Zafer Temiz
- Department of Urology, University of Health Sciences, Bağcılar Training and Research Hospital, İstanbul, Turkey
| | - Atilla Semerciöz
- Department of Urology, University of Health Sciences, Bağcılar Training and Research Hospital, İstanbul, Turkey
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16
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Serrated Colorectal Lesions: An Up-to-Date Review from Histological Pattern to Molecular Pathogenesis. Int J Mol Sci 2022; 23:ijms23084461. [PMID: 35457279 PMCID: PMC9032676 DOI: 10.3390/ijms23084461] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/16/2022] [Accepted: 04/17/2022] [Indexed: 12/10/2022] Open
Abstract
Until 2010, colorectal serrated lesions were generally considered as harmless lesions and reported as hyperplastic polyps (HPs) by pathologists and gastroenterologists. However, recent evidence showed that they may bear the potential to develop into colorectal carcinoma (CRC). Therefore, the World Health Organization (WHO) classification has identified four categories of serrated lesions: hyperplastic polyps (HPs), sessile serrated lesions (SSLs), traditional serrated adenoma (TSAs) and unclassified serrated adenomas. SSLs with dysplasia and TSAs are the most common precursors of CRC. CRCs arising from serrated lesions originate via two different molecular pathways, namely sporadic microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP), the latter being considered as the major mechanism that drives the serrated pathway towards CRC. Unlike CRCs arising through the adenoma-carcinoma pathway, APC-inactivating mutations are rarely shown in the serrated neoplasia pathway.
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17
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Miller Q, Saeed O, Mesa H. Clinical, Pathologic, and Molecular-Genetic Aspects of Colorectal Polyps. Gastrointest Endosc Clin N Am 2022; 32:313-328. [PMID: 35361338 DOI: 10.1016/j.giec.2021.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Most colorectal cancer arises from epithelial polyps. Polyps can be the result of acquired, germline, or inflammation-associated mutations in colonic stem cells (CSC). Their incidence and risk of progression are determined by factors that modify the baseline rate of spontaneous mutations occurring in CSC. In sporadic polyps, factors are primarily environmental; in individuals with germline mutations, it is the specific mutation, and in inflammation-associated polyps, it correlates with the extent, duration, and severity of the process. The different clinicopathologic and molecular genetic abnormalities underlying the different types of polyps are discussed.
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Affiliation(s)
- Quinn Miller
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, IU Health Pathology Laboratory, 350 West 11th Street, Indianapolis, IN 46202, USA
| | - Omer Saeed
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, IU Health Pathology Laboratory, 350 West 11th Street, Indianapolis, IN 46202, USA
| | - Hector Mesa
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, IU Health Pathology Laboratory, 350 West 11th Street, Indianapolis, IN 46202, USA.
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18
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Chu JE, Hamm J, Gentile L, Telford JJ, Schaeffer DF. Serrated Lesion Detection in a Population-based Colon Screening Program. J Clin Gastroenterol 2022; 56:243-248. [PMID: 33780220 DOI: 10.1097/mcg.0000000000001519] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 01/28/2021] [Indexed: 12/10/2022]
Abstract
BACKGROUND Serrated lesions give rise to 15% to 30% of all colorectal cancers, driven predominantly by the sessile serrated polyp (SSP). Fecal immunochemical test (FIT), has low sensitivity for SSPs. SSP detection rate (SSPDR) is influenced by performance of both endoscopists and pathologists, as diagnosis can be subtle both on endoscopy and histology. GOALS To evaluate the SSPDR in a population-based screening program, and the influence of subspecialty trained pathologists on provincial reporting practices. STUDY The colon screening program database was used to identify all FIT-positive patients that received colonoscopy between January 2014 and June 2017. Patient demographics, colonoscopy quality indicators, pathologic diagnoses, and FIT values were collected. This study received IRB approval. RESULTS A total of 74,605 colonoscopies were included and 26.6% had at least 1 serrated polyp removed. The SSPDR was 7.0%, with 59% of the SSPs detected having a concurrent conventional adenoma. The mean FIT value for colonoscopies with only serrated lesions was less than that for colonoscopies with a conventional adenoma or colorectal cancer (P<0.0001). Centers with a gastrointestinal subspecialty pathologist diagnosed proportionally more SSPs (P<0.0001), and right-sided SSPs than centers without subspecialists. CONCLUSIONS Serrated lesions often occur in conjunction with conventional adenomas and are associated with lower FIT values. Knowledge of the characteristics of SSPs is essential for pathologists to ensure accurate diagnosis of SSPs.
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Affiliation(s)
- Jenny E Chu
- Department of Pathology and Laboratory Medicine, Vancouver General Hospital
| | | | | | - Jennifer J Telford
- BC Cancer
- Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada
| | - David F Schaeffer
- Department of Pathology and Laboratory Medicine, Vancouver General Hospital
- BC Cancer
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19
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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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20
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Nagtegaal ID, Snover DC. Head to head: should we adopt the term "sessile serrated lesion"? Histopathology 2022; 80:1019-1025. [PMID: 35040174 PMCID: PMC9311759 DOI: 10.1111/his.14618] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/06/2022] [Accepted: 01/12/2022] [Indexed: 11/28/2022]
Abstract
The precursor lesion for the ~30% of colon carcinomas developing along the serrated pathway was first described in detail in 1996, and was named sessile serrated adenoma in 2003. Although the entity itself was controversial initially, over time the concept of a serrated pathway initiated by this lesion has become well accepted in the medical community. The name sessile serrated adenoma, however, has been controversial since the beginning and continues to be controversial. Alternative names, including serrated polyp with abnormal proliferation, sessile serrated polyp and, most recently, sessile serrated lesion, have been proposed. Despite the fact that the term sessile serrated lesion was adopted by the World Health Organization in 2019, none of these terms has received universal acceptance. In this article, arguments for and against adopting the term sessile serrated lesion are discussed in detail.
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Affiliation(s)
- Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Dale C Snover
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA
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21
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Mitra S, Paramaguru R, Das P, Katti SV. Preneoplastic Lesions and Polyps of the Gastrointestinal Tract. SURGICAL PATHOLOGY OF THE GASTROINTESTINAL SYSTEM 2022:593-698. [DOI: 10.1007/978-981-16-6395-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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22
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Alruwaii ZI, Chianchiano P, Larman T, Wilentz A, Wood LD, Montgomery EA. Familial Adenomatous Polyposis-associated Traditional Serrated Adenoma of the Small Intestine: A Clinicopathologic and Molecular Analysis. Am J Surg Pathol 2021; 45:1626-1632. [PMID: 34232600 DOI: 10.1097/pas.0000000000001770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Familial adenomatous polyposis (FAP) is an inherited cancer predisposition syndrome associated with numerous gastrointestinal tract adenomatous polyps, as well as gastric fundic gland polyps and pyloric gland adenomas in the upper gastrointestinal tract. While colonic FAP-associated traditional serrated adenomas (TSAs) have been reported in a few studies, small bowel FAP-associated adenomas with TSA morphology have not been characterized. This study describes the clinicopathologic and molecular findings of this type of adenoma in the small bowel of patients with FAP. We reviewed small bowel adenomas in 45 consecutive FAP patients to identify adenomas with zones showing slit-like serrations, cells with eosinophilic cytoplasm, ectopic crypt formation, and vesicular nuclei. Sporadic small bowel adenomas from 51 consecutive patients were also reviewed for adenomas with the same features. Of the 177 polyps from 45 FAP patients and 60 polyps from 51 nonsyndromic patients, 18 TSAs from 9 FAP patients (20%) and 10 TSAs from the sporadic group (19.6%) were identified. FAP patients presented at a younger age than nonsyndromic patients (median: 43 vs. 66; P=0.0048). FAP-associated TSAs were asymptomatic and smaller than sporadic TSAs (median size: 0.6 vs. 2.5 cm; P=0.00006). Immunostaining for β-catenin and testing for BRAF and KRAS mutations were performed in a subset of the cohort. Nuclear β-catenin was seen in 1 FAP-associated TSA and 3 nonsyndromic TSAs. All TSAs (FAP-associated and nonsyndromic) showed wild-type BRAF, while KRAS mutations were identified only in the nonsyndromic setting. In summary, small bowel FAP-associated and sporadic TSAs share a similar morphology, and the BRAF-serrated pathway does not contribute to their pathogenesis.
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Affiliation(s)
| | | | | | | | - Laura D Wood
- Department of Pathology, Johns Hopkins School of Medicine
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University of Medicine, Baltimore, MD
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23
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Heino S, Fang S, Lähde M, Högström J, Nassiri S, Campbell A, Flanagan D, Raven A, Hodder M, Nasreddin N, Xue HH, Delorenzi M, Leedham S, Petrova TV, Sansom O, Alitalo K. Lef1 restricts ectopic crypt formation and tumor cell growth in intestinal adenomas. SCIENCE ADVANCES 2021; 7:eabj0512. [PMID: 34788095 PMCID: PMC8598008 DOI: 10.1126/sciadv.abj0512] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 09/28/2021] [Indexed: 06/13/2023]
Abstract
Somatic mutations in APC or CTNNB1 genes lead to aberrant Wnt signaling and colorectal cancer (CRC) initiation and progression via-catenin–T cell factor/lymphoid enhancer binding factor TCF/LEF transcription factors. We found that Lef1 was expressed exclusively in Apc-mutant, Wnt ligand–independent tumors, but not in ligand-dependent, serrated tumors. To analyze Lef1 function in tumor development, we conditionally deleted Lef1 in intestinal stem cells of Apcfl/fl mice or broadly from the entire intestinal epithelium of Apcfl/fl or ApcMin/+ mice. Loss of Lef1 markedly increased tumor initiation and tumor cell proliferation, reduced the expression of several Wnt antagonists, and increased Myc proto-oncogene expression and formation of ectopic crypts in Apc-mutant adenomas. Our results uncover a previously unknown negative feedback mechanism in CRC, in which ectopic Lef1 expression suppresses intestinal tumorigenesis by restricting adenoma cell dedifferentiation to a crypt-progenitor phenotype and by reducing the formation of cancer stem cell niches.
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Affiliation(s)
- Sarika Heino
- Translational Cancer Medicine Program (CAN-PRO), iCAN Digital Precision Cancer Medicine Flagship and Wihuri Research Institute, Faculty of Medicine, HiLIFE-Helsinki Institute of Life Science, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
| | - Shentong Fang
- Translational Cancer Medicine Program (CAN-PRO), iCAN Digital Precision Cancer Medicine Flagship and Wihuri Research Institute, Faculty of Medicine, HiLIFE-Helsinki Institute of Life Science, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
- School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China
| | - Marianne Lähde
- Translational Cancer Medicine Program (CAN-PRO), iCAN Digital Precision Cancer Medicine Flagship and Wihuri Research Institute, Faculty of Medicine, HiLIFE-Helsinki Institute of Life Science, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
| | - Jenny Högström
- Translational Cancer Medicine Program (CAN-PRO), iCAN Digital Precision Cancer Medicine Flagship and Wihuri Research Institute, Faculty of Medicine, HiLIFE-Helsinki Institute of Life Science, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
| | - Sina Nassiri
- Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Andrew Campbell
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, Garscube Estate, Glasgow G61 1QH, UK
| | - Dustin Flanagan
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, Garscube Estate, Glasgow G61 1QH, UK
| | - Alexander Raven
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, Garscube Estate, Glasgow G61 1QH, UK
| | - Michael Hodder
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, Garscube Estate, Glasgow G61 1QH, UK
| | - Nadia Nasreddin
- Intestinal Stem Cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Hai-Hui Xue
- Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ 07110, USA
| | - Mauro Delorenzi
- Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Department of Oncology, University of Lausanne and CHUV, Epalinges, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Epalinges, Switzerland
| | - Simon Leedham
- Intestinal Stem Cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Tatiana V. Petrova
- Department of Oncology, University of Lausanne and CHUV, Epalinges, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Epalinges, Switzerland
| | - Owen Sansom
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, Garscube Estate, Glasgow G61 1QH, UK
| | - Kari Alitalo
- Translational Cancer Medicine Program (CAN-PRO), iCAN Digital Precision Cancer Medicine Flagship and Wihuri Research Institute, Faculty of Medicine, HiLIFE-Helsinki Institute of Life Science, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland
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Abstract
The serrated pathway of carcinogenesis has been the subject of intense investigation over the past 2 decades, but many gaps in our understanding still need to be resolved. Serrated polyp precursors include hyperplastic polyps, sessile serrated polyps, and traditional serrated adenomas. These are considered discrete entities, but there is emerging molecular data to suggest that they may be more closely related to each other than currently believed. The recent US Multi-Society Task Force surveillance guidelines for patients with serrated polyps are admittedly based on low quality evidence. In this brief review, we discuss the limitations in endoscopic detection and pathologic interpretation of serrated polyps and the implications of these diagnostic difficulties on risk prediction and postpolypectomy surveillance recommendations.
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25
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Kühl Svoboda Baldin R, Austrália Paredes Marcondes Ribas C, de Noronha L, Veloso da Silva-Camargo CC, Santos Sotomaior V, Martins Sebastião AP, Vasconcelos de Castilho AP, Rodrigues Montemor Netto M. Expression of Parkin, APC, APE1, and Bcl-xL in Colorectal Polyps. J Histochem Cytochem 2021; 69:437-449. [PMID: 34126796 PMCID: PMC8246528 DOI: 10.1369/00221554211026296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/01/2021] [Indexed: 11/22/2022] Open
Abstract
Colorectal cancer can develop through molecular, chromosomal, and epigenetic cumulative changes that transform the normal intestinal epithelium into the colorectal polyps, called conventional adenomas (CAs) or serrated polyps (SPs), recognized as precursors of invasive colorectal neoplasia. These benign lesions need to explore the morphology, histological diagnosis, and biomarkers profile to accurately characterize lesions with potential for evolution to cancer. This study aimed to correlate the immunohistochemical expression of Parkin and Adenomatous Polyposis Coli (APC; tumor suppressors), Human Apurinic/Apyrimidinic endonuclease 1 (APE1), and B-cell lymphoma-extra-large (Bcl-xL; oncogenic proteins) in sporadic colorectal polyps with clinical, endoscopic, and diagnostic data. Immunohistochemical analysis was performed on tissue microarray samples of 306 polyps. Based on the Allred score, the expressions were graduated in the cytoplasm and nucleus of superficial and cryptic cells. There was higher Parkin nuclear expression (p=0.006 and 0.010) and APC cytoplasmic expression in cryptic cells (p<0.001) in SPs. CAs, APE1 (p<0.001) and Bcl-xL (p<0.001) were more expressed in the nuclei and cytoplasms, respectively. These results are related to the biological role proposed for these proteins in cellular functions. They can contribute to the diagnosis criteria for polyps and improve the knowledge of biomarkers that could predict cancer development.
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Affiliation(s)
- Rosimeri Kühl Svoboda Baldin
- Group of Studies and Research in Tumor Markers, Faculdade Evangélica Mackenzie do Paraná, Curitiba, Brazil
- Department of Medical Pathology, Universidade Federal do Paraná, Curitiba, Brazil
| | | | - Lúcia de Noronha
- Department of Medical Pathology, Universidade Federal do Paraná, Curitiba, Brazil
- Group for Advanced Molecular Investigation, Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil
| | - Claudia Caroline Veloso da Silva-Camargo
- Group for Advanced Molecular Investigation, Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil
| | - Vanessa Santos Sotomaior
- Group for Advanced Molecular Investigation, Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil
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26
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Monreal-Robles R, Jáquez-Quintana JO, Benavides-Salgado DE, González-González JA. Serrated polyps of the colon and rectum: a concise review. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2021; 86:276-286. [PMID: 34116964 DOI: 10.1016/j.rgmxen.2021.06.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/26/2021] [Indexed: 02/07/2023]
Abstract
"Serrated polyps" is the term used for epithelial lesions of the colon and rectum that have a "sawtooth" pattern on the polyp's surface and crypt epithelium. The so-called serrated pathway describes the progression of sessile serrated adenomas and traditional serrated adenomas to colorectal cancer. Said pathway is well recognized as an alternative mechanism of carcinogenesis and accounts for 15-30% of the cases of colorectal cancer. It also explains a large number of the cases of interval colorectal cancer. Thus, due to their usually aggressive and uncertain behavior, serrated polyps are of the utmost importance in colorectal cancer screening. Our aim was to review the history, current nomenclature, pathophysiology, morphology, treatment, and surveillance of serrated polyps.
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Affiliation(s)
- R Monreal-Robles
- Servicio de Gastroenterología, Hospital Universitario Dr. José E. González, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico; Escuela de Medicina y Ciencias de la Salud, Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, Nuevo León, Mexico.
| | - J O Jáquez-Quintana
- Servicio de Gastroenterología, Hospital Universitario Dr. José E. González, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
| | - D E Benavides-Salgado
- Servicio de Gastroenterología, Hospital Universitario Dr. José E. González, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
| | - J A González-González
- Servicio de Gastroenterología, Hospital Universitario Dr. José E. González, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
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27
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Annexin A10 and HES-1 Immunohistochemistry in Right-sided Traditional Serrated Adenomas Suggests an Origin From Sessile Serrated Adenoma. Appl Immunohistochem Mol Morphol 2021; 28:296-302. [PMID: 30653033 DOI: 10.1097/pai.0000000000000740] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
There is increasing body of evidence to suggest that some colonic serrated polyps do not fit morphologically with any of the proposed categories for serrated polyps recommended by the World Health Organization. Most of these polyps have morphologic features of traditional serrated adenoma (TSA) admixed with areas resembling sessile serrated adenoma (SSA) or hyperplastic polyp (HP). Based on these findings it has been suggested that at least some TSAs may arise in association with precursor HP or SSA lesions, particularly those that develop in right colon. To further evaluate this hypothesis, 39 serrated polyps from right side of the colon (cecum, ascending, and transverse colon) with mixed features of TSA and SSA were evaluated by 2 immunostains previously shown to represent markers of SSA. One is Annexin A10 which shows upregulated expression in SSA and the other is Hes-1 which is shown to be down regulated in SSA. The expression patterns of these markers were evaluated in SSA and TSA components of hybrid polyps and compared with control groups (pure SSAs and TSAs of right colon). SSA component in hybrid polyps did not show any significant difference in staining pattern compared with that seen in TSA component of hybrid polyps or in pure TSA polyps. These findings further support the hypothesis that recognizes SSA as a precursor lesion for TSA in the right colon.
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Teriyapirom I, Batista-Rocha AS, Koo BK. Genetic engineering in organoids. J Mol Med (Berl) 2021; 99:555-568. [PMID: 33459801 PMCID: PMC8026415 DOI: 10.1007/s00109-020-02029-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 11/17/2020] [Accepted: 12/14/2020] [Indexed: 12/21/2022]
Abstract
Three-dimensional organoids have been widely used for developmental and disease modeling. Organoids are derived from both adult and pluripotent stem cells. Various types are available for mimicking almost all major organs and tissues in the mouse and human. While culture protocols for stepwise differentiation and long-term expansion are well established, methods for genetic manipulation in organoids still need further standardization. In this review, we summarized different methods for organoid genetics and provide the pros and cons of each method for designing an optimal strategy.
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Affiliation(s)
- Isaree Teriyapirom
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030, Vienna, Austria.
| | - Andreia S Batista-Rocha
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030, Vienna, Austria
| | - Bon-Kyoung Koo
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030, Vienna, Austria.
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Singhi AD, Waters KM, Makhoul EP, Parian A, Lazarev MG, Proksell SS, Dueker JM, Schwartz MB, Wald AI, Nikiforova MN, Montgomery EA. Targeted next-generation sequencing supports serrated epithelial change as an early precursor to inflammatory bowel disease-associated colorectal neoplasia. Hum Pathol 2021; 112:9-19. [PMID: 33727167 PMCID: PMC10113803 DOI: 10.1016/j.humpath.2021.03.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 12/12/2022]
Abstract
Serrated epithelial change (SEC) manifests in patients with long-standing inflammatory bowel disease (IBD) and is characterized by disorganized crypt architecture, irregular serrations, and goblet cell-rich epithelium. The serrated nature of SEC is reminiscent of serrated colorectal polyps, which frequently harbor KRAS/BRAF mutations. SEC is, however, not only histologically distinct from sporadic serrated polyps but also associated with colorectal neoplasia. Whether SEC is a precursor to IBD-associated neoplasia remains unclear. To further define the relationship of SEC with serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include the following: SEC without dysplasia/neoplasia (n = 10), SEC with separate foci of associated dysplasia/adenocarcinoma from the same patients (n = 17), and uninvolved mucosa (n = 10) from 14 patients. In addition, we molecularly profiled sessile serrated lesion (SSL)-like or serrated lesion, not otherwise specified (SL-NOS), specimens, from 11 patients who also had IBD. This control cohort included SSL-like/SL-NOS without dysplasia/neoplasia (n = 11), SSL-like/SL-NOS with associated low-grade dysplasia (n = 2), and uninvolved mucosa (n = 8). By next-generation sequencing, the most frequently mutated gene in SEC without neoplasia and associated dysplasia/adenocarcinoma from separate foci in the same patients was TP53. Recurrent TP53 mutations were present in 50% of SEC specimens without dysplasia/neoplasia. In addition, alterations in TP53 were detected at a prevalence of 71% in low-grade dysplasia, 83% in high-grade dysplasia, and 100% in adenocarcinoma. Paired sequencing of SEC and associated neoplasia revealed identical TP53 missense mutations for 3 patients. In contrast, 91% of SSL-like/SL-NOS specimens without dysplasia/neoplasia harbored KRAS/BRAF mutations, which were conserved in associated low-grade dysplasia. No genomic alterations were found in uninvolved mucosa from either patients with SEC or patients with SSL-like/SL-NOS. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in patients with IBD and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.
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Affiliation(s)
- Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Kevin M Waters
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Elias P Makhoul
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Alyssa Parian
- Department of Medicine, Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Mark G Lazarev
- Department of Medicine, Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Siobhan S Proksell
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Jeffrey M Dueker
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Marc B Schwartz
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Abigail I Wald
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Marina N Nikiforova
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Elizabeth A Montgomery
- Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, 21205, USA; Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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Bateman AC. The spectrum of serrated colorectal lesions-new entities and unanswered questions. Histopathology 2021; 78:780-790. [PMID: 33332664 DOI: 10.1111/his.14305] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hyperplastic polyps (HPs) of the colon and rectum were historically thought not to be associated with an increased risk of development of colorectal cancer (CRC). The recognition of variants of serrated colorectal lesions that possessed relatively subtle but significant morphological differences from those of HPs and that could be associated with epithelial dysplasia and CRC led to the characterisation of sessile serrated lesions (SSLs) and traditional serrated adenomas (TSAs). These links were supported by the identification of genetic alterations that are commonly found in HPs, SSLs, TSAs, and CRC, e.g. BRAF and KRAS mutations. The 'serrated pathway' to CRC may progress faster than the traditional 'adenoma-carcinoma sequence', underlining the importance of identifying these lesions. The diagnostic histological criteria for SSLs have since been more clearly defined, in parallel with a drive to increase the recognition of these lesions at endoscopy. The existence of lesions showing overlapping morphological and molecular features with those of HPs, SSLs and TSAs has most recently been highlighted-including mucin-rich TSA, serrated tubulovillous adenoma, and those showing mixed histological features, e.g. comprising differing combinations of HP, SSL, and TSA. Morphological and molecular studies of this range of lesions are providing insights into the relationships of serrated colorectal lesions with each other and with CRC. This article provides an overview of the current understanding of serrated colorectal lesions, including a discussion of those with overlapping and mixed features.
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Affiliation(s)
- Adrian C Bateman
- Department of Cellular Pathology, University Hospitals Southampton NHS Foundation Trust, Southampton, UK
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31
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Rubio CA. Two intertwined compartments coexisting in sporadic conventional colon adenomas. Intest Res 2021; 19:12-20. [PMID: 32079382 PMCID: PMC7873396 DOI: 10.5217/ir.2019.00133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/05/2019] [Accepted: 12/27/2019] [Indexed: 11/14/2022] Open
Abstract
Sporadic conventional colon adenomas are microscopically built of 2 intertwined compartments: one on top, harboring the dysplastic tissue that defines their histo-biomolecular attributes, and the other below, composed of non-dysplastic crypts with corrupted shapes (CCS). The CCS of 306 colon adenomas revealed asymmetric, haphazardly-distributed proliferating cell-domains (PC). In contrast, the PC-domains in normal controls were symmetric, being limited to the lower thirds of the crypts. In 28% out of 501 sporadic conventional adenomas, foci of p53-upregulated dysplastic tissue were found. The CCS in 30% of 108 sporadic adenomas showed p53-upregulated single cells, suggesting mounting somatic mutations. No p53-upregulated cells were found in the crypts of controls. In polypoid adenomas, the mucosa of the stalk without dysplastic tissue on top disclosed CCS with asymmetrical PC-domains and single p53-upregulated cells. The latter observations suggested that CCS had developed prior to and not after the growth of the dysplastic tissue on top. CCS were also found below colon adenomas in carcinogen-treated rats. It is concluded that the 2 intertwined histo-biological compartments of sporadic conventional colon adenomas are probably interdependent components. These findings may open new directions aimed to uncover the link between the normal colonic mucosa and the histogenesis of, conventional adenomas.
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Affiliation(s)
- Carlos A. Rubio
- Gastrointestinal Research Laboratory, Department of Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden
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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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Kuo E, Wang K, Liu X. A Focused Review on Advances in Risk Stratification of Malignant Polyps. Gastroenterology Res 2020; 13:163-183. [PMID: 33224364 PMCID: PMC7665855 DOI: 10.14740/gr1329] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer is the third most common cancer in both men and women in the United States, with most cases arising from precursor adenomatous polyps. Colorectal malignant polyps are defined as cancerous polyps that consist of tumor cells invading through the muscularis mucosae into the underlying submucosa (pT1 tumor). It has been reported that approximately 0.5-8.3% of colorectal polyps are malignant polyps, and the potential for lymph node metastasis in these polyps ranges from 8.5% to 16.1%. Due to their clinical significance, recognition of malignant polyps is critical for clinical teams to make treatment decisions and establish appropriate surveillance schedules after local excision of the polyps. There is a rapidly developing interest in malignant polyps within the literature as a result of an increasing number of identifiable adverse histologic features and recent advancements in endoscopic treatment techniques. The purpose of this paper is to have a focused review of the recent histopathologic literature of malignant polyps.
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Affiliation(s)
- Enoch Kuo
- Department of Pathology, Immunology & Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.,Both authors contributed equally to this manuscript
| | - Kai Wang
- Department of Pathology, Immunology & Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.,Both authors contributed equally to this manuscript
| | - Xiuli Liu
- Department of Pathology, Immunology & Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
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Clinicopathologic and Molecular Characteristics of Familial Adenomatous Polyposis-associated Traditional Serrated Adenoma. Am J Surg Pathol 2020; 44:1282-1289. [PMID: 32384323 DOI: 10.1097/pas.0000000000001502] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Colorectal carcinogenesis in familial adenomatous polyposis (FAP) follows a conventional adenoma-carcinoma sequence. However, previous studies have also reported the occurrence of traditional serrated adenomas (TSAs) in patients with FAP. In the present study, we analyzed the clinicopathologic and molecular features of 37 TSAs from 21 FAP patients. Histologically, the majority of FAP-associated TSAs showed typical cytology and slit-like serration; however, ectopic crypt formation was infrequent. Next-generation sequencing and Sanger sequencing identified KRAS and BRAF V600E mutations in 18 (49%) and 14 (38%) TSAs, respectively. Somatic APC mutations were detected in 26 lesions (84% of analyzed cases). Three lesions had BRAF non-V600E mutations, and 2 of them had a concurrent KRAS mutation. Seven TSAs (19%) were associated with a precursor polyp, 6 with a hyperplastic polyp, and 1 with a sessile serrated lesion, and all of them showed the BRAF V600E mutation. Additional sequencing analysis of 4 TSAs with a precursor polyp showed that the BRAF V600E mutation was shared between the TSA and precursor components, but APC mutations were exclusive to the TSA component in all the analyzed lesions. None of the lesions showed the high CpG island methylation phenotype. These results indicate that FAP-associated TSAs frequently have KRAS or BRAF mutations, similar to sporadic cases, and second-hit somatic APC mutations are commonly involved in their tumorigenesis as in other FAP-associated tumors. Although progression to adenocarcinoma is likely rare, tumorigenesis via the serrated pathway occurs in patients with FAP.
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35
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Brcic I, Dawson H, Gröchenig HP, Högenauer C, Kashofer K. Serrated Lesions in Inflammatory Bowel Disease: Genotype-Phenotype Correlation. Int J Surg Pathol 2020; 29:46-53. [PMID: 33030071 DOI: 10.1177/1066896920963798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) and hyperplastic/serrated polyposis have an increased risk of colorectal cancer. The aim of our study was to elucidate the nature of serrated lesions in IBD patients. MATERIALS AND METHODS Sixty-five lesions with serrated morphology were analyzed in 39 adult IBD patients. Lesions were classified according to the WHO 2019 criteria or regarded as reactive, and molecular analysis was performed. RESULTS 82.1% of patients had ulcerative colitis, 17.9% had Crohn's disease; 51.3% were female, and the mean age was 54.5 years. The duration of IBD varied significantly (16.7 ± 11.4 years). Endoscopy showed polypoid lesions in 80.3%; the size ranged from 2 to 20 mm. A total of 21.6% of the lesions were located in the right colon. Five lesions were classified as inflammatory pseudopolyps, 28 as hyperplastic polyp, 21 and 2 as sessile serrated lesion without and with dysplasia, respectively, and 9 as traditional serrated adenoma with low-grade dysplasia. Analysis of all true serrated lesions revealed 31 mutations in KRAS and 32 in BRAF gene. No mutations were identified in inflammatory pseudopolyps. In the right colon BRAF mutations were more frequent than KRAS (16 vs 3), while KRAS mutations prevailed on the left side (28 vs 16, P < .001). One patient with traditional serrated adenomas progressed to an adenocarcinoma after 61 months. CONCLUSION The molecular analysis could help discriminate true serrated lesions (IBD-associated or not) from reactive pseudopolyps with serrated/hyperplastic epithelial change. These should help in more accurate classification of serrated lesions.
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Affiliation(s)
- Iva Brcic
- Medical University of Graz, Graz, Austria
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36
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Serrated adenomas with a BRAF mutation in a young patient with familial adenomatous polyposis. Int J Colorectal Dis 2020; 35:1967-1972. [PMID: 32504335 DOI: 10.1007/s00384-020-03657-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/25/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Familial adenomatous polyposis (FAP) is typically characterized by more than hundred adenomatous polyps in the colorectum, caused by germline APC mutation. A small proportion of the polyps progress to colorectal adenocarcinoma via adenoma-carcinoma sequence. Serrated lesions and polyps, characterized by a serrated architecture of the epithelium, are noted for two types of genetic pathways in colorectal carcinogenesis. BRAF and KRAS mutations are observed in the serrated pathway. CASE REPORT We report a young FAP patient with rectal serrated adenomas that were removed by colonoscopic procedures. The histological features with villiform projections and slit-like serration indicated traditional serrated adenoma. A genetic examination with next-generation sequencing showed a somatic BRAF mutation in the serrated adenoma and APC mutations in the tubular adenomas. His germline mutation was found at APC p.Q1928fs*. CONCLUSION Serrated adenomas with dual genetic alterations in a FAP patient may be associated with colorectal carcinogenesis and should be considered a target lesion for treatment. The present study demonstrated the malignant potential of serrated adenoma in a FAP patient.
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Chino A, Kawachi H, Takamatsu M, Hatamori H, Ide D, Saito S, Igarashi M, Fujisaki J, Nagayama S. Macroscopic and microscopic morphology and molecular profiling to distinguish heterogeneous traditional serrated adenomas of the colorectum. Dig Endosc 2020; 32:921-931. [PMID: 31833094 DOI: 10.1111/den.13603] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 12/05/2019] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Serrated lesions of the colorectum often have complex histological morphology, and some groups include subtypes with different molecular biology. This study aimed to characterize serrated lesions with heterogeneous histology that was dominated by a traditional serrated adenoma (TSA) component. METHODS Representative lesions were selected based on both endoscopic and histological features. If a lesion had more than one component, each of the different structural parts was considered as a separate sample. DNA was extracted from 177 samples of 60 lesions and amplified to screen for BRAF and K/NRAS mutations. RESULTS Heterogeneous TSA samples were classified into four categories: sessile serrated lesion with TSA (SA-1); TSAs with microvesicular hyperplastic polyp (SA-2); TSAs with unclassified adenoma, characterized by tubulo-serrated histology (SA-3); and TSAs with conventional adenomas (SA-4). On endoscopy, SA-1 lesions had sessile-elevated morphology with the small reddish elevations; SA-2 lesions had a pedunculated appearance with a whitish mucosal component at the stalk; SA-3 lesions had a sessile-elevated component surrounded by flat spreading margins; and SA-4 lesions had mixed adenomatous morphology. Eighteen of the 19 category SA-1 and -2 lesions (95%) had BRAF mutations, and all of the SA-3 and -4 lesions had K/NRAS mutations. CONCLUSIONS Traditional serrated adenomas were classified into two phenotypes according to their molecular characteristics: microvesicular serrated subtypes with BRAF mutations (SA-1 and -2 lesions) and subtypes containing tubulo-serrated/conventional adenoma with K/NRAS mutations (SA-3 and -4 lesions). Each subtype had characteristic macroscopic and microscopic morphologies and was distinct on endoscopy.
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Affiliation(s)
- Akiko Chino
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Hiroshi Kawachi
- Department of Pathology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Manabu Takamatsu
- Department of Pathology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Hiroyuki Hatamori
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Daisuke Ide
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Shoichi Saito
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Masahiro Igarashi
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Junko Fujisaki
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
| | - Satoshi Nagayama
- Department of Digestive Surgery, The Cancer Institute Hospital of Japanese for Cancer Research, Tokyo, Japan
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Kiremitçi S, Cansız Ersöz C, Savaş B, Ensari A. Gastric and small intestinal traditional serrated adenomas: a detailed morphologic and immunohistochemical analysis. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 31:441-450. [PMID: 32721915 DOI: 10.5152/tjg.2020.19931] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIMS Traditional serrated adenomas (TSAs), despite their low incidence in colorectum, may originate in other parts of the gastrointestinal (GI) tract, including stomach and small intestine. Malignant transformation for upper GI TSAs has recently been reported in the literature. Here, we present a series of gastric and small intestinal TSAs with the aim to characterize their morphologic and immunophenotypic features as well as their neoplastic potential in a compartmental manner using digitalized images. MATERIALS AND METHODS The study comprised 12 GI polyps with TSA features-5 gastric and 7 small intestinal. The extent of the characteristic features of TSA, including eosinophilic cells, ectopic crypt foci (ECF), slit-like serration, foveolar epithelium, goblet cells, together with dysplastic-carcinomatous foci were assessed on digitalized H-E images and were used as reference for immunohistochemical analysis. RESULTS All polyps in the cohort contained eosinophilic cells as the most extensive morphologic feature followed by ECF and slit-like serration in decreasing order. Serrated dysplasia was more common in gastric polyps, which more frequently showed neoplastic progression compared with the intestinal ones. CK20 was the most widely expressed marker with a preference to eosinophilic cells while ECFs were mostly negative. Ki67 showed the opposite pattern of CK20. MUC6 and MUC2 were selectively expressed in the basal zone and goblet cells, respectively. CONCLUSION Our results showed that the presence of eosinophilic cells with pencillate nuclei commonly accompanied by ECF and slit-like serration are the defining features of gastric and small intestinal TSAs. They frequently harbor neoplastic foci, particularly in gastric location where serrated dysplasia seems to be more common.
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Affiliation(s)
- Saba Kiremitçi
- Department of Pathology, Ankara University School of Medicine, Ankara, Turkey
| | | | - Berna Savaş
- Department of Pathology, Ankara University School of Medicine, Ankara, Turkey
| | - Arzu Ensari
- Department of Pathology, Ankara University School of Medicine, Ankara, Turkey
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Gui H, Husson MA, Mannan R. Correlations of morphology and molecular alterations in traditional serrated adenoma. World J Gastrointest Pathophysiol 2020; 11:78-83. [PMID: 32587787 PMCID: PMC7303981 DOI: 10.4291/wjgp.v11.i4.78] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/27/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
Traditional serrated adenoma was first reported by Longacre and Fenoglio-Presier in 1990. Their initial study described main features of this lesion, but the consensus diagnostic criteria were not widely adopted until recently. Traditional serrated adenoma presents with grossly protuberant configuration and pinecone-like appearance upon endoscopy. Histologically, it is characterized by ectopic crypt formation, slit-like serration, eosinophilic cytoplasm and pencillate nuclei. Although much is now known about the morphology and molecular changes, the mechanisms underlying the morphological alterations are still not fully understood. Furthermore, the origin of traditional serrated adenoma is not completely known. We review recent studies of the traditional serrated adenoma and provide an overview on current understanding of this rare entity.
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Affiliation(s)
- Hongxing Gui
- Department of Pathology and Laboratory Medicine, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, PA 19107, United States
| | - Michael A Husson
- Department of Pathology and Laboratory Medicine, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, PA 19107, United States
| | - Rifat Mannan
- Department of Pathology and Laboratory Medicine, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, PA 19107, United States
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Multidirectional Colonoscopy Quality Improvement Increases Adenoma Detection Rate: Results of the Seoul National University Hospital Healthcare System Gangnam Center Colonoscopy Quality Upgrade Project (Gangnam-CUP). Dig Dis Sci 2020; 65:1806-1815. [PMID: 31732905 DOI: 10.1007/s10620-019-05944-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 11/06/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND To prevent colorectal cancer, high-quality colonoscopy is advocated, undertaken by endoscopists with high adenoma detection rates (ADRs). Despite reports that various factors may impact ADRs, the significance of such factors is still unclear. AIMS The analysis was aimed at quality-oriented interventions for boosting ADRs. METHODS Study enrollees were adults subjected to screening colonoscopy between September 2013 and August 2016 at the Gangnam Center of Seoul National University Hospital Healthcare System. The investigation entailed six periods (P1-6) of 6 months each, during which serial multidirectional quality improvement efforts were instituted. In particular, we sought to further educate endoscopists, provide feedback on individual ADRs, and introduce a split-dose regimen, gauging results via the Boston Bowel Preparation Score. Changes in polyp detection rates (PDRs) and ADRs were then analyzed. RESULTS A total of 13,430 colonoscopies were undertaken by 15 experienced endoscopists. Overall, the ADR increased from 45.6% (P1) to 48.2% (P6, p < 0.001). The PDR, ADR, and advanced adenoma detection rate (AdvADR) showed the greatest increases between P3 and P4 [PDR 67.8% → 71.2% (p < 0.001); ADR 44.1% → 47.7% (p = 0.001); AdvADR 2.3% → 3.3% (p = 0.028)] in keeping with the introduction of a split-dose regimen. The sessile serrated adenoma detection rate (SSADR) increased substantially from 2.1% (P1) to 7.9% (P6, p < 0.001), with the largest gain between P1 and P2, just after education (p = 0.023). CONCLUSIONS Successful quality improvement in colonoscopy was achieved through comprehensive multidirectional efforts in education, feedback, and enhanced bowel preparation. Achieving high-level bowel preparation was paramount in ADR improvement. The SSADR was improved through education.
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Nonconventional dysplasia in patients with inflammatory bowel disease and colorectal carcinoma: a multicenter clinicopathologic study. Mod Pathol 2020; 33:933-943. [PMID: 31822800 DOI: 10.1038/s41379-019-0419-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/19/2019] [Accepted: 11/05/2019] [Indexed: 02/06/2023]
Abstract
Several types of nonconventional dysplasia have been recently described in inflammatory bowel disease (IBD). However, strict morphologic criteria are lacking, and their clinicopathologic features (including potential association with conventional dysplasia and/or colorectal cancer [CRC]) are poorly understood. A total of 106 dysplastic or serrated lesions in 58 IBD patients with CRC were retrospectively identified from five institutions. Thirty-six cases of nonconventional dysplasia were identified in 26 (45%) of the 58 patients and occurred with similar frequency in men and women (58% and 42%, respectively), with a mean age of 54 years (range: 24-73) and a long history of IBD (mean: 17 years, range: 2-43). Six morphologic patterns were recognized. Hypermucinous dysplasia (n = 15; 42%) presented as either a 'pure type' (n = 5; 14%) or a 'mixed type' with either conventional or another nonconventional subtype (n = 10; 28%). Serrated lesions, as a group, were equally common (n = 15; 42%) and included three variants: traditional serrated adenoma-like (n = 10; 28%), sessile serrated lesion-like (n = 1; 3%), and serrated lesion, not otherwise specified (n = 4; 11%). Dysplastic lesions with increased Paneth cell differentiation (n = 4; 11%) and goblet cell deficient dysplasia (n = 2; 6%) were rare. Twelve (46%) of the 26 patients had only nonconventional dysplasia, whereas the remaining 14 patients (54%) had both nonconventional and conventional dysplasias. Nonconventional dysplasia was most often graded as low-grade dysplasia (81%), which was less common in conventional dysplasia (37%) (p = 0.003). When present alone, nonconventional dysplasia was predominantly found in the left colon (81%, p = 0.006) as a polypoid or raised lesion (75%, p < 0.001) compared with when it occurred simultaneously with conventional dysplasia (35% and 50%, respectively). When both nonconventional and conventional dysplasias occurred simultaneously, they were found in the same colonic segment in all but 3 patients (79%). Nonconventional dysplasia was also commonly detected in the same colonic segment as CRC or immediately adjacent to the CRC at a rate (85%) similar to conventional dysplasia (96%). CRC occurring in patients with only nonconventional dysplasia was more likely to be high-grade (poorly differentiated; 36%) than CRC that occurred in association with conventional dysplasia (10%) (p = 0.026). In conclusion, nonconventional dysplasia is common in IBD patients with CRC. It appears to develop in the same field of carcinomatous development, and it is not uncommonly associated with conventional dysplasia.
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Chan AWH, Pan Y, Tong JHM, Lung RWM, Kwan JSH, Chow C, Tin EKY, Chung LY, Li H, Wong SSY, Chau SL, Chan YY, Mak TWC, Ng SSM, To KF. Receptor tyrosine kinase fusions act as a significant alternative driver of the serrated pathway in colorectal cancer development. J Pathol 2020; 251:74-86. [PMID: 32162306 DOI: 10.1002/path.5418] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 02/18/2020] [Accepted: 03/02/2020] [Indexed: 02/06/2023]
Abstract
Serrated polyps are a clinically and molecularly heterogeneous group of lesions that can contribute to the development of colorectal cancers (CRCs). However, the molecular mechanism underlying the development of serrated lesions is still not well understood. Here, we combined multiple approaches to analyze the genetic alterations in 86 colorectal adenomas (including 35 sessile serrated lesions, 15 traditional adenomas, and 36 conventional adenomatous polyps). We also investigated the in vitro and in vivo oncogenic properties of a novel variant of the NCOA4-RET fusion gene. Molecular profiling revealed that sessile serrated lesions and traditional serrated adenomas have distinct clinicopathological and molecular features. Moreover, we identified receptor tyrosine kinase translocations exclusively in sessile serrated lesions (17%), and the observation was validated in a separate cohort of 34 sessile serrated lesions (15%). The kinase fusions as well as the BRAF and KRAS mutations were mutually exclusive to each other. Ectopic expression of a novel variant of the NCOA4-RET fusion gene promoted cell proliferation in vitro and in vivo, and the proliferation was significantly suppressed by RET kinase inhibitors. All of these underscored the importance of mitogen-activated protein kinase (MAPK) pathway activation in the serrated pathway of colorectal tumorigenesis. In addition, we demonstrated that the kinase fusion may occur early in the precursor lesion and subsequent loss of TP53 may drives the transformation to carcinoma during serrated tumorigenesis. In conclusion, we identified kinase fusions as a significant alternative driver of the serrated pathway in colorectal cancer development, and detecting their presence may serve as a biomarker for the diagnosis of sessile serrated lesions. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Anthony W-H Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Yi Pan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Joanna H-M Tong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Raymond W-M Lung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Johnny S-H Kwan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Chit Chow
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Edith K-Y Tin
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Lau-Ying Chung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Hui Li
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Shela S-Y Wong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Shuk-Ling Chau
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Yuk Yu Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Tony W-C Mak
- Division of Colorectal Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Simon Siu-Man Ng
- Division of Colorectal Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China
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Sekine S, Yamashita S, Yamada M, Hashimoto T, Ogawa R, Yoshida H, Taniguchi H, Kojima M, Ushijima T, Saito Y. Clinicopathological and molecular correlations in traditional serrated adenoma. J Gastroenterol 2020; 55:418-427. [PMID: 32052185 DOI: 10.1007/s00535-020-01673-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 01/22/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Traditional serrated adenoma (TSA) is the least common type of colorectal serrated polyp, which exhibits considerable morphological and molecular diversity. METHODS We examined the spectra of alterations in MAPK and WNT pathway genes and their relationship with clinicopathological features in 128 TSAs. RESULTS Sequencing analyses identified BRAF V600E, BRAF non-V600E, KRAS, and NRAS mutations in 77, 3, 45, and 1 lesion, respectively. Collectively, 124 lesions (97%) had mutations in MAPK pathway genes. Alterations in WNT pathway genes were identified in 107 lesions (84%), including RSPO fusions/overexpression, RNF43 mutations, ZNRF3 mutations, APC mutations, and CTNNB1 mutations in 47, 45, 2, 13, and 2 lesions, respectively. Ten lesions (8%) harbored GNAS mutations. There was significant interdependence between the altered MAPK and WNT pathway genes. RSPO fusions/overexpression was significantly associated with KRAS mutations (31/47, 66%), whereas most RNF43 mutations coexisted with the BRAF V600E mutation (40/45, 89%). Histologically, extensive slit-like serration was more common in lesions with the BRAF V600E mutation (71%) and those with RNF43 mutations (87%). Prominent ectopic crypt formation was more prevalent in lesions with RSPO fusions/overexpression (58%) and those with GNAS mutations (100%). CONCLUSIONS Our observations indicate that TSAs mostly harbor various combinations of concurrent WNT and MAPK gene alterations. The associations between genetic and morphological features suggest that the histological diversity of TSA reflects the underlying molecular heterogeneity.
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Affiliation(s)
- Shigeki Sekine
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
| | - Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Masayoshi Yamada
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Taiki Hashimoto
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Reiko Ogawa
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroshi Yoshida
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hirokazu Taniguchi
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Motohiro Kojima
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
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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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45
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Traditional Serrated Adenomas on CT Colonography: International Multicenter Experience With This Rare Colorectal Neoplasm. AJR Am J Roentgenol 2020; 214:355-361. [DOI: 10.2214/ajr.19.21882] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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46
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Miller GC, Liu C, Bettington ML, Leggett B, Whitehall VLJ, Rosty C. Traditional serrated adenoma-like lesions in patients with inflammatory bowel disease. Hum Pathol 2020; 97:19-28. [PMID: 31917154 DOI: 10.1016/j.humpath.2019.12.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/09/2019] [Accepted: 12/23/2019] [Indexed: 12/12/2022]
Abstract
Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal carcinoma. The significance of serrated lesions resembling traditional serrated adenoma (TSA) in IBD patients is unclear. In this retrospective study, we analyzed 52 TSA-like lesions arising in 30 IBD patients and diagnosed in colectomy or endoscopic specimens. The 27 colectomy lesions presented predominantly as ill-defined areas with granular appearance, with a median size of 15 mm, located throughout the large bowel and associated with synchronous advanced colorectal lesions in 58%. Low-grade serrated dysplasia was present in 56%, high-grade serrated dysplasia in 37%, and TSA-type cytology in 7%. Increased Ki-67 immunostaining and abnormal p53 expression were identified in 96% and 48%, respectively; 74% had a KRAS mutation, and 4% had a BRAF mutation. Endoscopically resectable TSA-like lesions were all discrete polypoid lesions, smaller in size (median 9 mm), predominantly in the distal large bowel, with an adjacent precursor polyp in 24%, and associated with synchronous and metachronous advanced colorectal lesions in 6%. Most (92%) show TSA-type cytology. p53 overexpression was present in 4%, KRAS mutation in 41%, and BRAF mutation in 32%. None of the 52 TSA-like lesions demonstrated loss of MLH1 or SATB2 expression by immunohistochemistry. On follow-up, 4 patients were diagnosed with colorectal carcinoma or high-grade adenomatous IBD-associated dysplasia. None of the patients with lesions showing TSA-type cytology only developed an advanced lesion. Our findings suggest that some TSA-like lesions, essentially from colectomy, may represent a form of IBD-associated dysplasia associated with an increased risk of advanced neoplasia.
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Affiliation(s)
- Gregory C Miller
- Envoi Specialist Pathologists, Kelvin Grove 4059, Queensland, Australia; Faculty of Medicine, University of Queensland, Herston 4006, Queensland, Australia
| | - Cheng Liu
- Envoi Specialist Pathologists, Kelvin Grove 4059, Queensland, Australia; Faculty of Medicine, University of Queensland, Herston 4006, Queensland, Australia; QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia
| | - Mark L Bettington
- Envoi Specialist Pathologists, Kelvin Grove 4059, Queensland, Australia; Faculty of Medicine, University of Queensland, Herston 4006, Queensland, Australia; QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia
| | - Barbara Leggett
- Faculty of Medicine, University of Queensland, Herston 4006, Queensland, Australia; QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia; Department of Gastroenterology and Hepatology, The Royal Brisbane and Women's Hospital, Herston 4029, Queensland, Australia
| | - Vicki L J Whitehall
- Faculty of Medicine, University of Queensland, Herston 4006, Queensland, Australia; QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia; Conjoint Internal Medicine Laboratory, Pathology Queensland, Herston 4029, Queensland, Australia
| | - Christophe Rosty
- Envoi Specialist Pathologists, Kelvin Grove 4059, Queensland, Australia; Faculty of Medicine, University of Queensland, Herston 4006, Queensland, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
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Traditional serrated adenoma has two distinct genetic pathways for molecular tumorigenesis with potential neoplastic progression. J Gastroenterol 2020; 55:846-857. [PMID: 32535664 PMCID: PMC7452875 DOI: 10.1007/s00535-020-01697-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 05/29/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recent studies have shown that traditional serrated adenoma (TSA) can be classified into BRAF and KRAS subtypes. Here, we examined the clinicopathological and molecular findings of 73 TSAs. MATERIALS AND METHODS TSAs were subclassified into BRAF type (46 cases, type A) and KRAS type (27 cases, type B) and divided into polyp head (TSA component) and base (precursor component [PC]) to identify pathological and molecular differences between the two components. BRAF and KRAS mutations, microsatellite instability (MSI), and DNA methylation status of the TSA component and PC were analyzed. In addition, immunohistochemical expressions of annexin A10, MUC2, MUC5AC, MUC6, and CD10 were also examined. Finally, we compared endoscopic findings with histological features. RESULTS We classified type As into 31 type A1s with mutation of the corresponding PC (42.5%) and 15 type A2s without mutation of the PC (20.5%). None of the corresponding PCs without KRAS mutation were observed in type Bs. MSI was not detected in the TSAs examined. There were significant differences in the frequency of annexin A10 and MUC5AC expression between the three subtypes. Furthermore, we compared the TSA component with the corresponding PC to identify the progression mechanism between the two components. Methylation status played an important role in the progression of type A1 from the corresponding PC, unlike type A2 and type B. Finally, specific endoscopic findings were well correlated with distinct histological findings. CONCLUSION TSAs were heterogeneous tumors with two or three pathways to neoplastic progression.
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Bozorg SR, Song M, Emilsson L, Ludvigsson JF. Validation of serrated polyps (SPs) in Swedish pathology registers. BMC Gastroenterol 2019; 20:3. [PMID: 31892305 PMCID: PMC6938642 DOI: 10.1186/s12876-019-1134-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 12/04/2019] [Indexed: 12/18/2022] Open
Abstract
Background Little is known about the natural history of serrated polyps (SPs), partly due to the lack of large-scale epidemiologic data. In this study, we examined the validity of SP identification according to SNOMED (Systematised Nomenclature of Medicine) codes and free text from colorectal histopathology reports. Methods Through the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, we retrieved data on SPs from all pathology departments in Sweden in 2015–2017 by using SNOMED codes and free-text search in colorectal histopathology reports. Randomly selected individuals with a histopathology report of SPs were validated against patient charts using a structured, retrospective review. Results SPs were confirmed in 101/106 individuals with a histopathology report of SPs, yielding a positive predictive value (PPV) of 95% (95%CI = 89–98%). By year of diagnosis, the PPV was 89% (95%CI = 69–97%), 96% (95%CI = 81–99%) and 97% (95%CI = 89–99%) for individuals diagnosed before 2001 (n = 19), between 2001 and 2010 (n = 26) and after 2010 (n = 61), respectively. According to search method, the PPV for individuals identified by SNOMED codes was 100% (95%CI = 93–100%), and 93% (95%CI = 86–97%) using free-text search. Recorded location (colon vs. rectum) was correct in 94% of all SP histopathology reports (95%CI = 84–98%) identified by SNOMED codes. Individuals with SPs were classified into hyperplastic polyps (n = 34; 32%), traditional serrated adenomas (n = 3; 3%), sessile serrated adenomas/polyps (SSA/Ps) (n = 70; 66%), unspecified SPs (n = 3, 3%), and false positive SPs (n = 5, 5%). For individuals identified by SNOMED codes, SSA/Ps were confirmed in 49/52 individuals, resulting in a PPV of 94% (95%CI: 84–98%). In total, 57% had ≥2 polyps (1: n = 44, 2–3: n = 33 and ≥ 4: n = 27). Some 46% of SPs (n = 71) originated from the proximal colon and 24% were ≥ 10 mm in size (n = 37). Heredity for colorectal cancer, intestinal polyposis syndromes, or both was reported in seven individuals (7%). Common comorbidities included diverticulosis (n = 45, 42%), colorectal cancer (n = 19, 18%), and inflammatory bowel disease (n = 10, 9%). Conclusion Colorectal histopathology reports are a reliable data source to identify individuals with SPs.
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Affiliation(s)
- Soran R Bozorg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Solna, Sweden.
| | - Mingyang Song
- Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Louise Emilsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Solna, Sweden.,Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Institute of Health and Society, University of Oslo, Oslo, Norway.,Vårdcentralen Värmlands Nysäter and Centre for Clinical Research, County Council of Värmland, Värmland, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Solna, Sweden.,Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.,Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK.,Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
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Sohier P, Sanson R, Leduc M, Audebourg A, Broussard C, Salnot V, Just PA, Pasmant E, Mayeux P, Guillonneau F, Romagnolo B, Perret C, Terris B. Proteome analysis of formalin-fixed paraffin-embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas. J Pathol 2019; 250:251-261. [PMID: 31729028 DOI: 10.1002/path.5366] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/23/2019] [Accepted: 11/12/2019] [Indexed: 12/11/2022]
Abstract
Traditional serrated adenoma (TSA) remains the least understood of all the colorectal adenomas, although these lesions have been associated with a significant cancer risk, twice that of the conventional adenoma (CAD) and of the sessile serrated adenoma (SSA/P). This study was performed to investigate the proteomic profiles of the different colorectal adenomas to better understand the pathogenesis of TSA. We performed a global quantitative proteome analysis using the label-free quantification (LFQ) method on 44 colorectal adenoma (12 TSAs, 15 CADs, and 17 SSA/Ps) and 17 normal colonic mucosa samples, archived as formalin-fixed paraffin-embedded blocks. Unsupervised consensus hierarchical clustering applied to the whole proteomic profile of the 44 colorectal adenomas identified four subtypes: C1 and C2 were well-individualized clusters composed of all the CADs (15/15) and most of the SSA/Ps (13/17), respectively. This is consistent with the fact that CADs and SSA/Ps are homogeneous and distinct colorectal adenoma entities. In contrast, TSAs were subdivided into C3 and C4 clusters, consistent with the more heterogeneous entity of TSA at the morphologic and molecular levels. Comparison of the proteome expression profile between the adenoma subtypes and normal colonic mucosa further confirmed the heterogeneous nature of TSAs, which overlapped either on CADs or SSA/Ps, whereas CADs and SSAs formed homogeneous and distinct entities. Furthermore, we identified LEFTY1 a new potential marker for TSAs that may be relevant for the pathogenesis of TSA. LEFTY1 is an inhibitor of the Nodal/TGFβ pathway, which we found to be one of the most overexpressed proteins specifically in TSAs. This finding was confirmed by immunohistochemistry. Our study confirms that CADs and SSA/Ps form homogeneous and distinct colorectal adenoma entities, whereas TSAs are a heterogeneous entity and may arise from either SSA/Ps or from normal mucosa evolving through a process related to the CAD pathway. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Pierre Sohier
- Department of Pathology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris Centre, Hôpital Cochin Department, Paris, France.,INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Romain Sanson
- INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Marjorie Leduc
- INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Plateforme de Protéomique de l'Université Paris Descartes (3P5), Paris, France
| | - Anne Audebourg
- Department of Pathology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris Centre, Hôpital Cochin Department, Paris, France
| | - Cédric Broussard
- INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Plateforme de Protéomique de l'Université Paris Descartes (3P5), Paris, France
| | - Virginie Salnot
- INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Plateforme de Protéomique de l'Université Paris Descartes (3P5), Paris, France
| | - Pierre-Alexandre Just
- Department of Pathology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris Centre, Hôpital Cochin Department, Paris, France.,INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Eric Pasmant
- INSERM, U1016, Institut Cochin, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Department of Molecular Genetics, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Cochin Hospital, Paris, France
| | - Patrick Mayeux
- INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Plateforme de Protéomique de l'Université Paris Descartes (3P5), Paris, France
| | - François Guillonneau
- INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France.,Plateforme de Protéomique de l'Université Paris Descartes (3P5), Paris, France
| | - Béatrice Romagnolo
- INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Christine Perret
- INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Benoît Terris
- Department of Pathology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris Centre, Hôpital Cochin Department, Paris, France.,INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
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Acquisition of WNT Pathway Gene Alterations Coincides With the Transition From Precursor Polyps to Traditional Serrated Adenomas. Am J Surg Pathol 2019; 43:132-139. [PMID: 30179900 DOI: 10.1097/pas.0000000000001149] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal traditional serrated adenomas (TSAs) are often associated with precursor polyps, including hyperplastic polyps and sessile serrated adenoma/polyps. To elucidate the molecular mechanisms involved in the progression from precursor polyps to TSAs, the present study analyzed 15 precursor polyp-associated TSAs harboring WNT pathway gene mutations. Laser microdissection-based sequencing analysis showed that BRAF or KRAS mutations were shared between TSA and precursor polyps in all lesions. In contrast, the statuses of WNT pathway gene mutations were different between the 2 components. In 8 lesions, RNF43, APC, or CTNNB1 mutations, were exclusively present in TSA. RNF43 mutations were shared between the TSA and precursor components in 3 lesions; however, they were heterozygous in the precursor polyps whereas homozygous in the TSA. In 4 lesions with PTPRK-RSPO3 fusions, RNA in situ hybridization demonstrated that overexpression of RSPO3, reflecting PTPRK-RSPO3 fusion transcripts, was restricted to TSA components. Consistent with the results of the genetic and in situ hybridization analyses, nuclear β-catenin accumulation and MYC overexpression were restricted to the TSA component in 13 and 12 lesions, respectively. These findings indicate that the WNT pathway gene alterations are acquired during the progression from the precursor polyps to TSAs and that the activation of the WNT pathway plays a critical role in the development of TSA rather than their progression to high-grade lesions.
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