1
|
Al Bakir I, Curtius K, Cresswell GD, Grant HE, Nasreddin N, Smith K, Nowinski S, Guo Q, Belnoue-Davis HL, Fisher J, Clarke T, Kimberley C, Mossner M, Dunne PD, Loughrey MB, Speight A, East JE, Wright NA, Rodriguez-Justo M, Jansen M, Moorghen M, Baker AM, Leedham SJ, Hart AL, Graham TA. Low-coverage whole genome sequencing of low-grade dysplasia strongly predicts advanced neoplasia risk in ulcerative colitis. Gut 2025; 74:740-751. [PMID: 39880602 PMCID: PMC12013573 DOI: 10.1136/gutjnl-2024-333353] [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: 07/12/2024] [Accepted: 12/19/2024] [Indexed: 01/31/2025]
Abstract
BACKGROUND The risk of developing advanced neoplasia (AN; colorectal cancer and/or high-grade dysplasia) in ulcerative colitis (UC) patients with a low-grade dysplasia (LGD) lesion is variable and difficult to predict. This is a major challenge for effective clinical management. OBJECTIVE We aimed to provide accurate AN risk stratification in UC patients with LGD. We hypothesised that the pattern and burden of somatic genomic copy number alterations (CNAs) in LGD lesions could predict future AN risk. DESIGN We performed a retrospective multicentre validated case-control study using n=270 LGD samples from n=122 patients with UC. Patients were designated progressors (n=40) if they had a diagnosis of AN in the ~5 years following LGD diagnosis or non-progressors (n=82) if they remained AN-free during follow-up. DNA was extracted from the baseline LGD lesion, low-coverage whole genome sequencing performed and data processed to detect CNAs. Survival analysis was used to evaluate CNAs as predictors of future AN risk. RESULTS CNA burden was significantly higher in progressors than non-progressors (p=2×10-6 in discovery cohort) and was a very significant predictor of AN risk in univariate analysis (OR=36; p=9×10-7), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. Within-LGD lesion genetic heterogeneity did not confound risk prediction. CONCLUSION Measurement of CNAs in LGD is an accurate predictor of AN risk in inflammatory bowel disease and is likely to support clinical management.
Collapse
Affiliation(s)
- Ibrahim Al Bakir
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Inflammatory Bowel Disease Unit, St Mark's Hospital, Harrow, UK
- Chelsea & Westminster Hospital, London, UK
| | - Kit Curtius
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, California, USA
- VA San Diego Healthcare System, San Diego, California, USA
- Moores Cancer Center, Univeristy of California San Diego, La Jolla, California, USA
| | - George D Cresswell
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- St. Anna Children's Cancer Research Institute, Vienna, Austria
| | - Heather E Grant
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Nadia Nasreddin
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Kane Smith
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Salpie Nowinski
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Qingli Guo
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | | | - Jennifer Fisher
- Inflammatory Bowel Disease Unit, St Mark's Hospital, Harrow, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Theo Clarke
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | | | - Maximilian Mossner
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Philip D Dunne
- Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK
| | - Maurice B Loughrey
- Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK
- Centre for Public Health and Patrick G. Johnston for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Ally Speight
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - James E East
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Univerity of Oxford, Oxford, UK
| | | | - Manuel Rodriguez-Justo
- Department of Pathology, University College London Hospital, London, UK
- UCL Cancer Institute, University College London, London, UK
| | - Marnix Jansen
- Department of Pathology, University College London Hospital, London, UK
- UCL Cancer Institute, University College London, London, UK
| | - Morgan Moorghen
- Department of Histopathology, St Mark's Hospital, Harrow, UK
| | - Ann-Marie Baker
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Simon J Leedham
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Univerity of Oxford, Oxford, UK
| | - Ailsa L Hart
- Inflammatory Bowel Disease Unit, St Mark's Hospital, Harrow, UK
- Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Trevor A Graham
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| |
Collapse
|
2
|
Lee GC. Surveillance and Management of Dysplasia and Malignancy in Inflammatory Bowel Disease. Surg Clin North Am 2025; 105:313-327. [PMID: 40015819 DOI: 10.1016/j.suc.2024.09.008] [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: 03/01/2025]
Abstract
The paradigm for surveilling and managing inflammatory bowel disease-associated colorectal dysplasia has changed as high-definition colonoscopy and chromoendoscopy have significantly improved the visualization of dysplasia, and endoscopic mucosal resection has made more lesions endoscopically resectable. However, these patients are at high risk of recurrent dysplasia and cancer and require intensive colonoscopic surveillance. Patients with invisible high-grade dysplasia, invisible multifocal low-grade dysplasia, and colorectal cancer should be considered for surgical resection. Total proctocolectomy removes all at-risk tissue. Subtotal colectomy with ileorectal anastomosis can be considered in select patients (ie, advanced age, poor functional status, and with no rectal inflammation or dysplasia).
Collapse
Affiliation(s)
- Grace C Lee
- Section of Colon & Rectal Surgery, Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, 15 Parkman Street, WAC-4-460, Boston, MA 02114, USA; Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
3
|
Te Groen M, Derks MEW, Nagtegaal ID, Peters CP, de Vries AC, Dijkstra G, Romkens TEH, Horjus CS, de Boer NK, de Jong ME, van Ruijven B, Hoentjen F, Vos S, Derikx LAAP. Gastrointestinal pathologist consensus of revised high-grade dysplasia in inflammatory bowel disease impacts the advanced neoplasia rate: a multicenter study. Eur J Gastroenterol Hepatol 2025; 37:287-294. [PMID: 39919003 DOI: 10.1097/meg.0000000000002897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Abstract
OBJECTIVE The diagnosis of inflammatory bowel disease (IBD) associated with high-grade dysplasia (HGD) has a significant impact on clinical management, including colectomy. However, the prognosis of HGD remains unclear due to diagnostic uncertainty and low-quality data on subsequent synchronous and metachronous neoplasia. We aimed to evaluate a diagnostic strategy with dedicated gastrointestinal (GI) pathologist consensus of revised HGD and the impact on synchronous and metachronous neoplasia rates. METHODS In this retrospective multicenter cohort study, we used the Dutch Nationwide Pathology Databank to identify IBD patients with HGD in seven hospitals. Histopathological specimens of the initial HGD were independently revised by two dedicated GI pathologists. Definitive diagnosis was established in a consensus meeting. Synchronous and metachronous neoplasia incidences were assessed with a competing risk analysis. RESULTS We included 54 IBD patients with HGD, of whom 33 (61.1%) with ulcerative colitis and 42 (77.8%) with extensive disease. After consensus, 18 (33.3%) lesions were downgraded to indefinite/low-grade dysplasia, and 6 (11.1%) were revised to colorectal cancer (CRC). Seven patients (13.0%) had synchronous CRC. Patients with downgraded lesions showed a lower cumulative advanced neoplasia (HGD/CRC) incidence compared with confirmed HGD [(Gray's test P < 0.01), 5-year cumulative incidence 0.0% vs. 26.6%]. CONCLUSIONS We demonstrated frequent downgrading of HGD, associated with lower metachronous neoplasia rates. This underlines the potential impact of dedicated GI pathologist consensus meetings. The high and synchronous and metachronous neoplasia rates after HGD underline the need for close surveillance.
Collapse
Affiliation(s)
- Maarten Te Groen
- Department of Gastroenterology, Inflammatory Bowel Disease Centre
| | - Monica E W Derks
- Department of Gastroenterology, Inflammatory Bowel Disease Centre
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen
| | - Charlotte P Peters
- Department of Gastroenterology, Amsterdam University Medical Centre, location AMC, Amsterdam
| | | | - Gerard Dijkstra
- Department of Gastroenterology, Groningen University Medical Centre, Groningen
| | | | | | - Nanne K de Boer
- Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam University Medical Centre, location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | | | | | - Frank Hoentjen
- Department of Gastroenterology, Inflammatory Bowel Disease Centre
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada
| | - Shoko Vos
- Department of Pathology, Radboud University Medical Centre, Nijmegen
| | - Lauranne A A P Derikx
- Department of Gastroenterology, Inflammatory Bowel Disease Centre
- Department of Gastroenterology, Erasmus Medical Centre, Rotterdam
| |
Collapse
|
4
|
Derks MEW, te Groen M, van Lierop LMA, Murthy S, Rubin DT, Bessissow T, Nagtegaal ID, Bemelman WA, Derikx LAAP, Hoentjen F. Management of Colorectal Neoplasia in IBD Patients: Current Practice and Future Perspectives. J Crohns Colitis 2024; 18:1726-1735. [PMID: 38741227 PMCID: PMC11479698 DOI: 10.1093/ecco-jcc/jjae071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/29/2024] [Accepted: 05/13/2024] [Indexed: 05/16/2024]
Abstract
Inflammatory bowel disease [IBD] patients are at increased risk of developing colorectal neoplasia [CRN]. In this review, we aim to provide an up-to-date overview and future perspectives on CRN management in IBD. Advances in endoscopic surveillance and resection techniques have resulted in a shift towards endoscopic management of neoplastic lesions in place of surgery. Endoscopic treatment is recommended for all CRN if complete resection is feasible. Standard [cold snare] polypectomy, endoscopic mucosal resection and endoscopic submucosal dissection should be performed depending on lesion complexity [size, delineation, morphology, surface architecture, submucosal fibrosis/invasion] to maximise the likelihood of complete resection. If complete resection is not feasible, surgical treatment options should be discussed by a multidisciplinary team. Whereas [sub]total and proctocolectomy play an important role in management of endoscopically unresectable CRN, partial colectomy may be considered in a subgroup of patients in endoscopic remission with limited disease extent without other CRN risk factors. High synchronous and metachronous CRN rates warrant careful mucosal visualisation with shortened intervals for at least 5 years after treatment of CRN.
Collapse
Affiliation(s)
- Monica E W Derks
- Inflammatory Bowel Disease Center, Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maarten te Groen
- Inflammatory Bowel Disease Center, Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lisa M A van Lierop
- Inflammatory Bowel Disease Center, Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Sanjay Murthy
- Ottawa Hospital IBD Center and Department of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - David T Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, University of Chicago, Chicago, IL, USA
| | - Talat Bessissow
- Division of Gastroenterology, Department of Medicine, McGill University Health Center, Montreal, QC, Canada
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Willem A Bemelman
- Department of Surgery, Amsterdam University Medical Center, AMC, Amsterdam, The Netherlands
| | | | - Frank Hoentjen
- Inflammatory Bowel Disease Center, Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
5
|
Feakins RM. Inflammatory disorders of the large intestine. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:709-857. [DOI: 10.1002/9781119423195.ch35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
6
|
Al Bakir I, Curtius K, Cresswell GD, Grant HE, Nasreddin N, Smith K, Nowinski S, Guo Q, Belnoue-Davis HL, Fisher J, Clarke T, Kimberley C, Mossner M, Dunne PD, Loughrey MB, Speight A, East JE, Wright NA, Rodriguez-Justo M, Jansen M, Moorghen M, Baker AM, Leedham SJ, Hart AL, Graham TA. Low coverage whole genome sequencing of low-grade dysplasia strongly predicts colorectal cancer risk in ulcerative colitis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.07.08.24309811. [PMID: 39040198 PMCID: PMC11261962 DOI: 10.1101/2024.07.08.24309811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC), and this risk increases dramatically in those who develop low-grade dysplasia (LGD). However, there is currently no accurate way to risk-stratify patients with LGD, leading to both over- and under-treatment of cancer risk. Here we show that the burden of somatic copy number alterations (CNAs) within resected LGD lesions strongly predicts future cancer development. We performed a retrospective multi-centre validated case-control study of n=122 patients (40 progressors, 82 non-progressors, 270 LGD regions). Low coverage whole genome sequencing revealed CNA burden was significantly higher in progressors than non-progressors (p=2×10-6 in discovery cohort) and was a very significant predictor of CRC risk in univariate analysis (odds ratio = 36; p=9×10-7), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. The measurement of CNAs in LGD lesions is a robust, low-cost and rapidly translatable predictor of CRC risk in IBD that can be used to direct management and so prevent CRC in high-risk individuals whilst sparing those at low-risk from unnecessary intervention.
Collapse
Affiliation(s)
- Ibrahim Al Bakir
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
- Inflammatory Bowel Disease Unit, St. Mark’s Hospital, Harrow, United Kingdom
- Chelsea & Westminster Hospital, London, United Kingdom
| | - Kit Curtius
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - George D Cresswell
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
| | - Heather E Grant
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | | | - Kane Smith
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | - Salpie Nowinski
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | - Qingli Guo
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | | | - Jennifer Fisher
- Inflammatory Bowel Disease Unit, St. Mark’s Hospital, Harrow, United Kingdom
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | - Theo Clarke
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
| | - Christopher Kimberley
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | - Maximilian Mossner
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | - Philip D Dunne
- Queen’s University Belfast, Northern Ireland, United Kingdom
| | | | - Ally Speight
- Newcastle NHS Foundation Trust, Newcastle, United Kingdom
| | - James E East
- Nuffield Department of Medicine, University of Oxford, United Kingdom
| | - Nicholas A Wright
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
| | | | - Marnix Jansen
- Department of Pathology, University College London Hospital NHS Trust, London, UK
- UCL Cancer Institute, University College London, London, UK
| | - Morgan Moorghen
- Inflammatory Bowel Disease Unit, St. Mark’s Hospital, Harrow, United Kingdom
| | - Ann-Marie Baker
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | | | - Ailsa L Hart
- Inflammatory Bowel Disease Unit, St. Mark’s Hospital, Harrow, United Kingdom
- Department of Metabolism, Digestion & Reproduction, Imperial College London, United Kingdom
| | - Trevor A Graham
- Barts Cancer Institute, Queen Mary University of London, United Kingdom
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| |
Collapse
|
7
|
Kucharzik T, Dignass A, Atreya R, Bokemeyer B, Esters P, Herrlinger K, Kannengiesser K, Kienle P, Langhorst J, Lügering A, Schreiber S, Stallmach A, Stein J, Sturm A, Teich N, Siegmund B. Aktualisierte S3-Leitlinie Colitis ulcerosa (Version 6.2). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:769-858. [PMID: 38718808 DOI: 10.1055/a-2271-0994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Affiliation(s)
- T Kucharzik
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Städtisches Klinikum Lüneburg, Lüneburg, Deutschland
| | - A Dignass
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt, Deutschland
| | - R Atreya
- Medizinische Klinik 1 Gastroent., Pneumologie, Endokrin., Universitätsklinikum Erlangen, Erlangen, Deutschland
| | - B Bokemeyer
- Interdisziplinäres Crohn Colitis Centrum Minden - ICCCM, Minden, Deutschland
| | - P Esters
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt, Deutschland
| | - K Herrlinger
- Innere Medizin I, Asklepios Klinik Nord, Hamburg, Deutschland
| | - K Kannengiesser
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Städtisches Klinikum Lüneburg, Lüneburg, Deutschland
| | - P Kienle
- Abteilung für Allgemein- und Viszeralchirurgie, Theresienkrankenhaus, Mannheim, Deutschland
| | - J Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg Klinikum am Bruderwald, Bamberg, Deutschland
| | - A Lügering
- Medizinisches Versorgungszentrum Portal 10, Münster, Deutschland
| | - S Schreiber
- Klinik für Innere Medizin I, Universitätsklinikum Schleswig Holstein, Kiel, Deutschland
| | - A Stallmach
- Klinik für Innere Medizin IV Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Jena, Jena, Deutschland
| | - J Stein
- Abteilung Innere Medizin mit Schwerpunkt Gastroenterologie, Krankenhaus Sachsenhausen, Frankfurt, Deutschland
| | - A Sturm
- Klinik für Innere Medizin mit Schwerpunkt Gastroenterologie, DRK Kliniken Berlin Westend, Berlin, Deutschland
| | - N Teich
- Internistische Gemeinschaftspraxis, Leipzig, Deutschland
| | - B Siegmund
- Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité Campus Benjamin Franklin - Universitätsmedizin Berlin, Berlin, Deutschland
| |
Collapse
|
8
|
Choi WT, Rabinovitch PS. DNA flow cytometry for detection of genomic instability as a cancer precursor in the gastrointestinal tract. Methods Cell Biol 2024; 186:25-49. [PMID: 38705603 DOI: 10.1016/bs.mcb.2024.02.013] [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: 05/07/2024]
Abstract
One of the earliest applications of flow cytometry was the measurement of DNA content in cells. This method is based on the ability to stain DNA in a stoichiometric manner (i.e., the amount of stain is directly proportional to the amount of DNA within the cell). For more than 40years, a number of studies have consistently demonstrated the utility of DNA flow cytometry as a potential diagnostic and/or prognostic tool in patients with most epithelial tumors, including pre-invasive lesions (such as dysplasia) in the gastrointestinal tract. However, its availability as a clinical test has been limited to few medical centers due to the requirement for fresh tissue in earlier studies and perceived technical demands. However, more recent studies have successfully utilized formalin-fixed paraffin-embedded (FFPE) tissue to generate high-quality DNA content histograms, demonstrating the feasibility of this methodology. This review summarizes step-by-step methods on how to perform DNA flow cytometry using FFPE tissue and analyze DNA content histograms based on the published consensus guidelines in order to assist in the diagnosis and/or risk stratification of many different epithelial tumors, with particular emphasis on dysplasia associated with Barrett's esophagus and inflammatory bowel disease.
Collapse
Affiliation(s)
- Won-Tak Choi
- Department of Pathology, University of California at San Francisco, San Francisco, CA, United States.
| | - Peter S Rabinovitch
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
| |
Collapse
|
9
|
Harpaz N, Itzkowitz SH. Pathology and Clinical Significance of Inflammatory Bowel Disease-Associated Colorectal Dysplastic Lesions. Gastroenterol Clin North Am 2024; 53:133-154. [PMID: 38280745 DOI: 10.1016/j.gtc.2023.09.005] [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
Timely diagnosis and effective management of colorectal dysplasia play a vital role in preventing mortality from colorectal cancer in patients with chronic inflammatory bowel disease. This review provides a contemporary overview of the pathologic and endoscopic classification of dysplasia in inflammatory bowel disease, their roles in determining surveillance and management algorithms, and emerging diagnostic and therapeutic approaches that might further enhance patient management.
Collapse
Affiliation(s)
- Noam Harpaz
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai; Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, Annenberg Building 5-12L, 1468 Madison Avenue, New York, NY 10029, USA.
| | - Steven H Itzkowitz
- Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, Annenberg Building 5-12L, 1468 Madison Avenue, New York, NY 10029, USA
| |
Collapse
|
10
|
Alipour Z, Stashek K. Recently described types of dysplasia associated with IBD: tips and clues for the practising pathologist. J Clin Pathol 2024; 77:77-81. [PMID: 37918911 DOI: 10.1136/jcp-2023-209141] [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: 10/17/2023] [Accepted: 10/25/2023] [Indexed: 11/04/2023]
Abstract
Longstanding inflammatory bowel disease (especially in patients with severely active disease or primary sclerosing cholangitis) is associated with an increased risk of developing dysplasia and adenocarcinoma. This review covers critical clinical aspects, such as risk factors and screening endoscopy basics, emphasising the SCENIC (Surveillance for Colorectal Endoscopic Neoplasia Detection in Inflammatory Bowel Disease International Consensus) guidelines. The histopathological and molecular features of both conventional (adenomatous) dysplasia and the non-conventional subtypes (hypermucinous dysplasia, goblet cell-deficient dysplasia, crypt cell dysplasia, serrated dysplasias) are discussed with an emphasis on challenging diagnostic areas and helpful tips to allow correct categorisation by the practising pathologist.
Collapse
Affiliation(s)
- Zahra Alipour
- Pathology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kristen Stashek
- Pathology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| |
Collapse
|
11
|
Kataria T, Rajamani S, Ayubi AB, Bronner M, Jedrzkiewicz J, Knudsen BS, Elhabian SY. Automating Ground Truth Annotations for Gland Segmentation Through Immunohistochemistry. Mod Pathol 2023; 36:100331. [PMID: 37716506 DOI: 10.1016/j.modpat.2023.100331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 08/14/2023] [Accepted: 09/08/2023] [Indexed: 09/18/2023]
Abstract
Microscopic evaluation of glands in the colon is of utmost importance in the diagnosis of inflammatory bowel disease and cancer. When properly trained, deep learning pipelines can provide a systematic, reproducible, and quantitative assessment of disease-related changes in glandular tissue architecture. The training and testing of deep learning models require large amounts of manual annotations, which are difficult, time-consuming, and expensive to obtain. Here, we propose a method for automated generation of ground truth in digital hematoxylin and eosin (H&E)-stained slides using immunohistochemistry (IHC) labels. The image processing pipeline generates annotations of glands in H&E histopathology images from colon biopsy specimens by transfer of gland masks from KRT8/18, CDX2, or EPCAM IHC. The IHC gland outlines are transferred to coregistered H&E images for training of deep learning models. We compared the performance of the deep learning models to that of manual annotations using an internal held-out set of biopsy specimens as well as 2 public data sets. Our results show that EPCAM IHC provides gland outlines that closely match manual gland annotations (Dice = 0.89) and are resilient to damage by inflammation. In addition, we propose a simple data sampling technique that allows models trained on data from several sources to be adapted to a new data source using just a few newly annotated samples. The best performing models achieved average Dice scores of 0.902 and 0.89 on Gland Segmentation and Colorectal Adenocarcinoma Gland colon cancer public data sets, respectively, when trained with only 10% of annotated cases from either public cohort. Altogether, the performances of our models indicate that automated annotations using cell type-specific IHC markers can safely replace manual annotations. Automated IHC labels from single-institution cohorts can be combined with small numbers of hand-annotated cases from multi-institutional cohorts to train models that generalize well to diverse data sources.
Collapse
Affiliation(s)
- Tushar Kataria
- Kahlert School of Computing, University of Utah, Salt Lake City, Utah; Kahlert School of Computing, Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah
| | - Saradha Rajamani
- Kahlert School of Computing, University of Utah, Salt Lake City, Utah; Kahlert School of Computing, Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah
| | - Abdul Bari Ayubi
- Department of Pathology, University of Utah, Salt Lake City, Utah
| | - Mary Bronner
- Department of Pathology, University of Utah, Salt Lake City, Utah; Department of Pathology, ARUP Laboratories, Salt Lake City, Utah
| | - Jolanta Jedrzkiewicz
- Department of Pathology, University of Utah, Salt Lake City, Utah; Department of Pathology, ARUP Laboratories, Salt Lake City, Utah
| | - Beatrice S Knudsen
- Kahlert School of Computing, Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah; Department of Pathology, University of Utah, Salt Lake City, Utah.
| | - Shireen Y Elhabian
- Kahlert School of Computing, University of Utah, Salt Lake City, Utah; Kahlert School of Computing, Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah.
| |
Collapse
|
12
|
Kucharzik T, Dignass A, Atreya R, Bokemeyer B, Esters P, Herrlinger K, Kannengiesser K, Kienle P, Langhorst J, Lügering A, Schreiber S, Stallmach A, Stein J, Sturm A, Teich N, Siegmund B. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:1046-1134. [PMID: 37579791 DOI: 10.1055/a-2060-0935] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/16/2023]
Affiliation(s)
- T Kucharzik
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Städtisches Klinikum Lüneburg, Lüneburg, Deutschland
| | - A Dignass
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt, Deutschland
| | - R Atreya
- Medizinische Klinik 1 Gastroent., Pneumologie, Endokrin., Universitätsklinikum Erlangen, Erlangen, Deutschland
| | - B Bokemeyer
- Interdisziplinäres Crohn Colitis Centrum Minden - ICCCM, Minden, Deutschland
| | - P Esters
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt, Deutschland
| | - K Herrlinger
- Innere Medizin I, Asklepios Klinik Nord, Hamburg, Deutschland
| | - K Kannengiesser
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Städtisches Klinikum Lüneburg, Lüneburg, Deutschland
| | - P Kienle
- Abteilung für Allgemein- und Viszeralchirurgie, Theresienkrankenhaus, Mannheim, Deutschland
| | - J Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg Klinikum am Bruderwald, Bamberg, Deutschland
| | - A Lügering
- Medizinisches Versorgungszentrum Portal 10, Münster, Deutschland
| | - S Schreiber
- Klinik für Innere Medizin I, Universitätsklinikum Schleswig Holstein, Kiel, Deutschland
| | - A Stallmach
- Klinik für Innere Medizin IV Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Jena, Jena, Deutschland
| | - J Stein
- Abteilung Innere Medizin mit Schwerpunkt Gastroenterologie, Krankenhaus Sachsenhausen, Frankfurt, Deutschland
| | - A Sturm
- Klinik für Innere Medizin mit Schwerpunkt Gastroenterologie, DRK Kliniken Berlin Westend, Berlin, Deutschland
| | - N Teich
- Internistische Gemeinschaftspraxis, Leipzig, Deutschland
| | - B Siegmund
- Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité Campus Benjamin Franklin - Universitätsmedizin Berlin, Berlin, Deutschland
| |
Collapse
|
13
|
Enea D, Lauwers G, Svrcek M. [Conventional and non-conventional dysplasia in patients with inflammatory bowel disease]. Ann Pathol 2023:S0242-6498(23)00049-4. [PMID: 36906454 DOI: 10.1016/j.annpat.2023.02.006] [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: 02/03/2023] [Revised: 02/16/2023] [Accepted: 02/20/2023] [Indexed: 03/11/2023]
Abstract
Compared to the general population, patients with inflammatory bowel disease (IBD), both ulcerative colitis (UC) or Crohn's disease (CD), are at increased risk of developing some cancers, particularly colorectal cancers (CRC). CRCs, the vast majority of which are adenocarcinomas, develop from a precancerous lesion called dysplasia (or intraepithelial neoplasia) via an inflammation-dysplasia-adenocarcinoma sequence. The advancements of new endoscopic techniques, including visualisation and resection techniques, has led to a reclassification of dysplasia lesions into visible and invisible lesions and their therapeutic management, with a more conservative approach to the colorectal setting. In addition, besides conventional dysplasia, of intestinal phenotype, classically described in IBD, non-conventional dysplasias (as opposed to conventional dysplasia of intestinal phenotype) are now described, including at least seven subtypes. Recognition of these unconventional subtypes, which are still poorly known from pathologists, is becoming crucial, as some of these subtypes appear to be at high risk of developing advanced neoplasia (i.e. high-grade dysplasia or CRC). This review briefly describes the macroscopic features of dysplastic lesions in IBD, as well as their therapeutic management, followed by the clinicopathological features of these dysplastic lesions, with particular emphasis on the new subtypes of unconventional dysplasia, both from a morphological and molecular point of view.
Collapse
Affiliation(s)
- Diana Enea
- Sorbonne université, Assistance publique-Hôpitaux de Paris, hôpital Saint-Antoine, service d'anatomie et cytologie pathologiques, SIRIC CURAMUS, Paris, France
| | - Grégory Lauwers
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute and Departments of Pathology and Oncologic Sciences, University of South Florida, Tampa, FL, États-Unis
| | - Magali Svrcek
- Sorbonne université, Assistance publique-Hôpitaux de Paris, hôpital Saint-Antoine, service d'anatomie et cytologie pathologiques, SIRIC CURAMUS, Paris, France.
| |
Collapse
|
14
|
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.
Collapse
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.
| |
Collapse
|
15
|
Al Bakir I, Kabir M, Yalchin M, Hart A. Optimising inflammatory bowel disease surveillance and dysplasia management-Where do we stand? United European Gastroenterol J 2022; 10:1054-1062. [PMID: 36349435 PMCID: PMC9752268 DOI: 10.1002/ueg2.12330] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/16/2022] [Indexed: 11/11/2022] Open
Abstract
Patients with longstanding extensive colitis are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into colonoscopy screening programmes with the aim of detecting pre-cancerous dysplastic change. However, current surveillance programs face multiple limitations relating to low levels of patient enrolment, missed lesions resulting in interval cancers, and uncertainties in the management of dysplasia. Patient counselling regarding the endoscopic and surgical management options of dysplastic lesions can prove particularly challenging, due to the variable risk of progression to cancer. In this review, we discuss the histopathological diagnosis of inflammatory bowel disease (IBD)-associated dysplasia, describe the techniques to maximise dysplasia detection, and present a standardised multi-disciplinary approach to managing patients with dysplasia. The challenges presented by this patient cohort highlight the clear clinical need for further research into the development and validation of non-invasive markers of CRC risk in IBD patients undergoing surveillance.
Collapse
Affiliation(s)
- Ibrahim Al Bakir
- Gastroenterology DepartmentChelsea and Westminster HospitalLondonUK
| | - Misha Kabir
- Gastroenterology DepartmentUniversity College HospitalLondonUK
| | - Mehmet Yalchin
- Inflammatory Bowel Disease UnitSt Mark's Hospital and Academic InstituteHarrowMiddlesexUK
| | - Ailsa Hart
- Inflammatory Bowel Disease UnitSt Mark's Hospital and Academic InstituteHarrowMiddlesexUK
| |
Collapse
|
16
|
Riggers DS, Gurtner C, Protschka M, Böttcher D, von Bomhard W, Alber G, Winter K, Steiner JM, Heilmann RM. Intestinal S100/Calgranulin Expression in Cats with Chronic Inflammatory Enteropathy and Intestinal Lymphoma. Animals (Basel) 2022; 12:2044. [PMID: 36009635 PMCID: PMC9404432 DOI: 10.3390/ani12162044] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
Diagnosing chronic inflammatory enteropathies (CIE) in cats and differentiation from intestinal lymphoma (IL) using currently available diagnostics is challenging. Intestinally expressed S100/calgranulins, measured in fecal samples, appear to be useful non-invasive biomarkers for canine CIE but have not been evaluated in cats. We hypothesized S100/calgranulins to play a role in the pathogenesis of feline chronic enteropathies (FCE) and to correlate with clinical and/or histologic disease severity. This retrospective case-control study included patient data and gastrointestinal (GI) tissues from 16 cats with CIE, 8 cats with IL, and 16 controls with no clinical signs of GI disease. GI tissue biopsies were immunohistochemically stained using polyclonal α-S100A8/A9 and α-S100A12 antibodies. S100A8/A9+ and S100A12+ cells were detected in all GI segments, with few significant differences between CIE, IL, and controls and no difference between diseased groups. Segmental inflammatory lesions were moderately to strongly correlated with increased S100/calgranulin-positive cell counts. Clinical disease severity correlated with S100A12+ cell counts in cats with IL (ρ = 0.69, p = 0.042) and more severe diarrhea with colonic lamina propria S100A12+ cells with CIE (ρ = 0.78, p = 0.021) and duodenal S100A8/A9+ cells with IL (ρ = 0.71, p = 0.032). These findings suggest a role of the S100/calgranulins in the pathogenesis of the spectrum of FCE, including CIE and IL.
Collapse
Affiliation(s)
- Denise S. Riggers
- Small Animals Department, College of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| | - Corinne Gurtner
- Institute of Animal Pathology, Department of Infectious Diseases and Pathobiology (DIP), Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
| | - Martina Protschka
- Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| | - Denny Böttcher
- Institute of Veterinary Pathology, College of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| | | | - Gottfried Alber
- Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| | - Karsten Winter
- Institute of Anatomy, Medical Faculty, Leipzig University, 04103 Leipzig, Germany
| | - Joerg M. Steiner
- Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Romy M. Heilmann
- Small Animals Department, College of Veterinary Medicine, Leipzig University, 04103 Leipzig, Germany
| |
Collapse
|
17
|
Cretara A, Knee A, Mueller J, Jawale R. Association Between Loss of SATB2 Expression in Inflammatory Bowel Disease Indefinite for Dysplasia and a Diagnosis of Definitive Dysplasia on Follow-up. Am J Surg Pathol 2022; 46:1137-1141. [PMID: 35405720 DOI: 10.1097/pas.0000000000001900] [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: 11/26/2022]
Abstract
Special AT-rich sequence-binding protein 2 (SATB2) is a sensitive and specific biomarker for sporadic colonic adenocarcinomas. Previous studies have found that SATB2 is lost in some adenocarcinomas and dysplasias associated with inflammatory bowel disease (IBD). In establishing these findings, the prior studies did not examine cases of IBD interpreted as indefinite for dysplasia. We examined SATB2 expression in this diagnostic category to determine if any potential loss is associated with a diagnosis of definitive dysplasia on follow-up. To investigate this possibility, we collected 87 biopsies of IBD indefinite for dysplasia from 62 patients and stained them with SATB2. Among patients' indefinite for dysplasia, we found SATB2 loss in 6/62 (9.7%). Among those with follow-up (n=51), we observed 5/6 (83%) with a future dysplasia in those with SATB2 loss compared with 10/45 (22%) in those with SATB2 retention, absolute difference 61.1% (95% confidence interval=28.9%-93.3%). We conclude that loss of SATB2 on biopsies otherwise interpreted as IBD indefinite for dysplasia may mark a population at high risk for showing definitive dysplasia on future biopsies.
Collapse
Affiliation(s)
| | - Alexander Knee
- Medicine, University of Massachusetts Medical School-Baystate
- Office of Research, Epidemiology/Biostatistics Research Core, Baystate Medical Center, Springfield, MA
| | | | | |
Collapse
|
18
|
Wan J, Wang X, Zhang Y, Chen M, Wang M, Wu K, Liang J. Systematic review with meta-analysis: incidence and factors for progression to advanced neoplasia in inflammatory bowel disease patients with indefinite and low-grade dysplasia. Aliment Pharmacol Ther 2022; 55:632-644. [PMID: 35166389 DOI: 10.1111/apt.16789] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/23/2021] [Accepted: 01/12/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Due to limited research on the natural history of indefinite for dysplasia (IND) and low-grade dysplasia (LGD) in inflammatory bowel disease (IBD), the management of these patients is controversial. AIMS This systematic review and meta-analysis aimed to estimate the incidence and identify the risk factors for advanced neoplasia in IBD patients with IND and LGD. METHODS PubMed, Embase and Cochrane Central Register of Controlled Trials were searched until 24 December, 2021, to identify studies that reported pathological results of follow-up colonoscopy or surgery in IBD patients with IND and LGD. The main outcomes were the incidence and risk factors for advanced neoplasia in IBD patients with IND and LGD. RESULTS Based on the analysis of 38 studies, the pooled incidences of advanced neoplasia in IBD patients with IND and LGD were 9.9% (95% CI 4.4%-15.4%) and 10.7% (95% CI 7.0%-14.4%) respectively. The risk factors for advanced neoplasia in IND patients were primary sclerosing cholangitis (PSC) and aneuploidy. The risk factors for advanced neoplasia in LGD patients included male, PSC, previous IND, colonic stricture, index lesion ≥1 cm, distal location, multifocal lesions, distal and flat lesions, nonpolypoid/flat lesions and invisible lesions. CONCLUSIONS The incidence of advanced neoplasia was similar between IND and LGD in IBD patients, as high as one in ten, so more rigorous surveillance is also suggested in IND patients. Since the effects of most factors were derived from the pooled results of only two to three studies, further research was needed to confirm our results.
Collapse
Affiliation(s)
- Jian Wan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Xuan Wang
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yujie Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.,Department of Histology and Embryology, School of Basic Medicine, Xi'an Medical University, Xi'an, China
| | - Min Chen
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Min Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Jie Liang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| |
Collapse
|
19
|
Symer M, Connolly J, Yeo H. Management of the Malignant Colorectal Polyp. Curr Probl Surg 2022; 59:101124. [DOI: 10.1016/j.cpsurg.2022.101124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
20
|
Wang J, Pei B, Yan J, Xu X, Fang AN, Ocansey DKW, Zhang X, Qian H, Xu W, Mao F. hucMSC-Derived Exosomes Alleviate the Deterioration of Colitis via the miR-146a/SUMO1 Axis. Mol Pharm 2022; 19:484-493. [PMID: 35084199 DOI: 10.1021/acs.molpharmaceut.1c00450] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Human umbilical cord mesenchymal stem cell-derived exosome (hucMSC-Ex) plays an important role in tissue repair and immunomodulation, leading to the mitigation of inflammatory bowel disease. However, the preventive function of hucMSC-Ex in the onset and progression of colitis-associated colon cancer (CAC) is poorly understood. In the current study, dextran sodium sulfate/azoxymethane-induced colitis mouse model was established, and the mice disease activity index, body weight, colon length, tumor counts, survival curve, tissue H&E/immunohistochemistry, and cytokines expression were analyzed to evaluate the effects of hucMSC-Ex on CAC. In addition, miR-146a mimics were transfected into colonic epithelial cells (fetal human cells) to evaluate their role in the hucMSC-Ex-mediated regulation of SUMO1. The results showed that hucMSC-Ex inhibits the expression of SUMO1 to reduce the process of CAC progression. Further analysis indicated that miR-146a targets and inhibits SUMO1 expression and its binding to β-catenin. In conclusion, our findings showed that hucMSC-Ex is effective in alleviating the deterioration of colitis via the miR-146a-mediated inhibition of SUMO1, which is crucial in this disease process.
Collapse
Affiliation(s)
- Jingyan Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.,Tongxiang First People's Hospital, Jiaochang Road 1918, Tongxiang, Zhejiang 314500, P. R. China
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, Jiangsu 223800, P. R. China
| | - Jialai Yan
- Department of Basic Medicine, Anhui Medical College, Hefei, Anhui 230601, P. R. China
| | - Xinwei Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - An-Ning Fang
- Department of Basic Medicine, Anhui Medical College, Hefei, Anhui 230601, P. R. China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.,Directorate of University Health Services, University of Cape Coast, Cape Coast 5007, Ghana
| | - Xu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Hui Qian
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Wenrong Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| |
Collapse
|
21
|
Abu-Farsakh S, Drage MG, Huber AR, Turner BM, Varghese S, Wang X, Whitney-Miller CL, Gonzalez RS. Interobserver Agreement in the Diagnosis of Anal Dysplasia: Comparison Between Gastrointestinal and Gynaecologic Pathologists and Utility of Consensus Conferences. Histopathology 2021; 80:648-655. [PMID: 34601750 DOI: 10.1111/his.14578] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/30/2021] [Accepted: 09/30/2021] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Management of anal dysplasia relies on the accurate diagnosis of anal biopsy specimens. As institutions move toward subspecialty signout (SSSO), decisions must be made regarding whether to assign anal biopsies to the gastrointestinal (GI) or gynaecologic (GYN) pathology service. MATERIALS AND METHODS We identified 200 archival tissue biopsies of anal mucosa and circulated them among three GI pathologists and three GYN pathologists. Each pathologist separately scored each biopsy as normal, atypical, LSIL, or HSIL. Every case that was called HSIL by at least one pathologist was stained with p16 immunostain and a "gold standard" interpretation of whether a case represented HSIL was made. RESULTS The GI pathologists agreed on 97 (49%) cases prior to consensus; the GYN pathologists agreed on 33 (17%). The sensitivities of the 3 GI pathologists in detecting HSIL against the "gold standard" were 47%, 100%, and 21%, and for the GYN pathologists the sensitivities were 74%, 89%, and 84%; the sensitivities of both the GI and GYN consensus diagnoses were 74% each. The specificities of the 3 GI pathologists in detecting HSIL were 99%, 90%, and 100%, and for the GYN pathologists the specificities were 99%, 92%, and 91%; the specificities of both the GI and GYN consensus diagnoses were 100%. CONCLUSIONS A mild to moderate degree of interobserver variability exists in the diagnosis of anal dysplasia among pathologists. Our study does indicate the utility of some form of consensus conference, as overall agreement among GI pathologists and among GYN pathologists improved following in-person consensus.
Collapse
Affiliation(s)
- Sohaib Abu-Farsakh
- Department of Pathology, University of Rochester Medical Center, Rochester.,Department of Pathology, Beth Israel Deaconess Medical Center, Boston
| | - Michael G Drage
- Department of Pathology, University of Rochester Medical Center, Rochester.,Department of Pathology, Beth Israel Deaconess Medical Center, Boston
| | - Aaron R Huber
- Department of Pathology, University of Rochester Medical Center, Rochester.,Department of Pathology, Beth Israel Deaconess Medical Center, Boston
| | - Bradley M Turner
- Department of Pathology, University of Rochester Medical Center, Rochester.,Department of Pathology, Beth Israel Deaconess Medical Center, Boston
| | - Sharlin Varghese
- Department of Pathology, University of Rochester Medical Center, Rochester.,Department of Pathology, Beth Israel Deaconess Medical Center, Boston
| | - Xi Wang
- Department of Pathology, University of Rochester Medical Center, Rochester.,Department of Pathology, Beth Israel Deaconess Medical Center, Boston
| | - Christa L Whitney-Miller
- Department of Pathology, University of Rochester Medical Center, Rochester.,Department of Pathology, Beth Israel Deaconess Medical Center, Boston
| | - Raul S Gonzalez
- Department of Pathology, University of Rochester Medical Center, Rochester.,Department of Pathology, Beth Israel Deaconess Medical Center, Boston
| |
Collapse
|
22
|
Parian AM, Limketkai BN, Chowdhury R, Brewer GG, Salem G, Falloon K, Selaru F, Melia J, Lazarev MG. Serrated Epithelial Change Is Associated With High Rates of Neoplasia in Ulcerative Colitis Patients: A Case-controlled Study and Systematic Review With Meta-analysis. Inflamm Bowel Dis 2021; 27:1475-1481. [PMID: 33295614 DOI: 10.1093/ibd/izaa312] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Patients with long-standing ulcerative colitis (UC) are at an increased risk of colorectal cancer. Risk stratification is important to identify patients who require more frequent endoscopic surveillance. Serrated epithelial change (SEC) found in patients with long-standing colitis may be associated with neoplasia and serve as a marker to stratify patients at higher risk of colorectal cancer (CRC). METHODS A case-control study was performed to compare the rates of neoplasia between UC patients with SEC and UC patients without SEC who were matched for age, disease duration, and disease extent. Paired tests, conditional logistic regression, and Kaplan-Meier analyses were used to compare groups. A systematic review with meta-analysis was performed, combining our local data with previously published data. RESULTS This study included 196 UC patients without prior neoplasia, 98 with SEC and 98 without SEC. Ulcerative colitis patients with SEC had a significantly higher rate of synchronous or metachronous neoplasia than UC patients without SEC (26.5% vs 3.1%; P < 0.001). Synchronous or metachronous high-grade dysplasia and CRC were found more frequently in UC patients with SEC than UC patients without SEC (11.2% vs 2.0%; P = 0.02). A meta-analysis was consistent with these findings, showing a higher rate of neoplasia in patients with SEC compared with those without SEC (16.4% vs 3.9%; P < 0.001). CONCLUSION Serrated epithelial change is associated with a significantly increased risk of synchronous and metachronous neoplasia including high-grade dysplasia and CRC in patients with UC. Histopathological findings of SEC should warrant closer endoscopic surveillance for CRC.
Collapse
Affiliation(s)
- Alyssa M Parian
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Berkeley N Limketkai
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA.,Vatche & Tamar Manoukian Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, CA, USA
| | - Reezwana Chowdhury
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Gala Godoy Brewer
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - George Salem
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Katie Falloon
- Department of Gastroenterology, Cleveland Clinic, Cleveland, OH, USA
| | - Florin Selaru
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Joanna Melia
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Mark G Lazarev
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| |
Collapse
|
23
|
Jin BR, Kim HJ, Sim SA, Lee M, An HJ. Anti-Obesity Drug Orlistat Alleviates Western-Diet-Driven Colitis-Associated Colon Cancer via Inhibition of STAT3 and NF-κB-Mediated Signaling. Cells 2021; 10:cells10082060. [PMID: 34440829 PMCID: PMC8394553 DOI: 10.3390/cells10082060] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/05/2021] [Accepted: 08/08/2021] [Indexed: 12/31/2022] Open
Abstract
Many researchers have argued that Western diet (WD)-induced obesity accelerates inflammation and that inflammation is a link between obesity and colorectal cancer (CRC). This study investigated the effect of WDs on the development and progression of colitis-associated colon cancer (CAC) and the efficacy of the anti-obesity agent orlistat on WD-driven CAC in mice. The results revealed that the WD exacerbated CAC in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mice, which showed increased mortality, tumor formation, and aggravation of tumor progression. Furthermore, WD feeding also upregulated inflammation, hyperplasia, and tumorigenicity levels through the activation of STAT3 and NF-κB signaling in an AOM/DSS-induced mouse model. In contrast, treatment with orlistat increased the survival rate and alleviated the symptoms of CAC, including a recovery in colon length and tumor production decreases in WD-driven AOM/DSS-induced mice. Additionally, orlistat inhibited the extent of inflammation, hyperplasia, and tumor progression via the inhibition of STAT3 and NF-κB activation. Treatment with orlistat also suppressed the β-catenin, slug, XIAP, Cdk4, cyclin D, and Bcl-2 protein levels in WD-driven AOM/DSS-induced mice. The results of this study indicate that orlistat alleviates colon cancer promotion in WD-driven CAC mice by suppressing inflammation, especially by inhibiting STAT3 and NF-κB activation.
Collapse
Affiliation(s)
- Bo-Ram Jin
- Department of Pharmacology, College of Korean Medicine, Sangji University, 83 Sangjidae-gil, Wonju-si 26339, Gangwon-do, Korea; (B.-R.J.); (H.-J.K.); (S.-A.S.)
| | - Hyo-Jung Kim
- Department of Pharmacology, College of Korean Medicine, Sangji University, 83 Sangjidae-gil, Wonju-si 26339, Gangwon-do, Korea; (B.-R.J.); (H.-J.K.); (S.-A.S.)
| | - Seo-Ah Sim
- Department of Pharmacology, College of Korean Medicine, Sangji University, 83 Sangjidae-gil, Wonju-si 26339, Gangwon-do, Korea; (B.-R.J.); (H.-J.K.); (S.-A.S.)
| | - Minho Lee
- Department of Life Science, Dongguk University-Seoul, 32 Dongguk-ro, Ilsandong-gu, Goyang-si 10326, Gyeonggi-do, Korea
- Correspondence: (M.L.); (H.-J.A.); Tel.: +82-33-738-7503 (H.-J.A.); Fax: +82-33-730-0679 (H.-J.A.)
| | - Hyo-Jin An
- Department of Pharmacology, College of Korean Medicine, Sangji University, 83 Sangjidae-gil, Wonju-si 26339, Gangwon-do, Korea; (B.-R.J.); (H.-J.K.); (S.-A.S.)
- Correspondence: (M.L.); (H.-J.A.); Tel.: +82-33-738-7503 (H.-J.A.); Fax: +82-33-730-0679 (H.-J.A.)
| |
Collapse
|
24
|
Yalchin M, Baker AM, Graham TA, Hart A. Predicting Colorectal Cancer Occurrence in IBD. Cancers (Basel) 2021; 13:2908. [PMID: 34200768 PMCID: PMC8230430 DOI: 10.3390/cancers13122908] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/13/2022] Open
Abstract
Patients with colonic inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into a surveillance programme aimed at detecting dysplasia or early cancer. Current surveillance programmes are guided by clinical, endoscopic or histological predictors of colitis-associated CRC (CA-CRC). We have seen great progress in our understanding of these predictors of disease progression, and advances in endoscopic technique and management, along with improved medical care, has been mirrored by the falling incidence of CA-CRC over the last 50 years. However, more could be done to improve our molecular understanding of CA-CRC progression and enable better risk stratification for patients with IBD. This review summarises the known risk factors associated with CA-CRC and explores the molecular landscape that has the potential to complement and optimise the existing IBD surveillance programme.
Collapse
Affiliation(s)
- Mehmet Yalchin
- Inflammatory Bowel Disease Department, St. Mark’s Hospital, Watford R.d., Harrow HA1 3UJ, UK
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Ann-Marie Baker
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Trevor A. Graham
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Ailsa Hart
- Inflammatory Bowel Disease Department, St. Mark’s Hospital, Watford R.d., Harrow HA1 3UJ, UK
| |
Collapse
|
25
|
Jin BR, Chung KS, Hwang S, Hwang SN, Rhee KJ, Lee M, An HJ. Rosmarinic acid represses colitis-associated colon cancer: A pivotal involvement of the TLR4-mediated NF-κB-STAT3 axis. Neoplasia 2021; 23:561-573. [PMID: 34077834 PMCID: PMC8180929 DOI: 10.1016/j.neo.2021.05.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/17/2021] [Accepted: 05/03/2021] [Indexed: 01/07/2023]
Abstract
Previously, we found that rosmarinic acid (RA) exerted anti-inflammatory activities in a dextran sulfate sodium (DSS)-induced colitis model. Here, we investigated the anti-tumor effects of RA on colitis-associated colon cancer (CAC) and the underlying molecular mechanisms. We established an azoxymethane (AOM)/DSS-induced CAC murine model for in vivo studies and used a conditioned media (CM) culture system in vitro. H&E staining, immunohistochemistry, western blot assay, enzyme-linked immunosorbent assay, molecular docking, co-immunoprecipitation, and immunofluorescence assay were utilized to investigate how RA prevented colorectal cancer. In the AOM/DSS-induced CAC murine model, RA significantly reduced colitis severity, inflammation-related protein expression, tumor incidence, and colorectal adenoma development. It significantly modulated toll-like receptor-4 (TLR4)-mediated nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, thus attenuating the expression of anti-apoptotic factors, which mediate transcription factor-dependent tumor growth. In vitro, RA inhibited CM-induced TLR4 overexpression and competitively inhibited TLR4-myeloid differentiation factor 2 complex in an inflammatory microenvironment. Thus, RA suppressed NF-κB and STAT3 activation in colon cancer cells in an inflammatory microenvironment. Therefore, RA suppressed colitis-associated tumorigenesis in the AOM/DSS-induced CAC murine model and abrogated human colon cancer progression in an inflammatory microenvironment by propitiating TLR4-mediated NF-κB and STAT3 activation, pleiotropically.
Collapse
Affiliation(s)
- Bo-Ram Jin
- Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju-si, Gangwon-do, Korea
| | - Kyung-Sook Chung
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Soonjae Hwang
- Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University at Wonju, Wonju-si, Gangwon-do, Republic of Korea
| | - Sam Noh Hwang
- Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University at Wonju, Wonju-si, Gangwon-do, Republic of Korea
| | - Ki-Jong Rhee
- Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University at Wonju, Wonju-si, Gangwon-do, Republic of Korea
| | - Minho Lee
- Department of Life Science, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, Republic of Korea.
| | - Hyo-Jin An
- Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju-si, Gangwon-do, Korea.
| |
Collapse
|
26
|
Pritzker KPH, Darling MR, Hwang JTK, Mock D. Oral Potentially Malignant Disorders (OPMD): What is the clinical utility of dysplasia grade? Expert Rev Mol Diagn 2021; 21:289-298. [PMID: 33682567 DOI: 10.1080/14737159.2021.1898949] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Oral epithelial dysplasia is considered a potential histologic precursor of subsequent squamous cell cancer. As standard clinical practice, pathologists grade dysplasia to assess risk for progression to malignancy. Except for the most advanced grade, severe dysplasia, dysplasia grading has failed to correlate well with the risk to develop invasive cancer. The questions of what process dysplasia grading best represents and what clinical utility dysplasia grading may have are explored. AREAS COVERED This narrative review is based on PubMed search with emphasis on papers since 2010. Epithelial dysplasia as a precursor lesion of cancer and dysplasia grading as a risk assessment tool for progression to cancer are discussed. The close clinical association of dysplasia with known carcinogens, alcohol, and tobacco products is presented. EXPERT OPINION Oral epithelial dysplasia is often, associated with prolonged exposure to tobacco and alcohol products. With reduction of carcinogen exposure, dysplasia is known to regress in some cases. It is proposed that histologic dysplasia grade together with macroscopic images of dysplastic clinical lesions be used as an educational tool to incentivize patients to reduce their known carcinogen exposure. This strategy has the potential to reduce lesion progression thereby reducing the disease burden of oral cancer.
Collapse
Affiliation(s)
- Kenneth P H Pritzker
- Professor Emeritus, Laboratory Medicine and Pathobiology; Surgery University of Toronto, Toronto, Ontario, Canada.,Proteocyte Diagnostics Inc., Toronto, Canada.,Department of Pathology and Laboratory Medicine, Pathology & Laboratory Medicine Mount Sinai Hospital, Toronto, Canada
| | - Mark R Darling
- Professor, Department of Pathology and Laboratory Medicine, Schulich Faculty of Medicine and Dentistry, Western University London Ontario, Canada
| | | | - David Mock
- Department of Pathology and Laboratory Medicine, Pathology & Laboratory Medicine Mount Sinai Hospital, Toronto, Canada.,Professor, Pathology/Oral Medicine & Dean Emeritus, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.,Department of Dentistry, Dentistry Mount Sinai Hospital, Toronto, Canada
| |
Collapse
|
27
|
Interobserver agreement and the impact of mentorship on the diagnosis of inflammatory bowel disease-associated dysplasia among subspecialist gastrointestinal pathologists. Virchows Arch 2021; 478:1061-1069. [PMID: 33392796 DOI: 10.1007/s00428-020-02998-z] [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: 08/05/2020] [Revised: 12/09/2020] [Accepted: 12/14/2020] [Indexed: 01/26/2023]
Abstract
The diagnosis of inflammatory bowel disease (IBD)-associated dysplasia is challenging, and past studies have demonstrated considerable interobserver variability in such diagnoses. This study aimed to assess interobserver agreement in IBD dysplasia diagnoses among subspecialty GI pathologists and to explore the impact of mentorship on diagnostic variability. Twelve GI pathologist mentees and 7 GI pathologist mentors reviewed 163 digitized slides. Participants rendered a diagnosis of negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, or high-grade dysplasia and provided a confidence level for each case. Interobserver agreement and reliability were assessed using Cohen's and Fleiss' kappa (κ) statistics and intraclass correlation coefficient (ICC) analysis. The overall κ coefficient was 0.42 (95% CI: 0.38-0.46). The overall ICC was 0.67 (95% CI: 0.62-0.72). Κ coefficients ranged from 0.31 to 0.49 for mentor/mentee pairs and from 0.34 to 0.55 for pairs of mentees of the same mentor. The combined κ coefficient was 0.44 (95% CI: 0.39-0.48) for all mentees and 0.39 (95% CI: 0.34-0.43) for all mentors. Common features in low agreement cases included mucosal atrophy, areas of stark contrast, serrations, decreased goblet cells, absent surface epithelium, and poor orientation. Participants were confident in most diagnoses, and increased confidence levels generally correlated with higher interobserver agreement. Interobserver agreement among subspecialist GI pathologists in this curated cohort of IBD dysplasia cases was fair to moderate. Mentorship during GI pathology fellowship does not appear to be a significant factor contributing to interobserver variability, but increased experience also does not seem to improve interobserver agreement.
Collapse
|
28
|
Rabbenou W, Ullman TA. Risk of Colon Cancer and Recommended Surveillance Strategies in Patients with Ulcerative Colitis. Gastroenterol Clin North Am 2020; 49:791-807. [PMID: 33121696 DOI: 10.1016/j.gtc.2020.08.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Longstanding and extensive ulcerative colitis (UC) are associated with the subsequent development of colorectal cancer (CRC). This article summarizes key strategies for colonoscopic surveillance, the most widely used and evidence-based method of CRC prevention. As currently constituted and practiced, surveillance examinations every 1 to 3 years with lesion detection and removal using high-definition endoscopic systems with or without pancolonic spray-dye chromoendoscopy is the best method for mitigating the development of CRC morbidity and mortality. For patients with primary sclerosing cholangitis with UC, surveillance should begin at the time of diagnosis and colonoscopy should be performed annually.
Collapse
Affiliation(s)
- Wendy Rabbenou
- Division of Gastroenterology, Montefiore Medical Center, Albert Einstein College of Medicine, 33030 Rochambeau Avenue, Bronx, NY 10461, USA
| | - Thomas A Ullman
- Division of Gastroenterology, Montefiore Medical Center, Albert Einstein College of Medicine, 33030 Rochambeau Avenue, Bronx, NY 10461, USA.
| |
Collapse
|
29
|
Kucharzik T, Dignass AU, Atreya R, Bokemeyer B, Esters P, Herrlinger K, Kannengießer K, Kienle P, Langhorst J, Lügering A, Schreiber S, Stallmach A, Stein J, Sturm A, Teich N, Siegmund B. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2020; 58:e241-e326. [PMID: 33260237 DOI: 10.1055/a-1296-3444] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Torsten Kucharzik
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Klinikum Lüneburg, Lüneburg, Deutschland
| | - Axel U Dignass
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt am Main, Deutschland
| | - Raja Atreya
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Deutschland
| | - Bernd Bokemeyer
- Gastroenterologische Gemeinschaftspraxis Minden, Deutschland
| | - Philip Esters
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt am Main, Deutschland
| | | | - Klaus Kannengießer
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Klinikum Lüneburg, Lüneburg, Deutschland
| | - Peter Kienle
- Allgemein- und Viszeralchirurgie, Theresienkrankenhaus und Sankt Hedwig-Klinik GmbH, Mannheim, Deutschland
| | - Jost Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Klinikum am Bruderwald, Bamberg, Deutschland
| | - Andreas Lügering
- Medizinisches Versorgungszentrum Portal 10, Münster, Deutschland
| | | | - Andreas Stallmach
- Gastroenterologie, Hepatologie und Infektiologie, Friedrich Schiller Universität, Jena, Deutschland
| | - Jürgen Stein
- Innere Medizin mit Schwerpunkt Gastroenterologie, Krankenhaus Sachsenhausen, Frankfurt/Main, Deutschland
| | - Andreas Sturm
- Klinik für Innere Medizin mit Schwerpunkt Gastroenterologie, DRK Kliniken Berlin Westend, Berlin, Deutschland
| | - Niels Teich
- Internistische Gemeinschaftspraxis für Verdauungs- und Stoffwechselkrankheiten, Leipzig, Deutschland
| | - Britta Siegmund
- Medizinische Klinik I, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland
| |
Collapse
|
30
|
Liu YJ, Rogers J, Liu YZ, Gui X, Jalikis F, Koch L, Swanson PE, Truong CD, Yeh MM. Interobserver agreement in pathologic evaluation of bile duct biopsies. Hum Pathol 2020; 107:29-38. [PMID: 33129823 DOI: 10.1016/j.humpath.2020.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 10/07/2020] [Accepted: 10/12/2020] [Indexed: 12/20/2022]
Abstract
Intraductal biopsy is commonly used for preoperative evaluation of the etiology of biliary strictures. Interpretation of intraductal biopsies is frequently challenging. The diagnosis often suffers from interobserver disagreement, which has not been studied in the literature. We sought to assess interobserver concordance in the interpretation of intraductal biopsies. Eighty-five biopsies were retrieved, falling into five diagnostic categories: negative for dysplasia (NED), indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and carcinoma (CA). Eight gastrointestinal pathologists blindly reviewed all the slides. Agreement among pathologists was analyzed using Fleiss κ and weighted concordance coefficient S∗. A face-to-face consensus/training session was held to discuss the classification criteria, followed by a second round review. The overall interobserver agreement was fair in the first round review (κ = 0.39; S∗ = 0.56) and improved to moderate in the second round review (κ = 0.48; S∗ = 0.69). The agreement before and after consensus meeting was substantial to nearly perfect for CA (κ = 0.65, S∗ = 0.83; and κ = 0.80, S∗ = 0.91), fair for HGD (κ = 0.28, S∗ = 0.69; and κ = 0.40, S∗ = 0.63), and moderate for NED (κ = 0.47, S∗ = 0.50; and κ = 0.47, S∗ = 0.53). Agreement improved from fair to moderate for LGD (κ = 0.36, S∗ = 0.61; and κ = 0.49, S∗ = 0.71) and slight to fair for IND (κ = 0.16, S∗ = 0.51; and κ = 0.33, S∗ = 0.50). Compared with Hollande's fixed specimens, the agreement was higher in almost all diagnostic categories in formalin-fixed biopsies. Overall, interobserver concordance was improved after a consensus/training session. Interobserver reproducibility was high at the end of the diagnostic spectrum (CA) but fair to moderate for other diagnostic categories.
Collapse
Affiliation(s)
- Yong-Jun Liu
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, WI, 53705, USA
| | - Jessica Rogers
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Yao-Zhong Liu
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, LA, 70112, USA
| | - Xianyong Gui
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Florencia Jalikis
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Lisa Koch
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Paul E Swanson
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Camtu D Truong
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Matthew M Yeh
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98195, USA.
| |
Collapse
|
31
|
Pathologist Experience and Concordance in the Diagnosis of Dysplasia in Long-standing Inflammatory Bowel Disease. Am J Surg Pathol 2020; 44:955-961. [PMID: 32235151 DOI: 10.1097/pas.0000000000001475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Surveillance colonoscopies focused to detect dysplasia are recommended to prevent colorectal cancer in patients with long-standing colonic inflammatory bowel disease (IBD). To date, histologic diagnosis and gradation of IBD-related dysplasia has been challenged by a high variability among pathologists. We aimed to analyze the observer characteristics that are correlated with concordance deviations in this diagnosis. Eight pathologists evaluated a set of 125 endoscopic biopsy samples with a representative distribution of nondysplastic and dysplastic lesions from long-standing IBD patients. Two rounds of diagnosis were carried out during a period of 18 months. The κ test was applied to analyze concordance. Pathologists were grouped on the basis of their experience. A subanalysis was performed by eliminating the highly prevalent nondysplastic samples, as well as an analysis after observers' grouping. Overall interobserver agreement was good (κ=0.73), with an even higher pairwise value (κ=0.86) as well as the intraobserver agreement values (best κ=0.85). After eliminating the highly prevalent nondysplastic samples, the interobserver agreement was still moderate to good (best overall κ=0.50; best paired κ=0.72). Notable differences were seen between the pathologists with a high-volume and low-volume practice (best overall κ=0.61 and 0.41, respectively). The agreement in the diagnosis of dysplasia in IBD endoscopic biopsies may have been undervalued over time. This is the first study evaluating pathologists' diagnostic robustness in this field. The results suggest that examining a large volume of samples is the key factor to increase the consistency in the diagnosis and gradation of IBD-related dysplasia.
Collapse
|
32
|
Leoncini G, Donato F, Reggiani-Bonetti L, Salviato T, Cadei M, Daperno M, Principi MB, Armuzzi A, Caprioli F, Canavese G, Villanacci V. Diagnostic interobserver variability in Crohn's disease- and ulcerative colitis-associated dysplasia: a multicenter digital survey from the IG-IBD Pathologists Group. Tech Coloproctol 2020; 25:101-108. [PMID: 33025294 DOI: 10.1007/s10151-020-02349-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 09/23/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Crohn's disease (CD) and ulcerative colitis, two forms of inflammatory bowel disease (IBD), are chronic and relapsing conditions of the gastrointestinal tract both characterized by long lasting chronic inflammation and increased risk of dysplasia and colorectal cancer (CRC). The aim of our study was to evaluate the interobserver agreement about IBD-associated dysplasia among pathologists belonging to the Italian Group for Inflammatory Bowel Diseases (IG-IBD P). METHODS The present multicenter survey was performed using telepathology, supported by an open source E-learning platform. Biopsy specimens from 30 colonoscopies and from 20 patients were included. The glass slides of any case, including clinical and endoscopic data, were digitalized and uploaded on the E-learning platform. All the digital slides were grouped in 54 diagnostic "blocks". Blinded histopathological evaluation on all the digital slides was performed by 20 gastrointestinal pathologists. Closed-ended questions about (1) the occurrence of IBD; (2) the classification of IBD (as UC or CD); (3) the presence of active versus quiescent disease; (4) the presence of dysplasia; (5) the possible association of dysplasia with the sites of disease (dysplasia-associated lesion or mass-DALM vs adenoma-like mass-ALM); (6) the grading of dysplasia according to the ECCO guidelines (negative, indefinite, low grade, high grade categories) and (7) the presence of associated serrated features, were proposed in each case. Inter-observer agreement was evaluated by mean agreement percentage and kappa statistic, when suitable. RESULTS The diagnosis of IBD was confirmed in 19 of 20 patients, 17 of 19 being classified as UC, 2 as CD. The mean interobserver agreement percentages about (1) the evidence of IBD, (2) the presence of either UC or CD and (3) the activity grading resulted to be 80%, 69% and 86%, respectively. Dysplasia was detected in 8/20 patients, with moderate agreement between pathologists (mean 72%, k 0.48). Particularly, low grade dysplasia was found in 13 biopsies (combined k 0.38), whereas high grade dysplasia in 8 (combined k 0.47). When the endoscopic and histopathological data were combined, features consistent with DALM were found in 6 of 20 patients with low grade dysplasia and those consistent with ALM in 2 patients with low grade dysplasia in a single biopsy (mean agreement: 86%). An associated serrated pattern was discovered in 4 patients (7 biopsies). CONCLUSIONS Our study showed moderate interobserver agreement about the histopathological detection and classification of IBD-associated dysplasia. Further efforts should be undertaken to integrate the histopathological data with both the ancillary tests and molecular investigations.
Collapse
Affiliation(s)
- G Leoncini
- Pathology Unit, ASST del Garda, Desenzano del Garda (BS), Brescia, Italy.
| | - F Donato
- Unit of Hygiene, Epidemiology and Public Health, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - L Reggiani-Bonetti
- Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - T Salviato
- Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - M Cadei
- Institute of Pathology, ASST Spedali Civili, Brescia, Italy
| | - M Daperno
- Gastroenterology Unit, Mauriziano Hospital, Turin, Italy
| | - M B Principi
- Emergency and Organ Transplantation Department, Section of Gastroenterology, AOU Policlinico, Bari, Italy
| | - A Armuzzi
- IBD Unit, Presidio Columbus Fondazione Policlinico Universitario A. Gemelli IRCCS Università Cattolica del Sacro Cuore, Rome, Italy
| | - F Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano, Milan, Italy
- Department of Pathophysiology, University of Milan, Milan, Italy
- Department of Transplantation, University of Milan, Milan, Italy
| | - G Canavese
- Pathology Department, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy
| | - V Villanacci
- Institute of Pathology, ASST Spedali Civili, Brescia, Italy
| |
Collapse
|
33
|
Abd El Hafez A, Mohamed AS, Shehta A, Sheta HAEAS. Neutrophil extracellular traps-associated protein peptidyl arginine deaminase 4 immunohistochemical expression in ulcerative colitis and its association with the prognostic predictors. Pathol Res Pract 2020; 216:153102. [PMID: 32853943 DOI: 10.1016/j.prp.2020.153102] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/27/2020] [Accepted: 07/05/2020] [Indexed: 02/06/2023]
Abstract
Neutrophil extracellular traps (NETs) are incriminated in several immune and inflammatory diseases including ulcerative colitis (UC). Analysis of colonic tissues for NETs-related markers in UC carries prognostic and therapeutic implications. This work aims to evaluate the immunohistochemical (IHC) expression of NETs-associated-protein arginine deaminase 4 (PAD4) in colonic biopsies from UC patients in comparison to normal colon (NC). Association between PAD4 expression level and histopathologic grade, patient's therapeutic response and other clinicopathological prognostic predictors in UC are determined. This cohort study included biopsies from 42 UC patients and 11 NC controls. Clinicopathological data including patient's age at diagnosis, gender, presenting symptoms, anatomical disease extent, extra-intestinal manifestations, type and response to therapy and surgical interventions were recorded and tabulated. Histopathological grading of disease activity and associated epithelial changes were assessed. PAD4 immunostaining was conducted using Horseradish Peroxidase technique and scored semiquantitatively considering intensity and percentage of nuclear staining of lamina propria inflammatory cells. Appropriate statistical tests were applied. Anti-PAD4 was localized mainly in the nuclei of lamina propria infiltrating neutrophils. It was expressed more significantly in UC (95.2 %) compared to NC (p 0.001). Increased PAD4 expression level was significantly associated with increasing histopathologic grade, anatomical disease extent, lacking response to therapy and subjection to radical surgery (p:0.001, = 0.038, 0.046, 0.046 respectively). Age, gender, presenting symptoms, extra-intestinal manifestations and epithelial changes showed insignificant associations. This study characterizes a subset of UC patients with high histopathological grade of activity, pancolonic involvement, strong/moderate PAD4 expression levels and who are unresponsive to routine medical therapeutic regimens rendering them candidates for radical surgery. In conjunction with histopathological grading, IHC evaluation of PAD4 in UC is recommended to guide patient's selection for targeted therapy using the novel-discovered selective PAD4 inhibitors.
Collapse
Affiliation(s)
- Amal Abd El Hafez
- Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Abdelaty Shawky Mohamed
- Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Al Maarefa University, Riyadh, Saudi Arabia.
| | - Ahmed Shehta
- Gastrointestinal Surgery Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | | |
Collapse
|
34
|
Kato T, Iwasaki T, Arihiro S, Saruta M. Endoscopic visualization of cancer and dysplasia in patients with ulcerative colitis following sensitization with oral 5-aminolevulinic acid. J Dig Dis 2020; 21:498-504. [PMID: 32686910 PMCID: PMC7590119 DOI: 10.1111/1751-2980.12923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 05/22/2020] [Accepted: 07/05/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Early diagnosis of colitis-associated cancer and dysplasia through surveillance endoscopy is vital for patients with ulcerative colitis (UC). This study aimed to evaluate the efficacy of autofluorescence endoscopy (AFE) using 5-aminolevulinic acid (ALA) and to investigate the fluorescence signal localization pattern following 5-ALA administration in tumorous lesions diagnosed as colitis-associated cancer and dysplasia. The sensitivity and specificity of tumorous lesions detected by white light endoscopy (WLE) with and without AFE were evaluated. METHODS Overall, 13 endoscopic procedures were performed in 11 patients with UC using WLE and AFE following the oral administration of 5-ALA. The biopsied lesions detected via endoscopy and resected specimens from cases underwent colectomy were assessed histopathologically. The sensitivity and specificity of detecting tumorous lesions by WLE with and without AFE were evaluated. RESULTS Of the 68 lesions detected and biopsied, 63 were detected via WLE, and five were detected via AFE alone. The sensitivity of detecting colitis-associated cancer and dysplasia via WLE combined with AFE was 36.4%, and the specificity, positive predictive value and negative predictive value were 94.2%, 57.1%, and 87.5%, respectively. Tumorous lesions displayed three types of fluorescence patterns on AFE. CONCLUSIONS AFE using 5-ALA can detect colitis-associated cancer and dysplasia in patients with long-standing UC and lesions that could not be detected via WLE. The distinctive fluorescence patterns in lesions may permit qualitative diagnoses of colitis-associated cancer and dysplasia.
Collapse
Affiliation(s)
- Tomohiro Kato
- Division of Gastroenterology and Hepatology, Department of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Tetsuyoshi Iwasaki
- Division of Gastroenterology and Hepatology, Department of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Seiji Arihiro
- Division of Gastroenterology and Hepatology, Department of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| |
Collapse
|
35
|
Lang-Schwarz C, Adler W, Geppert M, Seitz G, Sterlacci W, Falkeis-Veits C, Veits L, Drgac J, Melcher B, Lang-Schwarz K, Nikolaev S, Dregelies T, Krugmann J, Vieth M. Sporadic adenoma or ulcerative colitis associated neoplasia? The endoscopist's information has an impact on diagnosis and patient management. Pathol Res Pract 2020; 216:153162. [PMID: 32916446 DOI: 10.1016/j.prp.2020.153162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 11/16/2022]
Abstract
BACKGROUND Diagnosing low grade intraepithelial neoplasia (LGIN) in patients with ulcerative colitis (UC) is difficult. Distinguishing between sporadic adenoma (SA) and UC associated LGIN is even more challenging but has clinical impact. We aimed to examine, if the morphological distinction between both entities is reliably possible, how it influences patient's outcome and the role of the endoscopist in this decision with respect to current endoscopy classification schemes. METHODS Seven pathologists retrospectively reevaluated 425 cases of LGIN in UC patients, diagnosed between 2009 and 2017 with preceding expert consensus and follow up in two separate readings, based on published morphological differentiation criteria. In the first evaluation, the observers were blinded to any clinical data. In the second evaluation, they knew patients' age as well as endoscopic features. They also rated their subjective diagnostic certainty. RESULTS Diagnostic correctness improved significantly in the second assessment as did the pathologists' confidence in their diagnoses (p < 0.001 - p = 0.019). Knowledge of clinical and endoscopical data led to a higher percentage of SA (71.8% vs. 85.6%). UC associated LGIN showed significant earlier LGIN relapse as well as more high grade intraepithelial neoplasia and carcinoma during follow up (p < 0.001, p < 0.001, p = 0.005). CONCLUSIONS Distinction between SA and UC associated LGIN is important as it has an impact on patients' follow up and treatment. Morphological distinction remains difficult with moderate interobserver variability. Adequate clinical information significantly improves pathologists' diagnoses as well as their confidence in their diagnoses.
Collapse
Affiliation(s)
| | - Werner Adler
- Department of Biometry and Epidemiology, Friedrich-Alexander-University, Erlangen, Germany
| | - Michael Geppert
- Specialist for Internal Medicine, Gastroenterologist, Bayreuth, Germany
| | - Gerhard Seitz
- Institute of Pathology, Klinikum Bamberg, Bamberg, Germany
| | | | | | - Lothar Veits
- Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany
| | - Jan Drgac
- Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany
| | - Balint Melcher
- Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany
| | | | | | | | - Jens Krugmann
- Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany
| |
Collapse
|
36
|
Mahmoud R, Shah SC, Torres J, Castaneda D, Glass J, Elman J, Kumar A, Axelrad J, Harpaz N, Ullman T, Colombel JF, Oldenburg B, Itzkowitz SH. Association Between Indefinite Dysplasia and Advanced Neoplasia in Patients With Inflammatory Bowel Diseases Undergoing Surveillance. Clin Gastroenterol Hepatol 2020; 18:1518-1527.e3. [PMID: 31446183 PMCID: PMC7354098 DOI: 10.1016/j.cgh.2019.08.032] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 07/29/2019] [Accepted: 08/16/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Little is known about the clinical significance of indefinite dysplasia (IND) in patients with inflammatory bowel diseases (IBD) undergoing colonoscopic surveillance for colorectal neoplasia. METHODS We conducted a retrospective cohort analysis of 492 patients with colonic IBD for 8 or more years or concomitant primary sclerosing cholangitis, with no history of advanced colorectal neoplasia (high-grade dysplasia or colorectal cancer) or colectomy, undergoing colorectal neoplasia surveillance at a tertiary IBD referral center from 2001 through 2017. Subjects received consistent histopathologic grading of dysplasia. We collected data on time to development of (advanced) colorectal neoplasia or colectomy using Kaplan Meier methods. We identified factors independently associated with (advanced) colorectal neoplasia with multivariable Cox regression analysis. RESULTS After 2149 person-years of follow-up, 53 patients (10.8%) received a diagnosis of IND without prior or synchronous low-grade dysplasia (LGD). Compared to patients without dysplasia, patients with IND had a significantly higher risk of advanced colorectal neoplasia (adjusted hazard ratio, 6.85; 95% CI, 1.78-26.4) and colorectal neoplasia (adjusted hazard ratio, 3.25; 95% CI, 1.50-7.05), but not colectomy (P = .78). Compared to IND, LGD was associated with a significantly higher risk of advanced colorectal neoplasia (P = .05). Following a diagnosis of no dysplasia, IND only, or LGD, the incidence rates of advanced colorectal neoplasia were 0.4% per patient-year, 3.1% per patient-year, and 8.4% per patient-year, respectively. CONCLUSIONS In a retrospective analysis of patients with IBD undergoing colorectal neoplasia surveillance with consistent histopathologic grading of dysplasia, IND was independently associated with a significant increase in risk of advanced colorectal neoplasia. These findings require validation and if confirmed, a reappraisal of the colorectal neoplasia surveillance guidelines.
Collapse
Affiliation(s)
- Remi Mahmoud
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Shailja C. Shah
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Joana Torres
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Gastroenterology, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Daniel Castaneda
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jason Glass
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Internal Medicine, Division of Digestive and Liver Sciences, University of Texas Southwestern, Dallas, TX, USA
| | - Jordan Elman
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Akash Kumar
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jordan Axelrad
- Inflammatory Bowel Disease Center, NYU Langone Health, Division of Gastroenterology NYU School of Medicine, New York, NY, USA
| | - Noam Harpaz
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Thomas Ullman
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Gastroenterology, Montefiore Hospital, New York, NY, USA
| | - Jean-Frédéric Colombel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bas Oldenburg
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Steven H. Itzkowitz
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| |
Collapse
|
37
|
Risk of Development of More-advanced Lesions in Patients With Inflammatory Bowel Diseases and Dysplasia. Clin Gastroenterol Hepatol 2020; 18:1528-1536.e5. [PMID: 31202983 DOI: 10.1016/j.cgh.2019.05.062] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 04/30/2019] [Accepted: 05/29/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Patients with inflammatory bowel diseases (IBD) have increased risks of dysplasia and colitis-associated cancer (CAC). We evaluated the risk of development of high-grade dysplasia (HGD) or CAC after diagnosis of dysplasia using data from a national cohort of patients with IBD. METHODS We performed a multicenter retrospective analysis of data collected from 7 tertiary referral regional or academic centers in Belgium. In searches of IBD pathology databases, we identified 813 lesions (616 low-grade dysplasias [LGDs], 64 high-grade dysplasias [HGDs], and 133 CACs) in 410 patients with IBD: 299 had dysplasia (73%) and 111 had CAC (27%). The primary aim was to determine the risk of more-advanced lesions after diagnosis of LGD or HGD. RESULTS Of the 287 patients with LGD, 21 (7%) developed more-advanced lesions (HGD or CAC) after a median time period of 86 months (interquartile range, 34-214). Of the 28 patients with HGD, 4 (14%) developed CAC after a median time period of 180 months (interquartile range, 23-444). The overall cumulative incidence of CAC at 10 years after an initial diagnosis of HGD was 24.3% and after an initial diagnosis of LGD was 8.5% (P < .05). Metachronous lesions, non-polypoid lesions, and colonic stricture were associated with risk of occurrence of more-advanced lesions after LGD (P < .05). Of the 630 dysplastic lesions identified during endoscopy, 545 (86%) were removed during the same procedure or during a follow-up endoscopy or by surgery. Of 111 patients with CAC, 95 (86%) did not have prior detection of dysplasia and 64 of these 95 patients (67%) developed CAC outside of the screening or surveillance period recommended by the European Crohn's and Colitis Organisation. CONCLUSIONS In an analysis of pathology data from 7 medical centers in Belgium, we found a low rate of detection of more-advanced lesions following detection of LGD or HGD-taking into account that most of the lesions were removed. Main risk factors for development of more-advanced lesions after LGD were metachronous lesions, non-polypoid lesions, and colon strictures.
Collapse
|
38
|
Loss of SATB2 Expression Is a Biomarker of Inflammatory Bowel Disease-associated Colorectal Dysplasia and Adenocarcinoma. Am J Surg Pathol 2020; 43:1314-1322. [PMID: 31318711 DOI: 10.1097/pas.0000000000001330] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
SATB2 is a sensitive immunohistochemistry marker of colorectal carcinoma and non-neoplastic colorectal epithelium that is complementary to CDX2. However, its expression is affected by molecular alterations. Inflammatory bowel disease-associated neoplasia demonstrates molecular alterations that are different from those in sporadic colorectal neoplasia. Given these differences, we examined SATB2 expression in 73 cases of inflammatory bowel disease-associated neoplasia including 37 dysplasia cases and 36 carcinomas and compared the expression patterns with 50 cases of nondysplastic colorectal mucosa in patients with active inflammatory bowel disease, 40 sporadic colonic polyps (20 conventional adenomas and 20 sessile serrated lesions/polyps), and 343 sporadic colorectal adenocarcinomas to assess SATB2 immunohistochemistry as a biomarker of inflammatory bowel disease-associated neoplasia. Loss of SATB2 expression was only identified in colorectal dysplasia arising in inflammatory bowel disease (15/37, 41%) and was not seen in nondysplastic colorectal mucosa with active inflammatory bowel disease or sporadic colonic polyps (P<0.001). Loss of SATB2 expression was identified in both endoscopically visible dysplasia (11/28, 39%) and invisible (4/9, 44%) dysplasia. Loss of SATB2 expression was identified in 67% (24/36) of inflammatory bowel disease-associated carcinomas and was significantly more frequent compared with sporadic colorectal carcinomas (47/343, 14%, P<0.001). There was no difference in positive CDX2 expression between inflammatory bowel disease-associated colorectal carcinoma and sporadic colorectal carcinoma (89% vs. 85%, P=1.0). In conclusion, loss of SATB2 expression is common in inflammatory bowel disease-associated colorectal dysplasia and adenocarcinoma and may be a helpful ancillary biomarker when evaluating for inflammatory bowel disease-associated dysplasia.
Collapse
|
39
|
Farrukh A, Mayberry JF. Surveillance for colorectal cancer and chemoprevention in ulcerative and Crohn's colitis: The need for clinical strategies to increase effectiveness. JGH Open 2019; 3:370-373. [PMID: 31633040 PMCID: PMC6788365 DOI: 10.1002/jgh3.12173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/16/2019] [Accepted: 02/24/2019] [Indexed: 11/26/2022]
Abstract
This review considers why current strategies for surveillance and the prevention of colorectal cancer as a long‐term complication are ineffective. The role of endoscopists, pathologists, and patients are investigated. Colorectal cancer is linked to poor compliance with therapy, and attention may be better directed at improving adherence to treatment than strengthening current surveillance programs. Clearly, 5‐ASA compounds, particularly mesalazine, are the most appropriate agents to choose, but there may also be a place for the daily intake of folic acid. Currently, the evidence in support of ursodeoxycholic acid is mixed, and it cannot be recommended, in general, to patients for the prophylaxis of colorectal cancer risk. An alternative approach through better concordance with medications is considered. The situation in Crohn's colitis is less clear. Although the risk of colorectal cancer mirrors that in ulcerative colitis, there are no published community‐based studies that exclusively assess the effects of surveillance on the early detection of cancer, and the benefits of 5‐ASA compounds in treatment seem less certain than in ulcerative colitis. In addition, there have been no assessments of the effects of any medications on cancer risk in Crohn's disease.
Collapse
Affiliation(s)
- Affifa Farrukh
- Department of Digestive DiseasesUniversity Hospitals of Leicester NHS Trust Leicester UK
| | - John F Mayberry
- Department of Digestive DiseasesUniversity Hospitals of Leicester NHS Trust Leicester UK
| |
Collapse
|
40
|
Osone K, Yokobori T, Katayama C, Takahashi R, Kato R, Tatsuski H, Takada T, Yajima R, Motegi Y, Ogawa H, Fujii T, Ojima H, Nakamura J, Yao T, Shirabe K, Kuwano H. STMN1 accumulation is associated with dysplastic and neoplastic lesions in patients with ulcerative colitis. Oncol Lett 2019; 18:4712-4718. [PMID: 31611980 PMCID: PMC6781569 DOI: 10.3892/ol.2019.10814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 04/23/2019] [Indexed: 01/29/2023] Open
Abstract
Ulcerative colitis (UC) is thought to be associated with precancerous lesions that can ultimately lead to colon cancer. Therefore, diagnostic markers for colorectal dysplasia and cancer are urgently needed for patients with UC. Stathmin 1 (STMN1) is a novel cancer biomarker that is also a novel target for treatment in several cancers, including colon cancer. However, few studies have investigated the relationship between STMN1 expression and clinical features in colorectal dysplasia and cancer in patients with UC. The present study examined the clinical significance of STMN1 expression in colorectal dysplasia and cancer with UC. The present study performed an immunohistochemical analysis of 31 clinical colorectal samples from eight patients with colorectal dysplasia and/or cancer to assess the relationships between STMN1 expression and clinicopathological features including mismatch repair protein expression, rate of Ki-67 positivity, differentiation level, TNM stage, and UC duration. STNM1 expression was detected in 95.7% of dysplastic and cancerous lesions, whereas p53, the current diagnostic marker, was not expressed in 39.1% of dysplastic and cancerous lesions. Furthermore, STMN1 expression was associated with a high rate of positivity for Ki-67, a proliferation marker. Our data suggest that STMN1 in the colonic mucosa of UC patients may be useful as an early diagnostic marker of dysplasia and colitic cancer.
Collapse
Affiliation(s)
- Katsuya Osone
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Takehiko Yokobori
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.,Department of Innovative Cancer Immunotherapy, Gunma University, Maebashi, Gunma 371-8511, Japan.,Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma 371-8511, Japan
| | - Chika Katayama
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Ryo Takahashi
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Ryuji Kato
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hironori Tatsuski
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Takahiro Takada
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Reina Yajima
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Yoko Motegi
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hiroomi Ogawa
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Takaaki Fujii
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hitoshi Ojima
- Department of Gastroenterological Surgery, Gunma Prefectural Cancer Center, Ohta, Gunma 373-8550, Japan
| | - Junichi Nakamura
- Department of Gastroenterological Surgery, Saitama Red Cross Hospital, Ohmiya, Saitama 330-8553, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Bunkyouku, Tokyo 113-8421, Japan
| | - Ken Shirabe
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.,Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| |
Collapse
|
41
|
Wen KW, Umetsu SE, Goldblum JR, Gill RM, Kim GE, Joseph NM, Rabinovitch PS, Kakar S, Lauwers GY, Choi W. DNA flow cytometric and interobserver study of crypt cell atypia in inflammatory bowel disease. Histopathology 2019; 75:578-588. [DOI: 10.1111/his.13923] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 05/17/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Kwun Wah Wen
- Department of Pathology University of California at San Francisco San Francisco CAUSA
| | - Sarah E Umetsu
- Department of Pathology University of California at San Francisco San Francisco CAUSA
| | | | - Ryan M Gill
- Department of Pathology University of California at San Francisco San Francisco CAUSA
| | - Grace E Kim
- Department of Pathology University of California at San Francisco San Francisco CAUSA
| | - Nancy M Joseph
- Department of Pathology University of California at San Francisco San Francisco CAUSA
| | | | - Sanjay Kakar
- Department of Pathology University of California at San Francisco San Francisco CAUSA
| | - Gregory Y Lauwers
- Department of Pathology H. Lee Moffitt Cancer Center and Research Institute Tampa FL USA
| | - Won‐Tak Choi
- Department of Pathology University of California at San Francisco San Francisco CAUSA
| |
Collapse
|
42
|
Gulati S, Dubois P, Carter B, Cornelius V, Martyn M, Emmanuel A, Haji A, Hayee B. A Randomized Crossover Trial of Conventional vs Virtual Chromoendoscopy for Colitis Surveillance: Dysplasia Detection, Feasibility, and Patient Acceptability (CONVINCE). Inflamm Bowel Dis 2019; 25:1096-1106. [PMID: 30576449 DOI: 10.1093/ibd/izy360] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 09/27/2018] [Accepted: 11/05/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Chromoendoscopy (CE) is the recommended surveillance technique for colitis, but uptake has been limited and the literature provides scant information on patient experience (PE); imperative to adherence to surveillance programmes. Virtual CE (VCE) by Fujinon Intelligent Colour Enhancement digitally reconstructs mucosal images in real time, without the technical challenges of CE. We performed a multifaceted randomized crossover trial (RCT) to evaluate study feasibility and obtain preliminary comparative procedural and PE data. METHODS Patients were randomized to undergo either CE with indigo carmine or VCE as the first procedure. After 3-8 weeks, participants underwent colonoscopy with the second technique. Patient recruitment/retention, missed dysplasia, prediction of dysplasia, and contamination (memory/sampling of the first procedure) were recorded. PE was assessed by validated questionnaires, and pain was assessed using a visual analog scale (mm). RESULTS Sixty patients were recruited, and 48 patients (first procedure: 23 VCE, 25 CE) completed the trial (retention 80%) with no episodes of contamination. Eleven dysplastic lesions were detected in n = 7/48 (14.5%). VCE missed 1 lesion, and CE missed 2 lesions in n = 2 (data of VCE vs CE, respectively, for dysplasia diagnostic accuracy: 93.94% [85.2%-98.32%] vs 76.9% [66.9%-98.2%]; examination time [minutes]: 14 +/- 4 vs 20 +/- 7 (95% confidence interval, 3.5 to 8; P < 0.001); pain (mm): 27.4 +/- 17.5 vs 34.7 +/- 18; patient preference: 67% [n = 31] vs 33% [n = 15] in n = 46; P < 0.001). CONCLUSIONS This is the first RCT to include validated PE in a colitis surveillance program. VCE is safe, technically easier, quicker, and more comfortable test, with dysplasia detection at least as good as that of CE, overcoming many barriers to the wider adoption of CE. This trial may serve as a successful foundation for a a multicenter trial to confirm the value of VCE for colitis surveillance.
Collapse
Affiliation(s)
- Shraddha Gulati
- King's Institute of Therapeutic Endoscopy, King's College Hospital NHS Foundation Trust, London, UK
| | - Patrick Dubois
- King's Institute of Therapeutic Endoscopy, King's College Hospital NHS Foundation Trust, London, UK
| | - Ben Carter
- Biostatistics and Health Informatics, King's College London, London, UK
| | | | - Meredith Martyn
- Clinical Trial Statistics, Imperial College London, London, UK
| | - Andrew Emmanuel
- King's Institute of Therapeutic Endoscopy, King's College Hospital NHS Foundation Trust, London, UK
| | - Amyn Haji
- King's Institute of Therapeutic Endoscopy, King's College Hospital NHS Foundation Trust, London, UK
| | - Bu'Hussain Hayee
- King's Institute of Therapeutic Endoscopy, King's College Hospital NHS Foundation Trust, London, UK
| |
Collapse
|
43
|
Kawachi H. Histopathological diagnosis of ulcerative colitis-associated neoplasia. Dig Endosc 2019; 31 Suppl 1:31-35. [PMID: 30994228 DOI: 10.1111/den.13387] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 03/03/2019] [Indexed: 02/08/2023]
Abstract
In patients with ulcerative colitis, tumor development occurs with an increase in the duration of the disease. Such lesions, known as ulcerative colitis-associated neoplasia (UCAN), histologically show a broad variety of findings such as low-grade dysplasia, high-grade dysplasia, and invasive carcinoma. For pathologists, however, the histopathological diagnosis of UCAN is occasionally difficult. Problems in pathological diagnosis can be summarized into the following three categories: (i) difficulty in discriminating UCAN from non-neoplastic inflammatory change; (ii) difficulty in discriminating UCAN from sporadic epithelial neoplasm; and (iii) difficulty in histological grading of UCAN. For most lesions, pathologists can make conclusive histological diagnoses without any problems. However, pathologists occasionally face diagnostic difficulties, especially in cases of lesions with borderline or indefinite histology and, therefore, at least two experienced gastrointestinal pathologists are needed to confirm the diagnosis. Hence, a confirmation is usually preferable for the estimation of tumor depth and lymphovascular invasion in digestive tract cancers as well as in UCAN. Immunohistochemistry for p53 and Ki-67 (MIB-1) is occasionally useful as an ancillary tool. Since UCAN has distinct characteristics compared to sporadic epithelial neoplasia, its treatment strategy should be carefully discussed by a multidisciplinary team, especially for cases of lesions with indefinite histology. At present, although surgical intervention such as total colectomy is the most promising procedure for UCAN, recent advances in endoscopic diagnosis and therapy are expected to improve future treatment strategy.
Collapse
Affiliation(s)
- Hiroshi Kawachi
- Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
| |
Collapse
|
44
|
Wen KW, Rabinovitch PS, Wang D, Huang D, Mattis AN, Choi WT. Utility of DNA Flow Cytometric Analysis of Paraffin-embedded Tissue in the Risk Stratification and Management of 'Indefinite for dysplasia' in Patients With Inflammatory Bowel Disease. J Crohns Colitis 2019; 13:472-481. [PMID: 30423034 DOI: 10.1093/ecco-jcc/jjy193] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS The clinical significance of 'indefinite for dysplasia' [IND] in patients with inflammatory bowel disease remains unclear. Currently, no biomarker can reliably differentiate reactive changes from true dysplasia and/or risk stratify IND. METHODS A total of 52 IND colon biopsies were analysed by DNA flow cytometry. The follow-up result of each biopsy was determined by reviewing all subsequent biopsies and endoscopic reports for the occurrence of high-grade dysplasia [HGD] or colorectal cancer [CRC] at the site of previous biopsy or in the same segment of colon. RESULTS The overall 1-, 3-, 5-, and 7-year detection rates of HGD or CRC in all 52 IND cases were 4.6% (95% confidence interval [CI], 0.0%-10.6%), 18.2% [95% CI, 3.5%-30.7%], 26.3% [95% CI, 8.4%-40.7%], and 31.6% [95% CI, 11.2%-47.4%], respectively. More interestingly, 10.6% of IND cases with aneuploidy were subsequently found to have HGD or CRC within 1 year [95% CI, 0.0%-23.7%], with 36.4% [95% CI, 7.1%-56.5%], 51.7% [95% CI, 16.1%-72.2%], and 59.8% [95% CI, 21.4%-79.5%] detected within 3, 5, and 7 years, respectively. By comparison, in the setting of normal DNA content, 1-, 3-, 5-, and 7-year detection rates of HGD or CRC were 0.8% [95% CI, 0.0%-2.7%], 3.3% [95% CI, 0.0%-9.6%], 5.2% [95% CI, 0.0%-14.7%], and 6.5% [95% CI, 0.0%-18.1%], respectively. Only the presence of aneuploidy was found to be a significant predictor of HGD or CRC with the estimated univariate and multivariate hazard ratios of 13.8 [p = 0.016] and 50.3 [p = 0.010], respectively. CONCLUSIONS IND may not be a low-risk condition for HGD or CRC. In this regard, the presence of aneuploidy can identify a subset of IND cases that are at increased risk for subsequent detection of HGD or CRC.
Collapse
Affiliation(s)
- Kwun Wah Wen
- University of California at San Francisco, Department of Pathology, San Francisco, CA, USA
| | | | - Dongliang Wang
- SUNY Upstate Medical University, Department of Public Health and Preventive Medicine, Syracuse, NY, USA
| | - Danning Huang
- SUNY Upstate Medical University, Department of Public Health and Preventive Medicine, Syracuse, NY, USA
| | - Aras N Mattis
- University of California at San Francisco, Department of Pathology, San Francisco, CA, USA
| | - Won-Tak Choi
- University of California at San Francisco, Department of Pathology, San Francisco, CA, USA
| |
Collapse
|
45
|
Yang DH, Rey I. Endoscopic Submucosal Dissection for Colitis-Associated Dysplasia. Clin Endosc 2019; 52:120-128. [PMID: 30914628 PMCID: PMC6453849 DOI: 10.5946/ce.2019.047] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 03/17/2019] [Indexed: 12/15/2022] Open
Abstract
Dysplasia is a precancerous lesion of colorectal cancer in patients with long-standing inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn’s disease. Recent guidelines suggest endoscopic resection as a key modality for the treatment of endoscopically resectable dysplasia in patients with colitis. Endoscopic submucosal dissection (ESD) has been suggested as one of the therapeutic options for dysplasia that is potentially resectable but not suitable for the conventional endoscopic mucosal resection technique. Several recent studies supported the feasibility of ESD for the treatment of colitis-associated dysplasia in terms of the en bloc and complete resection rates and the risk of procedure-related complications. However, these studies were performed exclusively in expert centers. Moreover, the local and metachronous recurrence rates were relatively high, and long-term outcome data are still lacking. Endoscopists should be highly skilled in colorectal ESD and have an intensive understanding of not only the lesions but also the conditions of patients with IBDs. Therefore, the decision to perform ESD for colitis-associated dysplasia should be made scrupulously after careful discussion with patients, in collaboration with a multidisciplinary IBD team including physicians, surgeons, and pathologists specialized in IBDs.
Collapse
Affiliation(s)
- Dong-Hoon Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Imelda Rey
- Division of Gastroenterohepatology, Department of Internal Medicine, University of Sumatera Utara, Adam Malik General Hospital, Medan, Indonesia
| |
Collapse
|
46
|
Zhang L, Wu TT. Inflammatory Bowel Disease. SURGICAL PATHOLOGY OF NON-NEOPLASTIC GASTROINTESTINAL DISEASES 2019:373-424. [DOI: 10.1007/978-3-030-15573-5_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
47
|
Svrcek M, Borralho Nunes P, Villanacci V, Beaugerie L, Rogler G, De Hertogh G, Tripathi M, Feakins R. Clinicopathological and Molecular Specificities of Inflammatory Bowel Disease-Related Colorectal Neoplastic Lesions: The Role of Inflammation. J Crohns Colitis 2018; 12:1486-1498. [PMID: 30202940 DOI: 10.1093/ecco-jcc/jjy132] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Compared with the general population, patients with inflammatory bowel disease [IBD] have an increased risk of developing colorectal cancer. Molecular mechanisms underlying colorectal carcinogenesis in the setting of IBD are not well understood. However, modern molecular investigative tools have facilitated the identification of features that help distinguish IBD-related carcinoma from sporadic carcinoma. Moreover, with advances in endoscopic technology and improved understanding of the natural history, the management of colorectal neoplastic lesions in IBD patients has evolved. This review discusses the clinicopathological and molecular features of colorectal neoplastic lesions complicating IBD. Chronic inflammation is believed to promote the development of neoplasia, partly by producing reactive oxygen and nitrogen species [ROS and NOS], which may interact with genes involved in carcinogenetic pathways. Furthermore, alterations in microbiota and in the innate and adaptive immune responses might contribute to this process, particularly by initiating, regulating, and sustaining chronic inflammation. Earlier detection and better characterization of neoplastic colorectal lesions complicating IBD and a better knowledge of the molecular mechanisms underlying carcinogenesis in this setting should facilitate improvements in the risk stratification of patients with longstanding IBD and in the management of dysplastic and malignant colorectal lesions that arise in this setting.
Collapse
Affiliation(s)
- Magali Svrcek
- Department of Pathology, AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Saint-Antoine, Paris, France.,Sorbonne-Université, Université Pierre et Marie Curie - Paris 6, Paris, France
| | - Paula Borralho Nunes
- Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal & Serviço de Anatomia Patológica, Hospital Cuf Descobertas, Rua Mário Botas Lisbon, Portugal
| | | | - Laurent Beaugerie
- Sorbonne-Université, Université Pierre et Marie Curie - Paris 6, Paris, France.,Department of Gastroenterology, AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Saint-Antoine, Paris, France
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Gert De Hertogh
- Department of Pathology, University Hospital Leuven, Leuven, Belgium
| | - Monika Tripathi
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Roger Feakins
- Department of Cellular Pathology, Barts Health NHS Trust, London, UK
| | | |
Collapse
|
48
|
Chiu K, Riddell RH, Schaeffer DF. DALM, rest in peace: a pathologist's perspective on dysplasia in inflammatory bowel disease in the post-DALM era. Mod Pathol 2018; 31:1180-1190. [PMID: 29789648 DOI: 10.1038/s41379-018-0068-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/30/2018] [Accepted: 04/01/2018] [Indexed: 02/07/2023]
Abstract
There are few abbreviations in surgical pathology that are associated with as much immediate recognition, frustration, and confusion as DALM (dysplasia-associated lesion or mass). DALM is used to describe endoscopically visible dysplastic lesions in the surveillance of patients with inflammatory bowel disease. However, the diagnosis of DALM has been complicated by the inconsistent criteria and use of terminology for describing dysplasia in inflammatory bowel disease, and a tendency to relate DALM with the need for colectomy. Fortunately, advancements in both endoscopic visualization and local excision capability have allowed for a more defined management of dysplasia in inflammatory bowel disease. In 2015, the Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients International Consensus Recommendations (SCENIC) Development Panel, a panel of predominantly expert gastroenterologists and endoscopists in surveillance of inflammatory bowel disease, published a consensus statement. One recommendation was to abandon DALM-related terminology in favor of endoscopic descriptors modified from the Paris endoscopic classification. Recommendations on surveillance and management of dysplastic lesions were also provided. Nevertheless, interval carcinomas and metachronous neoplasia remain persistent issues. This review aims to provide an update on the post-DALM terminology and management recommendations for inflammatory bowel disease-associated dysplasia necessary for a meaningful communication between pathologists and clinicians.
Collapse
Affiliation(s)
- Kenrry Chiu
- Division of Anatomic Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Robert H Riddell
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - David F Schaeffer
- Division of Anatomic Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada.
| |
Collapse
|
49
|
Wu XR, Liu HS, Shi XY, Zhou WX, Jiang ZN, Huang Y, Karamchandani DM, Goldblum JR, Xiao SY, Zhu HF, Feely MM, Collinsworth AL, Esnakula A, Xie H, Shen B, Lan P, Liu XL. Interobserver Agreement in the Diagnosis of Inflammatory Bowel Disease-Associated Neoplasia in China in Comparison to Subspecialized American Gastrointestinal Pathologists. Gastroenterol Res Pract 2018; 2018:8715263. [PMID: 29849600 PMCID: PMC5937390 DOI: 10.1155/2018/8715263] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 12/12/2017] [Accepted: 01/15/2018] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The aim of this study was to evaluate the interobserver variability in diagnosing inflammatory bowel disease (IBD)-associated neoplasia among practicing pathologists from China using telepathology, a practice of remote diagnostic consultation increasingly used nationally and internationally, and its comparison with the interpretation of subspecialized gastrointestinal (GI) pathologists from the United States (US). METHODS Eight GI pathologists from the US and 4 pathologists from China with an interest in GI pathology participated in this study. A total of 50 colonic biopsies from patients with a clinical history of IBD from 8 medical centers in China were included. All microscopic slides in each case were digitized using an Aperio system. One pathologist (XL) reviewed the digitized full-slide images, and selected areas of interest were captured at low, medium, and high magnifications at a resolution of 1712 × 1072 pixels and saved as tagged image file format (TIFF) files on read-only DVD. Each pathologist evaluated the images and selected the most appropriate diagnostic category for each case (negative, indefinite, low-grade dysplasia [LGD], high-grade dysplasia [HGD], and carcinoma). A Fleiss' kappa coefficient (K) analysis was performed to determine interobserver agreement and the agreement of each pathologist from China with the consensus diagnosis (defined as diagnostic agreement by at least 4 participating US GI pathologists). RESULTS There was substantial interobserver agreement among 4 pathologists from China on the interpretation of IBD-associated neoplasia (kappa value 0.68, 95% confidence interval: 0.56-0.78). A consensus diagnosis included negative (n = 22), LGD (n = 22), HGD (n = 3), carcinoma (n = 2), and indefinite for dysplasia (n = 1). Using consensus diagnoses as references, the agreement between each pathologist from China and the consensus diagnosis was substantial with kappa values ranging from 0.75 to 0.80. CONCLUSIONS This study reveals substantial interobserver agreement for the interpretation of colonic neoplasia in IBD using digitized images among Chinese pathologists as well as between each Chinese pathologist and a consensus diagnosis generated by US GI pathologists.
Collapse
Affiliation(s)
- Xian-rui Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hua-shan Liu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xue-ying Shi
- Department of Pathology, Peking University Third Hospital, Beijing, China
| | - Wei-xun Zhou
- Department of Pathology, Peking Union Medical College Hospital, Beijing, China
| | - Zhi-nong Jiang
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yan Huang
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | | | | | - Shu-yuan Xiao
- Department of Pathology, The University of Chicago, Chicago, IL, USA
| | - Hong-fa Zhu
- Department of Pathology, The Mount Sinai Hospital, New York, NY, USA
| | - Michael M. Feely
- Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Amy L. Collinsworth
- Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Ashwini Esnakula
- Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Hao Xie
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Bo Shen
- Department of Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, OH, USA
| | - Ping Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiu-li Liu
- Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| |
Collapse
|
50
|
Driessen A, Geboes KP, Dewit O, Jouret-Mourin A. Dysplasia in Inflammatory Bowel Disease. COLITIS 2018:141-154. [DOI: 10.1007/978-3-319-89503-1_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|