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1
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Menon S, Norman R, Iyer PG, Ragunath K. Stratification of Barrett's esophagus surveillance based on p53 immunohistochemistry: a cost-effectiveness analysis by an international collaborative group. Endoscopy 2024; 56:727-736. [PMID: 38698618 DOI: 10.1055/a-2317-8184] [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: 05/05/2024]
Abstract
BACKGROUND Surveillance of nondysplastic Barrett's esophagus (NDBE) is recommended to identify progression to dysplasia; however, the most cost-effective strategy remains unclear. Mutation of TP53 or aberrant expression of p53 have been associated with the development of dysplasia in BE. We sought to determine if surveillance intervals for BE could be stratified based on p53 expression. METHODS A Markov model was developed for NDBE. Patients with NDBE underwent p53 immunohistochemistry (IHC) and those with abnormal p53 expression underwent surveillance endoscopy at 1 year, while patients with normal p53 expression underwent surveillance in 3 years. Patients with dysplasia underwent endoscopic therapy and surveillance. RESULTS On base-case analysis, the strategy of stratifying surveillance based on abnormal p53 IHC was cost-effective relative to conventional surveillance and a natural history model, with an incremental cost-effectiveness ratio (ICER) of $8258 for p53 IHC-based surveillance. Both the conventional and p53-stratified surveillance strategies dominated the natural history model. On probabilistic sensitivity analysis, the p53 IHC strategy ($28 652; 16.78 quality-adjusted life years [QALYs]) was more cost-effective than conventional surveillance ($25 679; 16.17 QALYs) with a net monetary benefit of $306 873 compared with conventional surveillance ($297 642), with an ICER <$50 000 in 96% of iterations. The p53-stratification strategy was associated with a 14% reduction in the overall endoscopy burden and a 59% increase in dysplasia detection. CONCLUSION A surveillance strategy for BE based on abnormal p53 IHC is cost-effective relative to a conventional surveillance strategy and is likely to be associated with higher rates of dysplasia diagnosis.
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Affiliation(s)
- Shyam Menon
- Gastroenterology, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom of Great Britain and Northern Ireland
| | - Richard Norman
- Health Economist, School of Population Health, Curtin University, Perth, Australia
| | - Prasad G Iyer
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States
| | - Krish Ragunath
- Curtin Medical School, Curtin University, Perth, Australia
- Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Australia
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2
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Choi Y, Bedford A, Pollack S. The Aberrant Expression of Biomarkers and Risk Prediction for Neoplastic Changes in Barrett's Esophagus-Dysplasia. Cancers (Basel) 2024; 16:2386. [PMID: 39001449 PMCID: PMC11240336 DOI: 10.3390/cancers16132386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 06/21/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Background: Barrett's esophagus (BE) is a pre-neoplastic condition associated with an increased risk of esophageal adenocarcinoma (EAC). The accurate diagnosis of BE and grading of dysplasia can help to optimize the management of patients with BE. However, BE may be missed and the accurate grading of dysplasia based on a routine histology has a considerable intra- and interobserver variability. Thus, well-defined biomarker testing remains indispensable. The aim of our study was to identify routinely applicable and relatively specific biomarkers for an accurate diagnosis of BE, as well as determining biomarkers to predict the risk of progression in BE-dysplasia. Methods: Retrospectively, we performed immunohistochemistry to test mucin 2(MUC2), trefoil factor 3 (TFF3), p53, p16, cyclin D1, Ki-67, beta-catenin, and minichromosome maintenance (MCM2) in biopsies. Prospectively, to identify chromosomal alterations, we conducted fluorescent in situ hybridization testing on fresh brush samples collected at the time of endoscopy surveillance. Results: We discovered that MUC2 and TFF3 are specific markers for the diagnosis of BE. Aberrant expression, including the loss and strong overexpression of p53, Ki-67, p16, beta-catenin, cyclin D1, and MCM2, was significantly associated with low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC histology, with a relatively high risk of neoplastic changes. Furthermore, the aberrant expressions of p53 and p16 in BE-indefinite dysplasia (IND) progressor cohorts predicted the risk of progression. Conclusions: Assessing the biomarkers would be a suitable adjunct to accurate BE histology diagnoses and improve the accuracy of BE-dysplasia grading, thus reducing interobserver variability, particularly of LGD and risk prediction.
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Affiliation(s)
- Young Choi
- Department of Pathology, Yale School of Medicine, 434 Pine Grove Lane, Hartsdale, NY 10530, USA
| | - Andrew Bedford
- Department of Internal Medicine, Yale School of Medicine, Bridgeport Hospital, 267 Grant St., Bridgeport, CT 06610, USA;
| | - Simcha Pollack
- Department of Business Analytics Statistics, St. John’s University Tobin College of Business, Queens, NY 11423, USA;
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3
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Erion Barner LA, Gao G, Reddi DM, Lan L, Burke W, Mahmood F, Grady WM, Liu JTC. Artificial Intelligence-Triaged 3-Dimensional Pathology to Improve Detection of Esophageal Neoplasia While Reducing Pathologist Workloads. Mod Pathol 2023; 36:100322. [PMID: 37657711 DOI: 10.1016/j.modpat.2023.100322] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 07/25/2023] [Accepted: 08/25/2023] [Indexed: 09/03/2023]
Abstract
Early detection of esophageal neoplasia via evaluation of endoscopic surveillance biopsies is the key to maximizing survival for patients with Barrett's esophagus, but it is hampered by the sampling limitations of conventional slide-based histopathology. Comprehensive evaluation of whole biopsies with 3-dimensional (3D) pathology may improve early detection of malignancies, but large 3D pathology data sets are tedious for pathologists to analyze. Here, we present a deep learning-based method to automatically identify the most critical 2-dimensional (2D) image sections within 3D pathology data sets for pathologists to review. Our method first generates a 3D heatmap of neoplastic risk for each biopsy, then classifies all 2D image sections within the 3D data set in order of neoplastic risk. In a clinical validation study, we diagnose esophageal biopsies with artificial intelligence-triaged 3D pathology (3 images per biopsy) vs standard slide-based histopathology (16 images per biopsy) and show that our method improves detection sensitivity while reducing pathologist workloads.
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Affiliation(s)
| | - Gan Gao
- Department of Mechanical Engineering, University of Washington, Seattle, Washington
| | - Deepti M Reddi
- Department of Laboratory Medicine & Pathology, University of Washington School of Medicine, Seattle, Washington
| | - Lydia Lan
- Department of Mechanical Engineering, University of Washington, Seattle, Washington; Department of Biology, University of Washington, Seattle, Washington
| | - Wynn Burke
- Department of Laboratory Medicine & Pathology, University of Washington School of Medicine, Seattle, Washington; Department of Medicine (Gastroenterology Division), University of Washington School of Medicine, Seattle, Washington
| | - Faisal Mahmood
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Harvard Data Science Initiative, Harvard University, Cambridge, Massachusetts
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jonathan T C Liu
- Department of Mechanical Engineering, University of Washington, Seattle, Washington; Department of Laboratory Medicine & Pathology, University of Washington School of Medicine, Seattle, Washington; Department of Bioengineering, University of Washington, Seattle, Washington.
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4
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Maev IV, Livzan MA, Mozgovoi SI, Gaus OV, Bordin DS. Esophageal Mucosal Resistance in Reflux Esophagitis: What We Have Learned So Far and What Remains to Be Learned. Diagnostics (Basel) 2023; 13:2664. [PMID: 37627923 PMCID: PMC10453919 DOI: 10.3390/diagnostics13162664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/21/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) has the highest prevalence among diseases of the digestive system and is characterized by a significant decrease in patients' quality of life, comparable to arterial hypertension and coronary heart disease. One in every ten cases of reflux esophagitis leads to the formation of Barrett's esophagus, which is associated with a high risk of esophagus adenocarcinoma. The key factors determining the progression of the disease are the frequency and duration of the reflux of the stomach's contents. As a result, refluxate, which includes hydrochloric acid, pepsin, and, in the case of concomitant duodeno-gastric reflux, bile acids and lysolecithin, is thrown into the overlying sections of the digestive tract. At the same time, in addition to aggression factors, it is necessary to take into account the state of resistance in the esophageal mucosa to the effects of aggressive refluxate molecules. This review was prepared using systematized data on the protective properties of the esophageal mucosa and modern methods to assess the mucosal barrier in reflux esophagitis. Lesions of the epithelial barrier structure in the esophagus are recognized as the main pathogenetic factor in the development of reflux esophagitis and are a potentially significant therapeutic target in the treatment of GERD and Barrett's esophagus. This article presents the characteristics of the esophageal mucosal barrier and the protective mechanisms of the esophagus's mucous membrane in conditions of gastroesophageal reflux. Diagnostic approaches for assessing the course of reflux esophagitis are described for both histological criteria and the possibility of a comprehensive assessment of the state of mucins, tight-junction proteins, and the proliferative activity of the mucosa, including under the conditions of ongoing therapy.
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Affiliation(s)
- Igor V. Maev
- Department of Propaedeutic of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia
| | - Maria A. Livzan
- Department of Internal Medicine and Gastroenterology, Omsk State Medical University, 644099 Omsk, Russia
| | - Sergei I. Mozgovoi
- Department of Pathological Anatomy, Omsk State Medical University, 644099 Omsk, Russia
| | - Olga V. Gaus
- Department of Internal Medicine and Gastroenterology, Omsk State Medical University, 644099 Omsk, Russia
| | - Dmitry S. Bordin
- Department of Propaedeutic of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia
- Department of Pancreatic, Biliary and Upper Digestive Tract Disorders, A.S. Loginov Moscow Clinical Scientific Center, 111123 Moscow, Russia
- Department of Outpatient Therapy and Family Medicine, Tver State Medical University, 170100 Tver, Russia
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5
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Chen X, Liu BL, Harpaz N, Zhu H, Polydorides AD, Liu Q. Aberrant p53 expression is associated with neoplastic progression in Barrett oesophagus diagnosed as indefinite for dysplasia. Histopathology 2023; 82:454-465. [PMID: 36251540 DOI: 10.1111/his.14828] [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: 07/16/2022] [Revised: 09/19/2022] [Accepted: 10/03/2022] [Indexed: 01/27/2023]
Abstract
The aim of this study was to investigate the role of immunohistochemical (IHC) expression of p53 and other potential clinical parameters as prognostic markers for predicting neoplastic progression in Barrett oesophagus (BE) patients diagnosed as indefinite for dysplasia (IND). The study included patients with established BE of any extent who had a diagnosis of IND accompanied by concurrent p53 immunohistochemistry (IHC) stain at the index endoscopic procedure and at least one follow-up examination between 2000 and 2021. Correlation between disease progression from IND to higher-grade dysplasia [low-grade dysplasia (LGD), high-grade dysplasia (HGD) and oesophageal adenocarcinoma (EAC)] and clinicopathological parameters were analysed. A total of 149 patients (99 males; mean age 63.3 ± 10.0 years, range = 35-89) were included in the final analysis. Median follow-up was 37.1 months [interquartile range (IQR) = 20.5-59.1 months]. Progression rates from IND to LGD and HGD were 12.1% (18 of 149) and 2.7% (four of 149), respectively. On multivariate analysis, the number of IND diagnoses was significantly associated with progression to both LGD and HGD (P = 0.016 and P < 0.001, respectively). Cox regression analysis showed that aberrant p53 expression was significantly associated with progression to LGD [hazard ratio (HR) = 4.87, 95% confidence interval (CI) = 1.91-12.45, P = 0.001] and HGD (HR = 21.81, 95% CI = 1.88-253.70, P = 0.014). Kaplan-Meier survival analysis also demonstrated that aberrant p53 expression was significantly associated with progression to LGD (P < 0.001) and HGD (P = 0.001). Our results suggest that frequency of IND diagnoses and status of p53 expression can help to stratify risk of neoplastic progression in BE patients with IND.
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Affiliation(s)
- Xiuxu Chen
- Department of Pathology, Molecular & Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bella Lingjia Liu
- Department of Pathology, Molecular & Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Noam Harpaz
- Department of Pathology, Molecular & Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hongfa Zhu
- Department of Pathology, Molecular & Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexandros D Polydorides
- Department of Pathology, Molecular & Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Qingqing Liu
- Department of Pathology, Molecular & Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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6
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Maslyonkina KS, Konyukova AK, Alexeeva DY, Sinelnikov MY, Mikhaleva LM. Barrett's esophagus: The pathomorphological and molecular genetic keystones of neoplastic progression. Cancer Med 2022; 11:447-478. [PMID: 34870375 PMCID: PMC8729054 DOI: 10.1002/cam4.4447] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/07/2021] [Accepted: 11/09/2021] [Indexed: 02/06/2023] Open
Abstract
Barrett's esophagus is a widespread chronically progressing disease of heterogeneous nature. A life threatening complication of this condition is neoplastic transformation, which is often overlooked due to lack of standardized approaches in diagnosis, preventative measures and treatment. In this essay, we aim to stratify existing data to show specific associations between neoplastic transformation and the underlying processes which predate cancerous transition. We discuss pathomorphological, genetic, epigenetic, molecular and immunohistochemical methods related to neoplasia detection on the basis of Barrett's esophagus. Our review sheds light on pathways of such neoplastic progression in the distal esophagus, providing valuable insight into progression assessment, preventative targets and treatment modalities. Our results suggest that molecular, genetic and epigenetic alterations in the esophagus arise earlier than cancerous transformation, meaning the discussed targets can help form preventative strategies in at-risk patient groups.
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7
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O'Farrell NJ, Phelan JJ, Feighery R, Doyle B, Picardo SL, Ravi N, O'Toole D, Reynolds JV, O'Sullivan J. Differential Expression Profiles of Oxidative Stress Levels, 8-oxo-dG and 4-HNE, in Barrett's Esophagus Compared to Esophageal Adenocarcinoma. Int J Mol Sci 2019; 20:ijms20184449. [PMID: 31509954 PMCID: PMC6770156 DOI: 10.3390/ijms20184449] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 09/03/2019] [Indexed: 12/22/2022] Open
Abstract
Barrett’s esophagus (BE), a chronic inflammatory condition, is the leading risk factor for esophageal adenocarcinoma (EAC). In inflammation to cancer pathways, oxidative stress profiles have been linked to cancer progression. However, the relevance of oxidative stress profiles along the BE-disease sequence remains to be elucidated. In this study, markers of oxidative stress; DNA adducts (8-oxo-dG) and lipoperoxidation (4-HNE), and markers of proliferation (Ki67) were measured in patient biopsies representing the BE-disease sequence. Differences in expression of these markers in Barrett’s patients with cancer-progression and non-progression were examined. Proliferation was reduced in Barrett’s specialized intestinal metaplasia (SIM) compared with EAC (p < 0.035). Correcting for cell proliferation levels, a confounding factor, linked to oxidative stress profiles, SIM demonstrated increased levels of 8-oxo-dG and 4-HNE (p < 0.05) compared with EAC. Longitudinal analysis of Barrett’s patients demonstrated decreased levels of 8-oxo-dG in SIM cancer progression (p < 0.05). BE is an environment of increased oxidative stress and inflammation. Patients with progressive disease demonstrated reduced oxidative stress levels in 8-oxo-dG. Perhaps these alterations facilitate Barrett’s progression, whereas in non-progressive disease, cells follow the rules of increased oxidative stress ultimately triggers cell apoptosis, thereby preventing propagation and survival.
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Affiliation(s)
- Naoimh J O'Farrell
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - James J Phelan
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - Ronan Feighery
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - Brendan Doyle
- Department of Histopathology, St. James' Hospital, Dublin 8, Ireland
| | - Sarah L Picardo
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - Narayanasamy Ravi
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - Dermot O'Toole
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James' Hospital, Dublin 8, Ireland
| | - John V Reynolds
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland
| | - Jacintha O'Sullivan
- Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James' Hospital, Dublin 8, Ireland.
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8
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Younes M, Brown K, Lauwers GY, Ergun G, Meriano F, Schmulen AC, Barroso A, Ertan A. p53 protein accumulation predicts malignant progression in Barrett's metaplasia: a prospective study of 275 patients. Histopathology 2017; 71:27-33. [PMID: 28226185 PMCID: PMC5466464 DOI: 10.1111/his.13193] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 02/18/2017] [Indexed: 12/20/2022]
Abstract
AIMS The purpose of this study was to determine prospectively whether p53 protein accumulation in biopsies of Barrett's metaplasia (BM) is a predictor of malignant progression, without relying on dysplasia grading. METHODS AND RESULTS Sections of formalin-fixed paraffin-embedded tissue from the initial biopsies of 275 patients with BM, who had no high-grade dysplasia (HGD) or oesophageal adenocarcinoma (EAC), were stained for p53 by immunohistochemistry. The mean follow-up was 41 months. p53-positive biopsies were divided into four groups: scattered positive cells, multifocal scattered positive cells, aggregates of positive cells, and multifocal aggregates of positive cells. Kaplan-Meier analysis with the log-rank test was used to determine the rate of progression to HGD/EAC. Of the 275 patients, 227 had initial biopsies that were completely negative for p53, and, of these, one (0.4%) progressed to HGD/EAC; none of 24 (0%) patients with scattered positive cells and none of four (0%) of patients with multifocal scattered positive cells progressed. In contrast, five of 16 (31.25%) patients with aggregates of positive cells and three of four (75%) of those with multifocal aggregates of positive cells progressed to HGD/EAC. Kaplan-Meier analysis with log-rank statistics showed the difference in progression rate between the five groups to be highly significant (P < 0.0001). CONCLUSIONS We conclude that p53 protein accumulation, detected by immunohistochemistry in aggregates of cells, is a significant predictor of malignant progression in patients with BM.
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Affiliation(s)
- Mamoun Younes
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, and Memorial Hermann Hospital-TMC, Houston, TX, USA
| | - Keith Brown
- Department of Pathology, Baylor College of Medicine, Houston, TX, USA
| | - Gregory Y Lauwers
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Gulchin Ergun
- Section of Gastroenterology, Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Frank Meriano
- Section of Gastroenterology, Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - A Carl Schmulen
- Section of Gastroenterology, Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Alberto Barroso
- Section of Gastroenterology, Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Atilla Ertan
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, and Memorial Hermann Hospital-TMC, Houston, TX, USA
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Denning KL, Al-Subu A, Elitsur Y. Immunoreactivity of p53 and Ki-67 for dysplastic changes in children with eosinophilic esophagitis. Pediatr Dev Pathol 2013; 16:331-6. [PMID: 23718721 DOI: 10.2350/13-03-1306-oa.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Eosinophilic esophagitis (EoE) has been recognized as a chronic disease of the esophagus with significant involvement of the mucosal immune system. Similar conditions in other gastrointestinal diseases have led to a malignant transformation (ie, inflammatory bowel disease, celiac disease, etc). MIB-1 (Ki-67) and p53 are monoclonal antibodies that are used to detect early markers for dysplastic changes, possibly leading to cancer development in adult patients with chronic gastroesophageal reflux disease (GERD), Barrett's esophagus, and/or the adenocarcinoma sequence of the esophagus. Only limited studies of these cell markers have been published in children with EoE. The aim of this study is to examine p53 and Ki-67 cell markers in children with EoE before and after medical therapy. The immunohistochemical staining of cell markers p53 and Ki-67 was examined in esophageal biopsies of children diagnosed with EoE, GERD, and normal esophagus. In addition, biopsies from adults with EoE and adenocarcinoma were used as positive controls. In 10 children who were successfully treated for EoE, immunohistochemical staining was compared before and after medical therapy. The immunohistochemical staining of p53 and Ki-67 was increased in children with EoE compared with children with a normal esophagus but not in children with GERD. Children with EoE posttherapy had significantly lower immunohistochemical staining for both markers compared to pretreatment staining. p53 and Ki-67 markers are associated with cell proliferation in children with EoE but do not represent a premalignant (dysplastic) condition of the esophagus.
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Affiliation(s)
- Krista L Denning
- 1 Department of Pathology, Joan C. Edwards School of Medicine at Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA
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10
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Ki-67 Antigen Overexpression Is Associated with the Metaplasia-Adenocarcinoma Sequence in Barrett's Esophagus. Gastroenterol Res Pract 2012; 2012:639748. [PMID: 22844273 PMCID: PMC3401558 DOI: 10.1155/2012/639748] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Accepted: 05/26/2012] [Indexed: 01/17/2023] Open
Abstract
Introduction. The objective of this study was to evaluate Ki-67 antigen expression in patients with Barrett's esophagus and esophageal adenocarcinoma and to assess its correlation with the metaplasia-esophageal adenocarcinoma progression. Methods. Using immunohistochemistry we evaluated the Ki-67 index in patients with Barrett's esophagus, esophageal adenocarcinoma, and controls. We included patients with endoscopically visible columnar mucosa of the distal esophagus (whose biopsies revealed specialized intestinal-type metaplasia), patients with esophageal and esophagogastric tumors types I and II, and patients with histologically normal gastric mucosa (control). Results. In the 57 patients studied there were no statistically significant differences between the groups with respect to age or race. Patients with cancer were predominantly men. The Ki-67 index averaged 10 ± 4
% in patients with normal gastric mucosa (n = 17), 21 ± 15
% in patients with Barrett's esophagus (n = 21), and 38 ± 16
% in patients with cancer (n = 19).
Ki-67 expression was significantly different between all groups (P < 0.05).
There was a strong linear correlation between Ki-67 expression and the metaplasia-adenocarcinoma sequence (P < 0.01).
In patients with cancer, Ki-67 was not associated with clinical or surgical staging. Conclusions. Ki-67 antigen has increased expression along the metaplasia-adenocarcinoma sequence. There is a strong linear correlation between Ki-67 proliferative activity and Barrett's carcinogenesis.
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11
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Nasr AO, Dillon MF, Conlon S, Downey P, Chen G, Ireland A, Leen E, Bouchier-Hayes D, Walsh TN. Acid suppression increases rates of Barrett’s esophagus and esophageal injury in the presence of duodenal reflux. Surgery 2012; 151:382-90. [DOI: 10.1016/j.surg.2011.08.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Accepted: 08/18/2011] [Indexed: 12/14/2022]
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12
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Green DA, Mlynarczyk CM, Vaccaro BJ, Capiak KM, Quante M, Lightdale CJ, Abrams JA. Correlation between serum gastrin and cellular proliferation in Barrett's esophagus. Therap Adv Gastroenterol 2011; 4:89-94. [PMID: 21694810 PMCID: PMC3105623 DOI: 10.1177/1756283x10392444] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Patients with Barrett's esophagus (BE) are commonly treated with proton-pump inhibitors (PPIs) to minimize the exposure of esophageal mucosa to stomach acid. However, the use of these medications can lead to significant hypergastrinemia in a subset of patients, which is concerning due to the known tumorigenic and proliferative effects of gastrin. The present pilot study aims to investigate a potential correlation between serum gastrin and cellular proliferation in BE. METHODS We performed a cross-sectional analysis of patients with nondysplastic BE on PPI therapy. Fasting serum gastrin was measured on the same day as esophageal biopsies were obtained. These biopsies were then stained with Ki-67 nuclear antibody. Pearson's correlation coefficient was calculated to assess the relationship between Ki-67 index and ln(gastrin). RESULTS A total of 10 patients were included in the study. The mean age was 62.6 (±8.4) years and 5 patients were male. The median serum gastrin level was 45.2 pM (interquartile range [IQR] 33-113) and the median Ki-67 index was 49.6% (IQR 23-64). We found a statistically significant positive correlation between Ki-67 index and ln(gastrin) (r = 0.64; p = 0.05). CONCLUSIONS In nondysplastic BE patients on PPI therapy, serum gastrin levels were significantly correlated with cellular proliferation. These pilot data lend support to a potential causal effect of gastrin on neoplastic progression in BE. Longitudinal studies of patients with BE are needed to determine whether hypergastrinemia is a risk factor for the development of dysplasia and adenocarcinoma or could be used as a biomarker for disease progression.
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Affiliation(s)
- Daniel A. Green
- Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY, USA
| | - Carrie M. Mlynarczyk
- Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY, USA
| | - Benjamin J. Vaccaro
- Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY, USA
| | - Kristina M. Capiak
- Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY, USA
| | - Michael Quante
- Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY, USA
| | - Charles J. Lightdale
- Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY, USA and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Julian A. Abrams
- Division of Digestive and Liver Diseases, Columbia University Medical Center, 622 West 168th Street, PH 20-303, New York, NY 10032, USA
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13
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Ashraf MJ, Maghbul M, Azarpira N, Khademi B. Expression of Ki67 and P53 in primary squamous cell carcinoma of the larynx. INDIAN J PATHOL MICR 2011; 53:661-5. [PMID: 21045388 DOI: 10.4103/0377-4929.72019] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
UNLABELLED We studied a series of untreated laryngeal carcinomas in an attempt to determine the relationship between Ki67 and p53 expression and clinicopathological findings. The relationship between expression of these markers in non-tumoral tissue was also evaluated in order to investigate the possible role of immunohistochemistry as a diagnostic aid in evaluating laryngeal biopsies. MATERIALS AND METHODS Samples from 54 patients with laryngeal squamous cell carcinoma (SCC) were analyzed retrospectively. The uninvolved vocal cord was evaluated as a non-tumoral sample. Paraffin sections of tumors were immunohistochemically stained for p53 and Ki67 expression. RESULTS Overall, p53 expression was found in 35 (64.8%) of the patients. There was a significant correlation among tumoral p53 expression and tumor location, tumor stage and lymph node involvement. Most grade I tumors had a Ki67 labeling index <50% and a labeling index ≥ 50 was found mainly in high-grade tumors. Tumoral Ki67 expression correlated significantly with tumor grade and mitotic count. There was no correlation between Ki67 labeling index and tumor region. In non-tumoral tissue, 95% of high-grade pre-neoplastic lesions revealed a high expression of Ki67. Non-tumoral p53 expression did not correlate with histological findings. CONCLUSION p53 and Ki67 expression in tumoral tissue may be a prognostic marker in patients with laryngeal SCC. Evaluation of the proliferative index in biopsy samples of dysplastic laryngeal mucosa is potentially useful for predicting the progression toward carcinoma.
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Affiliation(s)
- Mohamad Javad Ashraf
- Department of Pathology, Nemazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
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14
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Binato M, Fagundes R, Gurski R, Meurer L, Edelweiss MI. Immunohistochemical overexpression of the p53 protein and Ki-67 (MIB-1) antigen in patients with GERD and chronic esophagitis. Appl Immunohistochem Mol Morphol 2010; 18:236-243. [PMID: 20414055 DOI: 10.1097/pai.0b013e3181c49134] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND STUDY AIMS Patients with gastroesophageal reflux disease and Barrett esophagus have an increased risk of developing adenocarcinoma of the esophagus. It is uncertain whether molecular or proliferative alterations are present in the early stages of disease. METHODS One hundred thirty-eight patients with gastroesophageal reflux disease symptoms were subjected to upper gastrointestinal endoscopy with biopsies of the esophageal mucosa. p53 protein expression and the Ki-67 proliferation index were determined by immunohistochemical studies. Patients were divided into 4 groups according to histopathologic diagnosis: G1, normal epithelium (n=58); G2, mild esophagitis (n=42); G3, moderate esophagitis (n=23), and G4, severe esophagitis (n=15). RESULTS p53 overexpression was detected in 7% of G1, 21.4% of G2, 52.2% of G3, and 60% of G4 patients. There were significant differences between G1 and G3 or G4 (P<0.001) and between G2 and G4 (P<0.05). The Ki-67 index was 21.3+/-19.5% in G1, 30.8+/-23.4% in G2, 47.1+/-23.2% in G3, and 48.3+/-25.7% in G4. Significant differences in the Ki-67 index were found between groups: G1 x G3 (P<0.001), G1 x G4 (P<0.001), G2 x G3 (P=0.026), and G2 x G4 (P=0.046). p53 and Ki-67 overexpression were correlated with the severity of esophagitis (P<0.001). CONCLUSIONS p53 overexpression and the Ki-67 (MIB-1) index were correlated with histologic findings of inflammation in the esophageal mucosa, particularly in the moderate and severe forms of chronic esophagitis.
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Affiliation(s)
- Marcelo Binato
- Division of General Surgery of Hospital de Clínicas de Porto Alegre, School of Medicine, Universidade Federal do Rio Grande do Sul, Brazil.
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15
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Abstract
Barrett's esophagus is a condition in which the stratified squamous epithelium of the distal esophagus is replaced by specialized intestinal metaplasia. Clinical management of Barrett's esophagus, like many other "premalignant" conditions, is characterized by overdiagnosis of benign early changes that will not cause death or suffering during the lifetime of an individual and underdiagnosis of life-threatening early disease. Recent studies of a number of different types of cancer have revealed much greater genomic complexity than was previously suspected. This genomic complexity could create challenges for early detection and prevention if it develops in premalignant epithelia prior to cancer. Neoplastic progression unfolds in space and time, and Barrett's esophagus provides one of the best models for rapid advances, including "gold standard" cohort studies, to distinguish individuals who do and do not progress to cancer. Specialized intestinal metaplasia has many properties that appear to be protective adaptations to the abnormal environment of gastroesophageal reflux. A large body of evidence accumulated over several decades implicates chromosome instability in neoplastic progression from Barrett's esophagus to esophageal adenocarcinoma. Small, spatial scale studies have been used to infer the temporal order in which genomic abnormalities develop during neoplastic progression in Barrett's esophagus. These spatial studies have provided the basis for prospective cohort studies of biomarkers, including DNA content abnormalities (tetraploidy, aneuploidy) and a biomarker panel of 9p LOH, 17p LOH and DNA content abnormalities. Recent advances in SNP array technology provide a uniform platform to assess chromosome instability.
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Affiliation(s)
- Brian J Reid
- Fred Hutchinson Cancer Research Center, Divisions of Human Biology and Public Health Sciences, Department of Genome Sciences, University of Washington, Seattle, WA, USA.
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16
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Hritz I, Gyorffy H, Molnar B, Lakatos G, Sipos F, Pregun I, Juhasz M, Pronai L, Schaff Z, Tulassay Z, Herszenyi L. Increased p53 expression in the malignant transformation of Barrett's esophagus is accompanied by an upward shift of the proliferative compartment. Pathol Oncol Res 2009; 15:183-192. [PMID: 18752044 DOI: 10.1007/s12253-008-9095-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2008] [Accepted: 07/31/2008] [Indexed: 02/08/2023]
Abstract
Neoplastic progression in Barrett's esophagus (BE) occurs by a multistep process associated with early molecular and morphological changes. This study evaluated cell proliferation and p53 expression and their correlation in the development and progression of esophageal adenocarcinoma. PCNA and p53 expressions were analyzed in biopsy samples by immunohistochemistry including patients with reflux esophagitis, BE, BE with concomitant esophagitis, Barrett's dysplasia, esophageal adenocarcinoma and a control group without any histological changes. Progressive increase in cell proliferation and p53 expression was found in the sequence of malignant transformation of the esophageal mucosa. While cell proliferation was significantly lower in the control group compared with all other groups, there was no increase in p53 expression of esophageal tissues that were negative for dysplasia. Dysplastic BE tissues revealed significantly higher cell proliferation and p53 expression levels compared to BE, reflux esophagitis or BE with concomitant esophagitis. Both, cell proliferation and p53 expression were significantly higher in adenocarcinoma compared to BE or Barrett's dysplasia. Interestingly, while just BE with concomitant esophagitis showed significantly higher p53 expression levels than BE, both, BE with concomitant esophagitis and reflux esophagitis revealed significantly higher cell proliferation levels compared to BE. Alterations of cell proliferation and p53 expression showed a strong correlation. Simultaneous activation of cell proliferation and p53 expression strongly suggest their association with esophageal epithelial tumor genesis and particularly, their specific role in the biology of esophageal adenocarcinoma. Quantification of these parameters in BE is thought to be useful to identify patients at higher risk for progression to adenocarcinoma.
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Affiliation(s)
- Istvan Hritz
- 2nd Dept Medicine, Semmelweis University, 1088, Budapest, Szentkirályi u. 46, Hungary.
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17
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Pouw RE, Gondrie JJ, Rygiel AM, Sondermeijer CM, ten Kate FJ, Odze RD, Vieth M, Krishnadath KK, Bergman JJ. Properties of the neosquamous epithelium after radiofrequency ablation of Barrett's esophagus containing neoplasia. Am J Gastroenterol 2009; 104:1366-73. [PMID: 19491850 DOI: 10.1038/ajg.2009.88] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Endoscopic radiofrequency ablation (RFA) eradicates intestinal metaplasia and intraepithelial neoplasia associated with Barrett's esophagus (BE), restoring an endoscopically normal neosquamous epithelium (NSE). We evaluated the post-RFA NSE for genetic abnormalities and buried glandular mucosa. METHODS Eligible patients underwent RFA for BE containing early cancer and/or high-grade intraepithelial neoplasia with subsequent complete histological reversion to normal NSE. At baseline, the BE was sampled by brush cytology and biopsies. At least 2 months after RFA, the NSE was sampled by brush cytology, keyhole biopsies, and endoscopic resection. The untreated squamous epithelium was biopsied as a control. The baseline BE and post-RFA NSE were evaluated for immunohistochemical expression of Ki-67 and p53, and genetic abnormalities (DNA-fluorescent in situ hybridization: chromosome 1 and 9, p16 and p53). In addition, biopsy depth was compared for biopsies from the NSE and untreated squamous epithelium. The presence of buried glandular mucosa in NSE was assessed with primary and keyhole biopsy, and endoscopic resection. RESULTS All pretreatment specimens from all 22 patients showed abnormalities on immunohistochemical staining and fluorescent in situ hybridization, whereas all post-RFA NSE specimens were normal. All the post-RFA biopsies from the NSE contained full epithelia, whereas 37% contained lamina propria, a finding no different from biopsies from untreated squamous epithelium (36% lamina propria). Deeper keyhole biopsies contained lamina propria in 51%. All endoscopic resection specimens contained submucosa, whereas no biopsy or endoscopic resection specimen contained buried glandular mucosa. CONCLUSIONS Rigorous evaluation of the post-RFA NSE in patients who, at baseline, had BE containing early cancer high-grade intraepithelial neoplasia, showed neither persistent genetic abnormalities nor buried glandular mucosa.
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Affiliation(s)
- Roos E Pouw
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
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18
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Kaye PV, Haider SA, Ilyas M, James PD, Soomro I, Faisal W, Catton J, Parsons SL, Ragunath K. Barrett's dysplasia and the Vienna classification: reproducibility, prediction of progression and impact of consensus reporting and p53 immunohistochemistry. Histopathology 2009; 54:699-712. [PMID: 19438745 DOI: 10.1111/j.1365-2559.2009.03288.x] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
AIMS The Vienna classification is used to classify dysplasia in Barrett's oesophagus (BO), but reproducibility and value of diagnosis of lower grades in particular are often questioned. The aim was to test the diagnostic variability and correlation with patient outcome and to attempt to define histological features causing discrepant diagnoses, as well as to test the impact of adding p53 immunohistochemistry on reproducibility and prediction of outcome. METHODS AND RESULTS One hundred and forty-three patients with 154 sets of biopsy specimens originally diagnosed with Barrett's dysplasia were retrieved from the pathology records of Nottingham University Hospital. Thirty-two Barrett's patients without dysplasia were added. Anonymized slides were graded independently by five pathologists without and with p53-stained slides. Interobserver variation, correlation with outcome and diagnostic accuracy were determined. Weighted kappa scores between pairs of pathologists showed substantial agreement and improved after p53 immunohistochemistry. Agreement with the original diagnosis was substantially lower. Fourteen of 34 low-grade dysplasias (LGD) and 27 of 30 high-grade dysplasias on consensus progressed within 10 years compared with 18/94 and 28/39 of original diagnoses. Progression correlated with p53 positivity. CONCLUSION The Vienna classification is useful and reproducible in BO. Consensus diagnosis by gastrointestinal pathologists produces high specificity and predictive value, even for LGD. p53 immunohistochemistry assists in diagnosis in difficult cases and predicts progression.
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Affiliation(s)
- Philip V Kaye
- Department of Cellular Pathology, Nottingham University Hospitals, Queens Medical Centre Campus, Nottingham, UK.
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Binato M, Gurski RR, Fagundes RB, Meurer L, Edelweiss MI. P53 and Ki-67 overexpression in gastroesophageal reflux disease--Barrett's esophagus and adenocarcinoma sequence. Dis Esophagus 2009; 22:588-595. [PMID: 19302208 DOI: 10.1111/j.1442-2050.2009.00953.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastroesophageal reflux disease (GERD) is a major risk factor for the development of esophageal adenocarcinoma (ACE). Many molecular alterations occur in esophageal carcinogenesis, yet the exact mechanism of ACE development remains unknown. This study aims to determine p53 protein and Ki-67 expression in esophageal mucosa of patients with GERD and study the correlation between these markers and the progression from normal squamous epithelium to esophagitis, columnar epithelium with or without intestinal metaplasia and ACE. We analyzed p53 protein and Ki-67 expression in biopsies of 200 patients with GERD and 35 patients with ACE. Those biopsies were classified into five groups: (i) G1 normal squamous epithelium (58); (ii) G2 esophagitis (80); (iii) G3 columnar epitheliums without intestinal metaplasia (30); (iv) G4, columnar epitheliums with intestinal metaplasia (32); and (v) G5 ACEs (35). p53 protein overexpression was found in 7% (4) of G1, 37.5% (30) of G2, 30% (9) of G3, 62.5% (20) of G4, and 71.4% (25) of G5 (p < 0.001). Ki-67 index increased according to the severity of histopathological diagnoses. Ki67 index was 21.3 +/- 19.5% in G1, 38.8 +/- 24.9% in G2, 37.7 +/- 26.3% in G3, 52.8 +/- 24.6% in G4, and 57.1 +/- 25.1% in G5 (P < 0.001). Linear correlation between p53/Ki67 expression and the multistep progression from squamous epithelium to ACE was observed (P < 0.001 and P < 0.05). Our results indicate that overexpression of p53 and increased Ki-67 could be associated with the development and progression to ACE in patients with GERD.
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Affiliation(s)
- M Binato
- Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil.
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20
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Lopes CV, Mnif H, Pesenti C, Bories E, Monges G, Giovannini M. p53 and Ki-67 in Barrett's carcinoma: is there any value to predict recurrence after circumferential endoscopic mucosal resection? ARQUIVOS DE GASTROENTEROLOGIA 2008; 44:304-8. [PMID: 18317648 DOI: 10.1590/s0004-28032007000400005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2006] [Accepted: 05/02/2007] [Indexed: 11/21/2022]
Abstract
BACKGROUND There are situations in which the specimens obtained after endoscopic mucosal resection of superficial adenocarcinoma arising from Barrett's esophagus are not adequate for histopathological assessment of the margins. In these cases, immunohistochemistry might be an useful tool for predicting cancer recurrence. AIM To evaluate the value of p53 and Ki-67 immunohistochemistry in predicting the cancer recurrence in patients with Barrett's esophagus-related cancer referred to circumferential endoscopic mucosal resection. METHODS Mucosectomy specimens from 41 patients were analyzed. All endoscopic biopsies prior to endoscopic mucosal resection presented high-grade dysplasia and cancer was detected in 23 of them. Positive reactions were considered the intense coloration in the nuclei of at least 90% of the cells in each high-power magnification field, and immunostaining could be classified as superficial or diffuse according to the mucosal distribution of the stained nuclei. RESULTS Endoscopic mucosal resection samples detected cancer in 21 cases. In these cases, p53 immunohistochemistry revealed a diffuse positivity for the great majority of these cancers (90.5% vs. 20%), and Ki-67 showed a diffuse pattern for all cases (100% vs. 30%); conversely, patients without cancer revealed a superficial or negative pattern for p53 (80% vs. 9.5%) and Ki-67 (70% vs. 0%). During a mean follow-up of 31.6 months, 5 (12.2%) patients developed six episodes of recurrent cancer. Endoscopic mucosal resection specimens did not show any significant difference in the p53 and Ki-67 expression for patients developing cancer after endoscopic treatment. CONCLUSIONS p53 and Ki-67 immunohistochemistry were useful to confirm the cancer; however, they had not value for predicting the recurrent carcinoma after circumferential endoscopic mucosal resection of Barrett's carcinoma.
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Affiliation(s)
- César Vivian Lopes
- Endoscopy Unit and Department of Biopathology, Paoli-Calmettes Institute, Marseille, France.
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21
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p16, Cyclin D1, Ki-67, and AMACR as Markers for Dysplasia in Barrett Esophagus. Appl Immunohistochem Mol Morphol 2008; 16:447-52. [DOI: 10.1097/pai.0b013e318168598b] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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22
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Downs-Kelly E, Mendelin JE, Bennett AE, Castilla E, Henricks WH, Schoenfield L, Skacel M, Yerian L, Rice TW, Rybicki LA, Bronner MP, Goldblum JR. Poor interobserver agreement in the distinction of high-grade dysplasia and adenocarcinoma in pretreatment Barrett's esophagus biopsies. Am J Gastroenterol 2008; 103:2333-40; quiz 2341. [PMID: 18671819 DOI: 10.1111/j.1572-0241.2008.02020.x] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Grading Barrett's dysplasia at the lower end of the metaplasia-dysplasia spectrum (negative, indefinite, and low-grade dysplasia) suffers from poor interobserver agreement, even among gastrointestinal pathologists. Data evaluating interobserver agreement in Barrett's mucosal biopsies with changes at the upper end of the dysplasia spectrum (high-grade dysplasia, intramucosal, and submucosal adenocarcinoma) have not been published. The accurate categorization of pretreatment biopsies drives therapeutic decision making, but if the diagnostic distinction between cancer and high-grade dysplasia in Barrett's biopsies is inconsistent, then the use of these diagnoses to make management decisions is suspect. To this end, our aim was to assess interobserver reproducibility among a group of gastrointestinal pathologists in the interpretation of preresection biopsies. METHODS All study pathologists agreed upon the histologic criteria distinguishing four diagnostic categories, including high-grade dysplasia; high-grade dysplasia with marked distortion of glandular architecture, cannot exclude intramucosal adenocarcinoma; intramucosal adenocarcinoma; and submucosally invasive adenocarcinoma. The histologic criteria were used to independently review preresection biopsies from 163 consecutive Barrett's esophagus patients with at least high-grade dysplasia who ultimately underwent esophagectomy. Reviewers recorded the specific histologic criteria used to categorize each case and Kappa statistics were calculated to assess interobserver agreement. RESULTS Using kappa statistics, the overall agreement was only fair (kappa= 0.30). Agreement for high-grade dysplasia was moderate (kappa= 0.47), while agreement for high-grade dysplasia with marked architectural distortion, cannot exclude intramucosal adenocarcinoma and intramucosal adenocarcinoma were only fair (kappa= 0.21 and 0.30, respectively) and agreement for submucosal adenocarcinoma was poor (kappa= 0.14). CONCLUSIONS The overall poor interobserver reproducibility among gastrointestinal pathologists who see a high volume of Barrett's cases calls into question treatment regimens based on the assumption that high-grade dysplasia, intramucosal adenocarcinoma, and submucosal adenocarcinoma can reliably be distinguished in biopsy specimens.
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Affiliation(s)
- Erinn Downs-Kelly
- Cleveland Clinic Department of Anatomic Pathology, Cleveland, Ohio 44195, USA
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Volkweis BS, Gurski RR. Esôfago de Barrett: aspectos fisiopatológicos e moleculares da seqüência metaplasia-displasia-adenocarcinoma - artigo de revisão. Rev Col Bras Cir 2008. [DOI: 10.1590/s0100-69912008000200009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Griffiths EA, Pritchard SA, McGrath SM, Valentine HR, Price PM, Welch IM, West CML. Increasing expression of hypoxia-inducible proteins in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. Br J Cancer 2007; 96:1377-83. [PMID: 17437013 PMCID: PMC2360174 DOI: 10.1038/sj.bjc.6603744] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Hypoxia-associated markers are involved in the progression of several malignancies, but are relatively unstudied in Barrett's carcinogenesis. Our aim was to assess the immunohistochemical expression of hypoxia-inducible factor (HIF)-1α, HIF-2α, erythropoietin (Epo), Epo receptor (Epo-R), Glut-1 and vascular endothelial growth factor (VEGF) along with Ki67/MIB-1 in the Barrett's metaplasia–dysplasia–adenocarcinoma sequence. Endoscopic biopsies of normal squamous epithelium (NSE) (n=20), columnar-lined oesophagus (CLO) (n=15), CLO with intestinal metaplasia (n=20), dysplasia (n=17) and Barrett's type adenocarcinoma (n=20) were obtained. Immunohistochemistry was performed on the paraffin-embedded tissue. A score was calculated for each marker (range 0−300) by multiplying intensity (none 0, weak 1, moderate 2, strong 3) by percentage of expression (range 0–100). Significant increases in the expression of HIF-2α (P=0.014), VEGF (P<0.0001), Epo-R (P<0.0001) and Ki67 (P<0.0001) were found as tissue progressed from NSE to adenocarcinoma. HIF-2α was expressed late in the sequence and was only seen in dysplasia and adenocarcinoma. High HIF-2α expression was seen in 12 out of 20 Barrett's type adenocarcinoma. The late expression of HIF-2α in the Barrett's carcinogenesis sequence and its high expression in adenocarcinoma suggest that it is worth further investigation as a marker of disease progression and therapeutic target.
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Affiliation(s)
- E A Griffiths
- Academic Radiation Oncology, Division of Cancer Studies, Christie Hospital, The University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, UK
- Department of Gastrointestinal Surgery, University Hospitals NHS Trust, South Manchester, Manchester M23 9LT, UK
| | - S A Pritchard
- Department of Histopathology, University Hospitals NHS Trust, South Manchester, Manchester M23 9LT, UK
| | - S M McGrath
- Department of Histopathology, University Hospitals NHS Trust, South Manchester, Manchester M23 9LT, UK
| | - H R Valentine
- Academic Radiation Oncology, Division of Cancer Studies, Christie Hospital, The University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, UK
| | - P M Price
- Academic Radiation Oncology, Division of Cancer Studies, Christie Hospital, The University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, UK
| | - I M Welch
- Department of Gastrointestinal Surgery, University Hospitals NHS Trust, South Manchester, Manchester M23 9LT, UK
| | - C M L West
- Academic Radiation Oncology, Division of Cancer Studies, Christie Hospital, The University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, UK
- E-mail:
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Dvorak K, Ramsey L, Payne CM, Sampliner R, Fass R, Bernstein H, Prasad A, Garewal H. Abnormal expression of biomarkers in incompletely ablated Barrett's esophagus. Ann Surg 2007; 244:1031-6. [PMID: 17122630 PMCID: PMC1856620 DOI: 10.1097/01.sla.0000224913.19922.7e] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE The aim of this study was to evaluate expression of cancer risk-associated biomarkers in columnar epithelium at squamocolumnar junctions produced by an ablation procedure and proton pump inhibitors in incompletely ablated Barrett's esophagus (BE) patients that were nondysplastic prior to ablation. SUMMARY BACKGROUND DATA Ablation of BE to squamous epithelium is achievable by combining a re-injury method with acid suppression. We previously reported that, when there is complete ablation, the neo-squamous epithelium is normal histologically and in biomarker expression. However, squamous islands observed after prolonged use of PPIs were associated with abnormalities in p53 expression and Ki-67 labeling. METHODS Twenty-one nondysplastic BE cases with incomplete ablation were evaluated for the expression of Ki-67 (proliferation), cyclooxygenase-2 (COX-2), and p53 by immunohistochemistry. RESULTS Pre-ablation biopsies showed the normal staining patterns in columnar epithelium, ie, normal Ki-67 labeling, rare positive COX-2 staining of interstitial cells, and negative or mild staining for p53 in the majority of patients' biopsies. However, post-ablation biopsies demonstrated abnormal staining patterns in the glandular area at the new squamocolumnar junctions. In 13 of 21 post-ablation cases (62%), increased Ki-67 staining was seen in BE glands. In 8 of 21 patients (38%), increased COX-2 expression was seen in columnar epithelium. Similarly, in 8 of 21 post-ablation junctions (38%), there was increased p53 staining. CONCLUSIONS Our findings of increased expression of cancer-associated biomarkers in incompletely ablated BE patients raise a cautionary note regarding this procedure. We hypothesize that newly formed junctions contain cells undergoing replication, differentiation, etc, and are thus more susceptible to genomic damage.
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Affiliation(s)
- Katerina Dvorak
- Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ, USA
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Keswani RN, Noffsinger A, Waxman I, Bissonnette M. Clinical use of p53 in Barrett's esophagus. Cancer Epidemiol Biomarkers Prev 2006; 15:1243-9. [PMID: 16835318 DOI: 10.1158/1055-9965.epi-06-0010] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Barrett's esophagus is an established precursor to esophageal adenocarcinoma. Whereas most patients with Barrett's esophagus do not progress to adenocarcinoma, patients with progression have a poor prognosis. Current management strategies use frequent endoscopic surveillance and multiple nontargeted biopsies. This approach, however, may miss dysplastic areas. Furthermore, given the relatively high prevalence of Barrett's esophagus but low incidence of progression, this invasive and expensive approach has not been shown to be cost-effective. Thus, there is intense interest in using biomarkers to identify patients at increased risk of progressing to adenocarcinoma. This has included examination of mutations in the tumor suppressor gene, p53. In this report, we discuss the biology of p53 and the incidence of p53 mutations in Barrett's esophagus and review relevant studies regarding the ability of p53 to predict neoplastic progression. Additionally, we report our results of the expression of p53 by immunohistochemistry in a group of 18 patients that have undergone endoscopic esophageal mucosal resection for dysplasia. Although the presence of a p53 mutation increases the risk of neoplastic progression, the absence of this mutation does not abrogate the risk. Continuing efforts, therefore, are needed to define and prospectively validate a panel of biomarkers to risk-stratify patients with Barrett's esophagus. Determination of p53 mutational status may ultimately be a component of such a panel.
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Affiliation(s)
- Rajesh N Keswani
- Section of Gastroenterology, Department of Medicine, University of Chicago, IL 60637, USA.
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Buskens CJ, Hulscher JBF, van Gulik TM, Ten Kate FJ, van Lanschot JJB. Histopathologic evaluation of an animal model for Barrett's esophagus and adenocarcinoma of the distal esophagus. J Surg Res 2006; 135:337-44. [PMID: 16926029 DOI: 10.1016/j.jss.2006.04.023] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2006] [Revised: 04/03/2006] [Accepted: 04/24/2006] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Barrett's esophagus and adenocarcinoma of the esophagus are related to long-standing duodeno-gastroesophageal reflux. The development of an animal model in which Barrett's esophagus and/or carcinoma is induced by duodeno-(gastro-)esophageal reflux could provide better understanding of the pathogenesis of the metaplasia-dysplasia-carcinoma sequence and would create the possibility of investigating new treatment strategies for this aggressive disease. MATERIALS AND METHODS Two rat models were analyzed. In the first experiment, 44 male Sprague Dawley rats underwent end-to-side esophagojejunostomy with gastric resection, to ensure duodenoesophageal reflux without gastric acid. In the second experiment a side-to-side esophago-gastrojejunostomy was performed in 30 rats, ensuring duodeno-gastroesophageal reflux. In both experiments animals were not exposed to any exogenous carcinogens during the experiment. Sequential morphological changes (i.e., esophagitis, intestinal metaplasia, dysplasia, and carcinoma) were studied after 4, 6, and 12 months. To analyze histopathologic characteristics, evaluation of the hematoxylin and eosin specimens was combined with immunohistochemical stainings for high-iron diamine-alcian blue, alcian blue/periodic acid-Schiff, the proliferation marker PCNA, and mutations in the tumor suppressor gene p53. RESULTS In the first experiment, only 11 animals survived the postoperative period. These animals had to be sacrificed at a median of 11 weeks due to persistent weight loss and failure to thrive. Severe ulcerative esophagitis was seen in all animals, with a 2-mm segment of metaplastic epithelium found at the anastomosis. In four animals a large, well-differentiated, mucinous tumor without malignant characteristics was observed. In the second experiment, eight animals died postoperatively. Twelve animals were sacrificed according to protocol at 4 or 6 months. In these animals, extensive esophagitis with squamous cell hyperplasia was found. In addition, a short (2 mm) segment of metaplastic epithelium was observed, without dysplasia. The remaining animals survived 1 year. After 1 year, 9 of the 10 animals had developed a glandular metaplastic segment (median length, 10 mm), which was histologically and immunohistologically characteristic for the specialized columnar epithelium of Barrett's esophagus without signs of dysplasia. Finally, in seven animals a mucinous tumor with cytologic characteristics of a well-differentiated mucinous adenocarcinoma was found without infiltrative growth. These tumors were always found at the site of the anastomosis, originated in the submucosa, and did not reach either the luminal surface or the muscular layer. The mucinous lesions were not positive for p53, and PCNA was only slightly increased. Although they showed cytological characteristics of malignancy, histopathologic evaluation was more suggestive of a reactive mucous producing lesion fitting the diagnosis "esophagitis cystica profunda." CONCLUSION This study demonstrates the development of a long Barrett's segment in an animal duodeno-gastroesophageal reflux model. Although mucinous tumors resembling adenocarcinomas develop around the anastomosis, these are probably not reflux induced and are more likely to be reactive lesions. However, the true nature of these tumors remains to be elucidated.
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Affiliation(s)
- Christianne J Buskens
- Department of Surgery, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
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Wongsurawat VJ, Finley JC, Galipeau PC, Sanchez CA, Maley CC, Li X, Blount PL, Odze RD, Rabinovitch PS, Reid BJ. Genetic mechanisms of TP53 loss of heterozygosity in Barrett's esophagus: implications for biomarker validation. Cancer Epidemiol Biomarkers Prev 2006; 15:509-16. [PMID: 16537709 DOI: 10.1158/1055-9965.epi-05-0246] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND AND AIMS 17p (TP53) loss of heterozygosity (LOH) has been reported to be predictive of progression from Barrett's esophagus to esophageal adenocarcinoma, but the mechanism by which TP53 LOH develops is unknown. It could be (a) DNA deletion, (b) LOH without copy number change, or (c) tetraploidy followed by genetic loss. If an alternative biomarker assay, such as fluorescence in situ hybridization (FISH), provided equivalent results, then translation to the clinic might be accelerated, because LOH genotyping is presently limited to research centers. METHODS We evaluated mechanisms of TP53 LOH to determine if FISH and TP53 LOH provided equivalent results on the same flow-sorted samples (n = 43) representing established stages of clonal progression (diploid, diploid with TP53 LOH, aneuploid) in 19 esophagectomy specimens. RESULTS LOH developed by all three mechanisms: 32% had DNA deletions, 32% had no copy number change, and 37% had FISH patterns consistent with a tetraploid intermediate followed by genetic loss. Thus, FISH and LOH are not equivalent (P < 0.000001). CONCLUSIONS LOH develops by multiple chromosome mechanisms in Barrett's esophagus, all of which can be detected by genotyping. FISH cannot detect LOH without copy number change, and dual-probe FISH is required to detect the complex genetic changes associated with a tetraploid intermediate. Alternative biomarker assay development should be guided by appreciation and evaluation of the biological mechanisms generating the biomarker abnormality to detect potential sources of discordance. FISH will require validation in adequately powered longitudinal studies before implementation as a clinical diagnostic for esophageal adenocarcinoma risk prediction.
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Affiliation(s)
- V Jon Wongsurawat
- Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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Peters FP, Kara MA, Rosmolen WD, ten Kate FJW, Krishnadath KK, van Lanschot JJB, Fockens P, Bergman JJGHM. Stepwise radical endoscopic resection is effective for complete removal of Barrett's esophagus with early neoplasia: a prospective study. Am J Gastroenterol 2006; 101:1449-57. [PMID: 16863545 DOI: 10.1111/j.1572-0241.2006.00635.x] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Endoscopic therapy for early neoplasia in Barrett's esophagus (BE) is evolving rapidly. Aim of this study was to prospectively evaluate safety and efficacy of stepwise radical endoscopic resection (ER) of BE containing early neoplasia. METHODS Patients with early neoplasia (i.e., high-grade intraepithelial neoplasia or early cancer) in BE < or = 5 cm, without signs of submucosal infiltration or lymph node/distant metastases, were included. Patients underwent resection sessions (cap technique after submucosal lifting) with intervals of 6 wk. RESULTS Between January 2003 and December 2004, 39 consecutive patients were included. Therapy was discontinued in two patients due to unrelated comorbidity. Complete eradication of early neoplasia was achieved in all 37 treated patients in a median number of three sessions. Complete removal of all Barrett's mucosa was achieved in 33 (89%) patients: 4 patients (all had undergone APC [argon plasma coagulation]) were found to have small isles of Barrett's mucosa underneath neosquamous mucosa. Complications occurred in two out of 88 (2%) ER procedures: one asymptomatic perforation, one delayed bleeding. Symptomatic stenosis occurred in 10 of 39 (26%) patients and was effectively treated by endoscopic bougienage. During a median follow-up of 11 months, no patients died and none had recurrence of neoplasia or Barrett's mucosa. CONCLUSIONS Stepwise radical ER is effective for selected patients with early neoplasia in BE; provides optimal histopathological diagnosis; and may reduce recurrence rate, since all mucosa at risk is effectively removed. Use of APC should be limited to prevent buried Barrett's mucosa. Methods for prevention of stenosis should be developed.
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Affiliation(s)
- Femke P Peters
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
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Abstract
Oesophageal adenocarcinoma is a rare cancer; however, it is the most rapidly increasing cancer in the western world. Barrett's oesophagus is the only recognised precursor and is associated with the majority of cases of adenocarcinoma. The role of screening and surveillance in patients with Barrett's oesophagus remains controversial. There is insufficient evidence to show that screening improves survival and is cost-effective. Indirect evidence suggests that patients diagnosed with cancer while undergoing surveillance endoscopy are diagnosed at an earlier stage and have an improved survival. The problems with current surveillance techniques include lack of data on natural history of Barrett's oesophagus, test invasiveness, costs, lack of standardisation and validation of biopsy and treatment protocols, and endoscopy intervals. The use of novel endoscopic techniques and biomarkers combined with better identification of high-risk groups could make screening and surveillance a cost-effective practice in the future.
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Affiliation(s)
- Sachin Wani
- Division of Gastroenterology and Hepatology, University of Kansas School of Medicine, Department of Veterans Affairs Medical Center, 4801 East Linwood Boulevard, Kansas City, MO 64128-2295, USA
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Schuchert MJ, McGrath K, Buenaventura PO. Barrett’s Esophagus: Diagnostic Approaches and Surveillance. Semin Thorac Cardiovasc Surg 2005; 17:301-12. [PMID: 16428036 DOI: 10.1053/j.semtcvs.2005.09.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2005] [Indexed: 02/06/2023]
Abstract
In an effort to identify those patients at risk for developing esophageal adenocarcinoma, the American College of Gastroenterology recommends screening endoscopy in patients with chronic gastroesophageal reflux disease. Surveillance endoscopy is recommended every 3 years in those patients without dysplasia. For those patients with verified low-grade dysplasia, yearly surveillance endoscopy is recommended. In the case of high-grade dysplasia (HGD), either intensive endoscopic surveillance (focal HGD) or ablation/resection can be performed (multifocal HGD). Both observational and cost-effectiveness analyses suggest a potential benefit of endoscopic screening and surveillance, though these findings remain to be validated in controlled clinical trials. The development of new endoscopic imaging modalities may enhance the yield of biopsies obtained during screening and surveillance regimens.
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Affiliation(s)
- Matthew J Schuchert
- Division of Thoracic and Foregut Surgery, Department of Surgery, University of Pittsburgh, School of Medicine, UPMC Health System, Pittsburgh, PA 15213, USA.
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Koppert LB, Wijnhoven BPL, van Dekken H, Tilanus HW, Dinjens WNM. The molecular biology of esophageal adenocarcinoma. J Surg Oncol 2005; 92:169-90. [PMID: 16299787 DOI: 10.1002/jso.20359] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Barrett's esophagus is an acquired metaplastic change that occurs in the distal esophagus secondary to chronic gastroesophageal reflux. This premalignant condition forms the most important risk factor for developing esophageal adenocarcinoma, which is an extremely aggressive tumor with a 5-year survival rate of less than 25%. Carcinomas that arise in the setting of Barrett's esophagus are thought to develop as part of the metaplasia-dysplasia-carcinoma sequence. OBJECTIVE To review the current knowledge on the genomic alterations involved in the development of Barrett's esophagus and its progression to dysplasia and/or cancer. RESULTS Several changes in gene structure, gene expression, and protein structure are associated with the progression of Barrett's esophagus to adenocarcinoma. Accumulation of these changes seems to be essential, rather than the exact sequence of these changes. Multiple molecular pathways are involved and interact with each other. Alterations in tumor suppressor genes, amongst which p53 and p16, are early events in the metaplasia-dysplasia-adenocarcinoma sequence, followed by loss of cell cycle checkpoints. Ongoing genomic instability leads to cumulative genetic errors and thereby the generation of multiple clones of transformed cells. CONCLUSIONS Within the multistep process of esophageal adenocarcinogenesis, to date no single molecular marker came forward able to predict who will and who will not develop cancer in the setting of Barrett's esophagus. Instead, panels of markers need to be developed in the future allowing to indicate disease progression. Identification of crucial molecular pathways involved in esophageal adenocarcinogenesis would ultimately improve therapy and facilitate development of new treatment strategies.
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Affiliation(s)
- Linetta B Koppert
- Department of Surgery, Erasmus MC, University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands
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Koss K, Harrison RF, Gregory J, Darnton SJ, Anderson MR, Jankowski JAZ. The metabolic marker tumour pyruvate kinase type M2 (tumour M2-PK) shows increased expression along the metaplasia-dysplasia-adenocarcinoma sequence in Barrett's oesophagus. J Clin Pathol 2004; 57:1156-9. [PMID: 15509675 PMCID: PMC1770481 DOI: 10.1136/jcp.2004.018150] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Proliferating and tumour cells express the glycolytic isoenzyme, pyruvate kinase type M2 (M2-PK). In tumours cells, M2-PK usually exists in dimeric form (tumour M2-PK), causing the accumulation of glycolytic phosphometabolites, which allows cells to invade areas with low oxygen and glucose concentrations. AIMS To investigate the expression of tumour M2-PK during the metaplasia-dysplasia-adenocarcinoma sequence of Barrett's oesophagus, and to assess the prognostic usefulness of tumour M2-PK in oesophageal cancer. MATERIALS/METHODS One hundred and ninety cases selected from the histopathology archives as follows: 17 reflux oesophagitis, 37 Barrett's oesophagus, 21 high grade dysplasia, 112 adenocarcinomas, and three control tumours. Sections were stained immunohistochemically with antibody to tumour M2-PK. RESULTS Tumour M2-PK was expressed in all cases, and increased cytoplasmic expression was seen with progression along the metaplasia-dysplasia-adenocarcinoma sequence. All cases of adenocarcinoma showed 100% staining so that tumour M2-PK was not a useful prognostic marker. CONCLUSIONS Tumour M2-PK is not a specific marker of Barrett's adenocarcinoma, but may be important as a marker of transformed and highly proliferating clones during progression along the metaplasia-dysplasia-adenocarcinoma sequence.
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Affiliation(s)
- K Koss
- Department of Gastroenterology, University Hospital Birmingham, Edgbaston, Birmingham B15 2TH, UK.
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Abstract
The rising incidence and poor prognosis of esophageal adenocarcinoma in the Western world have intensified research efforts into earlier methods of detection of this disease and its relationship to Barrett's esophagus. The progression of Barrett's esophagus to adenocarcinoma has been the focus of particular scrutiny, and a number of potential tissue and serum-based disease biomarkers have emerged. The epidemiology and pathogenesis of esophageal adenocarcinoma are outlined. Tissue biomarkers allowing risk stratification of Barrett's are reviewed as well as strategies currently being used to discover novel biomarkers that will facilitate the early detection of esophageal adenocarcinoma. Finally, the uses of biomarkers as predictive tests for targeted treatments and as surrogate endpoints in chemoprevention trials are considered.
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Affiliation(s)
- Damian T McManus
- Histopathology/Cytopathologist, Belfast City Hospital Trust, Belfast, Northern Ireland
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Tytgat GNJ, Van Sandick JW, Lanschot JJBV, Obertop H. Role of surveillance in intestinal metaplasia of the esophagus and gastroesophageal junction. World J Surg 2003; 27:1021-5. [PMID: 12917755 DOI: 10.1007/s00268-003-7194-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
This article reviews current concepts of cancer surveillance in esophageal columnar metaplasia (Barrett's esophagus) and intestinal metaplasia at the gastroesophageal junction. An overview is given of the available data on the prevalence of intestinal metaplasia in biopsies from the distal esophagus and from the gastroesophageal junction. Furthermore, special attention is given to the endoscopic detection of dysplasia and early malignancy. Finally, the costs of endoscopic surveillance and its effect on mortality rates from esophageal adenocarcinoma are discussed.
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Affiliation(s)
- Guido N J Tytgat
- Department of Gastroenterology and Hepatology, Academic Medical Center at the University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
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Abstract
This article provides a framework for clinicians who are attempting the difficult task of interpreting the Barrett's biomarker literature with the goal of improving care for their patients. Although many articles. including more that 60 proposed biomarkers, have been published on this subject, only a few describe phase 3 and 4 studies that are of interest to the clinical gastroenterologist (Table 1). For year, dysplasia grade has been the sole means of risk stratification for patients with BE, and it likely will continue to be used in the foreseeable future. The current authors believe that dysplasia classification can be valuable using the team management approach and quality controls described previously. Significant problems, however, have emerged in phase 2 through 4 studies of dysplasia that make it imperative for the Barrett's field to incorporate additional biomarkers as they are validated. These problems include poor reproducibility of dysplasia interpretations, poor predictive value for negative, indefinite, and low-grade dysplasia, and inconsistent results for HGD in different centers, all of which makes it virtually impossible to develop national guidelines for surveillance. Some studies have even suggested that endoscopic biopsy surveillance using dysplasia may not be worthwhile. Currently, flow cytometric tetraploidy and aneuploidy have progressed furthest in biomarker validation (see Table 1). With proper handling, endoscopic biopsy specimens can be shipped to reference laboratories that have the instruments, computer analytic methods, and expertise to reproducibly detect tetraploidy and aneuploidy. The results of phase 4 studies indicate that flow cytometry appears to be useful in detecting a subset of patients who do not have HGD and yet have an increased risk of progression to cancer that cannot be identified by dysplasia grade. For many reasons, the authors anticipate that the number of validated biomarkers will increase substantially in the future. Biopsy repositories are now readily available for phase 3 studies that can evaluate and compare biomarkers. There are initiatives for multi-institutional Barrett's Centers of Excellence that could provide rapid progress in biomarker evaluation. In addition to new candidate biomarkers, the human genome project has provided high-throughput methodologies and methods for computer analysis of data, which can provide the volume and quality control required for clinically useful biomarkers. Currently, 17p (p53) LOH has progressed the furthest among molecular biomarkers. The authors do not recommend its routine clinical use at the present time, however. Finally, it is likely that clinicians will want to follow the results of clinical treatment-response studies and epidemiologic studies that evaluate relationship between clinical interventions or environmental risk and protective factors and surrogate endpoints, especially if the endpoints are progessing well along the phases of biomarker validation. These studies are likely to be of clinical interest because they may becoming the basis for randomized clinical trials to prevent cancer in BE.
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Affiliation(s)
- Brian J Reid
- Division of Human Biology, Fred Hutchinson Cancer Research Center, 100 Fairview Avenue North, Seattle, WA 98109, USA.
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Kleeff J, Friess H, Liao Q, Büchler MW. Immunohistochemical presentation in non-malignant and malignant Barrett's epithelium. Dis Esophagus 2002; 15:10-5. [PMID: 12060037 DOI: 10.1046/j.1442-2050.2002.00211.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Barrett's esophagus, which is histologically characterized by metaplastic columnar epithelium, is a common condition observed in approximately 10-20% of patients with gastroesophageal reflux disease. These lesions can typically progress from metaplasia with atypia to low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. It is of great clinical importance to correctly grade these lesions and to identify changes with a high risk of malignant transformation, inasmuch as high-grade dysplasias and early adenocarcinomas in patients with Barrett's esophagus have a high chance for cure. The identification of high-risk lesions in Barrett's esophagus by histologic evaluation has drawbacks, especially regarding sampling errors and frequent intra- and interobserver discrepancies in the histopathologic grading/staging of these lesions. Immunostaining with a variety of antibodies provides a better understanding of the process of malignant transformation and helps to identify early markers of malignant transformation in Barrett's esophagus lesions. In this review, we will summarize the current knowledge about the value of immunostaining in the diagnosis of malignant and non-malignant Barrett's epithelium and its role to better define lesions with high risk for malignancy in this disorder.
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Affiliation(s)
- J Kleeff
- Department of Visceral and Transplantation Surgery, University of Bern, Switzerland
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Xu M, Jin YL, Fu J, Huang H, Chen SZ, Qu P, Tian HM, Liu ZY, Zhang W. The abnormal expression of retinoic acid receptor-β, P53 and Ki67 protein in normal, premalignant and malignant esophageal tissues. World J Gastroenterol 2002; 8:200-2. [PMID: 11925591 PMCID: PMC4658350 DOI: 10.3748/wjg.v8.i2.200] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Esophageal cancer remains a significant health problem worldwide. It is important to investigate alterations in expression of retinoic acid receptor-β, P53 and Ki67 proteins in esophageal carcinogenesis.
METHODS: To find biomarkers for early identification of esophageal cancer, we analyzed the retinoic acid receptor-β, P53 protein and the proliferation marker Ki67 in surgical specimens of normal, mildly, and severely dysplastic and malignant esophageal tissues by in situ hybridization of RNA and immunohistochemistry.
RESULTS: RAR-β was expressed in 94.3% (33/35) of normal mucosae, 67.8% (19/28) of the mild, 58.1% (18/31) of the severe lesions and 53.2% (116/218) of tumor samples. RAR-β mRNA was expressed in 62.7% (42/67), 55.1% (43/78) and 29.2% (7/24) of well, moderated and poorly differentiated SSCs. The P53 and Ki67 proteins were 5.9% (2/34) of the normal mucosa. P53 and Ki67 stained positively in 10.7% (3/28) and 21.4% (6/28) of mild dysplasia, and 51.6% (16/31) and 58.1% (18/31) of severely dysplasia respectively. Samples from esophageal cancer showed no higher levers of P53 and Ki67 expression than seen in severely dysplastic lesions. There was significant difference of RAR-β、P53 and Ki67 expression between normal mucosa and dysplatic tissue or esophageal cancer.
CONCLUSION: Loss of RAR-β expression and accumulation of P53 and Ki67 proteins may serve as biomarkers for early identification of esophageal cancer in the high-risk populations.
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Affiliation(s)
- Min Xu
- Central Laboratory for Tumor Biology, Cancer Hospital (Institute), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China
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Ortner MA. Barrett's esophagus: is dysplasia a reliable marker in surveillance after endoscopic treatment? Curr Gastroenterol Rep 2001; 3:371-4. [PMID: 11560793 DOI: 10.1007/s11894-001-0075-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2023]
Affiliation(s)
- M A Ortner
- Department of Gastroenterology/Hepatology, Humboldt University, Medical Faculty Charité, CCM, Schumannstrasse 20-21, D 10117 Berlin, Germany.
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Abstract
Barrett esophagus is a premalignant condition that may progress to adenocarcinoma. The risk of developing cancer has been estimated to be approximately 1 in 250 patient-years of observation; however, there appear to be subsets of patients at much higher risk. Risk stratification has previously been determined by histological identification of dysplasia. Several new biomarkers are being tested to help clinicians better determine the risk of cancer development. Although none of these biomarkers has been proven in a prospective study to predict the onset of cancer, they have been correlated with cancer development. Most of these are factors that have been associated with cancer development in other organs. These include assessment of cell proliferation, expression of cyclooxygenase 2, growth factors and oncogenes, secretory factors, cell cycle proteins, adhesion molecules, and aneuploidy and other genetic abnormalities. In addition to their role as potential cancer biomarkers, these factors have increasingly been reported as surrogate markers to monitor the effectiveness of conservative treatments for Barrett esophagus. In this article, biological markers are reviewed for their relevance in Barrett esophagus. Although most biological markers need to be evaluated further and, for most, prospective follow-up studies are lacking, at present abnormal ploidy status, P16 and P53 gene abnormalities, or allelic losses are the most extensively documented.
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Weston AP, Banerjee SK, Sharma P, Tran TM, Richards R, Cherian R. p53 protein overexpression in low grade dysplasia (LGD) in Barrett's esophagus: immunohistochemical marker predictive of progression. Am J Gastroenterol 2001; 96:1355-62. [PMID: 11374668 DOI: 10.1111/j.1572-0241.2001.03851.x] [Citation(s) in RCA: 157] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The presence of low grade dysplasia (LGD) within Barrett's esophagus (BE) has a multitude of ramifications. Identification of markers that could risk stratify LGD would be of great clinical benefit. We aimed to prospectively evaluate the prognosis of the immunohistochemical overexpression of p53 protein in BE colocalized to LGD. METHODS Consecutive BE patients in whom LGD was found had a repeat esophagogastroduodenoscopy within 8-12 wk per an ongoing prospective study. At each esophagogastroduodenoscopy, a therapeutic scope was used in conjunction with the Seattle Biopsy Protocol. Patients were observed until development of multifocal high grade dysplasia (mHGD), presence of an HGD dysplasia-associated lesion or mass (DALM) lesion, or frank adenocarcinoma. p53 protein overexpression was determined by computerized immunoquantitation using image analysis software on step serial-sectioned specimens of BE segment(s) harboring LGD. Kaplan-Meier survival curves were made on the ability of p53 staining colocalized to areas of LGD to predict progression to mHGD, HGD DALM, or cancer during prospective follow-up. RESULTS Forty-eight BE patients with LGD were observed for a mean of 41.2+/-22.5 months. During this period, five of 48 patients progressed to mHGD with a focus in which intramucosal cancer could not be excluded (one), mHGD/DALM with one or more foci in which intramucosal cancer could not be excluded (two), cancer (one), or mHGD (one). Twelve had persistent LGD and 31 had regressed to no dysplasia. p53 staining was positive and colocalized to areas of LGD in 4/31 of patients that regressed, 3/12 that persisted, and 3/5 that progressed. Kaplan-Meier curves differed significantly between p53 positive and negative patients for outcome defined as progression of LGD. CONCLUSIONS p53 colocalization with LGD at index LGD diagnosis is a risk factor for progression of LGD. This can potentially be used to risk stratify BE LGD patients in terms of surveillance intervals or enrollment into secondary prevention studies.
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Affiliation(s)
- A P Weston
- Cancer Research Unit, Research Division, Veterans Administration Medical Center, Kansas City, Missouri 64128-2226, USA
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44
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Abstract
Barrett esophagus is a premalignant condition that may progress to adenocarcinoma. The risk of developing cancer has been estimated to be approximately 1 in 250 patient-years of observation; however, there appear to be subsets of patients at much higher risk. Risk stratification has previously been determined by histological identification of dysplasia. Several new biomarkers are being tested to help clinicians better determine the risk of cancer development. Although none of these biomarkers has been proven in a prospective study to predict the onset of cancer, they have been correlated with cancer development. Most of these are factors that have been associated with cancer development in other organs. These include assessment of cell proliferation, expression of cyclooxygenase 2, growth factors and oncogenes, secretory factors, cell cycle proteins, adhesion molecules, and aneuploidy and other genetic abnormalities. In addition to their role as potential cancer biomarkers, these factors have increasingly been reported as surrogate markers to monitor the effectiveness of conservative treatments for Barrett esophagus. In this article, biological markers are reviewed for their relevance in Barrett esophagus. Although most biological markers need to be evaluated further and, for most, prospective follow-up studies are lacking, at present abnormal ploidy status, P16 and P53 gene abnormalities, or allelic losses are the most extensively documented.
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Affiliation(s)
- K K Krishnadath
- Division of Gastroenterology and Hepatology and Internal Medicine, Mayo Clinic, Rochester, Minn 55905, USA
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45
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Abstract
OBJECTIVE To review the current knowledge on the genetic alterations involved in the development and progression of Barrett's esophagus-associated neoplastic lesions. SUMMARY BACKGROUND DATA Barrett's esophagus (BE) is a premalignant condition in which the normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. BE predisposes patients to the development of esophageal adenocarcinoma. Endoscopic surveillance can detect esophageal adenocarcinomas when they are early and curable, but most of the adenocarcinomas are detected at an advanced stage. Despite advances in multimodal therapy, the prognosis for invasive esophageal adenocarcinoma is poor. A better understanding of the molecular evolution of the Barrett's metaplasia to dysplasia to adenocarcinoma sequence may allow improved diagnosis, therapy, and prognosis. METHODS The authors reviewed data from the published literature to address what is known about the molecular changes thought to be important in the pathogenesis of BE-associated neoplastic lesions. RESULTS The progression of Barrett's metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure. Some of the molecular alterations already showed promise as markers for early cancer detection or prognostication. Among these, alterations in the p53 and p16 genes and cell cycle abnormalities or aneuploidy appear to be the most important and well-characterized molecular changes. However, the exact sequence of events is not known, and probably multiple molecular pathways interact and are involved in the progression of BE to adenocarcinoma. CONCLUSIONS Further research into the molecular biology of BE-associated adenocarcinoma will enhance our understanding of the genetic events critical for the initiation and progression of Barrett's adenocarcinoma, leading to more effective surveillance and treatment.
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Affiliation(s)
- B P Wijnhoven
- Department of Surgery, University Hospital Rotterdam, Erasmus University Rotterdam, Rotterdam, The Netherlands
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Peters FT, Ganesh S, Kuipers EJ, Sluiter WJ, Karrenbeld A, de Jager-Krikken A, Klinkenberg-Knol EC, Lamers CB, Kleibeuker JH. Effect of elimination of acid reflux on epithelial cell proliferative activity of Barrett esophagus. Scand J Gastroenterol 2000; 35:1238-44. [PMID: 11199360 DOI: 10.1080/003655200453557] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Barrett esophagus (BE) is a premalignant condition resulting from chronic acid gastroesophageal reflux and is associated with increased epithelial cell proliferation. Elimination of acid reflux might decrease cancer risk by affecting cell proliferation in BE. The effect of elimination of acid reflux on epithelial cell proliferation in BE was studied. METHODS Forty-five patients with long segment Barrett esophagus were treated in a randomized 2-year follow-up study with either omeprazole 40 mg b.i.d. (OME) or ranitidine 150 mg b.i.d. (RAN) and were compared for the effect on epithelial cell proliferation. Biopsies were taken 3 cm above the GE junction and just below the Z-line, at 0, 3, 9, and 24 months. Epithelial cell proliferation was determined by in vitro labeling with 5-bromo-2-deoxyuridine and immunohistochemistry. Labeling indices (LI) were established for luminal and crypt epithelium separately. Ambulatory 24-h esophageal pH-metry was performed at 0 and 3 months. Comparisons were made for the timeframes 0-3 months, 3-24 months, and 0-24 months. RESULTS OME reduced mean acid reflux to 0.1 %/24 h, RAN to 9.4%. In the distal and the proximal biopsies, change in LI after 3 months was n.s. at either level for both treatments. In the distal biopsies (OME 22, RAN 23 patients) luminal LI increased significantly for RAN from 3 to 24 months (+12.64% month, mean area under the curve (AUC)), while that for OME remained stable, RAN versus OME P < 0.05. Crypt LI increased in both groups, only in RAN significantly so (+30.75% month), RAN versus OME n.s. In the proximal biopsies luminal LI at 24 months (OME 20, RAN 21 patients) had increased slightly but not significantly in RAN (+8.86% month), RAN versus OME n.s., whereas in the crypts LI in OME it had increased significantly (+28.80% month), OME versus RAN n.s. CONCLUSION Elimination of acid reflux resulted in a stabilization of luminal cell proliferative activity of Barrett epithelium in the distal esophagus, whereas this activity increased during continued acid reflux. Whether this finding has any implication for the cancer risk in Barrett esophagus remains to be seen.
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Affiliation(s)
- F T Peters
- Dept of Gastroenterology and Hepatology, University Hospital, Groningen, The Netherlands
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Krishnadath KK, Wang KK, Taniguchi K, Sebo TJ, Buttar NS, Anderson MA, Lutzke LS, Liu W. Persistent genetic abnormalities in Barrett's esophagus after photodynamic therapy. Gastroenterology 2000; 119:624-30. [PMID: 10982754 DOI: 10.1053/gast.2000.18012] [Citation(s) in RCA: 108] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Photodynamic therapy (PDT) is a technique for nonsurgical treatment of patients with dysplasia in Barrett's esophagus. The primary endpoint for PDT has been resolution of dysplasia. We studied the effect of PDT at the genetic level. METHODS Archival material from 3 patients who had initial improvement in dysplasia after PDT but occurrence of high-grade dysplasia during follow-up was used. Biopsy specimens were analyzed for increased proliferation, aneuploidy, p53 protein overexpression, p53 mutations, and p16 promoter hypermethylation. RESULTS Patients developed high-grade dysplasia 16, 28, and 37 months after PDT. In all cases, one or more genetic markers were positive after PDT treatment, whereas histology was downstaged consistently after therapy. Increasing genetic abnormalities were noted by the end of follow-up. CONCLUSIONS Genetic abnormalities may persist after PDT despite phenotypical improvement of dysplasia. These patients may progress to high-grade dysplasia or develop adenocarcinoma. Histologic improvement in dysplasia is an inadequate endpoint for PDT in patients with Barrett's esophagus.
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Affiliation(s)
- K K Krishnadath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA
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Abstract
Barrett's metaplasia is associated with an increased risk for adenocarcinoma. Adenocarcinoma develops through a multistep process characterized by defects in genes and morphological abnormalities. The early morphological changes of the process are called 'dysplasia'. Dysplasia is defined as an unequivocal neoplastic (premalignant) transformation confined within the basement membrane. For most Western pathologists malignancy is defined as invasion and characterized by a breach through the basement membrane. Japanese pathologists rely on cytological atypia and complex branching of crypts. Cytological and architectural abnormalities allow identification of dysplasia on routinely stained sections. A distinction is made between low- and high-grade dysplasia. The differential diagnosis between low-grade dysplasia and reactive changes can be difficult. Therefore a second opinion is strongly recommended, not only for high-grade dysplasia but also for low-grade. Immunohistochemistry for p53 and flow cytometry for detection of aneuploidy can support the diagnosis. Identification of dysplasia and malignancy depends on the number of biopsy samples examined. The minimum number of biopsies required has not yet been determined and depends partly on the length of the metaplastic segment. It has been proposed to sample with four quadrant biopsies at 20-mm intervals. New endoscopic techniques can increase the diagnostic yield. Endoscopically visible lesions increase the risk of finding malignancy. The time sequence for the progression of dysplasia is not known but progression from low- to high-grade and cancer has been shown to occur over a period of years although it may not be inevitable.
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Affiliation(s)
- K Geboes
- Department of Pathology, University Hospital KUL, Leuven, Belgium
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49
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Affiliation(s)
- G N Tytgat
- Academic Medical Center, Department of Gastroenterology, Amsterdam, The Netherlands
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van Sandick JW, Baak JP, van Lanschot JJ, Polkowski W, ten Kate FJ, Obertop H, Offerhaus GJ. Computerized quantitative pathology for the grading of dysplasia in surveillance biopsies of Barrett's oesophagus. J Pathol 2000. [PMID: 10657016 DOI: 10.1002/(sici)1096-9896(200002)190:2%3c177::aid-path508%3e3.0.co;2-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Decision models for surveillance of Barrett's oesophagus (BO) are governed by the grade of dysplasia on endoscopic biopsy, but subjective grading is prone to observer variation. Computerized morphometry and immunoquantitation can objectively discriminate between different grades of dysplasia in oesophagectomy specimens with BO. The present study evaluated the feasibility of such quantitative analysis on surveillance biopsies of BO. Biopsy criteria for quantitative analysis were defined, excluding 101 (21%) of 472 archival BO surveillance biopsies. In the remaining haematoxylin and eosin (H&E) sections, 105 areas that distinctively displayed no dysplasia (ND), low-grade dysplasia (LGD) or high-grade dysplasia (HGD) were demarcated. Agreement on double-blind examination by two experienced pathologists was reached in 66 areas (63%; kappa: 0.44). For 21 ND/LGD and 11 LGD/HGD disagreement areas, corresponding sections for p53 and Ki67 immunohistochemistry were available. The best combination of two discriminating features was stratification index (SI) with p53 area % for ND versus LGD (89% correct classification), and SI with Ki67 area % for LGD versus HGD (91% correct classification). Fifteen of the 21 ND/LGD disagreement areas could be classified uniquely as either ND or LGD by SI and p53, and eight of the 11 LGD/HGD disagreement areas as either LGD or HGD by SI and Ki67. Correlation coefficients for repeated measurements of SI, Ki67, and p53 by the same observer were 0.94, 0.92, and 0.86, and by two independent observers 0.86, 0.93, and 0.92, respectively. Computerized quantitative pathology on BO surveillance biopsies is feasible provided that well-defined biopsy criteria are used. Using a combination of features associated with cellular differentiation and proliferation, such as SI, p53, and Ki67, quantitative pathological analysis assists in reducing diagnostic variability in the grading of dysplasia during surveillance of BO.
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Affiliation(s)
- J W van Sandick
- Department of Surgery, Academic Medical Center, University of Amsterdam, The Netherlands. j.w.vansandick@amc..uva.nl
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