Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: A follow-up study based on 138 cases from a diagnostic variability study

doi:10.1053/hupa.2001.23511

Human Pathology

Volume 32, Issue 4, April 2001, Pages 379-388

https://doi.org/10.1053/hupa.2001.23511 Get rights and content

Abstract

The objective of endoscopic surveillance in Barrett esophagus (BE) is to assess the risk of subsequent development of invasive carcinoma. Criteria for morphologic evaluation of dysplasia, the presumed precursor lesion, have been established, although there are surprisingly few data in the literature correlating biopsy diagnosis of dysplasia with outcome. We collected follow-up information on 138 patients with BE whose initial endoscopic biopsy specimens had been selected for submission in an interobserver variability study performed by 12 pathologists with special interest in gastrointestinal pathology and reviewed blindly twice each by all the participants. Cases were scored as BE with no dysplasia, atypia indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), intramucosal carcinoma, and frankly invasive carcinoma, thus generating 24 scores on each biopsy specimen. Clinical follow-up was obtained and correlated with both the submitting diagnoses and majority diagnoses. Kaplan-Meier statistics were used to compare both the submitting and majority diagnoses with outcome using detection or documentation of invasive carcinoma as the endpoint. Using the submitting diagnoses, no invasive carcinomas were detected in 44 cases diagnosed as BE (median follow-up, 38.5 months). Carcinomas were detected in 4 of 22 (18%) cases submitted as IND (median progression-free survival of 62 months), in 4 of 25 (15%) cases of LGD (median progression-free survival of 60 months), in 20 of 33 cases of HGD (median progression-free survival, 8 months), and all 13 (100%) cases submitted as adenocarcinoma. Grade on initial biopsy correlated significantly with progression to invasive carcinoma (log-rank P =.0001). Majority diagnosis was achieved in 99 of the cases. Using the majority diagnoses, no invasive carcinomas were found in 50 cases of BE (median follow-up, 48 months), and carcinomas were detected in 1 of 7 (14%) IND cases (80% progression-free survival at 2 months), 3 of 15 (20%) LGD (median progression-free survival, 60 months), 9 of 15 (60%) HGD (median progression-free survival, 7 months), and all 12 (100%) carcinoma. Initial grading again correlated significantly with progression to invasive carcinoma (log-rank P =.0001). However, there were 39 cases without a majority diagnosis. Among these, no carcinomas developed in 8 cases with an average score between BE and IND. Carcinomas were detected in 9 of 21 (43%) cases with an average score between IND and LGD, and 7 of 10 (70%) cases with an average score between LGD and HGD. There were ulcers in 8 of 39 cases (20%) of the “no-majority” group and in 13 of 99 (13%) of the majority cases. Of 21 total ulcerated cases, cancer was demonstrated in 15 (71%) of these on follow-up. These data support combining the IND and LGD categories for surveillance purposes. Cases without dysplasia may be followed up conservatively. The data obtained from submitted diagnoses as opposed to those from blind review suggest that knowledge of the clinical findings aids in diagnosis. The data also support the assertion that HGD is strongly associated with invasive carcinoma. Rebiopsy of ulcerated areas should be considered because they may harbor malignancy. Histologic grading of dysplasia using established criteria is a powerful prognosticator in BE. HUM PATHOL 32:379-388. Copyright © 2001 by W.B. Saunders Company

Section snippets

Materials and methods

From a series of 250 cases that were used to comprehensively test established criteria for grading dysplasia in BE, we obtained follow-up information on 138 patients.²⁸ An attempt was made to obtain follow-up information on all 250; adequate information was available on 138. Briefly, each of 10 participants from 10 institutions contributed slides, all of which were reviewed by 12 observers (2 reviewers did not contribute cases). Each contributor was instructed to supply slides from the initial

Results

Among the 138 patients with clinical follow-up, there were 100 men (72%) and 38 women ranging in age from 9 to 85 years (mean and median, 61 and 63 years, respectively). There were 2 pediatric cases among the lesions with follow-up, 1 from a 9-year-old and 1 from a 17-year-old. Race was known in 85 patients; of these, 83 were white, 1 was black, and 1 was Hispanic.

The submitting diagnoses included 44 cases with no dysplasia, 22 cases indefinite for dysplasia (IND), 26 LGD, 33 HGD, and 13

Discussion

It has been estimated that between 4% and 15% of patients with gastroesophageal reflux disease who undergo endoscopy have BE.³⁶ Given their risk for developing esophageal adenocarcinoma, a risk that has been estimated to be up to 125 times greater than that of the general population,24, 25, 26 most patients are followed up by regular endoscopy and biopsy once a diagnosis of BE is established. The morphologic recognition of dysplasia is the most widely used marker of increased cancer risk, and

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Barrett's Esophagus and Associated Dysplasia
2024, Gastroenterology Clinics of North America
Abnormal TP53 Predicts Risk of Progression in Patients With Barrett's Esophagus Regardless of a Diagnosis of Dysplasia
2022, Gastroenterology
Barrett’s esophagus (BE) is the precursor to esophageal adenocarcinoma. A major challenge is identifying the small group with BE who will progress to advanced disease from the many who will not. Assessment of p53 status has promise as a predictive biomarker, but analytic limitations and lack of validation have precluded its use. The aim of this study was to develop a robust criteria for grading abnormal immunohistochemical (IHC) expression of p53 and to test its utility as a biomarker for progression in BE.
Criteria for abnormal IHC of p53 were developed in BE biopsies and validated with sequencing to assess TP53 mutations. The utility of p53 IHC as a biomarker for progression of BE was tested retrospectively in 561 patients with BE with or without known progression. The findings were prospectively validated in a clinical practice setting in 1487 patients with BE.
Abnormal p53 IHC highly correlated with TP53 mutation status (90.6% agreement) and was strongly associated with neoplastic progression in the retrospective cohorts, regardless of histologic diagnosis (P < .001). In the retrospective cohort, abnormal p53 was associated with a hazard ratio of 5.03 (95% confidence interval, 3.88–6.5) and a hazard ratio of 5.27 (95% confidence interval, 3.93–7.07) for patients with exclusively nondysplastic disease before progression. In the prospective validation cohort, p53 IHC predicted progression among nondysplastic BE, indefinite for dysplasia, and low-grade dysplasia (P < .001).
p53 IHC identifies patients with BE at higher risk of progression, including in patients without evidence of dysplasia. p53 IHC is inexpensive, easily integrated into routine practice, and should be considered in biopsies from all BE patients without high-grade dysplasia or cancer.
Barrett's esophagus indefinite for dysplasia carries a definite risk of neoplasia
2021, Gastrointestinal Endoscopy
Forkhead box F1 induces columnar phenotype and epithelial-to-mesenchymal transition in esophageal squamous cells to initiate Barrett’s like metaplasia
2021, Laboratory Investigation
Multiple genome-wide association studies (GWAS) have linked Forkhead Box F1 (FOXF1) to Barrett's esophagus (BE). Understanding whether FOXF1 is involved in initiation of Barrett's metaplasia could allow FOXF1 to be used for risk stratification and for therapy. Two-dimensional cell cultures and three-dimensional organoid cultures and well-annotated human biopsies were used to determine the role of FOXF1 in BE pathogenesis. Multiple established esophageal squamous and BE cell lines were tested in gain- and loss-of-function studies. Initiation of a BE-like metaplastic change was evaluated by measuring characteristic cytokeratins and global gene expression profiling and by culturing organoids. Epithelial–mesenchymal transition (EMT) was evaluated by immunostaining for E-cadherin, vimentin and Snail, and by cell motility assay. Columnar esophageal epithelium of BE patients exhibited higher expression of FOXF1 compared to normal squamous esophageal epithelium of GERD patients (P < 0.001). Acidic bile salts induced nuclear FOXF1 in esophageal squamous cells. FOXF1 overexpression in normal esophageal squamous cells: (a) increased columnar cytokeratins and decreased squamous cytokeratins, (b) converted squamous organoids to glandular organoids, and (c) switched global gene profiles to resemble that of human BE epithelium (P = 2.1685e − 06 for upregulated genes and P = 8.3378e − 09 for downregulated genes). FOXF1 inhibition in BE cell lines led to loss of BE differentiation markers, CK7, and mucin 2. Also, FOXF1 induced EMT and promoted cell motility in normal esophageal squamous epithelial cells. FOXF1-induced genes mapped to pathways such as Cancer, Cellular Assembly and Organization, DNA Replication, Recombination, and Repair. In conclusion, FOXF1 promotes a BE-like columnar phenotype and cell motility in esophageal squamous epithelial cells, which may have a critical role in BE development. FOXF1 should be studied further as a biomarker for BE and as a target for BE treatment.
Massively Parallel Sequencing of Esophageal Brushings Enables an Aneuploidy-Based Classification of Patients With Barrett's Esophagus
2021, Gastroenterology
Aneuploidy has been proposed as a tool to assess progression in patients with Barrett’s esophagus (BE), but has heretofore required multiple biopsies. We assessed whether a single esophageal brushing that widely sampled the esophagus could be combined with massively parallel sequencing to characterize aneuploidy and identify patients with disease progression to dysplasia or cancer.
Esophageal brushings were obtained from patients without BE, with non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (EAC). To assess aneuploidy, we used RealSeqS, a technique that uses a single primer pair to interrogate ∼350,000 genome-spanning regions and identify specific chromosome arm alterations. A classifier to distinguish NDBE from EAC was trained on results from 79 patients. An independent validation cohort of 268 subjects was used to test the classifier at distinguishing patients at successive phases of BE progression.
Aneuploidy progression was associated with gains of 1q, 12p, and 20q and losses on 9p and 17p. The entire chromosome 8q was often gained in NDBE, whereas focal gain of 8q24 was identified only when there was dysplasia. Among validation subjects, a classifier incorporating these features with a global measure of aneuploidy scored positive in 96% of EAC, 68% of HGD, but only 7% of NDBE.
RealSeqS analysis of esophageal brushings provides a practical and sensitive method to determine aneuploidy in BE patients. It identifies specific chromosome changes that occur early in NDBE and others that occur late and mark progression to dysplasia. The clinical implications of this approach can now be tested in prospective trials.
Risk of progression in Barrett's esophagus indefinite for dysplasia: a systematic review and meta-analysis
2020, Gastrointestinal Endoscopy
Risk of progression in Barrett's esophagus (BE) with low-grade dysplasia (LGD) and high-grade dysplasia (HGD) has been established. However, the natural history of BE with indefinite dysplasia (BE-IND) remains unclear. We performed a systematic review and meta-analysis to estimate the pooled risk of progression to HGD and/or esophageal adenocarcinoma (EAC) in BE-IND.
We performed a systematic search of multiple databases to June 2018 to identify studies reporting the incidence of HGD, EAC, or HGD/EAC as an outcome in patients with BE-IND undergoing endoscopic surveillance. The pooled incidence rate of HGD and/or EAC and EAC alone was estimated.
We identified 8 studies reporting the incidence of HGD and/or EAC and 5 studies reporting the incidence of EAC in BE-IND. The pooled incidence of HGD and/or EAC (89 cases in 1441 patients over 5306.2 person-years) was 1.5 per 100 person-years (95% confidence interval [CI], 1.0-2.0). The pooled incidence of EAC (40 cases in 1266 patients over 4520.2 person-years) was 0.6 per 100 person-years (95% CI, 0.1-1.1). Substantial heterogeneity was noted in the analyses. On subgroup analysis, the incidence of EAC was higher in studies from Europe compared with North America (0.9% vs 0.1%, P = .01). The pooled incidence of LGD was 11.4 per 100 person-years (95% CI, 0.06-0.2).
The estimated incidence of HGD and/or EAC and EAC alone in BE-IND is similar to the previously reported progression risk in BE-LGD. Based on these risk estimates, patients with BE-IND should be placed on active endoscopic surveillance.

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Original ContributionsDysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: A follow-up study based on 138 cases from a diagnostic variability study

Abstract

Section snippets

Materials and methods

Results

Discussion

Increased expression of the cyclin D1 gene in Barrett's esophagus

Cancer Epidemiol Biomarkers Prev

Molecular analysis of the TP53 gene in Barrett's adenocarcinoma

Hum Mutat

Allelic loss of 9p21 and mutation of the CDKN2/p16 gene develop as early lesions during neoplastic progression in Barrett's esophagus

Oncogene

Evolution of neoplastic cell lineages in Barrett oesophagus

Nat Genet

17p allelic deletions and p53 protein overexpression in Barrett's adenocarcinoma

Cancer Res

Clonal ordering of 17p and 5q allelic losses in Barrett dysplasia and adenocarcinoma

Proc Natl Acad Sci U S A

p53 gene mutations in Barrett's epithelium and esophageal cancer

Cancer Res

Clinical implications of p53 gene mutation in the progression of Barrett's epithelium to invasive esophageal cancer

Am J Surg

p53 protein expression in Barrett's adenocarcinoma: A frequent event with no prognostic significance

Histopathology

Expression of c-erbB-2 oncogene product in Barrett's adenocarcinoma: Pathological and prognostic correlations

J Clin Pathol

Barrett's mucosa. From metaplasia... to cancer

Gastroenterol Clin Biol

17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus

Proc Natl Acad Sci U S A

Clonal expansion and loss of heterozygosity at chromosomes 9p and 17p in premalignant esophageal (Barrett's) tissue

J Natl Cancer Inst

Expansion of the Ki-67 proliferative compartment correlates with degree of dysplasia in Barrett's esophagus

Cancer

Cellular kinetics in Barrett's epithelium carcinogenic sequence: Roles of apoptosis, bcl-2 protein, and cellular proliferation

Mod Pathol

Barrett esophagus with dysplasia. Flow cytometric DNA analysis of routine, paraffin-embedded mucosal biopsies

Am J Clin Pathol

p53-mutant clones and field effects in Barrett's esophagus

Cancer Res

Barrett's esophagus. Correlation between flow cytometry and histology in detection of patients at risk for adenocarcinoma

Gastroenterology

Progression to cancer in Barrett's esophagus is associated with genomic instability

Lab Invest

Original Contributions
Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: A follow-up study based on 138 cases from a diagnostic variability study