Flow-cytometric and histological progression to malignancy in Barrett's esophagus: Prospective endoscopic surveillance of a cohort

doi:10.1016/0016-5085(92)90758-Q

Gastroenterology

Volume 102, Issue 4, Part 1, April 1992, Pages 1212-1219

https://doi.org/10.1016/0016-5085(92)90758-Q Get rights and content

Abstract

To determine whether or not flow-cytometric evidence of aneuploidy and increased G2/tetraploid fractions predispose to neoplastic progression in Barrett's esophagus, 62 patients with Barrett's esophagus were evaluated prospectively for a mean interval of 34 months. Nine of 13 patients who showed aneuploid or increased G2/tetraploid populations in their initial flow-cytometric analysis developed high-grade dysplasia or adenocarcinoma during follow-up, none of the 49 patients without these abnormalities progressed to high-grade dysplasia or cancer (P < 0.0001). Neoplastic progression was characterized by progressive flow-cytometric and histological abnormalities. Patients who progressed to high-grade dysplasia and carcinoma frequently developed multiple aneuploid populations of cells that were detectable flow-cytometrically. Similarly, patients appeared to progress through a phenotypic sequence that could be recognized histologically by the successive appearance of Barrett's metaplasia negative for dysplasia, abnormalities in the indefinite/low-grade dysplasia range, high-grade dysplasia, and eventually adenocarcinoma. These and prior results suggest that neoplastic progression in Barrett's esophagus occurs in a subset of patients who have an acquired genomic instability that generates abnormal clones of cells, some of which have aneuploid or increased G2/tetraploid DNA contents. With continued genomic instability, multiple aneuploid subclones may evolve, one of which may ultimately acquire the ability to invade and become an early carcinoma. The combination of histology and flow cytometry can be used to identify a subset of patients with Barrett's esophagus who merit more frequent endoscopie surveillance for the early detection of high-grade dysplasia or carcinoma.

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Cited by (454)

Significance of Crypt Atypia in Barrett's Esophagus: A Clinical, Molecular, and Outcome Study
2024, Clinical Gastroenterology and Hepatology
The aim of this study was to characterize baseline morphologic features of crypts in nondysplastic Barrett’s esophagus and correlate them with DNA content abnormalities and risk of progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC).
The morphologic features of nondysplastic crypts in baseline biopsy specimens from 212 BE patients (2956 biopsy specimens) were graded histologically using a 4-point scale (crypt atypia levels, 0–3). DNA content abnormalities were detected using flow cytometry.
In patients who had dysplasia in their baseline biopsy specimens, dysplasia was associated significantly with increasing grades of crypt atypia in the background nondysplastic Barrett’s esophagus (P < .001). In a subset of patients without dysplasia at baseline (N = 149), a higher grade of crypt atypia was associated with longer Barrett’s esophagus segment length (5.5 vs 3.3 cm; P = .0095), and a higher percentage of cells with 4N DNA content (3.67 ± 1.27 vs 2.93 ± 1.22; P = .018). Crypt atypia was associated with the development of any neoplasia (low-grade dysplasia and HGD/EAC). Although no significant association was noted between the grade of crypt atypia and increased 4N, aneuploidy, or progression to HGD/EAC, only patients with grade 2 or 3 crypt atypia showed increased 4N, aneuploidy, or progression to HGD/EAC.
Patients with Barrett’s esophagus likely develop dysplasia via a progressive increase in the level of crypt atypia before the onset of dysplasia, and these changes may reflect some alteration of DNA content.
Barrett's Esophagus and Associated Dysplasia
2024, Gastroenterology Clinics of North America
DNA flow cytometry for detection of genomic instability as a cancer precursor in the gastrointestinal tract
2024, Methods in Cell Biology
One of the earliest applications of flow cytometry was the measurement of DNA content in cells. This method is based on the ability to stain DNA in a stoichiometric manner (i.e., the amount of stain is directly proportional to the amount of DNA within the cell). For more than 40 years, a number of studies have consistently demonstrated the utility of DNA flow cytometry as a potential diagnostic and/or prognostic tool in patients with most epithelial tumors, including pre-invasive lesions (such as dysplasia) in the gastrointestinal tract. However, its availability as a clinical test has been limited to few medical centers due to the requirement for fresh tissue in earlier studies and perceived technical demands. However, more recent studies have successfully utilized formalin-fixed paraffin-embedded (FFPE) tissue to generate high-quality DNA content histograms, demonstrating the feasibility of this methodology. This review summarizes step-by-step methods on how to perform DNA flow cytometry using FFPE tissue and analyze DNA content histograms based on the published consensus guidelines in order to assist in the diagnosis and/or risk stratification of many different epithelial tumors, with particular emphasis on dysplasia associated with Barrett's esophagus and inflammatory bowel disease.
Surveillance in Barrett's Esophagus: Challenges, Progress, and Possibilities
2023, Gastroenterology
Endoscopic surveillance of Barrett’s esophagus, aiming to detect prevalent dysplasia and adenocarcinoma, followed by effective endoscopic treatment, is an integral part of the esophageal adenocarcinoma prevention paradigm. However, several limitations, such as the subtle appearance of dysplasia, sampling error (inherent in current surveillance protocols), and noncompliance with surveillance recommendations, lead to missed dysplasia and neoplasia, reducing the effectiveness of surveillance as currently practiced. Careful endoscopic assessment with high-resolution white-light endoscopy, dye-based or electronic chromoendoscopy, and comprehensive sampling of the BE mucosa, remains the cornerstone of endoscopic surveillance. Emerging innovations in this area span the gamut of more efficient sampling methods, advanced imaging tools, artificial intelligence, and molecular marker–powered approaches as adjuncts, to identify prevalent and predict incident dysplasia or adenocarcinoma. Development and implementation of validated quality indicators will allow additional advancement of this critical field. These approaches will hopefully enable efficient and effective cancer prevention and treatment.
Genomic instability signals offer diagnostic possibility in early cancer detection
2021, Trends in Genetics
Emerging evidence from the large numbers of cancer genomes analyzed in recent years indicates that chromosomal instability (CI), a well-established hallmark of cancer cells, is detectable in precancerous lesions. In this opinion, we discuss the association of this instability with tumor progression and cancer risk. We highlight the opportunity that early genomic instability presents for the diagnosis of esophageal adenocarcinoma (EAC) and its precancerous lesion, Barrett’s esophagus (BE). With a growing body of evidence suggesting that only a small pool of cancer-related genes are involved in early tumor development, we argue that general genomic instability may hold greater diagnostic potential for early cancer detection as opposed to the identification of individual mutational biomarkers.
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.

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: Supported by National Institutes of Health grant PO1 DK32971 and American Cancer Society Grant PDT 316A.

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Flow-cytometric and histological progression to malignancy in Barrett's esophagus: Prospective endoscopic surveillance of a cohort

Abstract

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Hum Pathol

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Barrett's esophagus

N Engl J Med

Pathogenesis of columnar cell-lined (Barrett's) esophagus

Adenocarcinoma in Barrett's epithelium

Barrett's esophagus. Comparison of benign and malignant cases

Ann Surg

Barrett's esophagus: A review

Am J Med

Rising incidence of adenocarcinoma of the esophagus and gastic cardia

JAMA

Incidence of cancer of the esophagus in the US by histologic type

Cancer

Endoscopic surveillance for patients with Barrett esophagus, does the cancer risk justify the practice?

Ann Intern Med

High grade dysplasia in Barrett's esophagus: a report of experience with 43 patients (abstr)

Gastroenterology