Use of DNA flow cytometry in the diagnosis, risk stratification, and management of gastric epithelial dysplasia

Abstract

The natural history of gastric epithelial dysplasia and the consequential surveillance strategies are not well defined in the West. To date, the diagnosis relies on morphology, and no reliable adjunct methods, either immunohistochemical or molecular, have reproducibly been able to confirm the diagnosis and/or risk stratify gastric epithelial dysplasia. Yet, such a tool would be useful in confirming the diagnosis, and developing objective and rational surveillance guidelines. DNA flow cytometry was performed using formalin-fixed paraffin-embedded gastric tissue from 23 cases of high-grade dysplasia and 38 cases of low-grade dysplasia. Twenty-four benign background mucosal samples from the same cohort (20 biopsies and 4 surgical resections from 16 low- and 8 high-grade dysplasia cases) were utilized as controls. The presence of DNA content abnormality (aneuploidy or elevated 4N fraction) correlated with increasing levels of dysplasia, as DNA content abnormality was detected in 18 (78%) of 23 high-grade dysplasia, 5 (13%) of 38 low-grade dysplasia, and none of 24 non-dysplastic samples. 1 and 4-year detection rates of high-grade dysplasia or gastric adenocarcinoma in low-grade dysplasia patients with DNA content abnormality were 80% (p = 0.003) and 100% (p = 0.005), respectively, whereas patients with low-grade dysplasia but with normal DNA content had 1, 4, and 12-year detection rates of 23, 32, and 54%, respectively. The univariate hazard ratio (HR) for subsequent detection of high-grade dysplasia or gastric adenocarcinoma in low-grade dysplasia patients with DNA content abnormality was 6.9 (p = 0.001). Older patients (HR = 1.1, p = 0.005) and those with familial adenomatous polyposis (HR = 9.7, p = 0.029) also had an increased risk for developing high-grade dysplasia or gastric adenocarcinoma in the univariate analysis, but only DNA content abnormality demonstrated a significantly elevated HR of 5.9 in the multivariate analysis (p = 0.005). While older age showed a minimally elevated risk (HR = 1.1, p = 0.013), no other potential risk factors, including male gender, ethnicity, polypoid endoscopic appearance, Helicobacter pylori infection, and intestinal metaplasia, were significantly associated with subsequent detection of high-grade dysplasia or gastric adenocarcinoma in the multivariate analysis. Among the 18 high-grade dysplasia cases with DNA content abnormality, 13 cases (72%) developed gastric adenocarcinoma within a mean follow-up time of 9 months, conferring a HR of 2.5; however, this did not reach statistical significance. In conclusion, the presence of DNA content abnormality can identify a subset of low-grade dysplasia patients who are at increased risk for subsequent detection of high-grade dysplasia or gastric adenocarcinoma. It can also provide confirmatory evidence to a morphologic impression or suspicion of high-grade dysplasia. The majority of gastric epithelial dysplasia patients with DNA content abnormality developed high-grade dysplasia or gastric adenocarcinoma within a year and thus may benefit from more thorough and rigorous endoscopic surveillance.