Value of cyclin A immunohistochemistry for cancer risk stratification in Barrett esophagus surveillance: A multicenter case-control study

Abstract

The value of endoscopic Barrett esophagus (BE) surveillance based on histological diagnosis of low-grade dysplasia (LGD) remains debated given the lack of adequate risk stratification. The aim of this study was to evaluate the predictive value of cyclin A expression and to combine these results with our previously reported immunohistochemical p53, AMACR, and SOX2 data, to identify a panel of biomarkers predicting neoplastic progression in BE.We conducted a case-control study within a prospective cohort of 720 BE patients. BE patients who progressed to high-grade dysplasia (HGD, n = 37) or esophageal adenocarcinoma (EAC, n = 13), defined as neoplastic progression, were classified as cases and patients without neoplastic progression were classified as controls (n = 575). Cyclin A expression was determined by immunohistochemistry in all 625 patients; these results were combined with the histological diagnosis and our previous p53, AMACR, and SOX2 data in loglinear regression models. Differences in discriminatory ability were quantified as changes in area under the ROC curve (AUC) for predicting neoplastic progression.Cyclin A surface positivity significantly increased throughout the metaplasia-dysplasia-carcinoma sequences and was seen in 10% (107/1050) of biopsy series without dysplasia, 33% (109/335) in LGD, and 69% (34/50) in HGD/EAC. Positive cyclin A expression was associated with an increased risk of neoplastic progression (adjusted relative risk (RR) 2.4; 95% CI: 1.7-3.4). Increases in AUC were substantial for P53 (+0.05), smaller for SOX2 (+0.014), minor for cyclin A (+0.003), and none for AMARC (0.00).Cyclin A immunopositivity was associated with an increased progression risk in BE patients. However, compared to p53 and SOX2, the incremental value of cyclin A was limited. The use of biomarkers has the potential to significantly improve risk stratification in BE.

Figure 1

Receiver operating characteristic (ROC) comparing different biomarker models with the basic pathological diagnosis of grade of dysplasia. Area under the curve (AUC) for predicting neoplastic progression was calculated (pathological diagnosis grade of dysplasia AUC of 0.62 (95% CI: 0.58–0.68), pathological diagnosis + p53 and SOX2 immunohistochemistry AUC of 0.72 (95% CI: 0.67–0.77) and pathological diagnosis + p53, SOX2, and cyclin A immunohistochemistry AUC of 0.72 (95% CI: 0.67–0.77)).