The test evaluates multiple epithelial and stromal processes in Barrett’s biopsies to produce an individualized risk score for progression to high grade dysplasia (HGD) or esophageal adenocarcinoma (EAC). The test employs multiplexed fluorescence labeling of 9 tissue system biomarkers, including epithelial biomarkers and biomarkers of immune cell subsets and stromal processes and also morphology, in anatomic pathology specimens. The labeled slides are scanned by whole slide digital imaging and analyzed by image analysis software to objectively quantify biomarkers in the context of tissue morphology. This is coupled to a multivariable classifier to integrate the biomarker and morphology data into a risk score that is correlated with risk of malignant progression within 5 years in Barrett’s esophagus patients. The risk score will provide the physician and patient with a clear indication of the likelihood that the patient will progress to esophageal cancer.