Hereditary diffuse gastric cancer (HDGC), an autosomal dominant cancer susceptibility syndrome, is largely attributable to germline mutations and deletions in the gene encoding E-cadherin, CDH1. Asymptomatic, mutation-positive individuals often choose prophylactic gastrectomy for cancer risk reduction. Examination of the entire mucosa of prophylactic gastrectomy specimens is essential and shows occult gastric cancers in most cases. We hypothesized that primary screening entire cases stained with periodic acid-Schiff (PAS) instead of hematoxylin and eosin (H&E) could improve diagnostic accuracy and speed of detecting invasive signet-ring adenocarcinoma. Serial sections from 6 prophylactic gastrectomy specimens with molecularly confirmed CDH1 mutations were stained with PAS and H&E, respectively (108 to 164 blocks per case). PAS-stained and H&E-stained slides were randomized for each case and examined microscopically for the presence of invasive signet-ring cells. The time to examine each slide was recorded. Our results showed that significantly fewer lesions were missed (ie, the lesion was initially identified on only 1 section, but present on both sections) on PAS-stained slides (6 missed lesions) than on H&E-stained slides (23 missed lesions); (P<0.05). Furthermore, it took significantly less time to screen a PAS-stained case (3 h 05+/-41 min) than an H&E-stained case (4 h 59+/-1 h 2 min) (P<0.05). Selected lesions were confirmed as epithelial by pan-keratin-positive immunohistochemistry. Thus, doing PAS staining instead of H&E on CDH1 mutation-positive prophylactic gastrectomy specimens may increase the detection rate of adenocarcinoma while reducing screening time.