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The management of hereditary diffuse-type gastric cancer revolves around surveillance biopsies and the timing of prophylactic gastrectomy. In the absence of a validated surveillance biopsy protocol, we modeled bioptic diagnostic yield on the basis of the topographic distribution of cancer foci in a series of 10 gastrectomies in CDH1-mutation carriers. Complete histologic examination was performed in all cases, and 1817 slides were evaluated for the presence of in situ, intramucosal, or submucosal diffuse-type carcinoma. Detailed maps determined the density of cancer foci. On the basis of the number of sampled glands per biopsy in routine surveillance preoperative endoscopy, we estimated the theoretical number of biopsies necessary for a 90% rate of detection of neoplastic foci, and we evaluated this number, taking into account the regional distribution of these foci. A total of 96 m of gastric mucosa with ≈ 1,193,453 gastric glands yielded 302 cancer foci [in situ (n=89), intramucosal (n=209), and submucosal (n=4)] spanning the width of a total of 1820 glands (8 to 1205 per case; average 182 ± 115). On the basis of the number of glands per stomach and the average number of glands sampled during surveillance biopsy (28.7 ± 1.7; range, 0 to 79; n=112), the theoretical number of biopsies necessary to capture at least 1 cancer focus was estimated to be 1768 (range, 50 to 5832) to assure a 90% detection rate. Mapping of cancer foci showed the highest density in the anterior proximal fundus (37%) and cardia/proximal fundus (27%). Our results argue for the incorporation of cancer focus distribution into any biopsy protocol, although detection is likely to remain extremely low, and they call into question the validity of endoscopic surveillance.