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As the histogenesis and development of α-fetoprotein–producing gastric cancer (AFPGC) have not yet been elucidated, we analyzed the histologic and immunologic relationship between the histologic type of the mucosal lesion considered to be the primary lesion, and that of its invasive lesion, in 36 cases of AFPGC.We reviewed 23 AFPGCs with mucosal lesions (1 mucosal and 22 submucosal or deeper invasive tumors) among 36 AFPGCs that had been resected endoscopically or surgically between 1970 and 2005. AFPGC was defined as a tumor showing immunohistochemical positivity for either α-fetoprotein (AFP) or glypican-3. Histologic types were divided into hepatoid (HPT), enteroblastic (ENT), yolk sac tumor, and common (COM) adenocarcinoma type. The tumor phenotypes were classified into gastric, gastrointestinal, and intestinal types on the basis of immunohistochemical analysis.Among the histologic types of mucosal lesions, the COM and ENT mixed type was observed in 65.2% of cases (15/23 patients), COM alone in 26.1% (6/23), and ENT alone in 8.7% (2/23) of cases. Among the invasive lesions, 16 cases (72.7%) were HPT. Both AFP and glypican-3 were positive in 60.9% (14/23) of mucosal lesions and in 90.9% (20/22) of invasive lesions. With regard to phenotypic expression, 82.6% (19/23) of mucosal lesions were the intestinal type, compared with 95.5% (21/22) of invasive lesions.These findings suggest that many cases of AFPGC develop as COM or ENT in the mucosa, which differentiate into ENT and HPT during the process of tumor invasion and proliferation, acquiring AFP production ability.