Context.-The identification of a precursor lesion is important to understanding the histopathologic and genetic alterations in carcinogenesis. There are a plethora of terminologies that describe precursor lesions of the pancreatobiliary tract, ampulla of Vater, and gallbladder. The current terminologies for precursor lesions may make it difficult to understand the tumor biology. Here, we propose the concept of tumoral and flat intraepithelial neoplasia to improve our understanding of precursor lesions of many epithelial organs, including the pancreatobiliary tract, ampulla of Vater, and gallbladder.Objective.-To understand the dichotomous pattern of tumoral and flat intraepithelial neoplasia in carcinogenesis of pancreatobiliary tract, ampulla of Vater, and gallbladder.Data Sources.-Review of relevant literatures indexed in PubMed.Conclusions.-Tumoral intraepithelial neoplasia presents as an intraluminal or intraductal, mass-forming, polypoid lesion or a macroscopic, visible, cystic lesion without intracystic papillae. Microscopically, tumoral intraepithelial neoplasia shows various proportions of papillary and tubular architecture, often with a mixed pattern, such as papillary, tubular, and papillary-tubular. The malignant potential depends on the degree of dysplasia and the cell phenotype of the epithelium. Flat intraepithelial neoplasia presents as a flat or superficial, spreading, mucosal lesion that is frequently accompanied by an invasive carcinoma. Tumoral and flat intraepithelial neoplasias are not homogeneous entities and may exhibit histopathologic spectrum changes and different genetic profiles. Although intraepithelial neoplasia showed a dichotomous pattern in the tumoral versus flat types, they can coexist. Tumoral and flat intraepithelial neoplasia can be interpreted as part of a spectrum of changes in the carcinogenesis pathway of each organ. A denoma is the prototype precursor lesion in carcinogenesis. The adenoma-carcinoma sequence is one of the well-characterized models of the carcinogenesis pathway. Through the adenoma-carcinoma sequence, many histopathologic and genetic alterations have been characterized in colorectal carcinogenesis.1,2 Another prototype precursor lesion is uterine cervix dysplasia, which also progresses to invasive squamous cell carcinoma of the uterine cervix through multistep carcinogenesis. Both colon adenoma and uterine cervix dysplasia correspond to intraepithelial neoplasia (IN), which can lead to invasive carcinoma. Most colorectal adenomas present as a polypoid lesion, whereas uterine cervix dysplasia presents as a nonpolypoid, flat, mucosal lesion. We think colon adenoma and uterine cervix dysplasia represent a mass-forming tumoral IN and a nonmass-forming, flat IN, respectively. In general, tumoral IN corresponds to a macroscopic or mass-forming lesion, and flat IN presents as invisible or microscopic lesions. Flat adenomas have been reported in the colorectum, which is much closer to a flat IN, and papillary squamous cell carcinoma of the uterine cervix, which is...