A Hypothesis of the Origin of Human Breast Cancer from the Terminal Ductal Lobular Unit

Abstract

The data reported and reviewed herein supports the hypothesis that most human mammary carcinomas, including the common scirrhous (infiltrating duct) type, arise in the terminal ductal lobular unit. The evidence is based on a study of the total pathology of 290 whole human breasts utilizing a three-dimensional subgross sampling technique with histological correlation. One hundred and eighty-three of the breasts were from random autopsies, and 107 were from patients who had mammary carcinoma. A total of over 16,000 lesions were observed in the 290 breasts. Almost all lesions observed, including epithelial cysts, apocrine metaplasia, sclerosing adenosis, fibroadenomas, atypical lobules (AL), atypical terminal ductal hyperplasia, papillomas of terminal ducts, ductal carcinoma-in-situ, and lobular carcinoma-in-situ are localized to the terminal ductal lobular unit (TDLU). Exceptions to this include: intraductal papillomas and rare instances of hyperplasia of the epithelium of ducts larger than terminal ducts. Lesions of all kinds are generally much more frequent in cancer-containing breasts, or in breasts contralateral to cancer, than in random-autopsy breasts. One very common lesion of the terminal ductal lobular unit, named “atypical lobule, type A”, or ALA, is of particular importance as the only lesion of the many observed than can be graded and arranged into an arbitrary series of increasing atypia, linking normal lobular structure to carcinoma-in-situ of the ductal type (DCIS). We conclude that most human mammary epithelial lesions, including those of mammary dysplasia (fibrocystic disease), and presumptively precancerous atypical epithelial proliferations, arise in the terminal ductal lobular units .