[Colorectal carcinogenesis: a historical review].

In view of the changing concepts of colorectal carcinogenesis during the past 20 years, a historical review of colorectal carcinogenesis is presented. The concept of colorectal carcinogenesis is presented in four different periods: 1) carcinogenesis based on surgical materials; 2) carcinogenesis based on polypectomy materials; 3) carcinogenesis based on nonpolypoid neomaterials; and 4) carcinogenesis based on molecular biology. In the first period, large adenomas were thought to play the most important role as precursors of colorectal carcinomas. The concept was referred to as the "adenoma-carcinoma sequence." However, in the second period, smaller and nonpedunculated adenomas were found to have a much higher malignancy potential than previously thought. The natural history of colorectal neoplasms revealed morphological changes from polypoid or sessile lesions to ulcerating carcinomas during a varying time span. The discovery of nonpolypoid neoplasms, including flat and depressed adenomas/carcinomas, shed light on new precursors of colorectal carcinomas that had not been recognized in the past. They tend to have a much higher malignant potential than polypoid neoplasms. Molecular biology clarified the absence of K-ras mutation in nonpolypoid, particularly depressed, neoplasms, suggesting the presence of a novel pathway of colorectal carcinogenesis different from that in polypoid neoplasms. The concept referred to as the "adenoma-carcinoma sequence" changed because colonoscopic polypectomy specimens were studied, and rather small nonpeduculated adenomas were found to play an important role as precursors of colorectal carcinomas. The discovery of nonpolyoid neoplasms provided us with new precursors of colorectal carcinomas. The genetic alterations in nonpolypoid neoplasms seem to differ from those in polypoid neoplasms. Carcinogenesis of so-called de novo carcinoma should be explained on a molecular basis. When sequential multistep genetic alterations take place very rapidly the carcinoma seems to arise de novo. Until the gene responsible for real de novo carcinoma is detected, the term de novo-type carcinoma should be used.