Purpose: In view of the changing concept of colorectal carcinogenesis during the last 20 years, a historical review of colorectal carcinogenesis is presented.
Methods: The changing concept of colorectal carcinogenesis was presented in four different periods: 1) carcinogenesis based on surgical materials; 2) carcinogenesis based on polypectomy materials; 3) carcinogenesis based on nonpolypoid neoplasms; 4) carcinogenesis based on molecular biology.
Results: In the first period, large adenomas were thought to play the most important role as precursors to colorectal carcinomas; however, in the second period, smaller and nonpedunculated adenomas were found to have a much higher malignancy potential than previously thought. The discovery of nonpolypoid neoplasms, including flat and depressed adenomas/carcinomas, shed light on the new precursor of colorectal carcinomas that were not recognized in the past. Molecular biology clarified a lack 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.
Conclusions: The concept referred to as the "adenoma-carcinoma sequence" changed because colonoscopic polypectomy specimens were studied, and rather small, nonpedunculated adenomas were found to play an important role as precursors of colorectal carcinomas. The discovery of nonpolypoid neoplasms provides us with new precursors of colorectal carcinomas. The genetic alterations in nonpolypoid neoplasms seem to differ from those in polypoid neoplasms, and genetic alterations in so-called de novo carcinomas need to be clarified.