Large intestinal carcinogenesis. III. Studies in low-incidence (Japanese) patients

Recent studies have demonstrated that at the early stages of carcinogenesis of the large intestine(s) (LI), severely dilated crypt(s) (SDC) appear followed by atypical and/or neoplastic crypt(s) (ANC) and, subsequently, carcinomas. Thus both SDC and ANC appear to be premalignant changes and are probably initiated foci. Since the Japanese in Japan (JIJ) show a much lower rate of large intestinal carcinomas (LIC) compared to people in the Western Hemisphere, a study was designed to answer the question: Is the difference between the rates due to a difference in initiation or promotion? If the difference is due to less initiation, large intestinal epithelium of JIJ should contain fewer initiated foci. For testing this hypothesis, a retrospective histopathologic study was conducted on 100 LI of JIJ resected at the Cancer Institute, Tokyo, Japan, between 1977 and 1978, and mucosae remote from carcinomas were examined for SDC and ANC. In sharp contrast to a 100% incidence of SDC in the cases in the United States, only 1 of 100 LI of patients with LIC at the Cancer Institute demonstrated the presence of SDC. However, ANC was seen in 10 of 100 LI (10%), a figure comparable to that in the United States (7%). The extreme rarity of SDC in JIJ represents lesser initiation of that type. The presence of a comparable number of ANC in JIJ indicates that ANC is the predominant morphologic type of initiated foci in JIJ. This study suggests that not only promotional agents but also different initiating factors may be responsible for the difference in incidence and prevalence of LIC in the two populations. Comparative studies of parallel experimental animal models with the use of high and low doses of azoxymethane support this conclusion.