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Treatment of rats with low doses of hepatocarcinogens is associated with a number of phenomena, including nuclear enlargement and altered nucleocytoplasmic compartmentation, which potentially reflect initiatory changes. Since a number of investigations have indicated that changes in ploidy may relate to the development of altered foci and/or hepatocellular carcinomas in liver, and since nuclear enlargement may be associated with changes in DNA content, we examined the ploidy of rat hepatocytes following essentially nontoxic low-dose carcinogen treatment. Treatments with thioacetamide, 2-acetylaminofluorene, or dimethylnitrosamine were all associated with a notable shift of nuclei from diploid to tetraploid, in the apparent absence of nuclear replication. These changes were similar in magnitude to that associated with the substantial liver regeneration induced by carbon tetrachloride. If it is argued that cell replication is a necessary prerequisite for the completion of initiation, these data suggest that there may be thresholds for initiation.

We wished to determine whether DNA flow cytometric analysis could detect DNA abnormalities in normal-appearing mucosa of patients with colonic neoplasia. Eighty-five patients were studied either at colonoscopy or at surgical resection. Forty-five had macroscopically normal colonoscopy; 13 had adenomatous polyps, and 27 had colorectal carcinoma. Biopsies were obtained from the cancer and from normal-appearing mucosa 5 cm from the lesion. The patients who had normal colonoscopy had rectal biopsies. The samples were prepared for analysis on a Coulter EPICS C flow cytometer. Cells were analyzed for presence of aneuploidy (%AN), percent in DNA synthetic phase (%S), and percent growth fraction (%GF = %S + %G2M). Aneuploidy was present in 12 of 27 carcinomas (44%), but in none of the samples from polyps or normal-appearing colorectal mucosa adjacent to cancers. The %S from cancers was greater than those from polyps (9.6 +/- 6.3 vs. 5.1 +/- 1.8, p less than 0.005). However, %S from specimens arising from normal-appearing mucosa 5 cm distant from cancer could not be differentiated from the rectal mucosa of macroscopically normal colons (5.9 +/- 2.5 vs. 5.2 +/- 2.7). The %GF of cancer specimens was greater than those from adenomas (26.0 +/- 11.0 vs. 10.8 +/- 3.7, p less than 0.005). However, the %GF of normal-appearing mucosa 5 cm distant from the cancer was similar to the findings from mucosa arising from macroscopically normal colons (10.5 +/- 3.3 vs. 11.0 +/- 3.4). In conclusion, DNA flow cytometric analysis of normal-appearing colonic mucosa from patients with colonic carcinoma does not demonstrate abnormalities of DNA content or cell cycle kinetics, and therefore, cannot predict the presence of colonic neoplasia.

Ten granulosa cell tumors of the ovary were investigated using clinicopathologic and flow cytometric parameters. Three of the patients had recurrent or metastatic lesions 3 to 9 years after resection of the primary ovarian tumor. These three cases demonstrated diploidy in both the primary tumor and metastatic or recurrent lesions. Among the seven cases without recurrence, five had diploid DNA indexes. One case was characterized by a high degree of cytologic atypia and tetraploidy (DNA index, 1.98); this patient died of metastatic breast cancer 4 years after resection of the ovarian tumor. Another case demonstrated a high mitotic rate and exhibited aneuploidy (DNA index, 1.33); this woman was alive and well at 5 years of follow-up. In this study, no correlation was found between the recurrence rate and ploidy but, in view of the small numbers and limited follow-up, we cannot definitively analyze these prognostic factors. It does not appear feasible to predict the clinical course of granulosa cell tumors by DNA flow cytometry. However, it can be concluded that: (1) most granulosa cell tumors have diploid DNA content and (2) DNA ploidy correlates well with histologic factors, such as cellular anaplasia and high mitotic activity, which may have predictive prognostic value for granulosa cell tumors.