p53 mutation has been shown to be associated with chromosomal instability (CI) in many human dysplastic and neoplastic lesions. However, the precise role of p53 in the pathogenesis of prostate carcinoma (Pca) is unknown. Topographic analysis of p53 alteration using immunohistochemistry (IHC) was performed on 35 archived prostatectomy specimens containing Pca foci; high-grade prostrate intraepithelial neoplasia (HPIN) foci intermingled with cancer (HPINI) and situated away (HPINA). Specimens from 2 patients were topographically genotyped using laser capture microdissection, PCR amplification, and direct sequencing of p53 exons 5-9. CI was evaluated in the same tissue foci by interphase in situ hybridization (IFISH) using centromere probes for chromosomes 7, 8, and Y. p53 immunoreactivity was found in 20%, 17%, 0, and 0 in Pca, HPINI, HPINA, and benign epithelium, respectively. p53 molecular analysis in the specimens examined confirmed the IHC findings. IFISH revealed numerical chromosomal alterations in keeping with CI in 71% and 25% of p53؉ and p53؊ Pca, respectively (P ‫؍‬ .1), 67% and 0 of p53؉ and p53؊ HPIN, respectively (P < .02), and in 27% and 0 of HPINI and HPINA, respectively. We concluded that p53 mutation is an early change in at least a subset of Pca. HPINI foci tend to have higher overall p53 immunoreactivity and CI than HPINA. The presence of p53 mutation in HPIN was associated with the presence of CI as determined by IFISH. Our study also provided additional evidence in support of the concept that HPIN might be the earliest precursor of cancer. Furthermore, our studies identify genomic similarities in HPINI and Pca, implying that carcinoma may arise from progression of certain HPIN foci that most likely harbor p53 mutation and/or more CI. KEY WORDS: Chromosomal instability, Immunohistochemistry, In situ hybridization, p53 sequencing, Prostate carcinoma, Prostate intraepithelial neoplasia.

Context.—High-grade prostate intraepithelial neoplasia (HPIN) is the most likely precursor of prostate cancer. The condition of many patients with a diagnosis of HPIN in prostate needle core biopsy could, if left untreated, progress to invasive cancer. Currently there is no available clinical, immunohistochemical, or morphologic criteria that are predictive of this progression. Objective.—To determine whether chromosomal instability in these precursor lesions could increase their predictive value for cancer detection. Design.—Dual-color interphase fluorescence in situ hybridization analysis was performed on archived prostate needle core biopsies from 54 patients with initial diagnosis of isolated HPIN and follow-up of 3 years or more. We used commercially available centromere probes for chromosomes 4, 7, 8, and 10. We had interpretable results in 44 patients as follows: (1) group A: 24 HPIN patients with persistent HPIN and/or benign lesions in the follow-up biopsies, and (2) group B: 20 HPIN patients with progression to prostate carcinoma. Results.—Twenty-five percent of the patients in group B displayed numeric chromosomal aberrations. Only 8.3% of the patients from group A had chromosomal abnormalities (P = .1). The observed overall chromosomal changes in HPIN were higher than those in normal or hyperplastic epithelium, with a statistically significant difference (P &lt; .05). All aberrations were detected in the form of chromosomal gain. Overall, the commonest aberration was gain of chromosome 8, followed by gains of chromosomes 7 and 10. Conclusion.—These results indicated that although no single numeric chromosomal abnormality could be assigned as a predictor of HPIN progression to carcinoma, the overall level of numeric chromosomal abnormalities shows a trend of elevation in HPIN patients whose condition subsequently progressed to carcinoma.