Candidate serous cancer precursors in fallopian tube epithelium of BRCA1/2 mutation carriers.

Occult invasive and intraepithelial carcinomas have been identified in the tubal fimbria of BRCA mutation carriers undergoing prophylactic surgery, and recently described lesions overexpressing p53 in the distal tubes of mutation carriers, and non-carriers, have been proposed as histological precursors of high-grade serous carcinoma. The aim of this study was to confirm these findings in a larger, independent case set, to further characterize the cancer precursor lesions, and to determine their frequency in BRCA mutation-positive (n=176) and control groups (n=64). For the purposes of this study, we excluded cases without documentation of a germline mutation of BRCA1/2, and without histological examination of the entire tube, and cases with a diagnosis of invasive carcinoma. Controls included salpingectomies from women undergoing surgery for reasons other than ovarian malignancy. Diagnostic categories were assigned based on combined histological review and immunostaining results. Histological abnormalities were identified in 23% of the BRCA group and in 25% of the control group, and included localized p53 overexpression in 20% of the BRCA group and 25% of the control group. Tubal intramucosal carcinoma was identified in 8% of the BRCA cases and in 3% of the control group. Four cases of intraepithelial carcinoma (21%) did not overexpress p53. There was no significant difference in the median age, frequency of histological abnormalities, p53 signatures, or tubal intraepithelial carcinoma between the BRCA mutation-positive and control groups. This large, blinded review of tubes from BRCA mutation carriers confirms previous reports of putative cancer precursors in distal tubal mucosa, and that p53 signatures occur with similar frequency in women at low and high genetic risk of tubal/ovarian carcinoma. Tubal intraepithelial carcinoma, which, like invasive serous cancer, usually but not always overexpresses p53 protein, is more frequent in BRCA mutation carriers.