Absence of premalignant histologic, molecular, or cell biologic alterations in prophylactic oophorectomy specimens fromBRCA1 heterozygotes

Abstract

BACKGROUND The high mortality associated with ovarian carcinoma is largely a reflection of the inability to diagnose the disease at an early stage; the identification of a histologic lesion or molecular marker associated early stages of transformation would represent an important advance in understanding the natural history of this cancer. The existence of individuals with germline mutations in the ovarian and breast carcinoma susceptibility gene BRCA1 represents a unique opportunity to search for such premalignant alterations in ovarian tissues that are at unusually high risk for tumorigenesis. In this study, the authors addressed the hypothesis that pathologically normal ovaries removed from BRCA1 heterozygotes are likely to display premalignant histologic, molecular, and/or cell biologic alterations that may provide insight into early stages of ovarian tumorigenesis. METHODS Ovarian tissues from 18 BRCA1 heterozygotes and from 20 age‐matched controls were examined in a blinded fashion for histologic evidence of surface epithelial pseudostratification, epithelial inclusion cysts, deep cortical invaginations of surface epithelium, increased stromal cell activity, and surface papillomatosis. Immunohistochemical analyses for expression of BRCA1, p53, and ERBB‐2 and quantitation of cell proliferation (Ki‐67 expression) and apoptosis (TUNEL assay), were also performed on all specimens. RESULTS Although histologic alterations were observed, there was no difference in frequency between cases and controls. Analysis of BRCA1 expression revealed ubiquitous nuclear immunoreactivity in the surface epithelial cells of all ovaries. Similarly, no evidence was found of p53 overexpression in any ovarian tissue or of a difference in ERBB‐2 expression between cases and controls. Finally, no differences were observed in epithelial cell proliferation or apoptosis. CONCLUSIONS Clinically, normal ovaries from BRCA1 heterozygotes do not show evidence of premalignant alterations in histology, molecular markers, cell proliferation, or apoptosis, indicating that such changes are likely rare. Cancer 2000;89:383–90. © 2000 American Cancer Society.

A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations

“…22 However, p53 positive CICs were not documented in another study of a similar population. 6 The findings in this study are consistent with the last study; only one p53 positive focus was detected on the ovarian surface and it was not associated with immunohistochemical evidence of DNA damage. No CICs contained positive staining.…”

“…5 Similar changes were not found in the OSE of women with BRCA mutations. 6 Others have described dysplastic changes in the ovarian surface epithelium. 2,7 Other candidate sites of origin, including the peritoneum, have been proposed for cases with minimal ovarian involvement.…”

Origins and molecular pathology of ovarian cancer

“…Several other groups have failed to demonstrate epithelial atypia in the prophylactic oophorectomy specimens from women with a strong family history of ovarian cancer 16 or with known BRCA1 or 2 mutations. 17,18 Two groups of investigators have noted mild atypia of the surface epithelium in uninvolved ovaries contralateral to ovarian carcinomas or borderline tumors; 4,19 the latter group, however, failed to detect atypia in epithelial inclusion glands. Several other investigators were unable to demonstrate a statistically significant increase in atypia in ovaries contralateral to ovarian tumors over control ovaries.…”

“…16 The remainder of the recent studies 4,15,17,18,24 have failed to demonstrate any differences in the frequency of these histologic features between cases and controls. A few such studies have shown an increase in the number of inclusion cysts in prophylactic oophorectomy specimens 15 and in ovaries contralateral to ovarian carcinoma, 25 others have failed to confirm these findings.…”

“…Several small studies have examined the immunohistochemical expression of proliferation and differentiation-related proteins in nonatypical ovarian surface epithelium and SEIG in prophylactic oophorectomy specimens compared to controls. 15,18,24,36,37 Most of these studies failed to document differences in expression of p53, c-erbB2, and Ki67 in surface epithelium or SEIG. Additionally, Piek et al 24 also failed to note differences in expression of p21, p27, cyclin A, cyclin D, and estrogen receptor in surface epithelium or SEIG in prophylactic oophorectomy specimens vs controls.…”