Proliferation in the Normal Tubal Epithelium Is a Hallmark of the Follicular Phase Not BRCA1 Mutation Status
Sophia HL George, Anca Milea, Patricia A Shaw. University Health Network, University of Toronto, Toronto, Canada
Background: BRCA1/2 mutation carriers are at increased risk of ovarian/tubal high grade serous carcinoma. We recently demonstrated that the fallopian tube epithelium (FTE) of BRCA1 mutation carriers have altered signaling pathways compared to controls. We sought to determine whether these differences give a proliferative advantage to the epithelial cells in this high-risk patient population and whether the differences are also due to intraepithelial immune infiltrating cells.
Design: Immunohistochemistry for Ki67 and p53 were performed on histologically normal tubal epithelium (ampulla, TMA n=76, BRCA1/2 versus non-BRCA1/2) and histologically normal fimbria (whole sections, n=18) with known ovarian cycle status at the time of surgery. To determine whether fimbria with cancer precursor lesions have an overall increased proliferative index, we analyzed precursor lesions (n=44) from women with and without BRCA1/2 mutations who underwent risk-reducing salpingo-oophorectomy. We determined the contribution of CD3+, CD8+, CD20+ and CD68+ cells within the tube epithelium in the TMA and fimbria and in 15 cases of Serous Tubal Intraepithelial Carcinoma (STIC). Analysis of the Ki67 stain was performed by 3 independent observers (blinded) using digital slides, where 0 < 1%, 1 = 1%, 2 = 2-4%, 3 = 5-15% and 4 > 4% positive FTE cells.
Results: There was no significant difference (p=0.5711, p=0.7577) in Ki67 positivity between BRCA1/2 (n=42) vs nonBRCA (n=34). A significant increase in CD68+ cells, intercalated in the FTE, was observed in the luteal (n=32) compared to the follicular phase (n=44); (p=0.0027). No significant differences were observed by ovarian cycle or mutational status for CD3+ CD8+ or CD20+ cells. As demonstrated by gene expression profiling (previously published), the FTE-BRCA cases have a higher immune signature particularly in the luteal phase (GO terms: MHC class II p=0.0055, MHC protein complex p=0.021 and chemokine receptor binding p=0.014) than FTE-nonBRCA in either phase of the menstrual cycle.
Conclusions: BRCA1/2 mutation carriers exhibited no significant increase in proliferation of the tube epithelial cells in either the ampulla or fimbriated ends. There was a significant increase in proliferation as measured by Ki67 staining in follicular phase epithelium. A subset of immune cells within the epithelium are increased during the luteal phase. We also demonstrated a marked increase in lymphocytes invading cancer precursor lesions, suggesting lymphocytes may have a role early in tumor formation.
Category: Gynecologic & Obstetrics
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 186, Tuesday Morning