Piek J M, van Diest P J, Zweemer R P, Jansen J W, Poort-Keesom R J, Menko F H, Gille J J, Jongsma A P, Pals G, Kenemans P, Verheijen R H
Department of Obstetrics and Gynaecology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
J Pathol. 2001 Nov;195(4):451-6. doi: 10.1002/path.1000.
The aim of this study was to investigate the occurrence of (pre)neoplastic lesions in overtly normal Fallopian tubes from women predisposed to developing ovarian carcinoma. The presence of (pre)neoplastic lesions was scored in histological specimens from 12 women with a genetically determined predisposition for ovarian cancer, of whom seven tested positive for a germline BRCA1 mutation. A control group included 13 women. Immunohistochemistry was used to determine the expression of p21, p27, p53, cyclin A, cyclin D1, bcl-2, Ki67, HER-2/neu, and the oestrogen and progesterone receptors. Loss of heterozygosity (LOH) analysis on the BRCA1 locus was also assessed on dysplastic tissue by PCR studies. Of the 12 women with a predisposition for ovarian cancer, six showed dysplasia, including one case of severe dysplasia. Five harboured hyperplastic lesions and in one woman no histological aberrations were found in the Fallopian tube. No hyperplastic, dysplastic or neoplastic lesions were detected in the Fallopian tubes of control subjects. In the cases studied, morphologically normal tubal epithelium contained a higher proportion of Ki67-expressing cells (p=0.005) and lower fractions of cells expressing p21 (p<0.0001) and p27 (p=0.006) than in the control group. Even higher fractions of proliferating cells were found in dysplastic areas (p=0.07) and accumulation of p53 was observed in the severely dysplastic lesion. Expression patterns of other proteins studied, including the hormone receptors, were similar in cases and controls. One subject, a germline BRCA1 mutation carrier, showed loss of the wild-type BRCA1 allele in the severely dysplastic lesion. In conclusion, the Fallopian tubes of women predisposed to developing ovarian cancer frequently harbour dysplastic changes, accompanied by changes in cell-cycle and apoptosis-related proteins, indicating an increased risk of developing tubal cancer.
本研究旨在调查易患卵巢癌的女性明显正常的输卵管中（癌）前病变的发生情况。对12名具有遗传性卵巢癌易感性的女性的组织学标本进行（癌）前病变评分，其中7名检测到种系BRCA1突变呈阳性。对照组包括13名女性。采用免疫组织化学法检测p21、p27、p53、细胞周期蛋白A、细胞周期蛋白D1、bcl-2、Ki67、HER-2/neu以及雌激素和孕激素受体的表达。还通过PCR研究对发育异常组织进行BRCA1基因座杂合性缺失（LOH）分析。在12名有卵巢癌易感性的女性中，6名出现发育异常，包括1例重度发育异常。5名有增生性病变，1名女性的输卵管未发现组织学异常。对照组的输卵管未检测到增生性、发育异常或肿瘤性病变。在所研究的病例中，形态学上正常的输卵管上皮中表达Ki67的细胞比例较高（p=0.005），而表达p21（p<0.0001）和p27（p=0.006）的细胞比例低于对照组。在发育异常区域发现更高比例的增殖细胞（p=0.07），在重度发育异常病变中观察到p53的积累。所研究的其他蛋白质的表达模式，包括激素受体，在病例组和对照组中相似。一名种系BRCA1突变携带者在重度发育异常病变中显示野生型BRCA1等位基因缺失。总之，易患卵巢癌的女性的输卵管经常出现发育异常变化，并伴有细胞周期和凋亡相关蛋白的变化，提示患输卵管癌的风险增加。
