Prophylactic oophorectomy: a morphologic and immunohistochemical study.
ABSTRACT The tumorigenesis of ovarian carcinoma is poorly understood. The authors studied morphologic features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries, normal ovaries, and papillary serous ovarian carcinomas to identify possible preneoplastic changes in ovarian surface epithelium.
Morphologic features and immunohistochemical expression patterns of CA-125, Ki-67, p53, E-cadherin, and Bcl-2 were evaluated in 21 normal ovaries, 31 ovaries that were removed prophylactically for increased carcinoma risk, and 7 ovarian papillary serous carcinomas. Representative slides from formalin-fixed, paraffin-embedded tissue blocks were submitted to immunohistochemical staining and were evaluated independently by three gynecologic pathologists. For statistical analyses, Fisher exact tests, multivariate analyses, Spearman rank correlation coefficients, Wald statistics, Kruskal-Wallis tests, and Mann-Whitney tests were used. Immunohistochemical staining results were correlated with morphologic findings.
The authors found progressive increases in reactivity with the lowest expression in normal ovarian epithelium, stronger expression in epithelium from prophylactically removed ovaries, and the highest expression in carcinomas for Ki-67 and p53. A similar trend was observed for CA-125. Positivity for Ki-67 and p53 was seen predominantly in the epithelium of inclusion cysts and deep invaginations, including those areas that had been identified as hyperplastic or dysplastic on routine hematoxylin and eosin-stained sections.
The current results suggest biologic/molecular evidence for the existence of preneoplastic changes in ovarian surface epithelium and support the previously proposed concept of ovarian dysplasia. Subtle morphologic alterations of the ovarian epithelium may be biologically significant.
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ABSTRACT: In the last two decades there have been significant advances in our understanding of female genital tract tumours. The discovery of BRCA1 and BRCA2 genes in ovarian cancer and the mismatch repair genes in endometrial carcinoma has revolutionized our approach to the diagnosis and screening of women for ovarian and uterine cancers. This review discusses the pathogenesis of these two hereditary syndromes in depth and explains how the molecular genetics is tailoring the manner in which these diseases are diagnosed and potentially treated. Other, less common hereditary conditions associated with gynaecological tract manifestations, such as Cowden syndrome, Peutz-Jeghers syndrome, Gorlin syndrome and hereditary leiomyomatosis and renal cell carcinoma, are also summarized briefly.Histopathology 01/2013; 62(1):2-30. · 2.86 Impact Factor
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ABSTRACT: PURPOSE: Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and pre-invasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC) and tubo-ovarian dysplasia (TOD). 51 TOD from prophylactic salpingo-oophorectomies with BRCA 1 or 2 mutation, 12 STICs, 53 tubo-ovarian high grade serous carcinoma and 36 non-cancerous controls were laser-capture microdissected from formalin-fixed paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time polymerase chain reaction based on the Cawthon's method). TOD and STICs were defined by morphological scores and immunohistochemical expressions of p53, Ki67 and γH2AX. RESULTS: TOD showed marked telomere shortening compared to non-cancerous controls (p< 10-7). STICs had even shorter telomeres than TOD (p= 0.0008). Ovarian carcinoma had shorter telomeres than controls, but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in case of BRCA1 mutation than in case of BRCA2 mutation (p = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (p < 10-7). In dysplastic epithelium, we found subtle genomic alterations, in contrast to more important genomic imbalances in STICs. The total number of genetic alterations was the highest in ovarian cancers. CONCLUSIONS: These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and non invasive dysplasia are likely an important step in early serous ovarian neoplasia.Clinical Cancer Research 04/2013; · 7.84 Impact Factor
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ABSTRACT: Epithelial ovarian cancer is the most lethal gynecological malignancy among US women. The etiology of this disease, although poorly understood, may involve the ovarian surface epithelium or the epithelium of the fallopian tube fimbriae as the progenitor cell. Disruptions in the transforming growth factor beta (TGFβ) pathway and p53 are frequently found in chemotherapy-resistant serous ovarian tumors. Transgenic mice expressing a dominant negative form of Smad2 (Smad2DN), a downstream transcription factor of the TGFβ signaling pathway, targeted to tissues of the reproductive tract were created on a FVB background. These mice developed epithelium-lined inclusion cysts, a potential precursor lesion to ovarian cancer, which morphologically resembled oviductal epithelium but exhibited protein expression more closely resembling the ovarian surface epithelium. An additional genetic "hit" of p53 deletion was predicted to result in ovarian tumors. Tissue specific deletion of p53 in the ovaries and oviducts alone was attempted through intrabursal or intraoviductal injection of Cre-recombinase expressing adenovirus (AdCreGFP) into p53 (flox/flox) mice. Ovarian bursal cysts were detected in some mice 6 months after intrabursal injection. No pathological abnormalities were detected in mice with intraoviductal injections, which may be related to decreased infectivity of the oviductal epithelium with adenovirus as compared to the ovarian surface epithelium. Bitransgenic mice, expressing both the Smad2DN transgene and p53 (flox/flox), were then exposed to AdCreGFP in the bursa and oviductal lumen. These mice did not develop any additional phenotypes. Exposure to AdCreGFP is not an effective methodology for conditional deletion of floxed genes in oviductal epithelium and tissue specific promoters should be employed in future mouse models of the disease. In addition, a novel phenotype was observed in mice with high expression of the Smad2DN transgene as validated through qPCR analysis, characterized by teratoma-like lesions implicating Smad signaling in teratoma development.PLoS ONE 01/2013; 8(5):e65067. · 3.73 Impact Factor