The Study On The Origin And Diagnosis Of Ovarian Serous Carcinoma

Ovarian cancer is the most lethal cause of cancer death among women. Its carcinogenesis and cell origin has been a matter of debate for years and the incessant ovulation theory is most widely accepted. Induced damages by constant ovulation and subsequent repair of ovarian epithelium cause its transformation to cancers. However, many studies have supplied evidences that ovarian epithelial cancer might not arise from ovarian epithelium. Morphologic, molecular and epidemiologic differences exist between ovarian epithelium and ovarian epithelial cancers such as the expression of HOX, PAX8and PAX2, which reveals that the pathologic properties of ovarian epithelial cancers show striking similarities to Mullerian epithelia rather than ovarian epithelia. In addition, the precancerous lesions of ovarian cancers have not been found in the ovaries, which is abnormal in view of carcinogenesis progression. Recent studies have suggested that fallopian tube is the likely source of most pelvic high-grade serous cancers and TIC might be the true precancerous lesions for ovarian serous cancers. It was also found in our previous study that OEI and low-grade ovarian epithelial cancer might arise from fallopian tube, not the ovarian epithelia. The assumption that the malignant tubal epithelial cells with p53mutation shed on the surface of ovary or pelvic cavity to develop into cancers, has already gotten some evidences. Recently, there are mainly morphological and immunohistochemical evidences. However, the further genetic evidences are needed to support the fallopian origin of ovarian serous carcinoama. To find the homology in the aspect of gene expression profile between ovarian serous carcinoma and fallopian tube, and select candidate markers, will be beneficial for the carcinognenesis study. Ovarian carcinomas are commonly associated with rapid progression, poor prognosis, and the majority of cancer deaths in women. Ovarian cancers frequently result in metastases, which are commonly encountered in peritoneal fluids or pelvic washings. There is one diagnostic problem that ovarian serous cancer can overlap morphologically with malignant mesothelioma. The limitation of cytology is the problem that reactive mesothelial cells in effusion specimens can morphologically mimic ovarian serous carcinoma, which can make the diagnosis difficult. Wilms tumor suppressor gene1(WT1) was regarded as a useful marker in the diagnosis of ovarian serous carcinomas, which has been challenged by a diagnostic pitfall in effusion cytology, because mesothelial cells can demonstrate immunoreactivity for WT1. PAX genes encode a family of nine well-characterized paired box transcription factors (PAX1-PAX9), which play important roles in embryogenesis and disease. Recently, PAX8was recommended as an additional marker for tumors of Mullerian origin and showed complete negative expression in mesothelial cells. Moreover, it is known that the mutation of the p53tumor-suppressor gene and overexpression of p53protein is a frequent event in human oncogenesis. Many studies have reported that high expression of p53protein occurs in almost80%of high-grade ovarian cancers. It is therefore reasonable to develop a PAX8and p53expression-based molecular assay for detection in pelvic washings. The overall purpose of this study is to evaluate the detection of PAX8and p53expression with immunohistochemistry (IHC) in pelvic washings, especially in cases with suspicious cytology, which will be beneficial for the staging and treatment strategy.Based on this, the content included two parts:Part I The study on gene expression profiling of ovarian serous carcinomaBackground and ObjectiveOvarian cancer is the most lethal cause of cancer death among women. Its carcinogenesis and cell origin has been a matter of debate for years. Recent studies have suggested that fallopian tube is the likely source of most pelvic high-grade serous cancers. Until now, there are mainly morphological and evidences. To find the homology in the aspect of gene expression profile between ovarian serous carcinoma and fallopian tube, and select candidate markers, will be beneficial for the carcinognenesis study.Materials and Methods1. Three types of fresh tissues were collected, including ovarian serous carcinoma, fallopian tube epithelium, and ovarian surface epithelium2. RNA was extracted for gene microarray.3. The gene expression profiles of ovarian serous carcinoma, fallopian tube epithelium, and ovarian surface epithelium were compared for homology analysis, and processed with SAM and GO analysis.4. Candidated genes were selected and tested with Real time PCR.Results1. Cluster Analysis showed the similar genome of ovarian serous carcinoma to that of fallopian tube epithelium.2.6differntial expression genes were selected including S100P, RASIP1, TACSTD2, PTGES, DKK3and LDOC1.3. Real time PCR showed the differential expression of6abovementioned candidate genes between ovarian serous carcinoma and fallopian epithelium cells.Conclusion1. Ovarian serous carcinoma showed the similar genome to fallopian tube epithelium, suggesting the possibility of homology.2. The candidate gene might relate with carcinogenesis of ovarian serous carcinoma, which needs further study. Part II The cytochemistry study on pelvic washings of ovarian cancerBackground and ObjectiveOvarian cancers frequently result in metastases, which are commonly encountered in peritoneal fluids or pelvic washings. There is one diagnostic problem that ovarian serous cancer can overlap morphologically with malignant mesothelioma. The limitation of cytology is the problem that reactive mesothelial cells in effusion specimens can morphologically mimic ovarian serous carcinoma, which can make the diagnosis difficult. The aim of this study is to evaluate the detection of paired box gene8(PAX8) and p53with immunohistochemistry in pelvic washing cell block sections.Materials and MethodsA total of92cases were used in this study, which were assigned to three groups according to the cytopathology files. The first group with positive cytology including endometrial and ovarian carcinomas comprised32cases. The second group with suspicious cytology for endometrial or ovarian carcinomas consisted of29cases. The third group with negative cytology (regarded as mesothelial cells) included31cases. The pelvic washing cell blocks underwent immunohistochemistry to detect PAX8and p53(as the primary Ab) expression.ResultsImmunoreactivity for PAX8was found in75%(24/32) of the cases in the group with positive cytology, in6.9%(2/29) of the cases with suspicious cytology, and in none of the31cases with negative cytology (sensitivity:75%; specificity:100%; p<0.05). p53expression was detected in37.5%(12/32) of the cases in the first group, in3.4%(1/29) of the cases in the second group, and in none of the cases in the third group (sensitivity:37.5%; specificity:100%; p<0.05). Moreover, the combined expression of PAX8and p53showed the same result as the single expression of p53in the three groups.ConclusionThe detection of PAX8and p53is beneficial in recognizing metastatic carcinomas in pelvic washings, especially in cases with suspicious cytology, which additionally supports the Mullerian origin of these carcinomas.