| Two broad clinicopathologic subtypes of endometrial cancer have been recognized since 1983.The prototype of Typeâ…¡cancer is the endometrial serous carcinoma(ESC),which is also called uterine papillary serous carcinoma(UPSC),and clear cell carcinoma(CCC).Typeâ…¡endometrial cancer frequently arise in a background of atrophic or resting endometrium, which is different from Typeâ… cancer.Serous endometrial intraepithelial carcinoma(EIC) was previously considered as "precancer" of ESC.However, patients with EIC are commonly associated with extrauterine serous carcinoma and EIC does not behave like a truly intraepithelial carcinoma.It is currently unknown what are the exact mechanisms of EIC with extrauterine disease.Morphologically,serous EIC shows indisputably malignant glandular cells within the endometrium,which is indifferent from the malignant cells in ESC.Based on previously described the process of EIC development, EIC arises directly from atrophic or resting endometrium.This was called as a de novo process.It is apparent that something is missing between the completely benign endometrium and obviously malignant endometrial glands. Therefore,our group recently described a new entity called endometrial glandular dysplasia(EmGD),which bridges benign resting endometrium and serous EIC.Based on our findings,we conclude that EmGD may represent the earliest morphologically identifiable intraepithelial precursor lesion in the process of ESC development.The objectives of this study were to further search for the genetic evidence supporting the precancer nature of EmGD for ESC and to study the relationship between serous EIC and its frequently associated extrauterine serous carcinoma and to explore the possible molecular mechanisms of this phenomenon. Partâ… Detecting the p53 alteration by sequence analysis and IHC staining in EmGD,serous EIC and ESC lesionsObjective To investigate the development of ESC and search for the genetic evidence of EmGD as a precancer of ESC by comparing the p53 gene alteration among the lesions of EmGD and ESC or serous EIC within each uterus.Method Tissue sections containing areas of invasive ESC,serous EIC, EmGD,as well as benign RE were selected for LCM,DNA extraction,PCR and p53 gene mutation analysis,p53 immunohistochemical stainings were performed on at least one representative section from each case in the study group and the RE section in benign control group.Result 1) Overall p53 mutations detected in the studied cases:12(80.0%) cases from the study group showed at least one p53 mutation in each of the disease category.No p53 gene mutations were found in RE samples.2) EmGD contained frequent p53 gene mutations,and the mutation rate is up to 43.2%.3) Load of p53 mutations increased from lesions of EmGD to serous EIC and/or ESC,and the difference of p53 mutation rate between serous EIC and ESC reached the level of statistical significance(p= 0.0375,p = 0.0001). 4) The finding that at least one identical p53 gene mutation was found among lesions of EmGD and ESC or serous EIC within each uterus in 6(55%) study group cases indicates that at least some of ESC/serous EIC are derived from lesions of EmGD.5) 14(93.3%) neoplastic cases show positive p53 immunohistochemical staining.The concordance rate in neoplastic uteri between immunohistochemical and sequence-proven analysis was 85.2%(23 of 27),which was significantly correlated(p = 0.0002).Conclusions The findings that the mutation rate of EmGD is up to 43.2%,the load of p53 mutations increased from lesions of EmGD to serous EIC and/or ESC,and the difference reached the level of statistical significance and a high concordant p53 mutations occurs among the lesions of EmGD, serous EIC,and/or ESC strongly supports that EmGD represents the precancer of ESC or serous EIC.p53 gene mutation may represent one of the earliest genetic alterations in the process of endometrial serous carcinogenesis.Correct identification of EmGD will provide us an opportunity of early diagnosis and a potentially effective therapeutic modality to control ESC.Partâ…¡Exploring the molecular mechanisms of EIC with extrauterine disease by p53 sequence analysis and clonality assayObjective To investigate whether the extrauterine serous carcinoma frequently associated with serous EIC represents a true transtubal metastasis from serous EIC or a simultaneous "field effect".Method Tissue sections containing areas serous EIC,benign RE,and extrauterine serous carcinoma were selected for LCM,DNA extraction,PCR, p53 gene mutation analysis as well as clonality assay of HUMARA gene.p53 immunohistochemical stainings were performed on representative serous EIC and extrauterine serous carcinoma section.Result The majority of DNA specimens from 12(57%) cases were applicable to be used for the clonality assay of HUMARA gene and the vast majority of DNA specimens were applicable to sequence analysis.At least one serous EIC focus showed identical molecular changes in 9(42.9%) cases.No identical molecular changes were detected between serous EIC and extrauterine serous carcinoma in 7 cases(33.3%).For 5 cases(23.8%),at least one serous EIC focus show identical molecular changes with some foci of the extrauterine serous carcinoma,however,not all the extrauterine diseases foci showed identical molecular changes.Conclusions Extrauterine serous carcinoma frequently associated with EIC may have multiple sources:1) At least for some cases,the extrauterine disease derive from serous EIC cells.2) For some cases,the extrauterine serous carcinoma is caused by "field effect".3) For some cases,the extrauterine serous carcinoma or carcinomatosis derived from both of the two aforementioned ways.Conclusions1.p53 gene mutations occur frequently inEmGD,which provides a solid genetic evidence that EmGD is the precancer of ESC.The findings of this study further support the model of ESC development,which is from RE to EmGD,to serous EIC,and then to ESC.2.Extrauterine serous carcinoma associated with EIC may have multiple sources.There are basically three explanations,that is,transtubal metastasis, simultaneous "field effect" and both of the two aforementioned ways. |
