Study On The Role Of Tumor Markers In Carcinogenesis Of Endometrioid Adenocarcinoma

Background and ObjectiveEndometrial hyperplasia is a common disease. Many different classification systems for endometrial hyperplasia have been proposed and used over the past few decades. In 1994, the WHO proposed its classification for endometrial hyperplasia (WHO1994).This classification system subdivided hyperplasia according to architectural complexity and cytological atypia (to) four categories:simple hyperplasia(SH), complex hyperplasia(CH), simple atypical hyperplasia(SAH) and complex atypical hyperplasia(CAH). Although this practice has been widespread and has had a benefit of unifying the terminology, it fails to optimally stratify patient accoeding to those pathological mechanisms and cancer risks necesarry for appropriate therapeutic triaging. In practice, the diagnostic criteria are difficult to apply reproducibly, because they largely are subjective. Since the WHO1994 classification was difined, molecular genetic endopoints for disease classification have emerged as an adjunation tool to clinical outcome in establishing functional subclasses of disease. The WHO2003 book also includes a new section on the genetics of endometrial precancers which, together with morphometrical and clinical outcome studies,is presented as the basis for EIN classification. The aims of this study were to observe the relation between WHO2003 and EIN classification on endometrial hyperplasia, to explore the practicality of EIN histological criteria in clinipathological diagnosis of endometrial hyperplasia.MethodsA respective study was applied.83 cases of endometrial hyperplasia in accordance with WHO1994 or 2003 classification were rediagnosed and reclassified accoding to EIN histological criteria and classification system, relations between EIN lesion and atypical hyperplasia, EIN classification and WHO 1994 or 2003 Schema were compared. Results1.24 EIN lesions (28.9%) were rediagnosted in 83 endometrial hyperplasia, in which,2 EIN (8.3%) were from cases of the simple hyperplasia,6 EIN(25.0%) were from complex hyperplasia without atypia,16 EIN(66.7%) were from complex atypical hyperplasia.2. The detected rate of EIN was not same among various category of endometrial hyperplasia, in which,2 were from 33 (6%) simple hyperplasia,6 were from 30 (20%) complex hyperplasia without atypia and 16 were from 20 (80%) complex atypical hyperplasia. The frequency of EIN detection in complex atypical hyperplasia was much higher than those in simple hyperplasia and complex hyperplasia without atypia(p< 0.01).3. The relation between detected rate of EIN and grade of atypical hyperplasia was not obvious(p> 0.05).4. Accoding to EIN classification system,83 endometrial hyperplasia in this study is categorized into 59 benign hyperplasia and 24 EIN lesion.Conclusions1. Becouse of diagnostic criteria was different, so there was not fixed corresponding relations between EIN classification and WHO (2003)endometrial hyperplasia schema, but most cases of EIN was overlapping with cases of complex atypical hyperplasia.2. EIN histological diagnosis was proved a more objective and accurate method for endometrial hyperplasia as EIN computerized morphometric analysis(D-score). Background and ObjectiveThere are two main types of endometrial carcinoma:typeⅠtumors related to hormonal imbalances and typeⅡtumors that seem largely unrelated to estrogen. The new EJN classification, originally proposed by Mutter and the International Collaborative Group, is based on integrated morphological, genetic molecular, cell biologic,and prognostic morphometrical studies. According to EIN schema, endometrial hyperplasia may be divided into 2 functional categories:benign endometrial hyperplasia caused by an abnormal hormonal state, and endometrial intraepithelial neoplasia(EIN) caused by a separate category of monoclonal premalignant disease. A let of studies have demonstrated that the use of EIN diagnostic criteria and classification for endometrial hyperplasia will provide benefits for patient as a result pf more consistent and appropriate management of disease, but it will also present special challenges for pathologists.Carcinogenesis is a multistep process involving successive stages of initation, promotions, and progression of lesions from normal epithelium to benign and malignant tumors.Each step is accompanied by a variety of biochemical, morphologic, and cytologic changes that result from either quantitative or qualitative changes in various cellular genes. Molecular genetic evidence indicates that endometrial carcinoma, as described in other malignancies, likely develops as the result of a stepwise accumulation of alterations in cellular regulatory pathways, such as oncogene activation and tumor suppressor gene inactivation, which lead to dysfunctional cell growth. Biological markers have become increasing important sine additional variables are needed to give imformation that can lead to a better understanding of the biology of the carcinoma and give a biological basis for treatment.The aim of this study was to detecte the expressions ofβ-catenin, Glut-1, PTEN, p16, CyclinD1, COX-2 in tumorigenesis for endometrioid adenocarcinoma, to explore the potentiality of 6 proteins as markers in endometrial intraepithelial neoplasia (EIN) diagnosis.MethodsExpressions ofβ-catenin, Glut-1, PTEN, p16, CyclinD1,COX-2 protein were detected in 10 proliferative endometrium,59 benign endometrial hyperplasia,24 EIN, and 24 endometrioid adenocarcinoma by immunohistochemistry, and analysed by statistics.Results1. Normal (membranous) expression ofβ-catenin was present in 10 cases of proliferative endometrium. The abnormal (marked cytoplasmic and/or nuclear or negative) expression rate ofβ-catenin in EIN lesion (50%,12/24) and endometrioid adenocarcinoma (66.7%,16/24) were significantly higher than one of benign hyperplasia(10.2%,6/59) respectively (p<0.01), but difference was not obvious in EIN lesion and endometrioid adenocarcinoma (p>0.05)2. Low expressions of Glut-1 were present in proliferative endometrium and benign hyperplasia. Overexpressions of Glut-1 were present in 58.3%(14/24) of EIN and 70.8%(17/24) of endometrioid adenocarcinoma, but difference was not distinct in EIN and endometrioid adenocarcinoma(p>0.05).3. Expression loss rate of PTEN showed no differences between EIN lesion (37.5%,9/24) and proliferative endometrium (20.0%,2/10), benign hyperplasia (28.8%,17/59),endometrioid adenocarcinoma (62.5%,15/24) (p>0.05), but PTEN expression loss rate in endometrioid adenocarcinoma was significantly higher than ones in proliferative endometrium and benign hyperplasia (p<0.05)4. Differences in positive expression and overexpression rate of p16 among proliferative endometrium(70.0%; 10.0%), benign hyperplasia(67.8%; 16.9%), EIN (70.0%; 16.7%), endometrioid adenocarcinoma(87.5%; 25.0%) were not statistically significant(p>0.05).5. Differences in positive expression of cyclin D1 among proliferative endometrium(30.0%), benign hyperplasia(20.3%), EIN(29.1%), endometrioid adenocarcinoma(20.8%) were not statistically obvious(p>0.05); differences in overexpression rate were not distinct between other various groups(p>0.05) except that overexpression rate of cyclin D1 in endometrioid adenocarcinoma was higher than one in benign hyperplasia(p<0.05).6. positive expression and overexpression rates of COX-2 in EIN(79.2%,50.0%) and endometrioid adenocarcinoma(86.6%,58.3%) were significantly higher than ones in proliferative endometrium(20.0%,10.0%) and benign hyperplasia(18.7%,11.9%), respectively(p<0.01 or p<0.05). But difference was not obvious in EIN lesion and endometrioid adenocarcinoma (p>0.05)ConclusionsAbnormal expression ofβ-catenin, overexpressions of Glut-1 and COX-2 can be an early event in the tumorigenesis for endomerioid adenocarcinoma. The expressions of these proteins were useful tumor markers in distinguishing benign hyperplasia from EIN and endometrioid adenocarcinoma. Background and Objectiveβ-catenin, encoded by the CTNNB1 gene, represents an oncoprotein with transcription activity downstrean the Wnt signal pathway. Cellularβ-catenin levels are tightly regulated by a multi-protein complex comprised of serine/threonine kinase GSK3β, the APC(adenomatous polyposis coli) tumor suppressor gene product, and axin, which facilitates phosphorylation and subsequent degradation of theβ-catenin protein. Abnormalities of suppressor genes, such as the APC gene or exon 3 mutation ofβ-catenin gene have been shown to cause dysregulation ofβ-catenin degradation, leading to a cytoplasmic and nuclear accumulation of the protein. Abnormal expression and accumulation ofβ-catenin protein has been implicated in a wide variety of malignancies including those of the endometrium. The aims of this study were to detect protein expression and the exon 3 mutation ofβ-catenin in benign hyperplasia, EIN, endometrioid adenocarcinoma, to investigate relationship between abnormal expression and exon 3 mutation ofβ-catenin in carcinogenesis of endometrioid adenocarcinoma.MethodsA total of 117 endometrial samples (10 proliferative endometrium,59 benign hyperplasia,24 EIN and 24 endometrioid adenocarcinoma) were obtained from the Department of Pathology, Zhongnan Hospital of Wuhan University, between 2001 and 2006 in this study. Expression ofβ-catenin protein was detected by immunohistochemistry. DNA sequence alterations of exon 3 ofβ-catenin gene were investigated by polymerase chain reaction (PCR) and direct sequencing.Results1. Normal (membranous) expression ofβ-catenin was present in 10 cases of proliferative endometrium (no any case of abnormal expression).53 of 59(89.8%) cases presented normal, and 6 of 59 (10.2%) cases were abnormal (marked membranous/cytoplasmic and/or nuclear or negative) expression ofβ-catenin in benign hyperplasia. Normal and abnormal expressions ofβ-catenin were 12 cases (50.0%) respectively in 24 EIN.8 of 24 (33.3%) cases showed normal,16 of 24 (66.7%) manifested abnormal expressions ofβ-catenin in endometrioid adenocarcinoma. Membranous/cytoplasmic expression ofβ-catenin was a predominant pattern for abnormal expressions in EIN and endometrioid adenocarcinoma. Abnormal expression rates ofβ-catenin in EIN (50%) and endometrioid adenocarcinoma (66.7%) were significantly higher than one of benign hyperplasia(10.2%) respectively (p<0.01), but difference was not obvious in EIN and endometrioid adenocarcinoma (p>0.05)2. PCR and direct sequencing failed to reveal any exon 3 mutation ofβ-catenin gene in 117 endometrial specimens (particularly in benign hyperplasia, EIN and endometrioid adenocarcinoma).Conclusions1. abnormal expression ofβ-catenin may be an useful marker in distinguishing benign hyperplasia from EIN and endometrioid adenocarcinoma.2. The exon 3 mutation ofβ-catenin gene may not be an important cause,which result in abnormal expression ofβ-catenin and tumorigenesis of endometrioid adenocarcinoma.