A Clinicopathology And Immunohist Ochemistry Analysis On80Cervical Glandular Intraepithelial Neoplasia

Background:Cervical cancer is a common gynecological malignancies. The incidence of cervical adenocarcinoma and precancerous lesion has significantly increased in recent years.In recent studies, the incidence of invasive cervical adenocarcinoma (IA) and adenocarcinoma in situ (AIS) have increased from5%to25%in the United States and in Europe.Therefore,studies on the precancerous lesion of cervical adenocarcinoma has drawn increasing attention.In the daily work,early detection of early cervical adenocarcinoma and precancerous lesion is very difficult because of its occult lesions,lacking of specific gross morphology which makes it difficult to identify by colposcopy and its high negative rate of cytology.The inflammatory proliferative lesions of cervical glandular epithelium may be confused with neoplastic lesion.While endometriosis or tubal metaplasia is also difficult to identify with adenocarcinoma in situ.The etiology and pathogenesis of cervical adenocarcinoma is unclear. Its clinical and molecular characteristics is different from cervical squamous cell carcinoma,and it has a lower5-year survival rate and poor prognosis.So,early diagnosis is an important part of cancer prevention and the key to early treatment and the basis for surgical approach.Variety of immunohistochemical markers are used for the study of cervical adenocarcinoma and precancerous lesion in recent years.However,no evidence has shown which antibody is specificity.Ki-67is the first one of the antibodies used to study cervical epithelial lesion.Ki-67antigen is a class of non-histone nucleoprotein.It is expressed in all other cell cycle except Go phase and it is rapidly cleaved after leaving the cell cycle.So,Ki-67antibody has its advantages as a cell proliferation marker.Ki-67labeling index can reflect the normal and pathological proliferative activity.It is a valuable supplementary indicator to identify benign and malignant tumors and commonly used in the expression of tumor cell proliferation.High index of Ki-67can reach76%in cervical adenocarcinoma in situ.While it is less than10%in most tubal-endometrial metaplasia,endometriosis and micro gland hyperplasia.In some studies,occasionally it can up to50%but with a weak and scattered positive expression in some benign lesion. High grade cervical glandular intraepithelial neoplasia has a strong nuclear expression.Bcl-2is now recognized as anti-apoptotic gene,located on chromosome18.It can block apoptosis which is caused by a variety of reasons and prolong cell survival.Studies have shown that cytoplasm of bcl-2expression is positive in the tubal-endometrial metaplasia and endometriosis,meanwhile normal oviductal epithelium and endometrial hyperplasia is strongly expressed and most cervical glandular intraepithelial neoplasia is negative.But its positive expression mechanism is unclear. Experiments show that the infection of high-risk human papillomavirus(HR-HPV),especially the HPV16,18and31is closely related to the occurrence and development of cervical adenocarcinoma and adenosquamous carcinoma.However,in situ hybridization and polymerase chain reaction(PCR) are not yet universal,and thus we require a immunohistochemical markers which is closely related to HPV to identify.P161NK4A gene product is a cyclin-dependent kinase inhibitor,located on human chromosome9p21,and it is a tumor suppressor gene that directly involved in cell cycle regulation.Recent experiments show that p161NK4A upregulated through a negative feedback mechanism in cervical cancer and precancerous lesion.Its overexpression is relative to HR-HPV infection of all squamous and glandular epithelium. Also it improves the specificity and the sensitivity compared with HR-HPV testing and it is colored diffuse, uniform, strong in CGIN lesions.While in the control group, for the micro-gland hyperplasia cases it is negative expression.Benign lesions such as tube-endometrial metaplasia and endometriosis cases,it has no color or focal weak non-uniform coloring.Liang etal observed the expression of CEA、Mib-1and p16in cervical glandular lesion through semi-quantitative method.This study found that the expression of p16and CEA was significantly higher in EGD group than in benign gland lesion and it was significantly increased in high-grade glandular dysplasia group.This confirmed the significance of p16and CEA in the diagnosis of cervical epithelial lesion.CA125is a high molecular weight glycoprotein which is recognized by OC125monoclonal antibody and has the intracellular,the transmembrane and the extracellular domains.The binding site of OC125and M11is in the extracellular domain.CA125expresses in the pleuroperitoneum and fallopian tubes,endometrium and other tissues which is derived from the embryonic body cavity epithelium.The positive rate of CA125is very low in cervical squamous cell carcinoma,while it is significantly increased in cervical adenocarcinoma and adenosquamous carcinoma.Gadducci etal have shown that cervical adenocarcinoma can be expressed as elevated CA125,this suggested that CA125can be used as the preferred method which can identify cervical adenocarcinoma and cervical squamous cell carcinoma.Research Objective:To assess the clinicopathologic characteristics of high grade cervical glandular intraepithelial neoplasia(HCGIN) and evaluate the usefulness of immunohistochemical method in identifying early invasive cervical adenocarcinoma and its precursors. We can improve the understanding of cervical precancerous lesion.Research Methods:Collected cervical biopsy cases and surgical resection cases between2008and2011in department of Pathology, Women’s Hospital, School of Medicine, Zhejiang University.In these cases there are80cases of HCGIN,20cases of IA(6cases of mucinous adenocarcinoma,4cases of endometrial adenocarcinoma,9cases of mixed carcinoma,1case of non-special type adenocarcinoma) and20cases of cervicitis.All sections were confirmed by more than3pathologists.To analyze the clinical and pathological morphology characteristics of80HCGIN (,20IA, and20cervicitis. Then immunohistochemistry with p16. Ki-67. CEA. CA125. bcl-2was performed in them. Fomwitz Comprehensive Scoring for semi-quantitative analysis to determine.All data were analyzed by SPSS15.0statistical software.Chi-square test or Fisher exact test,and correlation between the two uses non-parametric Spearman rank correlation analysis.Results:Cervical glandular intraepithelial neoplasia primarily presents in reproductive-age women.This study shows that there are45cases in the HCGIN group who was in pregenancy more than3times,accounting for56.3%. The first symptom of the main is contact bleeding (51.2%).Cervical erosion is the main performance in cervical gynecological examination. The clinical performance of HCGIN was similar as it in high grade cervical intraepithelial neoplasia (CIN), and44cases (55.0%) accompanied with CIN,9cases (11.3%) accompanied with early cervical squamous cell carcinoma (SCC). The pathologic morphology characteristics in cases of HCGIN was the glandular atypical hyperplasia in situ.Immunohistochemical staining results:1.In HCGIN group,IA group and cervicitis group, the positive rates of p16were100%,90%,5%;the positive rates of CEA were64%,80%,5%;the positive rates of Ki-67were74%,100%,15%.2. There was significantly increased expression of p16、CEA and Ki-67in IA and HCGIN compared with cervicitis (P<0.01). Ki-67expression was increased in IA compared to HCGIN (P<0.05). There was no statistical difference in CEA expression between IA and HCGIN (P>0.05).3. CA125had a strong non-specific response and had a high positive rate of normal gland even more than abnormal gland,so there is no significance inddifferential diagnosis.4. Bcl-2displayed negative or occasionally positive in each groups. Conclusions:1.Cervical glandular intraepithelial neoplasia primarily presents in reproductive-age women and the proportion of multiple pregnancies is high. The high proportion may be related to cervical injury which was susceptible to infection.2.HCGIN easily occurs with CIN and squamous cell carcinoma at the same time,and usually occurs in the squamous columnar junction where CIN occurred.This suggests that there may be common pathogenic factor between the two,such as HPV infection and similar pathogenesis.3.There is no characteristic clinical manifestations by gynecological examination. Cervical erosion is the main performance.4.Pathomorphism is characterized by the atypia of gland in situ,and lacking of infiltration and stromal reaction.5.The joint detection of p16,CEA and Ki-67contributes to the diagnosis of early cervical adenocarcinoma and precancerous lesion.P16has the good sensitivity and specificity in identification HCGIN and IA with benign lesion.P16and Ki-67are more sensitive than CEA in HCGIN group.CEA has a certain significance in differential diagnosis.If CEA positive in glandular epithelial cell accompanied by Ki-67positive index increased,this suggests the possibility of malignant lesion.6.CA125and bcl-2have little significance in differential diagnosis of HCGIN.