Connective tissue activating peptide III expression disappears progressively with increased dysplasia in human cervical epithelium

OBJECTIVE: The aim of this study was to explore the possible involvement of CTAP-III in the development of cervical cancer as it progresses through several cervical intraepithelial neoplasia (CIN) stages. MATERIAL AND METHODS: Twenty-four cervical specimens were obtained by direct punch biopsy, conization, or hysterectomy. Diagnosis of CIN I to CIN III was based on standard morphological criteria in 12 specimens. Tissue specimens were also obtained from 4 normal uteri and 8 cases of invasive squamous cell cervical carcinoma. RT-PCR, using CTAP-III-specific primers, was used to identify CTAP-III mRNA and polyclonal antibodies, directed against the N-terminus of CTAP-III, for immunostaining of the CTAP-III protein. RESULTS: RT-PCR yielded amplified fragments in RNA derived from normal cervical tissue, while no PCR product was detected in the invasive cervical carcinoma tissue. The PCR product corresponded to a CTAP-III plasmid PCR product. Both tissues expressed the same amounts of GAPDH mRNA as the control for the integrity and equal amounts of the isolated RNA. In each of the 16 specimens of normal cervices and of CIN tissues, epithelial cells were stained with the anti-CTAP-III antibodies. In normal epithelium, CTAP-III staining was homogeneously distributed in all epithelial layers, except in the highly active and proliferating basal cells. CTAP-III was localized at the epithelial cell membrane or between adjacent epithelial cells in a granular, chain-like pattern of staining. In the CIN specimens, CTAP-III staining was no longer seen in the deep epithelial layers, consistent with the dysplastic appearance of the cells, and remained in the seemingly normal superficial epithelial layers. Cells of invasive cervical carcinoma did not stain for CTAP-III and were detected in endothelial cells of capillary blood vessels. CONCLUSION: The specific localization of CTAP-III between adjacent epithelial cells suggests a possible role of this chemokine in maintaining the normal architecture of epithelial tissues. Its progressive disappearance in increasingly severe CIN may be applied to distinguish between specific stages in the progression of cervical carcinoma.     

细胞凋亡和P53在宫颈癌及宫颈上皮内瘤变中的表达

目的：探讨细胞凋亡和P53在宫颈癌及宫颈上皮内瘤变中的作用。方法：用DNA缺口末端标记技术(TUNEL)和免疫组化技术原位观察15例正常宫颈、22例CIN*"I/Ⅱ、16例CINⅢ和52例浸润性宫颈鳞癌(ISCC)组织中细胞凋亡标记指数(A-LI)、PCNA(增殖细胞核抗原)标记指数(PCNA-LI)和P53表达阳性率及P53标记指数(P53-LI)。结果：在正常宫颈上皮未检测到凋亡细胞,随着CIN病变的进展,A-LI增高(P＜005),在ISCC,A-LI明显低于CIN(P＜001);PCNA-LI随宫颈癌各级病变的进展逐渐增高(Ｐ＜005);在正常宫颈和CINI/Ⅱ均未检测到P53表达,在CINⅢ,P53-LI明显低于ISCC(P＜001)。结论：细胞凋亡在宫颈癌发生发展过程中发挥重要作用,P53蛋白的积聚可能对细胞凋亡起抑制作用。     

Distribution of involucrin in normal and pathological human uterine cervix

A study was undertaken to determine the potential value of involucrin immunostaining, a protein synthesized by mature squamous epithelial cells, in distinguishing benign from neoplastic lesions in cervical pathology. A total of 146 cervical biopsies were analyzed using an indirect immunoperoxidase method and polyclonal antibody. A suprabasal homogeneous cytoplasmic staining pattern was consistently observed in normal squamous cervical epithelium. In contrast, 43.7% of cervical condylomas showed involucrin at all levels of the epithelium including the basal layer. Variable patterns were seen in cervical intraepithelial neoplasia (CIN), with 46% of full-thickness stainings, although no significant difference was obtained among the different grades of CIN lesions. Distribution of involucrin was correlated (P less than 0.05) with the degree of tumor differentiation in squamous cell carcinomas, being absent in 71.4% of poorly differentiated carcinomas and focally present in 75% of well-differentiated carcinoma. Lesions of endocervical origin, either benign or malignant, were entirely negative for involucrin. It is concluded that involucrin seems unable to establish a reliable differential diagnosis between benign and neoplastic conditions in cervical pathology, and should therefore be considered only a specific marker of squamous differentiation in both normal and pathological human uterine cervix.     

Immunohistochemical demonstration of histiocytes in normal ectocervical epithelium and epithelial lesions of the uterine cervix

The numbers of Langerhans cells and lysozyme-positive macrophages were assessed quantitatively in normal ectocervical epithelium, cervical intraepithelial neoplasia (CIN), microinvasive squamous cell carcinoma (MICA), clinical invasive squamous cell carcinoma (CICA), and koilocytotic atypia using the avidin-biotin-peroxidase complex (ABC) method. The distribution of Langerhans cells was different from that of lysozyme-positive macrophages in that the former were intermingled with the cervical lesion, while the latter were present mainly surrounding the cervical lesion and/or on the edge of the cervical lesion. The numbers of Langerhans cells and lysozyme-positive macrophages in CIN were significantly larger than those in normal ectocervical epithelium and significantly smaller than those in invasive squamous cell carcinoma (MICA + CICA). Langerhans cell number significantly increased as the grade of CIN advanced. In contrast, the number of lysozyme-positive macrophages did not differ significantly between progressive grades of CIN. As for koilocytotic atypia, the numbers of Langerhans cells and lysozyme-positive macrophages in koilocytotic atypia were significantly greater than those in normal ectocervical epithelium but did not differ significantly from those in CIN 1 and CIN 2. With respect to stromal lymphoid infiltration, invasive squamous cell carcinoma with moderate or dense stromal lymphoid infiltration showed significantly greater numbers of Langerhans cells and lysozyme-positive macrophages than that with no or scattered stromal lymphoid infiltration, but such a correlation was not found in CIN.     

E-Cadherin and Integrin Cell Adhesion Molecule Expression in Invasive andin SituCarcinoma of the Cervix

Integrin and E-cadherin cell adhesion molecules are important in the maintenance of normal epithelial structures, and altered expression of these molecules may be important in epithelial tumors, particularly in the processes of invasion and metastasis. This study examines the immunohistochemical expression of the α2β1, α3β1, α6, and β4 integrins and of E-cadherin in high-grade cervical intraepithelial neoplasia (CIN) and in invasive carcinoma of the cervix. Abnormal expression of E-cadherin and of all of the integrin subunits examined was detected in the dysplastic epithelium in CIN in the majority of cases, but in a minority of cases this expression was lost in the superficial layers of the dysplastic epithelium. Diffuse expression of E-cadherin and of all of the integrins was seen in the majority of cases of invasive cervical carcinoma. Abnormal expression of integrin cell adhesion molecules occurs in the majority of cases of high-grade CIN, and E-cadherin expression is retained in the dysplastic epithelium. Diffuse expression of integrins and of E-cadherin also occurs in invasive carcinoma, but as the expression pattern was similar in all cases of carcinoma, no correlation with outcome is possible and the significance of this expression is unclear.     

Expression of cytokeratin polypeptides in human papillomavirus (HPV) lesions of the uterine cervix: 1. Relationship to grade of CIN and HPV type

A series of 74 punch biopsies, derived from 513 women prospectively followed for cervical human papillomavirus (HPV) infections (including HPV-NCIN, HPV-CIN I, HPV-CIN II, and HPV-CIN III lesions), and 43 control cases (consisting of normal epithelia, nonspecific cervicitis, and classical CIN lesions) were analysed for expression of cytokeratin polypeptides using the ABC technique and monoclonal antibodies SK 56-23 (wide-spectrum antibody), SK 60-61 (specific for keratins 8 and 18), and SK 2-27 (detecting keratins 14, 16, and 17). HPV typing was carried out using the in situ hybridization technique with DNA probes for HPV 6, 11, 16, 18, and 31. All layers of the exocervical epithelium were regularly stained with the antibody SK 56-23, and the staining pattern remained unaltered in all cervical lesions studied. In contrast to the normal exocervical epithelium, which remained negative with SK 60-61, positive staining was observed in 3 of 15 cervicitis cases and 6 of 23 classical CIN lesions. Interestingly, the majority (69 of 74, 93.2%) of both HPV-NCIN and HPV-CIN lesions showed positive staining with this antibody either in all layers or in suprabasal cells. Antibody SK 2-27 stained the basal cells of the normal exocervical epithelium with remarkable specificity. In 18 of 19 HPV-NCIN lesions, basal cells could not be stained by SK 2-27 monoclonal, but the suprabasal cells were stained instead. In HPV-CIN, but not in classical CIN, this antibody demonstrated the presence of the epitope typical of the cytokeratins 14, 16, and 17 in all layers of the epithelium, the highest frequency (9 of 12, 75%) being found in HPV 16-induced lesions. These disturbances of cytokeratin patterns in cervical epithelium could be associated with cell transformation by HPV, leading to development of HPV-CIN, and could be specific for this virus. The present data are of interest in assessing the stage of maturation of the squamous cells in progressing cervical HPV infections.     

Immunohistochemical and ultrastructural study of Langerhans's cells in squamous cell carcinoma of the cervix

OBJECTIVE: To study Langerhans's cells (LCs) in cervical squamous cell carcinoma. STUDY DESIGN: The study was carried out in the Shatby University Hospital, Alexandria, Egypt. Thirty cases with squamous cell carcinoma, 10 cases with cervical intra-epithelial neoplasia (CIN) and 10 cases with normal exocervix were recruited. Sections from the exocervix were stained with gold chloride, immunostaining with S-100 protein antiserum, adenosine triphosphatase ATPase and electron microscopy. Statistical evaluation was done using the t-test. RESULTS: Gold chloride staining revealed significantly increased number of LCs in all cases of CIN compared to normal controls and with increasing grade of CIN (p < 0.001). No relationship between LCs number and the grade of carcinoma. Least branched LCs were predominant in the normal tissue while in neoplasia, these cells were of the most branched type, indicating a hyperactivity. S-100 protein positive LCs were almost absent in normal controls while their number were almost lower than the corresponding cases of CIN and invasive carcinoma after gold chloride or ATPase stainings. Signs of hyperactivity were evident in LCs of neoplastic cases after electron microscopy. CONCLUSIONS: Proliferation and increased number of LCs in CIN is an immune response, while such reaction is suppressed by invasive carcinoma.     

260例电子阴道镜下图像特点与宫颈活检病理诊断的关系

目的:探讨电子阴道镜下的宫颈异常表现图像与宫颈活检病理诊断的相互关系。方法:选择2011年9～11月就诊于本院阴道镜门诊的260例患者,以活检病理学诊断结果为标准,对组织病理学结果和阴道镜表现特点进行分析。结果:①电子阴道镜在宫颈疾病诊断中敏感性97.9%,特异性71.2%,阳性预测值89.7%,假阴性率2.1%;②阴道镜下扁平醋白上皮可出现在宫颈炎到CINⅢ的各级宫颈病变中,致密醋白上皮出现于CINⅡ及以上级别的宫颈病变中。二联征中CIN的检出率为77.4%,三联征和醋白上皮+非典型血管中CINⅢ及宫颈癌(ICC)的检出率分别是78.6%和72.4%。③不典型鳞状上皮(ASC)和(或)非典型腺细胞(AGC)出现在各级宫颈病变,在低度鳞状上皮内瘤变(LSIL)中CINⅠ的检出率为40.9%,在高度鳞状上皮内瘤变(HSIL)(包括HSIL+AGC)中CINⅡ、CINⅢ及ICC的检出率为96.9%。④宫颈表面是否光滑及糜烂程度与宫颈自身病变无关。结论:电子阴道镜是辅助诊断宫颈疾病的可靠而重要的手段,典型的异常阴道镜图像对诊断宫颈癌前病变和宫颈癌有重要价值。     

Involucrin expression in cervical intraepithelial neoplasia: a critical evaluation

Involucrin is a keratinocyte envelope protein precursor which is synthesized at an early stage of differentiation in normal squamous epithelium. Recent studies suggest that this protein may be a marker for neoplastic epithelium. To address this issue, we analyzed involucrin expression in 105 biopsies containing 119 areas of normal, condylomatous, and neoplastic epithelium. Overall, 88, 75, and 55% of condylomata, well-differentiated CIN, and poorly differentiated CIN (carcinoma in situ) contained positive staining for involucrin. Excluding lesions with severe inflammation, 100, 88, and 55% of these lesions, respectively, were positive. Staining patterns in neoplastic lesions differed from those in the normal epithelium and condylomata; the staining in CIN tended to be focal, and intensity of staining varied widely from cell to cell in all layers of the epithelium. In high grade CIN, staining correlated with increases in cell size and cytoplasmic differentiation. These studies suggest that involucrin will not differentiate between lesions of low versus high risk for progressing to invasive carcinoma. However, the patterns of involucrin expression confirm the marked differences in patterns of cellular differentiation between classical condylomata and CIN.     

Hormone receptors in cervical intraepithelial neoplasia

The presence or absence of steroid hormone receptors has been associated with predicting response to exogenous hormone therapy in breast tumors and in the treatment of metastases. This study was conducted to determine whether hormone receptors are present in cervical epithelium showing intraepithelial neoplasia. 18 biopsies of normal cervical epithelium were collected from hysterectomy patients with normal cervical cytology. 32 abnormal epithelium specimens were similarly obtained from patients with abnormal cervical cytology. An assay method using dextran-coated charcoal was performed to determine the values of estrogen and progesterone receptors in the cervical samples. Among those with normal epithelium, 67% were found to be estrogen receptor + compared to 77% of those with cervical intraepithelial neoplasia (CIN). Progesterone receptor sites were found in 61% of normal patients and 65% of CIN patients. The % of tumors (invasive cervical carcinoma) that are estrogen receptor positive have been found to vary from 0 to 25%. This study suggests a higher % of estrogen and progesterone receptor positivity in CIN than in invasive carcinoma with increasing concentration of receptors proportionate to the degree of dedifferentiation. Further studies should be done to determine whether hormone manipulation of cervical epithelium is of therapeutic and clinical value.     

E-cadherin and alpha-catenin expression during tumor progression of cervical carcinoma

OBJECTIVE: The objective of this study was to determine whether a relationship between the E-caherin molecule and the E-cadherin-associated cytoplasmic molecule, alpha-catenin, could provide additional information in the neoplastic progression of cervical cancer. METHODS: In this study we investigated by immunohistochemistry E-cadherin (E-cad) and alpha-catenin (alpha-cat) expression in 57 cervical biopsy samples representative of normal exocervical epithelium, viral (human papillomavirus (HPV) infection) and dysplastic lesions (low- and high-grade lesions), and invasive squamous cell carcinoma. The presence of immunostaining and the pattern of distribution of these molecules were correlated with the histological diagnosis (normal cervical epithelium vs HPV, cervical intraepithelial neoplasia (CIN), and invasive carcinoma). RESULTS: The correlation between alpha-cat expression and the histological diagnosis was statistically significant (chi2 test, P < 0.0077); moreover, E-cad and alpha-cat distributions were significantly correlated with the histological classification (P < 0.0001 and P < 0.0043, respectively). CONCLUSION: These results suggest that not only E-cad but also alpha-cat are associated with the loss of differentiation in CIN and squamous cell carcinomas; thus the coexpression of E-cad and alpha-cat may represent a discriminant of malignant potential and could provide an additional criterion to define high-grade CIN.     

Cervix dysplasias: study of Rb and p53 gene expression and correlation with mitotic activity

OBJECTIVE: Certain HPV types have transforming properties. These oncogenic activities are related to the abilities of the viral proteins E6 and E7 to inhibit the products of two cellular tumor suppressor genes (p53 and Rb respectively). But the early steps of cervical carcinogenesis are not well known. The goal of our study was to evaluate cervical intraepithelial neoplasia (CIN) for the tumor suppressor genes p53 and pRb, the HPV status and the mitotic activity, in order to better understand the mechanism of carcinogenesis. MATERIAL AND METHODS: Twenty formalin-fixed paraffin-embedded cone biopsies were selected because they contained adjacent to normal epithelium different grades of CIN. Immunohistochemistry was performed for evaluation of PCNA, pRb and p53. Expression of these different biomarkers was assessed with the help of an image analysis system, in the different epithelial layers of the different normal and pathological cervical areas. The results were compared to normal controls. RESULTS: There is an increase of PCNA expression in normal epithelium adjacent to CIN, compared to normal controls. As tissues progress from adjacent normal epithelium to condylomatous lesion and to the different grades of CIN, PCNA expression increases (mainly in the superficial epithelial layers). For p53 and pRb, the expression is increased in the basal and parabasal layers of adjacent normal epithelium and condylomatous lesions. The observance of histologic signs of CIN is associated with a disappearance of p53 and pRB expression. CONCLUSIONS: These results indicate that the early steps of cervical carcinogenesis involve proliferative dysregulation in relation to the p53 and pRb modulatory mechanism. So expression of viral proteins of HPV is probably the earlier step of carcinogenesis in cervical carcinoma.     

Tissue polypeptide antigen and keratins in cervical neoplasia

Antibodies against tissue polypeptide antigen (TPA) and keratins of high molecular weight (62-67 kD) were used to indicate different stages of cell differentiation. The immunohistochemical study was carried out by indirect immunofluorescence. In dysplasia, particularly in CIN grades II to III, TPA labeling comprised not only basal layer cells (as seen in normal mucosa) but more superficial layers as well. Expression of keratins of high molecular weight was reduced to small foci of keratinization and scattered dyskeratotic cells. In typical small cell anaplastic carcinoma in situ, TPA antibodies were observed to label all epithelial cell layers. There was no reactivity with antibodies against keratins of high molecular weight. In invasive cancer, TPA staining was closely related to the degree of maturation. Nonkeratinized tumor zones were entirely labeled by TPA antibodies, whereas keratinized tumor foci were negative for TPA except for peripheral tumor cell layers. In invasive cancer, keratins of high molecular weight were restricted to differentiated portions of the tumor. Our immunohistochemical findings support the present concepts of TPA (as a member of the heterogeneous keratin family) as an indicator of cell differentiation. Immunohistochemical demonstration of keratins of different molecular weight offers a method of assessing squamous differentiation at the cervical transformation zone and in cervical cancer and precancer.     

Stromal cells play a role in cervical cancer progression mediated by MMP-2 protein

Metalloproteinases, especially metalloproteinase-2 (MMP-2), are known for their role in the degradation of the extracellular matrix. Nevertheless, a thorough understanding of MMP-2 expression in neoplastic lesions of the uterine cervix has yet to be accomplished. This study aimed to analyze the MMP-2 expression in cervical intraepithelial neoplasia III (CIN3) and in cervical squamous cell carcinoma, in tumor cells and adjacent stromal cells. MMP-2 expression was assessed by an immunohistochemical technique. MMP-2 expression was greater in the stromal cells of invasive carcinomas than in CIN3 (p < 0.0001). MMP-2 expression in stromal cells correlates with the clinical stage, gradually increasing as the tumor progresses (p = 0.04). This study corroborates that stromal cells play an important role in tumor invasion and progression, mediated by the progressive enhancement of MMP-2 expression from CIN3 to advanced invasive tumor. The intense MMP-2 expression most probably is associated with poor tumor prognosis.     

Patterns of mRNA for epidermal growth factor receptor and keratin B-2 in normal cervical epithelium and in cervical intraepithelial neoplasia.

Patterns of epidermal growth factor receptor (EGFR) and keratin B-2 (KB2) mRNA localization were studied in samples of normal cervical squamous epithelium and in samples of cervical intraepithelial neoplasia (CIN). 35S-Labeled EGFR and KB2 DNA probes were used for in situ hybridization on formalin-fixed tissue sections. Normal cervical squamous epithelium showed predominantly basal and parabasal expression of EGFR mRNA and suprabasal and midepithelial localization of KB2 mRNA. CIN lesions with moderate to severe dysplasia were generally characterized by continued expression of EGFR mRNA and decreased KB2 mRNA in midepithelial locations. Ratios of KB2 mRNA levels at the basal layer to KB2 mRNA levels at the midepithelial location were increased in moderate and severe dysplasia (CIN II and III) compared with normal epithelium (P less than .01). Ratios of EGFR mRNA levels at the midepithelial level to those of EGFR mRNA at the basal layer were increased in moderate to severe dysplasia compared with normal epithelium. These findings indicate a possible in vivo role of EGFR gene expression in normal and neoplastic proliferation and in prevention of differentiation of the cervical epithelium.     

Death receptors and ligands in cervical carcinogenesis: an immunohistochemical study

OBJECTIVE: Increasing imbalance between proliferation and apoptosis is important in cervical carcinogenesis. The death ligands FasL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis by binding to their cognate cell-surface death receptors Fas or death receptor (DR) 4 and DR5. This study aims to examine if changes in death ligand and death receptor expression during different stages of cervical carcinogenesis are related to an imbalance between proliferation and apoptosis. METHODS: The immunohistochemical expression and localization of Fas/FasL and DR4/DR5/TRAIL were assessed in 11 normal cervices, 15 cervical intraepithelial neoplasia (CIN) grade I, 15 CIN II, 13 CIN III, and 25 (microinvasive) squamous cell cervical cancers. The number of apoptotic cells was determined by morphological criteria and the number of proliferating cells by counting Ki-67-positive cells. RESULTS: A marked increase in proliferation as well as apoptosis percentage was found with increasing severity of neoplasia. In normal cervix and CIN I samples, FasL, DR4, DR5, and TRAIL staining was mainly observed in the basal/parabasal layer, whereas Fas staining was localized in the superficial, more differentiated epithelial layer. Frequency of Fas-positive staining decreased with increasing severity of CIN. In contrast, homogeneous FasL, DR4, DR5, and TRAIL expression throughout the lesions was more frequently observed in CIN III and cervical cancer. FasL, DR4, DR5, and TRAIL staining patterns were correlated, although TRAIL expression was more intense in low-grade lesions. No association was found between death receptor or ligand expression with the percentage of apoptosis or proliferation. CONCLUSION: The loss of Fas and the deregulation of FasL, DR4, DR5, and TRAIL in the CIN-cervical cancer sequence suggest a possible functional role of these death ligands and receptors during cervical carcinogenesis. The frequent expression of DR4 and DR5 presents these receptors as promising targets for innovative therapy modalities in cervical cancer.     

Detection of human papillomavirus DNA in human cervical lesions by tissue in situ nucleic acid hybridization

Cervical cancer is one of the most common female cancers in Taiwan. Certain types of human papillomavirus (HPV) are frequently detected in the epithelial precancerous and cancerous lesions of the cervix. By the use of tissue in situ hybridization, we investigated the relationship of various types of HPV (group I, HPV-6 & 11, group II, HPV-16 & 18, group III, HPV-31, 33 & 35) with cervical condyloma, carcinoma as well as precancerous lesions. Group I HPV DNAs were mainly found in cervical condylomatous lesions (2/2) of the cervix and cervical intraepithelial neoplasia I (CIN I) (2/4), but were only occasionally found in CIN II (1/4), CIN III (1/9) or non-keratinized squamous cell carcinoma (1/15). HPV DNAs of groups II and III were mainly detected in lesions of CIN III (5/9) and invasive squamous cell carcinoma (large cell, keratinized type: 4/7; large cell, non-keratinized type: 11/15). HPV DNA sequences were invariably detectable only in the cell nuclei of condyloma or dysplastic epithelium or invasive carcinoma. However, they could not only be detected in the upper layer dysplastic cells and koilocytes but also in the well and poorly differentiated cervical cancer cells. The distribution of HPV DNA positive cells in the carcinomas fell into four different patterns: (1) upper zone and non-invasive regions of the carcinoma (11/22, 50%), (2) basal zone and invasive regions (2/22, 9%), (3) randomly scattered (7/22, 32%), and (4) extensively distributed over the whole tumor lesions (2/22, 9%). Thus, our results are consistent with a strong correlation between the presence of HPV-16, 18, 31, 33 and 35 and malignant conversion of cervical epithelial cells.     

Expression of bcl-2 and bax in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix

Bcl-2 protein together with the pro-apoptotic protein bax, are thought to function by forming homo- and heterotypic dimers which control the progression to apoptosis. In this immunohistochemical study we investigated the expression of bcl-2 and bax apoptosis related proteins in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix. Twenty-four cervical intraepithelial neoplasias grade 1-2 (CIN I/II), 38 grade 3 (CIN III), and 53 invasive squamous cell carcinomas (ISCC) were investigated by immunohistochemical staining for bcl-2 and bax protein. Bcl-2 immunoreactivity was found in five of the 24 CIN I/II cases (20.8%), 18 of 38 CIN II cases (47.4%) and nine of 53 ISCC cases (17%). The positivity for CIN III was significantly higher than for CIN I/II or ISCC (p=0.0351 and p=0.0018, respectively). The percentage of bax immunopositivity was somewhat higher in CIN III than in CIN I/II but this slight difference was not statistically significant. Correlation of the immunostaining results with tumor grade revealed a significant difference for bcl-2 which was more frequently immunopositive in well-differentiated tumors than in poorly-differentiated tumors. There was no significant relation between bax expression and tumor differentiation. Our results suggest that alterations of bcl-2 and bax expression may occur as a relatively early event in cervical tumorigenesis.     

Differential expression of human Dlg in cervical intraepithelial neoplasias

OBJECTIVES: To evaluate the potential role of human discs large (hDlg) protein in the pathogenesis of cervical neoplasia by examining the changes of hDlg protein expression in normal cervical epithelium as well as various stages of cervical dysplasia. MATERIALS AND METHOD: Archived formalin-fixed, paraffin-embedded cervical tissue sections with known status of human Papillomavirus (HPV) infection were examined for hDlg expression using immunohistochemical staining by a monoclonal antibody generated against hDlg. The specimens include normal epithelium, low-grade and high-grade squamous intraepithelial lesions, and squamous cell carcinoma. RESULTS: The hDlg protein localized primarily in the basolateral membrane of glandular columnar cells in normal endocervical epithelium. In the squamous epithelium, the hDlg staining is strong in the basal and parabasal layers and rapidly fades away in the superficial layers. Although predominantly membrane-associated, some cytoplasmic staining of hDlg is also detectable that decreases in intensity from basal to superficial layers. In low-grade squamous intraepithelial lesion, there is a moderate increase in the membranous as well as cytoplasmic staining of hDlg in the cells of superficial layer and a modest loss of membranous staining of hDlg in the basal layer. This "reverse staining pattern" for hDlg is more prominent and constant feature of high-grade squamous intraepithelial lesions. The changes of the hDlg expression are, however, invariable regardless the subtypes of HPV infection of the specimens. In the invasive squamous cell carcinoma, membranous staining of hDlg is reduced or absent with some mitotic cells showing evidence of hDlg accumulation in the midbody zone. CONCLUSIONS: These data suggest a functional role of hDlg in the development and progression of cervical neoplasia with implications in cytokinesis, viral trafficking, and metastasis pathways.     

Comparative study of MMP-2 (matrix metalloproteinase 2) immune expression in normal uterine cervix, intraepithelial neoplasias, and squamous cells cervical carcinoma

OBJECTIVE: This study was undertaken to evaluate the levels of matrix metalloproteinase 2 (MMP-2) in the precursors lesions and in the invasive cervical carcinoma and to quantify the immune reactive expression of MMP-2, using MMP-2 immunohistochemistry, in intraepithelial cervical neoplasias and in the invading cervical carcinoma. STUDY DESIGN: We evaluated 60 samples of cervical tissues using immunohistochemistry for MMP-2 in 5 distinct groups. The groups were divided in control, cervical intraepithelial neoplasia I (CIN I), CIN II, CIN III, and cervical invading carcinoma. RESULTS: MMP-2 expression was found gradually increased according to the degree of cervical intraepithelial neoplasia and cervical carcinoma. (Control相似文献