Immunohistochemical expression of laminin-5 in cervical intraepithelial neoplasia

OBJECTIVES: Laminin-5 is an attachment protein for epithelial cells. Several studies of a variety of cancers have reported increased expression of laminin-5 in carcinoma in situ and invasive cancer. This study was designed to investigate the correlation between the grade of cervical intraepithelial neoplasia and the immunohistochemical expression of laminin-5 in the cytoplasm and in the basement membrane underlining dysplastic squamous cells. METHODS: We used immunohistochemical methods to stain paraffin-embedded sections of cervical cone biopsies with a monoclonal antibody specifically targeting the 2-chain of human laminin-5 protein. The study sample included 175 slides: 7 normal cervical epithelium, 36 lesions of mild dysplasia, 50 lesions of moderate dysplasia, 81 lesions of severe dysplasia, and 1 invasive squamous cell carcinoma. RESULTS: We found a statistically significant correlation between the grade of cervical intraepithelial neoplasia and laminin-5 immunoreactivity in the cytoplasm (P < 0.01) and in the basement membrane (P = 0.03) by use of the Wilcoxon rank-sum test. CONCLUSIONS: According to previously published reports we confirmed with a higher number of cases a correlation of laminin-5 expression in the cytoplasm and/or basement membrane and grade of dysplastic lesion in the cervical epithelium. This study warrants further investigations with special interest to follow-up to investigate whether laminin-5 is a marker to predict the risk of progression of cervical intraepithelial neoplasia lesions.     

The clinicopathologic significance of laminin-5 γ2 chain expression in cervical squamous carcinoma and adenocarcinoma

Carcinoma of the uterine cervix is one of the most prevalent malignancies among women in developing countries and the third most common type worldwide. Squamous cell carcinoma predominates in the cervix uteri, while adenocarcinoma and adenosquamous carcinomas represent about 10-15% of all cervical cancers. Many studies have confirmed that the human papillomavirus (HPV) is the most important etiologic factor in the development of cervical cancer. The aim of our study was to investigate the expression of the laminin-5 gamma2 chain in primary malignancies of the cervix uteri and to focus on the clinicopathologic significance of the expression of the laminin-5 gamma2 chain in cervical squamous carcinoma and adenocarcinoma with respect to age and survival of the patients. The study consisted of a total of 89 cases of invasive cervical cancer (54 squamous carcinomas and 35 adenocarcinomas). The laminin-5 gamma2 chain was found in 80% of all the squamous carcinoma and in 66% of cervical adenocarcinoma. There was no correlation of the high expression of laminin-5 with survival. The univariate analysis in squamous cell carcinoma showed that factors such as the stage of the disease and positive lymph nodes had an impact on the survival of the patients, whereas in the multivariate analysis, only age at diagnosis was an independent prognostic factor. However, in cases with cervical adenocarcinoma, only the stage of the disease was an independent prognostic factor. There was no difference between HPV-positive and HPV-negative tumors concerning the high expression of laminin-5 gamma2 chain. Our results indicate that the majority of the primary cervical tumors, especially squamous cell carcinoma, showed expression of laminin-5 gamma2 chain immunoreactivity. Independent prognostic values for the survival of the patients were age and stage of the disease.     

Laminin-5 gamma2 chain expression facilitates detection of invasive squamous cell carcinoma of the uterine cervix.

Because it has been suggested that laminin-5 can be used as a sensitive marker for epithelial cell invasion, specimens from patients with invasive squamous cell carcinoma of the uterine cervix with a previous history of preinvasive lesions were evaluated by a newly developed monoclonal antibody directed against the gamma2 chain of laminin-5. Thirty-two archival paraffin specimens consisting of the matched preinvasive and invasive lesions from 15 women were evaluated to determine whether gamma2 chain laminin-5 staining was present in lesions that progressed to invasive cancer. With the exception of one tumor (a small cell nonkeratinizing squamous carcinoma), all squamous cell carcinomas exhibited positive staining. Five of 17 preinvasive lesions also were immunoreactive for the laminin-5 protein. A blinded histologic reevaluation revealed invasion or lesions suspicious for invasion in four of five preinvasive lesions. Our findings suggest that laminin-5 determined by a monoclonal antibody facilitates the identification of invasive lesions that are difficult or impossible to identify on routinely stained histologic sections.     

Laminin-5 γ 2 chain as an invasivity marker for uni- and multifocal lesions in the lower anogenital tract

Abstract. Nordström B, Einhorn N, Silfverswärd C, Sjövall K, Tryggvason K, Auer G. Laminin-5 γ 2 chain as an invasivity marker for uni- and multifocal lesions in the lower anogenital tract.
During recent decades it has become apparent that there are two types of vulvar disease: the classic type found in elderly women with unicentric and unifocal lesions, and the type found in younger women, in which precancerous and invasive changes develop in the anogenital lower tract in a multicentric and multifocal fashion, often over a long period of observation.
The laminin-5 γ 2 chain is an extracellular protein that is a component of the basement membrane. Recently its expression has been recognized as a marker in cervical cancer that permits identification of invasive capacity.
The aim of our study was to determine if laminin-5 γ 2 chain antibody can act as a sensitivity marker of invasive capacity in precancerous and invasive carcinoma in women with uni- and multifocal changes in the anogenital tract. The result showed that all patients in the older group of women with invasive carcinoma of the vulva had moderate to high positive expression of the laminin-5 γ 2 chain. In the group of younger patients with multifocal precancerous changes observed over long periods, most of the patients with vulva intraepithelial neoplasia (VIN) 3 showed laminin-5 γ 2 chain positivity already in the precancerous changes, and all of them developed invasivity during the period of observation. Normal epithelium without atypia was mostly negative or of low immunoreactivity of laminin-5. In conclusion, positive laminin-5 γ 2 chain expression seems to indicate the invasiveness potential of precancerous lesions and is also expressed in all investigated invasive carcinomas of the anogenital tract.     

Clinical significance of p27 and Skp2 protein expression in uterine cervical neoplasm.

The loss of p27 indicates a poor prognosis in various solid tumors, and a decrease in p27 level is the result of increased degradation by Skp2. We evaluated the relationship of p27 and Skp2 protein expression to various clinicopathologic factors in 332 cases of untreated uterine cervical neoplasm using tissue microarray method. After immunohistochemical staining, 313 and 300 tumor samples were retrieved for interpretation for p27 and Skp2, respectively. High p27 protein expression (nuclear staining in more than 30% of the tumor cells) was seen in 39.9% (125/313 cases), including 32 cervical intraepithelial neoplasia (CIN) III (55.2%), 58 microinvasive squamous cell carcinoma (SCC) (56.9%), 21 invasive SCC (17.1%), 11 adenocarcinoma (55.0%), and 3 cases of other tumors (30.0%). High Skp2 protein expression was noted in 28.3% (85/300 cases), including 14 cervical intraepithelial neoplasia III (25.0%), 18 microinvasive SCC (18.75%), 45 invasive SCC (37.8%), 6 adenocarcinoma (30.0%), and 2 cases of other tumors (22.2%). Low p27 protein expression was correlated with large tumor size (P < 0.005), depth of invasion in squamous lesion (P < 0.0005), high stage (P < 0.0005), and poor survival (P < 0.005). High Skp2 protein expression was correlated with large tumor size (P < 0.05), depth of invasion in squamous lesion (P < 0.05), and high stage (P < 0.005), but not with patient survival. There was no significant correlation between p27 and Skp2 protein expression. Only tumor stage had prognostic significance in the multivariate analysis (P = 0.041). Patients with low p27 protein expression had worse prognosis, indicating that p27 may participate in the progression of cervical squamous cell lesions.     

Role of human papillomavirus DNA testing in management of women with atypical squamous cells of undetermined significance

To find the sensitivity, specificity, and positive and negative predictive values of the high-risk group human papillomavirus (HPV) DNA testing as a triage tool to detect high-grade squamous intraepithelial lesions (HSILs, ie, cervical intraepithelial neoplasia [CIN] 2 or worse) in women with a cytologic smear showing atypical squamous cells of undetermined significance (ASC-US). All new cases with cytologic smears showing ASC-US that presented in King Chulalongkorn Memorial Hospital from January 2003 to November 2003, excluding known cases of HSILs and pregnancies, were enrolled. Cervical cell samplings were done by cervical cytobrush technique and tested for high-risk group HPV with the Hybrid Capture 2 (HC2) test. All participants were examined under a colposcope. Then cervicographs were taken before colposcopic-directed cervical biopsies were done. Of the 90 ASC-US cases enrolled, the pathologic results were normal in 30.0%, squamous metaplasia in 16.7%, CIN 1 in 37.8%, CIN 2 in 1.1%, CIN 3 in 11.1%, and microinvasive cervical carcinoma in 3.3%. The prevalence of HSILs and the prevalence of high-risk HPV detection were 15.6% and 38.9%, respectively. Using pathologic results from cervical biopsy as the gold standard, the HC2 has the sensitivity, specificity, and positive and negative predictive values of 85.7%, 69.7%, 34.3%, and 96.4%, respectively, to detect HSILs. High-risk group HPV detection can be used as an additional triage test to detect HSILs in women having ASC-US with high sensitivity and negative predictive value.     

Reduced Fhit expression in cervical carcinoma: correlation with tumor progression and poor prognosis

OBJECTIVE: The fragile histidine triad (FHIT) gene is located at chromosome 3p14.2 and encompasses the common fragile site, FRA3B, which may contribute to chromosome breakage and rearrangement of cancer cells. Aberrant protein expression and inactivation of the FHIT gene have been identified in a variety of precancerous and cancerous lesions. To identify the potential implications of the FHIT gene in the development of cervical carcinoma and explore the clinical importance of change in gene expression, we assessed the level of Fhit protein in precancerous lesions and carcinomas of the cervix. METHODS: In our study, 15 low-grade squamous intraepithelial lesions (LSIL), 35 high-grade squamous intraepithelial lesions (HSIL), 12 microinvasive carcinomas, and 103 invasive carcinomas were evaluated. The expression of Fhit was studied by immunohistochemistry using a polyclonal antibody specific for the protein. RESULTS: All samples of normal epithelium and LSIL exhibited intermediate to strong immunostaining of Fhit. Reduced Fhit protein expression was observed in 30 of 103 (29.1%) invasive carcinomas, 1 of 12 (8.3%) microinvasive carcinomas, and 3 of 35 (8.6%) HISL. Compared with normal epithelium and dysplasia, microinvasive and invasive carcinomas showed significantly lower Fhit expression. Fhit expression was also correlated with clinicopathological status. Reduced Fhit expression was significantly associated with lymph node metastasis (P = 0.005), parametrial invasion (P = 0.023), and vaginal involvement of the tumor (P = 0.016). In univariate analysis, Fhit expression was found to be a significant predictor of survival (relative risk 2.54, P = 0.0091): the patient with reduced Fhit expression had a 154% higher risk of dying from cervical cancer than the patient with opposite values. CONCLUSION: Our results indicate that immunostaining of Fhit expression has potential as a prognostic marker in the management of cervical cancer. The trend of reduced Fhit expression in microinvasive and invasive carcinomas suggests that down-regulation of Fhit is strongly linked to cancer progression. Moreover, loss of Fhit expression was related to lymph node metastasis, parametrial invasion, and vaginal involvement in cervical carcinoma. These results imply that loss of Fhit protein is associated with highly aggressive phenotypes of cervical carcinoma.     

The Reliability of a Cytological Prediction of Cervical Adenocarcinoma In Situ

A spectrum of changes precedes clinical invasive adenocarcinoma of the cervix. Cytological and histological criteria for the diagnosis of adenocarcinoma in situ (ACIS) are becoming more clearly defined. A 5-year prospective study was undertaken to test the accuracy of a cytological prediction of ACIS. From a total of 290,000 cervical smears 54 predictions of ACIS were made: 33 (61%) alone and 21 (39%) with associated squamous carcinoma in situ (SCIS). The rate of reporting ACIS was compared to the rates for intraepithelial and invasive squamous lesions and for frank invasive adenocarcinoma. The findings suggest that ACIS is being underdiagnosed. Forty-seven patients were adequately investigated; 46 had intraepithelial or invasive malignancy. There were 10 cases of ACIS, 10 ACIS with SCIS, 9 microinvasive adenocarcinoma, 5 invasive adenocarcinoma, 2 microinvasive adenosquamous carcinomas, 1 invasive adenosquamous carcinoma, 8 SCIS and 1 endometrial carcinoma. There was one true false positive report. Thus cervical glandular neoplasia was confirmed in 37 patients (79%), 13 of these having adenosquamous tumours. Because 98% of patients had in situ or invasive malignancy and because 36% of cases were invasive (though mostly microinvasive) prompt investigation, by cone biopsy, must follow a cytological report of ACIS.     

Angiogenesis in cervical intraepithelial neoplasia and the risk of recurrence.

OBJECTIVE: We sought to investigate whether angiogenesis can predict the risk of recurrence of cervical intraepithelial neoplasia after treatment. STUDY DESIGN: Microvessel density was studied in 75 patients with grade 3 cervical intraepithelial neoplasia and in 20 patients with microinvasive squamous carcinoma (International Federation of Gynecology and Obstetrics stage IA1) of the uterine cervix by staining representative tissue sections with the specific endothelial marker anti-CD31. The microvessel density was determined with a digital image analyzer. The results were correlated with clinical and histopathologic data. RESULTS: The mean vessel density was 264 per field (range, 86-674 per field) in grade 3 cervical intraepithelial neoplasia and 378 per field (range, 161-848 per field; P = .001) in microinvasive squamous carcinoma. Thirteen patients with grade 3 cervical intraepithelial neoplasia had recurrent cervical intraepithelial neoplasia (microvessel density, recurrent vs nonrecurrent; not significant). Multiple regression analysis in the noninvasive group confirmed that the mean vessel density (P = .121) had no prognostic value. Furthermore, it showed that the age at diagnosis (P = .011), menopausal status (P = .052), and treatment modality (P = .022) proved to be independent prognostic factors for recurrence. CONCLUSIONS: During the progression from noninvasive to microinvasive cervical carcinoma, the microvessel density increases significantly. However, the vessel density does not predict recurrence of noninvasive lesions.     

Fascin, an actin-bundling protein expression in cervical neoplasms

PURPOSE OF INVESTIGATION: Our objectives were (1) to examine expression of fascin in cervical tissues with chronic inflammation, intraepithelial neoplasms and invasive carcinomas, and (2) to investigate the role of fascin on endothelial migration and angiogenesis in cervical neoplasms. METHODS: In this study we investigated by means of immunohistochemistry fascin expression in 92 cervical biopsy samples representative of chronic inflammation (n=13), squamous intraepithelial lesions (SILs, n = 33) and invasive carcinomas (n = 46). RESULTS: Various degrees of fascin expression were observed in 94% of the samples of SILs, in 67% of the samples of invasive cervical carcinoma and in 69% of the samples of chronic inflammation. Total epithelial fascin scores of samples were significantly higher in high-grade (H)SILs compared to low-grade (L)SILs, invasive carcinoma and chronic inflammation of the cervix (p < 0.05). Mean microvessel count was 55.00 +/- 5.17 in HSILs, 40.76 +/- 3.57 in LSILs, 37.11 +/- 2.91 in carcinoma and 25.69 +/- 3.98 in chronic inflammation. We found a significantly higher microvessel count in HSILs compared to invasive carcinoma and chronic inflammation (respectively, p = .004, p = .000). CONCLUSION: Epithelial fascin expression up-regulated when the malignant tumor cell phenotype had occurred in the cervix. Similarly, microvessel count increased with the beginning of cervical tumorigenesis.     

Down-regulation of p27 is associated with malignant transformation and aggressive phenotype of cervical neoplasms

OBJECTIVES: p27Kip1 (p27) is a member of the cyclin-dependent kinase inhibitor family. The level of p27 protein expression decreases during tumor development and progression in some epithelial tumors. To identify the potential implications of the p27 gene in the development of cervical carcinoma and explore the clinical importance of change in gene expression, we assessed the level of p27 protein in precancerous lesions and carcinomas of the cervix. METHODS: In our study, 20 low-grade squamous intraepithelial lesions (LSIL), 35 high-grade squamous intraepithelial lesions (HSIL), 12 microinvasive carcinomas, and 103 invasive carcinomas were evaluated. The expression of p27 was studied by immunohistochemistry using a monoclonal antibody specific for the protein. RESULTS: p27 was expressed in all samples of normal epithelium, LSIL, and HSIL, and the mean values of expression were 55.1, 52.8, and 45.4%, respectively. Conversely, the expression of p27 was significantly reduced in microinvasive (15.9%) and invasive carcinomas (11.2%). Furthermore, loss of p27 expression was significantly associated with lymph node metastasis (P = 0.009). However, p27 down-regulation had no influence on overall survival using univariate analysis. CONCLUSIONS: The trend of reduced p27 expression in microinvasive and invasive carcinomas suggests that down-regulation of p27 expression is strongly linked to neoplastic transformation of cervical epithelium, and inactivation of p27 may be an early event in cervical carcinogenesis. Moreover, loss of p27 expression was related to lymph node metastasis in cervical carcinoma. These results imply that inactivation of p27 is associated with highly aggressive phenotype of cervical carcinoma.     

人乳头瘤病毒L1壳蛋白在筛查宫颈鳞状上皮内病变中的应用

目的:探讨人乳头瘤病毒(HPV)L1壳蛋白筛查HPV阳性妇女宫颈脱落细胞中宫颈鳞状上皮内病变的应用价值。方法:选取2012年5月至2014年12月就诊于温州市人民医院的妇女212例,收集宫颈脱落细胞并行HPV L1壳蛋白检测、HPV DNA分型、TCT(液基细胞学)及阴道镜下活检,比较HPV阳性妇女的宫颈脱落细胞中HPV L1壳蛋白的表达情况。结果:212例细胞学标本中HPV L1壳蛋白阳性率为33.9%,其中未见上皮内病变/恶性细胞组(NILM)、无明确诊断意义的鳞状上皮细胞病变组(ASCUS)、低度鳞状上皮内病变组(LSIL)、不能排除高度鳞状上皮内病变组(ASC-H)、高度鳞状上皮内病变组(HSIL)中阳性率分别为47.1%、35.1%、54.2%、29.2%、16.1%,各组比较差异有统计学意义(P0.05);两两比较,HSIL组与LSIL组和NILM组比较,差异均有统计学意义(P均0.005);进行数据合并后,LSIL/ASCUS组与ASC-H/HSIL组比较差异有统计学意义(P=0.001)。178例宫颈细胞学异常患者中,宫颈低级别病变和宫颈高级别病变的HPV L1壳蛋白阳性率比较,在ASCUS组(P=0.000)、LSIL组(P=0.004)中均有差异,在ASC-H组(P=0.127)、HSIL组(P=0.515)中均无差异。HPV 16/18感染患者的HPV L1壳缺失同宫颈高级别病变有更紧密的关系(P=0.003)。结论:子宫颈脱落细胞HPV L1壳蛋白检测在HPV阳性妇女的子宫颈病变筛查中具有一定的价值,可能成为一种合适的分流方法。     

Three-group metaphase as a morphologic criterion of progressive cervical intraepithelial neoplasia.

OBJECTIVE: The purpose of our study was to investigate the presence of three-group metaphase in progressive cervical intraepithelial neoplasia. STUDY DESIGN: This was a retrospective histologic study on the conization specimens of 41 women with microinvasive cervical carcinoma, 28 of whom were enrolled in the study. Three-group metaphase was scored in the invasive part of the lesion and in the adjacent cervical intraepithelial neoplasia. RESULTS: Three-group metaphase was found in 93% of cervical intraepithelial neoplasia adjacent to the invasive part of the lesion. However, three-group metaphase was found in 11% of the microinvasive cervical carcinoma cases with an infiltration depth of less than 2.5 mm and in 60% of the microinvasive cervical carcinoma cases with an infiltration depth of between 2.5 and 5.0 mm. CONCLUSION: The chance of finding three-group metaphase seems to be limited by the area of the lesion examined for three-group metaphase on the slide. Given the relation between three-group metaphase and aneuploid cervical intraepithelial neoplasia found in the literature and the occurrence of three-group metaphase in the cervical intraepithelial neoplasia adjacent to the microinvasive cervical carcinoma in this study, three-group metaphase can be considered a morphologic criterion for progressive cervical intraepithelial neoplasia and can be of value for practical use.     

Cyclooxygenase-2 and c-erbB-2 expression in uterine cervical neoplasm assessed using tissue microarrays

OBJECTIVES: Cyclooxygenase-2 (COX-2) and c-erbB-2 are involved in the pathogenesis of solid organ tumors. Chemotherapeutic agents targeting COX-2 and c-erbB-2 are used to treat colon and breast cancers. This study evaluated the significance and relationship of COX-2 and c-erbB-2 protein expression in untreated uterine cervical neoplasm. METHODS: This study included 332 patients with uterine cervical neoplasm. We constructed tissue microarray blocks that included two cores from each donor tumor and immunostained them with primary anti-cyclooxygenase-2 and anti-c-erbB-2 monoclonal antibodies. The clinical features and survival data were compared. RESULTS: Three hundred and eighteen tumor samples (95.8%) could be interpreted after immunohistochemical staining. COX-2 protein expression was noted in 140 cases of uterine cervical neoplasm (44.0%): In 26.7% of the cervical intraepithelial neoplasia III (16/60 cases), 37.9% of the microinvasive squamous cell carcinoma (39/103 cases), 51.6% of the invasive squamous cell carcinoma (64/124 cases), and 76.2% of the adenocarcinomas (16/21 cases) (P < 0.005). By contrast, except for one case of adenoid cystic carcinoma, none of the uterine cervical neoplasm expressed c-erbB-2 protein. COX-2 protein expression correlated with histology (P < 0.005) and stage (P < 0.05), but was not associated with patient survival. CONCLUSION: COX-2 may participate in the progression of cervical squamous cell lesions, while the contribution of c-erbB-2 to cervical carcinogenesis is probably small.     

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.     

p53 and p21 expression in precancerous lesions and carcinomas of the uterine cervix: overexpression of p53 predicts poor disease outcome

OBJECTIVES: Abnormal expression of the p53 and p21(waf1/cip1) tumor suppressor genes has been observed in a variety of human tumors, but little is known about its expression during cervical tumorigenesis. To identify the potential implications of both genes in the development of cervical carcinoma and explore the clinical importance of changes in gene expression, we assessed the levels of both proteins in precancerous lesions and carcinomas of the cervix. METHODS: In our study, 10 low-grade squamous intraepithelial lesions (LSIL), 35 high-grade squamous intraepithelial lesions (HSIL), 12 microinvasive carcinomas, and 103 invasive carcinomas were evaluated. The expression of p53 and p21 was studied by immunohistochemistry using monoclonal antibodies specific for these proteins. RESULTS: p21 was expressed in all samples of normal epithelium, LSIL, and HSIL, and the mean values of expression were 50.3, 42.5, and 44.5%, respectively. Conversely, the expression of p21 was significantly reduced in microinvasive (30.7%) and invasive carcinomas (9.9%). p53 nuclear staining was not detected in normal epithelium samples or LSILs, while 4 (11.4%) of 35 HSILs, 1 (8.3%) of 12 microinvasive carcinomas, and 38 (36.9%) of 103 invasive carcinomas were positive for p53. Compared with the results of the control group, precancerous lesions, and microinvasive carcinoma, the mean value of p53 expression (4.8%) in invasive carcinoma was significantly higher. Furthermore, p53 overexpression was significantly associated with advanced stage of the tumor (P < 0.001) [16/67 (23.9%) stage I, 15/28 (53.6%) stage II, and 7/8 (87.5%) stage III/IV]. In univariate analysis, p53 overexpression was a significant predictor of poor survival, whereas it had no independent influence on overall survival using the Cox regression method. Our data also revealed that no association between p53 immunostaining and p21 expression was found. CONCLUSIONS: The trend of reduced p21 expression in microinvasive and invasive carcinomas suggests that p21 may play a tumor-suppressor function in neoplastic transformation in cervical epithelium and inactivation of p21 may be an early event in cervical carcinogenesis. Our results indicated that p53 overexpression was a significant predictor of poor disease outcome in univariate analysis. Moreover, significantly increased expression of p53 in advanced-stage cervical carcinoma implies that inactivation of p53 is associated with tumor progression. Finally, this study further supports the notion that induction of p21 expression can be regulated in a p53-independent manner.     

5-hmC在宫颈上皮内瘤变病理诊断中的意义及其与HPV感染的相关性#br#

目的探讨5-羟甲基胞嘧啶(5-hmC)在宫颈上皮内瘤变和宫颈鳞癌中的表达,高危型HPV在上述病变中的感染率,分析两者之间的相关性。方法应用免疫组织化学技术分别检测正常组(31例)、LSIL(42例)、HSIL(61例)和宫颈鳞癌(91例)5-hm C的表达和高危型HPV感染率。结果5-hm C阳性率在正常组、LSIL、HSIL以及宫颈鳞癌组逐渐降低,差异有统计学意义(χ²=21.146,P=0.000);高危型HPV感染率随着病变的加重逐渐增高,差异有统计学意义(χ²=69.964,P=0.000);5-hm C和高危型HPV感染率都与宫颈上皮内瘤变的组织学分级具有相关性(r=-0.512,P=0.000)、(r=0.541,P=0.000);且两者之间呈负相关(r=-0.315,P=0.000)。结论5-hm C的表达水平对宫颈上皮内瘤变分级诊断具有鉴别意义并且与高危型HPV感染密切相关,两者可能共同促进了宫颈上皮内瘤变向宫颈鳞癌的转化。     

Potential hazards of following atypical and low-grade cervical cytology without colposcopy

Objective: To determine the frequency of high-grade cervical intraepithelial neoplasia in patients with atypical and low-grade cervical cytology and to assess the optimal evaluation and follow-up.Methods: Prospective observational study of 367 of 7,651 private patients who had cytologic, virologic, or colposcopic changes suggesting cervical intraepithelial neoplasia or cervical carcinoma. The study was performed to determine the frequency of cervical intraepithelial neoplasia in the various cytologic groups and to assess the effect of testing for human papillomavirus on the sensitivity, specificity, and positive predictive value of these tests.Results: Papanicolaou smears that included all non-negative tests (high- and low-grade squamous intraepithelial lesions and atypical squamous or glandular epithelial cells of undetermined significance) had the maximal sensitivity (89%) for high-grade cervical intraepithelial neoplasia and cancer. The combined cytologic categories of high- and low-grade squamous intraepithelial lesions had a sensitivity of 58%, this was reduced to 24% if only high-grade squamous intraepithelial lesions were considered relevant for additional evaluation. If we had not evaluated the patients with atypical squamous and glandular cells of undetermined significance, we would have missed diagnosing one third of high-grade and one half of low-grade cervical intraepithelial neoplasia. Cervical cytology was false negative in 8% of patients with high-grade and in 14% of those with low-grade cervical intraepithelial neoplasias. High-risk human papillomavirus deoxyribonucleic acid was detected in 40% of women with high-grade and in 24% of those with low-grade grade cervical intraepithelial neoplasias. The positive predictive value of cytology with atypical squamous cells of undetermined significance increased from 5% to 38% for high-grade and from 30 to 85% for high- and low-grade cervical intraepithelial neoplasias in patients with detectable high-risk human papillomavirus deoxyribonucleic acid. Virologic studies produced no significant improvement on these diagnoses in women with high- or low-grade cytology.Conclusions: Because of the poor sensitivity of cytology suggesting high-grade squamous intraepithelial lesions, we recommend that all women with atypical or low-grade cytology be recalled for colposcopy and high-risk human papillomavirus deoxyribonucleic acid testing, if available. Decisions whether to perform a biopsy should be based on the result of colposcopic examination. Performing colposcopy only on those patients who have cytologic high-grade squamous intraepithelial lesions and following those with lower grade cytologic anomalies without colposcopic diagnosis appears inadequate to rule out high-grade cervical intraepithelial neoplasia.     

Invasive carcinoma after cone biopsy for cervical intraepithelial neoplasia

A retrospective review of 578 patients with invasive cervical cancer identified 8 patients with a history of one or more cone biopsies for treatment of cervical intraepithelial neoplasia. The cone biopsy and hysterectomy specimens were reviewed to identify factors predictive of the subsequent development of invasive cancer. The mean interval from cone biopsy to diagnosis of invasive carcinoma was 6.7 years (range 1.5-16.5 years). High-grade intraepithelial neoplasia is a potentially invasive lesion. Adenocarcinoma in situ was identified as a high-risk lesion that may be inadequately treated by cone biopsy. Four patients developed invasive squamous cancer in spite of complete excision of the initial lesion. Patients who have high-grade intraepithelial neoplasia treated with cone biopsy require long-term follow-up, and conization may hamper the subsequent diagnosis of preinvasive lesions.     

The role of p53, Bcl-2 and Ki-67 in premalignant cervical lesions and cervical cancer

PURPOSE: The aim of this study was to determine the role of p53, Bcl-2 and Ki-67 expression in the carcinogenesis of cervical carcinoma and aggressiveness of cervical intraepithelial neoplasia (CIN). METHODS: The pathology specimens of 63 patients with a diagnosis of normal squamous epithelium (22 cases), CIN I (14), CIN II (5), CIN III (8) and squamous cell carcinoma (14) were evaluated immunohistochemically for the expression of p53, Bcl-2 and Ki-67 in paraffin sections. RESULTS: The expression of p53 and Ki-67 increased proportionally to the grade of CIN and cervical cancer, but only the increase of p53 expression was statistically significant (p = 0.002). There was no significant correlation between Bcl-2 expression and premalignant and malignant cervical lesions. CONCLUSION: p53 expression may have a role in the carcinogenesis of squamous cell cervical carcinoma whereas Bcl-2 expression has no role. Ki-67 expression can not be used in determining the aggressiveness of CIN lesions.