Skp2和p27在宫颈癌组织的表达及临床意义

目的:探讨Skp2、p27在宫颈癌的表达、两者的相关性,以及与临床病理因素和预后的关系。方法:用免疫组化SP法检测65例宫颈鳞状细胞癌(SCC),20例高级别宫颈上皮内瘤变(CIN)中Skp2、p27的表达,以60例正常宫颈组织(NCT)为对照。结果:(1)Skp2在SCC组的阳性表达率为55.4%,明显高于高级别CIN组的25.0%(P0.05)及NCT组的6.7%(P0.01);(2)p27在SCC组的阳性表达率为52.3%,明显低于高级别CIN组的85.0%(P0.01)及NCT组的98.3%(P0.01);(3)半定量分析表明SCC中Skp2、p27表达与年龄、肿瘤大小、临床分期无明显关系(P0.05),而与肿瘤的病理分级、浸润深度、脉管浸润、淋巴结转移密切相关(P0.05);(4)宫颈癌中Skp2阳性表达组的5年生存率(52.78%)明显低于Skp2阴性组(68.93%),Kaplan-Meier生存率分析,Log-rank=8.60,P=0.0034。而p27阳性表达组的5年生存率(70.59%)明显高于阴性表达组(58.38%),Log-rank=8.33,P=0.0039;经Spearman等级相关分析表明,宫颈癌中Skp2和p27的表达呈显著负相关,相关系数r=-0.311,P=0.015。结论:Skp2表达增强与宫颈癌的发生、发展密切相关,其表达水平越高提示患者预后越差;p27的表达正相反,并且两者的表达呈负相关。联合检测Skp2和p27的表达对判断宫颈癌的恶性潜能和预后具有重要的参考价值;两者可作为宫颈癌的预后指标,为宫颈癌的治疗提供新的靶点。     

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.     

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.     

Laminin-5 gamma 2 chain expression in cervical intraepithelial neoplasia and invasive cervical carcinoma

BACKGROUND. To analyze the expression of laminin-5 gamma 2 chain, a protein which plays a major role in keratinocyte migration, in cervical intraepithelial neoplasia (CIN), and invasive cervical carcinoma associated with high-risk oncogenic human papillomaviruses (HR-HPVs). MATERIAL AND METHODS. The expression of laminin-5 gamma 2 chain protein has been analyzed by immunohistochemistry in 17 cases of low-grade squamous intraepithelial lesions (LSIL-CIN1), 35 high-grade squamous intraepithelial lesions (HSIL-CIN2/3), 18 microinvasive or invasive carcinomas, and three metastatic lymph nodes. All these lesions have been proved to contain HR-HPVs and were also positive for p16 protein which classically is overexpressed at all stages of cervical neoplasia and dysplasia linked with HR-HPVs. 20 cases of normal cervix served as controls. RESULTS. The expression of laminin-5 gamma 2 chain protein was observed in 100% of invasive or microinvasive carcinoma and in their related lymph node metastasis with an immunoreactivity located preferentially at the invasive front of the lesions. All the HSILs (100%) associated with invasive carcinoma were also positive. In contrast, in HSILs without associated invasive component, the expression of the protein has been found in only 34% of cases. In positive HSILs, laminin-5 gamma 2 protein was expressed in basal layers. In LSILs and normal epithelium, no expression of the protein was noted. CONCLUSIONS. We conclude the following: (i) the expression of laminin-5 gamma 2 is a late event in cervical carcinogenesis increasing with the grade of dysplastic lesions; (ii) laminin-5 gamma 2 expression facilitates the identification of invasive and microinvasive lesions which could be difficult to diagnose on the basis of routine stains; (iii) laminin-5 gamma 2 expression in HSILs could potentially identify those lesions with a more increased risk of tumor progression.     

Increased expression of SKP2 and phospho-MAPK/ERK1/2 and decreased expression of p27 during tumor progression of cervical neoplasms

OBJECTIVE: The objective of this study was to investigate whether the expression of SKP2, p27 and phospho-MAPK/ERK1/2 is associated with the progression of human cervical neoplasia. METHODS: We performed immunohistochemical detection to stain formalin-fixed paraffin-embedded cervical tissues with anti-SKP2 and anti-p27 monoclonal antibodies and anti-phospho-p42/44 MAPK antibody. The study sample included 23 normal cervical epithelium, 25 low-grade squamous intraepithelial lesion (LSIL), 19 high-grade squamous intraepithelial lesion (HSIL), and 31 squamous cell carcinomas (SCC). In addition, 14 frozen cervical biopsies, including 1 normal, 6 HSIL, 2 adenocarcinoma and 5 SCC, and a human cervical cancer cell line (HeLa), were analyzed the expression levels of mRNA and protein of SKP2 and p27 by RT-PCR and Western blot analysis, respectively. RESULTS: The expression of SKP2, p27 and phospho-MAPK/ERK1/2 were strongly associated with cervical neoplastic progression (P<0.0001, P=0.006, P=0.003, respectively; Fisher's Exact Test). In addition, SKP2 expression was positively correlated with phospho-MAPK/ERK1/2 expression (Spearman correlation coefficient=0.480, P=0.0002). The association between SKP2 and phospho-MAPK/ERK1/2 was significant after controlling for the four histologic grades (P=0.038, Mantel-Haenszel test). CONCLUSIONS: These results suggest that expression levels of SKP2, p27 and phospho-MAPK/ERK1/2 may serve as markers for progression in human cervical carcinoma and may also play roles in cervical carcinoma progression and cervical carcinogenesis.     

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.     

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.     

Expression of p27, p21, and p16 protein in early squamous cervical cancer and its relation to prognosis

OBJECTIVE: To examine the prognostic significance of the protein expression of the cyclin-dependent kinase (cdk) inhibitors p27, p21, and p16 in early squamous cervical cancer (SCC). METHODS: From 221 [corrected] patients who underwent radical hysterectomy and bilateral lymphadenectomy at our institution for stage IB SCC between 1987 and 1993, tissue blocks were available for this study. Immunohistochemistry using monoclonal antibodies against p27, p21, and p16 was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolaps served as controls. RESULTS: p21 and p16 expression were increased in SCC and high expression was observed in 20% (44/221) and 43% (94/220) of tumors, respectively. p27 was decreased in SCC and low expression was found in 80% (177/221) of tumors. In univariate analysis all classical clinicopathological parameters were associated with prognosis. Low p16 expression was significantly related to decreased overall (P = 0.036) but not disease-free survival (P = 0.103). In multivariate analysis, deep stromal invasion but none of the cdk inhibitors was independently related to survival. CONCLUSION: The cdk inhibitors p27, p21, and p16 are not independently associated with prognosis in stage IB SCC.     

肿瘤干细胞相关基因ABCB1、ABCG2表达与宫颈上皮恶变及发展关系的研究

目的:探讨肿瘤干细胞相关基因ABCB1、ABCG2表达与宫颈癌形成及临床病理参数之间的关系。方法:应用组织芯片技术和免疫组织化学检测宫颈浸润癌34例、微小浸润癌30例、CINⅢ30例、宫颈慢性炎症30例患者ABCB1、ABCG2的表达,并与临床病理资料进行相关性分析。结果:ABCB1在浸润癌、微小浸润癌、CINⅢ、宫颈慢性炎症中的阳性表达率分别是为76%(26/34)、60%(18/30)、40%(12/30)、20%(6/30),其阳性表达率随病变级别升高而明显增加;ABCB1在浸润癌中表达水平与肿瘤分化程度、TNM分期、淋巴结转移密切相关(P<0.05),与肿瘤体积无关(P>0.05);ABCG2在浸润癌、微小浸润癌、CINⅢ、宫颈慢性炎症中的阳性表达率分别为80%(27/34)、70%(21/30)、40%(12/30)、30%(9/30),其阳性表达率随病变级别增加而上升;ABCG2表达水平与肿瘤体积、TNM分期密切相关(P<0.05),与淋巴结转移、肿瘤分化程度无关(P>0.05)。结论:ABCB1、ABCG2在促进宫颈癌变过程中发挥主要作用,并且ABCB1的阳性表达是提示宫颈癌预后不良的客观指标。     

Frozen section evaluation of cervical cold knife cone specimens is accurate in the diagnosis of microinvasive squamous cell carcinoma

OBJECTIVES: The purpose of this study was to determine the accuracy of frozen section evaluation of cervical cold knife cone (CKC) specimens in the diagnosis of microinvasive squamous cell carcinoma (SCC). METHODS: Using ICD-9 codes for invasive and microinvasive carcinoma of the cervix, a medical record from 1986 to 1998 identified 110 potential study subjects. Society of Gynecologic Oncologists criteria including depth of invasion < or =3 mm and absence of lymph-vascular space involvement were utilized for the diagnosis of microinvasion. Twenty-seven patients met study criteria including a frozen section diagnosis of microinvasive SCC on a cervical CKC specimen at our institution. A pathologist, blinded to patient diagnosis, reevaluated the histologic findings, including grade, depth of invasion, and cell type. RESULTS: Median age of diagnosis was 41 years. Median follow up was 3.6 years. The median time for pathologic review was 28 min (range 15-44 min). Independent retrospective pathologic review of the permanent sections confirmed the diagnosis of microinvasion in 100% (27/27) of patients. No patient experienced a cervical SCC recurrence. At 10 years, disease-specific survival is 100%. CONCLUSIONS: Frozen section is reliable in the evaluation of CKC specimens with microinvasive SCC: this may afford a simplified surgical approach in certain cases. This accuracy should not be assumed to apply to adeno- or adenosquamous carcinoma of the cervix. At our institution which relies heavily on intraoperative pathologic evaluation, utilizing frozen section diagnosis as the basis for definitive surgical approach did not negatively impact disease-free survival.     

半乳凝素-3在宫颈上皮内瘤变及宫颈鳞状细胞癌中的表达及其意义

目的:探讨半乳凝素-3(Galectin-3)在宫颈上皮内瘤变(CIN)及宫颈鳞状细胞癌(SCC)中的表达及其意义。方法:选择经病理确诊为CIN和SCC患者的石蜡标本60例,以同时期因子宫肌瘤行全子宫切除患者的正常宫颈组织(NC)石蜡标本10例作为对照,采用免疫组化方法分析CIN及SCC中Galectin-3表达情况。结果:NC、CIN、SCC及SCCⅠ、SCCⅡ、SCCⅢ组Galectin-3表达阳性率分别为40.00%、50.00%、83.33%及70.00%、90.00%、90.00%。NC、CIN、SCC3组间Galectin-3表达阳性率差异有统计学意义(χ2=9.559,P=0.049);NC组Galectin-3表达阳性率与SCCⅡ期组及Ⅲ期组比较,差异有统计学意义(χ2=5.495,P=0.029)。宫颈肿瘤>2cm组Galectin-3表达阳性率高于≤2cm组,差异有统计学意义(χ2=4.690,P=0.047)。结论:SCC中Galectin-3的阳性表达与肿瘤大小有关;Galectin-3表达阳性率随宫颈病变发展而升高。Galectin-3可能在SCC的发生、进展中发挥作用。     

宫颈鳞癌中Cyclin E的表达和HPV16感染的相关研究

目的探讨Cyclin E在宫颈鳞状细胞癌中的表达及其与HPV16感染的关系.方法应用免疫组化S-P法对34例宫颈鳞状细胞癌组织进行Cyclin E与HPV16的检测,并与宫颈不典型增生和正常宫颈组织进行比较.结果正常宫颈组织无Cyclin E表达,宫颈不典型增生组织仅有少量袁达(11.11%),宫颈鳞状细胞癌有58.52%表达(P＜0.001),且与HPV16感染有明显相关性(P＜0.05).结论高危HPV感染是宫颈癌的重要病因,HPV感染通过多种途径改变了细胞的周期性调控,诱发细胞周期GI-S期检测点异常,引起细胞恶性增生,HPV感染与Cyclin E异常表达在宫颈癌的发生发展中起重要作用.     

磷酸化蛋白激酶B和p27在宫颈癌组织的表达及意义

目的:探讨宫颈癌组织中磷酸化蛋白激酶B(P-PKB)和p27蛋白的表达及其在子宫颈癌发生、发展中的意义。方法:采用免疫组化SP法检测51例宫颈癌组织,36例宫颈上皮内瘤变(CIN)组织和20例正常宫颈组织中P-PKB蛋白和P27蛋白的表达,并分析它们与宫颈癌临床病理因素的关系。结果:宫颈癌组织中P-PKB的阳性表达率(74.5%)明显高于CIN组(52.8%)和正常宫颈组(15%)(P<0.05),P-PKB蛋白的表达随宫颈癌分化程度下降、临床分期升高而升高(P<0.05),在无淋巴结转移的宫颈癌中的表达明显低于有淋巴结转移癌(P<0.05)。p27蛋白在宫颈癌组织中的阳性表达率(49.0%)明显低于CIN组(80.1%)和正常宫颈组(90.0%)(P<0.05),p27蛋白的表达随宫颈癌分化程度下降、临床分期升高而降低(P<0.05),在无淋巴结转移的宫颈癌中的表达明显高于有淋巴结者(P<0.05)。宫颈癌中P-PKB蛋白表达与p27蛋白表达呈负相关(r=-0.326,P<0.05)。结论:P-PKB蛋白在宫颈癌中过表达,p27蛋白在宫颈癌中表达明显降低,与P-PKB蛋白表达呈负相关,P-PKB蛋白可能通过抑制p27蛋白的表达,促进肿瘤的发生发展。     

Cyclooxygenase-2 expression in cervical intraepithelial neoplasia III and squamous cell cervical carcinoma, and its correlation with clinicopathologic variables

The objective of the study was to compare cyclooxygenase-2 (COX-2) expression in cervical intraepithelial neoplasia III (CIN III) and squamous cell carcinoma (SCC) of the cervix, and its correlation with clinicopathologic factors of SCC with a review of the available literature. This study included 25 patients with CIN III and 67 patients with stage I-IIa SCC. All patients in the SCC group were treated with radical hysterectomy plus pelvic and para-aortic lymphadenectomy and postoperative chemoradiotherapy based on their histopathologic risk factors. Immunohistochemical analysis was performed on paraffin-embedded sections with COX-2 antibody. COX-2 expression in the SCC group was significantly higher than in the CIN III group (55.2% [37/67] vs 24% [6/25]; P= 0.008). Significantly higher expression of COX-2 was observed in patients with lymphovascular space invasion (LVSI) compared to patients without LVSI (61.9% [34/55] vs 33.3% [3/9]; P= 0.02). Additionally, patients with tumor sizes >4 cm had significantly higher COX-2 expression than patients with tumor sizes <4 cm (65.9% [27/41] vs 39% [10/26] P= 0.028). There was no significant relationship with respect to COX-2 expression and parametrial involvement, lymph node metastasis, recurrences, and survival. In multivariate analysis, LVSI was the only statistically significant determinant for COX-2 expression (P= 0.024; OR = 2.35; 95% CI = 1.1-4.9). Our results and a review of the literature both suggest that COX-2 expression may have a role in the development and progression of CIN III and it is related to some clinicopathologic variables of cervical carcinoma. Further studies are needed to clarify the role of COX-2 inhibitors in the management of CIN and SCC.     

Usefulness of combining testing for p16 protein and human papillomavirus (HPV) in cervical carcinoma screening

OBJECTIVE: To evaluate the value of the combination of p16 and HPV detection in the screening for cervical cancer. METHODS: 186 patients with previous abnormal cervical lesion were studied. After colposcopic examination, two conventional Pap slides were prepared: the first was Papanicolaou-stained and examined by cytologist; the second was immunocytochemically stained for p16. Cervical cells were collected by brush using for HPV detection by Hybrid Capture II. Biopsy of any colposcopically abnormal lesions was performed. RESULTS: The 186 cervical samples were classified cytologically as normal (148), ASCUS (13), low-grade (11), high-grade (12) dysplasia and squamous cell carcinoma (2). P16 and HPV were found in all high-grade dysplasia and SCC, and in 64% and 27% of low-grade dysplasia, 62% and 0% of ASCUS and 7.4% and 3.4% of normal, respectively. 18 of p16-positive cases (11%) were HPV-negative, 14 of them in the ASCUS and normal group. Compared to histological results, all of the p16-positive cases of squamous metaplasia, CIN II/III and SCC were HR-HPV-positive. Therefore, the cases that were positive for both with normal cytology (5 cases) or low-grade dysplasia (3 cases) may comprise a high-risk group for neoplastic change. CONCLUSION: The combination of p16 and HPV detection may be useful in cervical cancer screening to identify high-risk patients requiring early and proper management.     

Prognostic value of EphA2 and EphrinA-1 in squamous cell cervical carcinoma

OBJECTIVES: To analyze the expressions of the protein and mRNA of EphA2 and EphrinA-1 in squamous cell cervical carcinomas and explore their prognostic value in cervical carcinoma. METHODS: Immunohistochemistry was used to assess the protein expressions of EphA2 and EphrinA-1 in 206 patients with squamous cervical carcinoma FIGO stage Ia-IVb. Frozen tissues from 20 cases in which the tumors showed variable EphA2 and EphrinA-1protein expressions were used for laser capture microdissection (LCM). About 50 cancer cells in each frozen section were captured with the LCM method and processed for RT-PCR detection of EphA2 and EphrinA-1 mRNA. RESULTS: Among the 206 squamous cervical carcinomas, 23 (11.2%) showed negative, 94(45.6%) weakly positive, 72 (35.0%) moderately positive, and 17 (8.3%) strongly positive for EphA2 immunostaining. For EphrinA-1 protein expression, 17 tumors (8.3%) showed negative, 95 (46.1%) weakly positive, 71(34.5%) moderately positive, and 23 (11.2%) strongly positive. EphA2 and EphrinA-1 often colocalized in the same tumor areas and vascular endothelial cells. Variable amount of mRNA expressions of EphA2 and EphrinA-1 were observed in the 20 tumors analyzed. There was no significant correlation between the overexpressions of EphA2/EphrinA-1 and age and FIGO stage. High level of EphA2 was significantly associated with overall survival in univariate and multivariate analysis. Moderate to high EphrinA-1 protein expression was significantly associated with overall survival in multivariate analysis. The combined high level of expression of EhpA2 and moderate to high level of expression of EphrinA-1 was a strong predictor of overall survival. CONCLUSIONS: High levels of EphA2 together with moderate to high level of EphrinA-1 protein expressions in squamous cervical carcinoma were predictive for a shorter overall survival and these proteins may be valuable prognostic markers.     

pax1蛋白在子宫颈癌中的表达及与预后的关系

目的:研究配对盒基因1(pax1)在子宫颈组织中的蛋白表达及其临床意义,探讨pax1蛋白与子宫颈癌预后的关系。方法:采用免疫组化法检测中日友好医院2011年8月至2017年10月收治的101例子宫颈癌、120例子宫颈上皮内瘤变(CIN)及20例正常子宫颈组织(对照组)中pax1蛋白表达水平,分析其子宫颈癌临床病理参数,采用受试者工作曲线(ROC)评估其诊断效能并随访,探讨其与子宫颈鳞癌(SCC)及子宫颈腺癌(AC)预后的关系。结果:①对照组的pax1蛋白表达水平(90.0%)高于CIN(73.3%)及子宫颈癌(38.6%),SCC患者pax1蛋白阳性表达率(20.9%)明显低于AC(70.0%)及特殊类型子宫颈癌(100.0%),差异有统计学意义(P<0.05)。②ROC曲线显示,pax1蛋白曲线下面积(AUC)为0.829,诊断子宫颈癌的灵敏度90.0%,特异度61.3%。③pax1蛋白阳性表达率与子宫颈癌患者的HPV感染、分化程度、组织类型及脉管浸润有关(P<0.05)。④SCC患者中pax1蛋白阳性组的生存时间明显高于阴性组(P=0.040),AC患者中pax1蛋白阳性组的生存时间与阴性组比较,差异无统计学意义(P=0.589)。结论:pax1蛋白的表达缺失与CIN及子宫颈癌进展密切相关,其诊断CINⅡ及以上的效能较高。pax1蛋白的表达缺失与SCC的发生发展及预后有一定的关系,pax1蛋白有望成为监测SCC患者预后的有效指标。     

Value of squamous cell carcinoma antigen levels in invasive cervical carcinoma

Squamous cell carcinoma (SCC) antigen (Ag) levels were measured by radioimmunoassay in 64 patients with invasive squamous cell cervical carcinoma and 9 patients with nonsquamous carcinoma before the initiation of treatment. The mean antigen level in the squamous group was 10.5 ng/ml compared with 1.3 ng/ml in the nonsquamous group. In the patients with squamous cell carcinoma, mean SCC Ag level correlated well with stage, except for bulky stage IB tumors (P less than 0.05), where mean level was much higher than expected. Patients with exophytic tumors had significantly higher SCC Ag levels than those with nonexophytic tumors. Follow-up on 62 evaluable patients ranged from 20 to 40 months. The mean pretreatment SCC Ag level for patients free of disease at last contact was 5.6 ng/ml, in contrast to 16.1 ng/ml for those with recurrent disease. Only 32% of patients free of disease had pretreatment levels of 4.0 ng/ml or greater, while 86% of those with recurrent disease had such values (P less than 0.05). Forty patients had follow-up samples drawn 1 to 14 months after treatment. Mean post-treatment SCC Ag levels dropped to 1.8 ng/ml in 21 patients free of disease (73% decrease), but remained elevated at 13.4 ng/ml (17% decrease) in 19 patients with recurrences. The specificity of follow-up SCC Ag levels as a predictive test for outcome was 90%, with a sensitivity of 63%. We conclude that pretreatment SCC Ag levels correlate well with tumor stage, lesion morphology, and extent of disease. SCC antigen levels may be used to follow patients to determine effectiveness of treatment.     

Does regular cervical screening protect women from microinvasive squamous cell carcinoma of the cervix? A retrospective case-control study

OBJECTIVES: To compare the smear histories of women with microinvasive squamous cell carcinoma (SCC) of the cervix to those of women with cervical intraepithelial neoplasia grade 3 (CIN3). DESIGN: Retrospective case-control study. SETTING: A large public hospital gynaecology unit. Sample Twenty-nine consecutive women with microinvasive SCC FIGO stage 1A1 (cases). Fifty-five age-matched controls with histologically confirmed CIN3 (controls). METHODS: The cases and controls were selected from institutional databases; smear histories and other information was retrieved from hospital notes or following consent from other records. MAIN OUTCOME MEASURES: The time from index smear to prior screening smear and participation in the National Screening Programme (NCSP). RESULTS: Only 35% of cases compared with 78% controls had a smear in the last 3 years (P = 0.00008.) Cases had a longer median interval between the abnormal smear that resulted in diagnosis and the previous screening smear (4 years) compared with controls (2 years). Cases were less likely to be enrolled in the NCSP (65%) prior to their index smear than controls (85%). CONCLUSION: Delayed interval screening was more frequent in women with 1A1 SCC than CIN3.