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   

Gene expression profiles in squamous cell cervical carcinoma using array-based comparative genomic hybridization analysis

Our aim was to identify novel genomic regions of interest and provide highly dynamic range information on correlation between squamous cell cervical carcinoma and its related gene expression patterns by a genome-wide array-based comparative genomic hybridization (array-CGH). We analyzed 15 cases of cervical cancer from KangNam St Mary's Hospital of the Catholic University of Korea. Microdissection assay was performed to obtain DNA samples from paraffin-embedded cervical tissues of cancer as well as of the adjacent normal tissues. The bacterial artificial chromosome (BAC) array used in this study consisted of 1440 human BACs and the space among the clones was 2.08 Mb. All the 15 cases of cervical cancer showed the differential changes of the cervical cancer-associated genetic alterations. The analysis limit of average gains and losses was 53%. A significant positive correlation was found in 8q24.3, 1p36.32, 3q27.1, 7p21.1, 11q13.1, and 3p14.2 changes through the cervical carcinogenesis. The regions of high level of gain were 1p36.33-1p36.32, 8q24.3, 16p13.3, 1p36.33, 3q27.1, and 7p21.1. And the regions of homozygous loss were 2q12.1, 22q11.21, 3p14.2, 6q24.3, 7p15.2, and 11q25. In the high level of gain regions, GSDMDC1, RECQL4, TP73, ABCF3, ALG3, HDAC9, ESRRA, and RPS6KA4 were significantly correlated with cervical cancer. The genes encoded by frequently lost clones were PTPRG, GRM7, ZDHHC3, EXOSC7, LRP1B, and NR3C2. Therefore, array-CGH analyses showed that specific genomic alterations were maintained in cervical cancer that were critical to the malignant phenotype and may give a chance to find out possible target genes present in the gained or lost clones.     

血清SCCAg及CA125在诊断宫颈鳞癌及评价预后中作用的研究

目的:探讨血清SCCAg及CA125用于宫颈鳞癌诊断、手术治疗及预后的价值。方法:选取ⅠA2～ⅡA期宫颈鳞状细胞癌为研究组,20例CIN及20例慢性宫颈炎分别为对照组1和对照组2。采用固相夹心法酶联免疫吸附实验(ELISA)检测血清SCCAg的数值,采用化学发光免疫分析法(CLIA)检测血清CA125数值。比较分析血清SCCAg及CA125与宫颈鳞癌临床病理特征、手术疗效及预后的关系。结果:宫颈鳞癌组术前血清SCCAg及CA125水平均高于慢性宫颈炎组,差异均具有统计学意义(P<0.01)。宫颈鳞癌组术前SCCAg水平高于CIN组,差异有统计学意义(P<0.001);宫颈鳞癌组术前CA125水平与CIN组的差异无统计学意义(P=0.049,P>0.0167)。血清SCCAg、CA125诊断宫颈鳞癌的临界值分别为1.03ng/ml、8.16U/ml。血清SCCAg、CA125及两项联合诊断宫颈癌的ROC曲线下面积分别为0.954、0.718、0.960,两项联合后诊断性能无明显增加。宫颈鳞癌术前血清SCCAg随临床分期增加具有线性增加的趋势。脉管有否癌栓、盆腔淋巴结有否转移也与术前血清SCCA水平有关,差异有统计学意义(P=0.011,P=0.043)。宫颈鳞癌组手术治疗后的血清SCCAg及CA125水平均有逐渐降低趋势,差异有统计学意义(P均<0.001)。结论:血清SCCAg对宫颈鳞癌有较高的诊断价值,可考虑作为诊断及手术疗效评估指标之一,有助于初步判断脉管及盆腔淋巴结转移。血清CA125对于宫颈鳞癌诊断、手术评估及随访的价值均低于SCCAg,与SCCAg联合不能增加诊断的敏感度和特异度。     

CARM1、p16INK4a在子宫颈鳞状细胞癌中的表达及临床意义

目的 检测子宫颈鳞状细胞癌(CSCC)、宫颈上皮内病变及正常宫颈组织中组蛋白精氨酸甲基转移酶1(CARM1)、p16INK4a的表达,探讨两者在子宫颈鳞癌发生发展中的作用.方法 运用免疫组化技术检测CSCC、宫颈上皮内病变及正常宫颈组织中CARM1、p16INK4a表达,分析二者表达与子宫颈鳞状细胞癌临床病理特征及生存...     

Angiogenesis in cervical intraepithelial neoplasia and early-staged uterine cervical squamous cell carcinoma: clinical significance

The objective of this study is to evaluate angiogenesis in cervical intraepithelial neoplasia (CIN), microinvasive squamous cell carcinoma (MIC), and early-staged squamous cell carcinoma (SCC), stage IB-IIA of the cervix. Microvessel density (MVD) was evaluated and correlated with other pathologic prognostic factors and disease outcomes. Four hundred seventy-four cervical specimens were studied. Among these, 100 were designated normal cervix, 30 CIN1, 32 CIN2, 178 CIN3, 74 MIC, and 60 early-staged SCC. MVD per high-power field (x400) of early-staged SCC, MIC, and CIN3 were significantly higher in comparison to CIN2, CIN1, and control subjects (P<0.05). There was no statistically significant difference in MVD between control group, CIN1, and CIN2. In early-staged SCC, no correlation between MVD and pelvic lymph node status, parametrial involvement, depth of stromal invasion, and lymphovascular space invasion was found. Patients with bad outcomes (recurrence or death) showed no statistically different MVD from the ones who had unremarkable clinical courses.     

Age-period-cohort analysis of cervical cancer incidence in Taiwan: differences between squamous cell carcinoma and adenocarcinoma

To examine the etiologic distinction between squamous cell carcinoma and adenocarcinoma of the cervix, the relationship between the incidence of both histotypes of cancer and age at diagnosis, time period at diagnosis and birth cohort was analyzed using data from the Taiwan Cancer Registry. Included in the study were all cases of both histotypes occurring during the period 1979–90 within a population of Taiwanese women aged 25 to 75 years. A log-linear model modified from the method of Osmond and Gardner was used for the analyses. Age-period-cohort analyses of age effect indicated that, prior to the age group of 49–51, there is an almost identical incidence of both histotypes with an approximate linear trend of age effect but that, after this time, there is a divergence, with the age effect of increase slightly declining with age for squamous cell carcinoma and clearly declining for adenocarcinoma. In regard to period and cohort effects, a substantial moderation of squamous cell carcinoma risk was exhibited with both advancing recent calendar periods and birth cohorts, while adenocarcinoma risk also has a moderation but to a lesser extent. The model also identified the changes in female sex hormones after the menopause as a determinant of the differing age effects, the efficiency of Pap smear screening practices as a determinant of the differing period effects, and changes in reproductive patterns as a determinant of the differing cohort effects. These findings may provide clues with which to develop etiologic hypotheses and support the contention of etiologic distinctions between both histologic types.     

High cyclooxygenase-2 expression in cervical adenocarcinomas

OBJECTIVE: The purpose of this study was to examine the relationships between cyclooxygenase-2 (COX-2) expression and prognostic factors in cervical carcinomas. METHODS: We studied COX-2 expression in 53 women with cervical cancers, including 35 squamous cell carcinomas (SCCs), 1 adenosquamous cell carcinoma (ASCC), and 17 adenocarcinomas (ACs), using commercially available polyclonal antibodies on Formalin-fixed, paraffin-embedded tissues. Normal cervical tissues were obtained as from other patients with uterine myomas treated with a total hysterectomy (n = 16). The immunoreactivity was quantified using an immunohistochemical scoring system that approximates the use of an image analysis-based system. RESULTS: Twenty-two cervical cancer tissues (41.5%), including 10 SCCs and 12 ACs, expressed COX-2 at a moderate to strong level, which significantly, differed from the negligible expression found in the control group of 16 normal cervical tissues (P = 0.001). Different cell types showed significantly different expression levels of COX-2 (SCC at 28.6% vs AC at 70.6%, P = 0.004). The presence of deep stromal invasion (n = 40) showed a significant inverse relationship to COX-2 expression (32.5% vs 69.2%, P = 0.02). The expression of COX-2 in well-differentiated carcinomas was significantly increased compared to that in moderately and poorly differentiated carcinomas (72.7% vs 33.3%, respectively, P = 0.018). CONCLUSIONS: Overexpression of COX-2 was found in both SCC and AC, but SCCs showed infrequent and low expression. These findings suggest that increased COX-2 expression may play an important role in cervical adenocarcinomas.     

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.     

膀胱鳞状细胞癌中环氧合酶—2的表达情况

目的:探讨COX-2在膀胱鳞状细胞癌发生、发展中的作用。方法:采用免疫组化SP法,检测37例膀胱鳞状细胞癌和5例正常膀胱组织中COX-2的表达。结果:膀胱鳞状细胞癌中COX-2的表达阳性细胞数及强度均高于在膀胱尿路上皮癌中的表达,正常的膀胱组织中未见COX-2的表达。结论:COX-2的表达水平与膀胱鳞状细胞癌的发生、发展关系密切。     

Increased expression level of squamous cell carcinoma antigen 2 and 1 ratio is associated with poor prognosis in early-stage uterine cervical cancer

Squamous cell carcinoma antigen (SCCA) is a tumor marker for patients with squamous cell carcinoma of uterine cervix, lung, and esophagus. It was encoded by two highly homologous genes, SCCA1 and SCCA2. However, the relevance of SCCA genes to squamous cell carcinogenesis and patient outcome remains far from clear. In this study, by using laser microdissection and real-time quantitative polymerase chain reaction procedures, the messenger RNA (mRNA) expression of the SCCA1 and SCCA2 genes in normal, dysplastic, and malignant squamous epithelia from uterine cervical tissues were analyzed and correlated with outcome of cancer patients. We found that the SCCA2/A1 mRNA ratios were progressively increased from normal, dysplastic, to cancer cells, and the mean ratio was significantly higher in cancer tissues than that in normal epithelium (P= 0.02). The SCCA2/A1 mRNA ratios were not significantly associated with types of human papillomavirus infection (P > 0.05). High SCCA2/SCCA1 mRNA ratios (ratio >1) were an independent predictor of disease recurrence (relative risk: 3.58; P= 0.003). Of the 38 patients with cervical cancer, 12 patients with high SCCA2/SCCA1 mRNA ratios had a significant lower 2-year disease-free survival of only 50%, while it was 92% in those with low SCCA2/SCCA1 mRNA ratios (P < 0.001). In conclusion, our study indicated that the ratios of SCCA2 to SCCA1 RNA were increased during the process of cervical carcinogenesis, and patients with elevated SCCA2/A1 ratio carried a higher risk for recurrence in early-stage uterine cervical cancer.     

The clinical values of squamous cell carcinoma antigen and carcinoembryonic antigen in patients with cervical cancer treated with concurrent chemoradiotherapy

The objective of this study was to determine the prognostic significance of the pre- and posttreatment serum levels of the squamous cell carcinoma antigen (SCC-Ag) and carcinoembryonic antigen (CEA). From 2001 to 2005, 211 patients were treated with concurrent chemoradiotherapy (CCRT). The SCC-Ag and CEA levels were measured before treatment, 1 month after treatment, and during the follow-up. The association between the pretreatment tumor marker levels and the clinical prognostic factors was evaluated. The frequency of complete remission (CR) and the normalization of the posttreatment tumor marker were also analyzed. The pretreatment serum levels of CEA and SCC-Ag were elevated in 68 (32.2%) and 148 (70.1%) patients, respectively. The number of patients with an elevated pretreatment SCC-Ag level was associated with the FIGO stage, tumor volume, and pelvic lymph node status. The pretreatment CEA was only significantly related to the tumor volume and pelvic lymph node involvement. One month after completing CCRT, the CEA and SCC-Ag levels were normalized in almost all patients with an incidence of 88.2% (60/68) and 93.2% (138/148), respectively. Among the patients who gained CR with a previously elevated pretreatment CEA and SCC-Ag, the values were normalized in 92.1% (58/63) and 96.4% (134/139) at 1 month, respectively. Combination assays of the pre- and posttreatment serum CEA and SCC-Ag levels appear to be useful for both predicting the prognosis and estimating the clinical response in cervical cancer. However, the routine combined measurement with SCC-Ag of CEA in all patients had limited additional effect in predicting the prognostic significance.     

Impact of histological subtype on survival of patients with surgically-treated stage IA2-IIB cervical cancer: Adenocarcinoma versus squamous cell carcinoma

Objectives

To evaluate the significance of adenocarcinoma (AC) compared with squamous cell carcinoma (SCC) with regard to the survival of surgically-treated early stage cervical cancer patients.

Methods

We retrospectively reviewed the medical records of 520 patients with FIGO stage IA2-IIB cervical cancer who were treated with radical hysterectomy with or without adjuvant radiotherapy between January 1998 and December 2008. The patients were classified according to (i) pathological risk factors (low-, intermediate-, or high-risk group) and (ii) adjuvant radiotherapy (concurrent chemoradiotherapy [CCRT group] or radiotherapy alone [RT group]). Survival outcomes were examined by Kaplan-Meier method and compared with Log-rank test. Multivariate analysis for disease-specific survival (DSS) was performed using Cox proportional hazards regression model to investigate the prognostic significance of histological subtype.

Results

AC histology was associated with significantly decreased DSS compared with SCC histology in the intermediate- and high-risk groups (hazard ratio: 3.06 and 2.88, respectively, both P < 0.05) while there was no survival difference in the low-risk group (P = 0.1). Among patients who received any types of adjuvant radiotherapy, DSS of AC histology patients were significantly poorer than SCC histology. Multivariate analysis demonstrated AC histology to be an independent predictor of decreased DSS in both CCRT and RT groups. Moreover, pelvic nodal metastasis significantly predicted the poor survival of patients with AC histology who received CCRT in multivariate analysis

Conclusions

Adenocarcinoma is an independent prognostic indicator of poor survival in early stage cervical cancer patients with intermediate- and high-risk factors, regardless of the type of adjuvant radiotherapy after radical hysterectomy.     

子宫颈上皮内瘤变及子宫颈鳞癌中增殖细胞核抗原和C-myc基因过度表达及其临床意义

目的：研究增殖细胞核抗原（ＰＣＮＡ）及Ｃ－ｍｙｃ基因过度表达在子宫颈上皮内瘤变（ＣＩＮ）及子宫颈鳞癌中的变化及其临床意义。方法：用免疫组化方法检测ＣＩＮ及子宫颈鳞癌手术标本石蜡包埋切片中的ＰＣＮＡ及Ｃ－ｍｙｃ基因蛋白变化并分析子宫颈癌临床病理资料。结果：从正常子宫颈、ＣＩＮ到子宫颈鳞癌，ＰＣＮＡ含量及Ｃ－ｍｙｃ阳性表达呈增高趋势。ＣＩＮⅢ及子宫颈鳞癌的ＰＣＮＡ标记指数（ＰＣＮＡＬＩ）及Ｃ－ｍｙｃ阳性表达明显高于正常子宫颈及ＣＩＮⅠ－Ⅱ，并且Ｃ－ｍｙｃ基因阳性表达与ＰＣＮＡ大量出现呈正相关。ＰＣＮＡＬＩ及Ｃ－ｍｙｃ阳性表达随细胞分化程度而增加。子宫颈鳞癌分期及有无淋巴结转移对ＰＣ－ＮＡＬＩ及Ｃ－ｍｙｃ阳性表达差异无显著性。结论：检测ＣＩＮ及子宫颈鳞癌中ＰＣＮＡ数量及Ｃ－ｍｙｃ基因表达可了解宫颈癌的发生、发展，早期发现癌前病变及估计肿瘤的恶性潜能。     

Comparison of gene expression in squamous cell carcinoma and adenocarcinoma of the uterine cervix

OBJECTIVES: Microarray expression analysis of cervical tumors has revealed differential expression of genes that may be useful as markers or targets for treatment. We question the application of array findings across the major categories of cervical cancer. We sought to identify differences between normal squamous epithelium (NSQ) and glandular epithelium (NGL) of the uterine cervix and their malignant variants: squamous cell cancer (SCC) and adenocarcinoma (ACA). METHODS: Eight genes were selected: 12-lipoxygenase (12-LOX), keratin 4, trypsinogen 2 (TRY2), Rh glycoprotein C (RhGC), collagen type V alpha 2, integrin alpha 5, integrin alpha 6, and c-myc. Ten cases each of SCC and ACA of the cervix were selected from our tumor bank. NSQ and NGL epithelia were obtained from consecutive patients undergoing surgery for benign disease. RNA extraction, cDNA synthesis, and DNA amplification of all samples were performed according to an established protocol. Electrophoresis of the multiplexed polymerase chain reaction (PCR) products was performed under standard conditions, followed by digital image capture. A ratio of target to control gene (beta-actin) was obtained for each sample. Analysis of variance was applied to the mean ratios for each tissue to establish significant differences. Individual pairwise comparisons were made by Student t tests and verified with the Tukey-Kramer test. RESULTS: Clinically valid comparisons are NSQ to NGL, NSQ to SCC, NGL to ACA, and SCC to ACA. Various expression patterns were observed between the epithelia and their malignant phenotypes. Significant differences in gene expression were observed between benign squamous and glandular epithelium in four of the eight genes and between malignant squamous and glandular epithelium in three of the eight genes. Significant differences in gene expression between benign and malignant tissues were demonstrated in four of the eight genes. CONCLUSIONS: We have defined significant differential expression changes between the two principal cervical tumor types. Differences in genes are demonstrated and must be considered if array technology is applied to the study of the biologic behavior of these tumors as well as their screening and management. The observed differential expression should be a compelling argument to perform type-specific expression analysis for other tumors with histological variants.     

Comparison of treatment outcomes between squamous cell carcinoma and adenocarcinoma in locally advanced cervical cancer

Objective

To compare the treatment outcomes between squamous cell carcinoma (SCC) and adenocarcinoma (ACA) in locally advanced cervical cancer patients.

Methods

All medical records of stages IIB-IVA of cervical cancer patients who had completed treatment between 1995 and 2008 were reviewed. ACA 1 case was matched for SCC 2 cases with clinical stage, tumor size, treatment modalities (radiation therapy (RT) vs concurrent chemoradiation (CCRT)). Treatment outcomes including response to RT/CCRT, time to complete response (CR), patterns of treatment failure and survival outcomes were analyzed.

Results

A total of 423 patients with stages IIB-IVA (141 ACA: 282 SCC) were included. Most of the patients (about 60%) had stage IIB. The overall complete responses (CR) between ACA and SCC were 86.5% and 94.7%, respectively (p = 0.004). Median time to clinical CR from RT/CCRT of ACA were 2 months (0-5 months) compared with 1 month (0-4 months) for SCC (p = 0.001). Pelvic recurrence and distant failure were found in 2.1% and 14.9% in ACA, and corresponding with 3.9% and 15.6% in SCC. The 5-year overall survival rates of ACA compared to SCC were 59.9% and 61.7% (p = 0.191), respectively. When all prognostic factors are adjusted, clinical staging was the only factor that influenced overall survival.

Conclusion

ACA in locally advanced cervical cancer had poorer response rate from treatment and also used longer time to achieve CR than SCC. However, these effects were not determinants of survival outcomes.     

子宫颈鳞癌Ⅰb～Ⅱa期患者预后预测系统的建立及其临床意义

目的分析子宫颈鳞癌Ⅰb~Ⅱa期患者的预后影响因素并建立预后预测系统,以探讨其在指导术后辅助治疗中的作用。方法回顾性分析接受手术治疗的306例Ⅰb~Ⅱa期宫颈鳞癌患者的临床病理资料,对影响其预后的因素进行单因素和多因素分析。结果306例患者的5年生存率为78 1%。单因素分析结果显示,与其预后有关的因素为淋巴结转移、病理分化程度、肿瘤直径、宫旁组织浸润、深肌层浸润和脉管内瘤栓(P<0 05);多因素分析结果显示,淋巴结转移、深肌层浸润、宫旁组织浸润是影响其预后的独立危险因素(P<0 05)。根据危险因素的不同建立预后预测系统,即将患者分为低危组、中危组和高危组3组,其5年生存率分别为90 3%、83 9%和43 1%。低危组(无危险因素或仅宫旁组织浸润)局部复发的发生率仅为2 2%;中危组(深肌层浸润或合并有宫旁组织浸润)局部复发的发生率为13 5%,远处转移的发生率为1 3%, 局部复发合并远处转移的发生率为0 6%;高危组(淋巴结转移或合并其他危险因素)局部复发和远处转移的发生率分别为25 9%和48 3%,局部复发合并远处转移的发生率为10 3%。结论淋巴结转移、深肌层浸润、宫旁组织浸润是影响Ⅰb~Ⅱa期宫颈鳞癌患者预后的独立因素;根据预后影响因素建立的预后预测系统有助于指导术后辅助治疗。     

宫颈鳞癌和上皮内瘤变组织中TRF1、TRF2及HPV16、HPV18的检测及其意义

目的研究端粒结合蛋白TRF1、TRF2在宫颈鳞癌发生发展中的作用并分析HPV16、HPV18感染与TRF1、TRF2蛋白表达的关系。方法随机选择南华大学附属第一医院病理科2005年9月至2006年10月期间的组织石蜡块标本共86例,采用原位杂交方法检测HPV16、HPV18在15例正常宫颈上皮、36例宫颈上皮内瘤变(CIN)和35例宫颈鳞癌组织中的感染情况;采用免疫组化方法检测所有组织标本中TRF1、TRF2蛋白的表达。结果(1)HPV16、HPV18阳性感染率CIN组[63.9%(23/36)]和宫颈鳞癌组[97.1%(34/35)]显著高于正常组[20.0%(3/15)](χ2=30.639,P<0.01)。(2)TRF1阳性表达率宫颈鳞癌组[40.0%(14/35)]显著低于CIN组[63.9%(23/36)]和正常组[86.7%(13/15)](χ2=10.237,P<0.01);CINⅢ组[42.9%(6/14)]显著低于CINⅠ组[90.0(9/10)](χ2=5.531,P<0.01)。TRF2阳性表达率宫颈鳞癌组[80.0%(28/35)]显著高于CIN组[52.8%(19/36)]和正常组[...