宫颈细胞内p16/Ki67表达与宫颈癌及癌前病变的关系及其用于HPV阳性人群分流的诊断价值

摘 要：［目的］ 探讨p16/Ki67双染技术对宫颈癌及癌前病变的检出能力,比较其用于HPV阳性人群分流的诊断价值。［方法］ 选取2016年9月至2017年5月山西长治三家三甲医院21~70岁参加宫颈癌筛查的妇女及门诊患者共计497例,所有入组研究对象均进行HPV E6/E7mRNA检测、液基细胞学检测（LBC）与p16/Ki67双染。［结果］ p16/Ki67双染的阳性率随细胞学诊断及病理诊断的严重程度的增加而升高(P<0.05）;p16/Ki67对62例宫颈上皮内瘤变2级及以上（CIN2+）研究对象检出的灵敏度、特异性分别为69.4%、83.6%,HPV E6/E7mRNA检测分别为82.3%、74.6%,LBC检测分别为80.6%、65.2%。对49例CIN3+研究对象检出的灵敏度、特异性分别为69.4%、81.9%,HPV E6/E7mRNA检测分别为85.7%、73.3%。在CIN2+/CIN3+病例中p16/Ki67的灵敏度与LBC均衡可比,但其特异性明显高于 LBC 和HPV E6/E7mRNA检测。在HPV E6/E7mRNA检测阳性人群中p16/Ki67双染对CIN2+检出的灵敏度和特异性分别为82.4%和56.9%,LBC检测为90.2%和29.4%;p16/Ki67双染对CIN3+检出的灵敏度和特异性分别为81.0%和53.2%,LBC检测为88.1%和27.0%。p16/Ki67双染中对CIN2+及CIN3+检出的灵敏度与LBC检测相比均无明显差异（P>0.05）,但其特异性明显高于LBC检测（P<0.001）。［结论］ p16/Ki67双染技术用于HPV阳性人群的分流具有优于LBC的特异性和与LBC检测相似灵敏度的特性。在经济条件允许或者缺乏病理医生的地区,可以考虑使用p16/Ki67代替细胞学用于宫颈癌的初筛或HPV阳性人群的分流。     

HPV16在年轻与中老年宫颈癌患者中感染状态差异性研究

目的:了解不同年龄段宫颈癌患者中HPV16感染状态(病毒负荷、整合状态)及其临床意义.方法:采用一种条件优化后的双重实时定量PCR的方法鉴定标准品的HPV16整合率以评估该方法在检验临床样本病毒整合程度方面的可靠性和灵敏度,根据E2同E6基因的比值判断病毒的整合程度,同时通过定量E6的拷贝数检测病毒负荷,并对41例HPV16阳性的宫颈癌术后样本进行感染状态的检测.结果:(1)双重实时定量PCR检测HPV16病毒整合程度方法学可行,并且该方法具有很好的可重复性、可靠性和灵敏度;(2)当所有样本按35岁分组,年轻宫颈癌组同中老年宫颈癌组间的病毒负荷差异没有统计学意义(P=0.143,Mann-Whitney Test);将分组标准提高到40岁,病毒负荷在年轻宫颈癌组要明显高于中老年宫颈癌组(P=0.021).不论按35岁或者40岁分组,中老年宫颈癌组中的病毒整合程度均明显高于年轻宫颈癌组(P值分别为0.001和0.003);(3)将HPV16感染状态同肿瘤分期、浸润深度、淋巴转移等临床资料做Spearman相关性分析后发现,年龄同病毒负荷之间存在较强的负相关性(r=-0.402,P=0.009),而年龄同病毒整合程度存在明显的正相关性(r=0.565,P=0.000).结论:(1)相比中老年患者,年轻的宫颈癌患者的HPV16感染数量可能会更高,而且病毒负荷可能会随着病毒感染周期的延长而逐渐减少;(2)患者的年龄越大,HPV16整合程度越高,病毒的物理状态为整合型的可能性也就越大.     

影像学在评估宫颈癌淋巴结转移中的应用价值

宫颈癌是最常见的妇科恶性肿瘤,既往以临床分期决定患者的治疗方案及预后情况,而在2018年FIGO新分期中强调了淋巴结转移对宫颈癌预后的影响,肯定了影像学检查在术前判定宫颈癌新分期中的价值,指导宫颈癌患者精准治疗.全文就常用影像学检查,如超声、CT、MRI、PET-CT在宫颈癌淋巴结转移中的应用价值展开综述,旨在为宫颈癌...     

HPV感染与宫颈癌及癌前病变关系的研究

[目的]探讨HPV感染与宫颈癌及癌前病变的关系。[方法]采用实时荧光定量PCR方法检测23例宫颈癌、86例宫颈癌前病变（CINI28例、CINⅡ26例、CINⅢ32例），35例慢性宫颈炎中HPV感染及分型、构成、年龄分布状况。[结果]HPV总阳性率为41．7％，在慢性宫颈炎（8．6％）、宫颈癌前病变（CINI＋Ⅱ＋Ⅲ）（48．8％）和宫颈癌（65．2％）三者比较中，差异具有显著性（X^2趋势=22．84，P〈0．01）；HPV感染在不同宫颈疾病亚型不同，在慢性宫颈炎、CINI中HPV6、11占优势，CINII、CINⅢ和宫颈癌中以HPV16、18为主；不同宫颈疾病HPV感染构成比。在慢性宫颈炎、宫颈癌前病变及宫颈癌中分别为5．0％、70．O％、25．0％，宫颈癌前病变与宫颈癌HPV感染显著高于慢性宫颈炎（P〈0．01）；HPV感染在青年组占50．0％，中年组占44．9％，老年组17．4％，尤其46～55岁为高，占52．2％，青年组与老年组（X2=6．15，P〈0．05）及中年组与老年组（X2=5．82，P〈0．05）比较有统计学差异。[结论]HPV感染是宫颈癌前病变和宫颈癌的主要致病因素，HPV16、18和宫颈癌密切相关，青年妇女和中年妇女HPV感染比例较大。     

不同高危型HPV检测方案对宫颈癌患者的筛查价值比较

目的比较不同高危型人乳头瘤病毒(HPV)检测方案对宫颈癌患者的筛查价值,探讨宫颈癌早期筛查最佳方法。方法以120例健康体检的妇女作为研究对象,采用实时荧光定量PCR(PCR)及2代杂交捕获实验(HC2-HPV-DNA),检测高危型人乳头瘤病毒的感染情况。结果 PCR及HC2-HPV-DNA两种方法高危型HPV病毒阳性检出率分别为15.83%(19/120)和10.83%(13/120),两者比较有统计学意义。两种方法检测结果均为41~50岁及51~60岁年龄组中高危型HPV感染率明显较高。结论对于高危型HPV的检测HC2-HPV-DNA优于定量PCR,HC2-HPVDNA更适合大规模宫颈癌的早期筛选。     

不同检测方法在宫颈病变和早期宫颈癌筛查中的价值

目的:评价目前临床使用的几种筛查方法在宫颈病变和早期宫颈癌筛查中的价值,针对不同经济、文化及地理背景下的人群,探讨合理、经济、高灵敏度的筛查方案.方法:巴氏涂片、5%醋酸肉眼观察(VIA)、薄层液基细胞涂片法(TCT)结合TBS分类报告系统、HPV-DNA检测(HC-II)、阴道镜检查结合评分系统、镜下定点活检病理组织...     

白介素-6 对肺癌诊断及预后评价的临床价值

 目的　探讨血清白介素 - 6(IL- 6)水平测定对肺癌诊断以及远道转移之间关系。方法　采用放免方法测定 44例不同组织类型肺癌与 34例健康对照组血清中白介素 - 6水平。结果　肺癌组患者 IL- 6水平显著高于对照组 (P<0 .0 1 )。不同组织来源肺癌组之间 IL- 6变化无显著性差异(P>0 .0 5) ,有远道转移组 (M1组 )较无转移组 (M0 组 ) IL- 6水平显著下降 (P<0 .0 5)。结论　测定血清中 IL- 6水平对肺癌的诊断 ,有无远道转移及预后评估均有重要临床意义。     

Health-Related Quality of Life of Patients with Cervical Cancer According to the Duration of Treatment and Cancer Progression

Objective: The purpose of this study was to assess health-related quality of life (HRQoL) in Korean patients with cervical cancer according to the duration of treatment and cancer progression of cervical cancer. Methods: This study included 452 outpatients with cervical intraepithelial neoplasia (CIN) or invasive cervical cancer from six tertiary hospitals in South Korea. The questionnaire included the EQ-5D-3L instrument, patients’ age, cancer progression (CIN or invasive cervical cancer), treatment duration (<1 year, ≥1 year but <2 years, and ≥2 years), treatment method (surgery, chemotherapy, radiation therapy), and presence of recurrence. HRQoL indices were calculated for these independent factors, and the mean was compared using ANOVA. Multiple regression analysis was performed to analyze factors affecting HRQoL in patients with cervical cancer. Results: The EQ-5D index was 0.93 for patients with CIN, 0.87 for patients with invasive cervical cancer, and 0.78 for patients with recurrent invasive cervical cancer. HRQoL was significantly lower as the CIN progresses to cervical cancer. HRQoL of patients with invasive cervical cancer was lowest within 1 year of treatment in all stages. In addition, the HRQoL of patients with CIN or invasive cervical cancer who received chemotherapy and radiotherapy was lower than that of patients who underwent surgery. Multiple regression analysis showed that the HRQoL decreased significantly as increasing age, the first year of treatment after diagnosis, cancer recurrence, or chemotherapy. Conclusion: The HRQoL of patients with cervical cancer is affected not only by the stage of cancer progression but also by the duration of treatment and the type of treatment. As a result, when trying to apply the quality of life of patients with cervical cancer to cost-utility analysis, it is necessary to consider the duration and the type of treatment they receive.     

DC瘤苗的研究新进展

人乳头瘤病毒（HPV）是由核酸和衣壳蛋白组成的DNA病毒，基因组编码10个开放阅读框（ORF），分为早期区（E区），晚期区（L区）和上游调节区（URR），早期区包含E1，E2，E4，E5，E6及E7 6个早期基因，编码合成蛋白，调控病毒转录，复制和转化；晚期区L1和L2编码病毒的主要和次要衣壳蛋白，高危型HPV感染与宫颈癌有关。高危型HPV E6／E7被证实为转化基因，在相关组织中构成性表达，具有很强的抗原性，被首选用来制备HPV基因疫苗，HPV晚期基因L1的产物具有诱导产生中和抗体及细胞免疫的表位，也是制备基因疫苗的理想候选基因。针对E6，E7和L1等基因序列构建的基因疫苗可同时激活体液免疫和细胞免疫，对宫颈癌有预防和治疗作用。     

HPV and Cervical Cancer Epidemiology - Current Status of HPV Vaccination in India

Cervical cancer (CaCx) is the second most fatal cancer contributing to 14% of cancers in Indian females, which account for 25.4% and 26.5% of the global burden of CaCx prevalence and mortality, respectively. Persistent infection with high-risk human papilloma virus (HPV- strains 16 and 18) is the most important risk factor for precursors of invasive CaCx. Comprehensive prevention strategies for CaCx should include screening and HPV vaccination. Three screening modalities for CaCx are cytology, visual inspection with acetic acid, and HPV testing. There is no Indian national policy on CaCx prevention, and screening of asymptomatic females against CaCx is practically non-existent. HPV vaccines can make a major breakthrough in the control of CaCx in India which has high disease load and no organized screening program. Despite the Indian Government's effort to introduce HPV vaccination in the National Immunization Program and bring down vaccine cost, challenges to implementing vaccination in India are strong such as inadequate epidemiological evidence for disease prioritization, duration of vaccine use, parental attitudes, and vaccine acceptance. This paper reviews the current epidemiology of CaCx and HPV in India, and the current status of HPV vaccination in the country. This article stresses the need for more research in the Indian context, to evaluate interventions for CaCx and assess their applicability, success, scalability and sustainability within the constraints of the Indian health care system.     

子宫颈癌放射治疗后宫颈阴道细胞学检查及其价值

目的 :了解子宫颈癌放射治疗后宫颈 阴道涂片的细胞学特点及临床价值。方法 :采用TBS诊断方法 ,观察 30 0例宫颈癌放疗后涂片的阴道细胞学的改变情况 ,并评价该检查结果与病理组织学检查结果的符合情况及其临床意义。结果 :30 0例涂片中 ,发现异常涂片 12 0例 ,占 4 0 % ;12例涂片后行病理组织学检查患者中 ,TBS诊断与病理组织学检查结果定性符合者 11例 ,符合率 91 6 7%。结论 :放疗后定期行宫颈 阴道涂片细胞学检查 ,有助于临床医师观察疗效 ,了解肿瘤的局部情况     

Limited Value of Vaginal Cytology in Detecting Recurrent Disease After Radical Hysterectomy for Early Stage Cervical Carcinoma

The objective of this study was to evaluate the value of vaginal cytology in routine surveillance for recurrentcervical cancer after surgery. We reviewed the medical records of 565 patients with stage IB-IIA cervical cancer whowere treated with radical hysterectomy and pelvic lymphadenectomy (RHPL) and attended follow- up at ChiangMai University Hospital between January 2000 and May 2006. With the median follow-up of 35 months (range 1-76months), 23 (4%) patients developed recurrence. The interval from surgery to detection of recurrence ranged from5-61 months with a median of 23 months. Of the total 4,376 vaginal smears, 5 (0.1%) showed abnormal cytology butonly 1 had malignant cells and tumor recurrence. The sensitivity and specificity of vaginal cytology for detection ofrecurrence were 4.3% and 99.3%, respectively. In conclusion, vaginal cytology has limited value in detection ofrecurrence after RHPL for early-stage cervical cancer.     

子宫颈癌放射治疗后宫颈／阴道细胞学检查及其价值

目的：了解子宫颈癌放射治疗后宫颈／阴道涂片的细胞学特点及临床价值。方法：采用TBS诊断方法，观察300例宫颈癌放疗后涂片的阴道细胞学的改变情况，并评价该检查结果与病理组织学检查结果的符合情况及其临床意义。结果：300例涂片中，发现异常涂片120例，占40％；12例涂片后行病理组织学检查患者中，TBS诊断与病理组织学检查结果定性符合者11例，符合率91.67％。结论：放疗后定期行宫颈／阴道涂片细胞学检查，有助于临床医师观察疗效，了解肿瘤的局部情况。     

子宫颈部放射治疗后宫颈／阴道细胞学检查及其价值

目的：了解子宫颈癌放射治疗后宫颈／阴道涂片的细胞学特点及临床价值。方法：采用TBS诊断方法，观察300例宫颈癌放疗后涂片的阴道细胞学的改变情况，并评价该检查结果与病理组织学检查结果的符合情况及其临床意义。结果：300例涂片中，发现异常涂片120例，占40％；12例涂片后行病理组织学检查患者中，TBS诊断与病理组织学检查结果定性符合者11例，符合率91．67％。结论：放疗后定期行宫颈／阴道涂片细胞学检查，有助于临床医师观察疗效，了解肿瘤的局部情况。     

HPV Genotyping Linear Assay Test Comparison in Cervical Cancer Patients: Implications for HPV Prevalence and Molecular Epidemiology in a Limited-resource Area in Bandung,Indonesia

Background: Persistent infection with high risk human papillomavirus (hrHPV) is strongly associated withcervical cancer. Normal cervical cells may also harbor hrHPV, and detection of early hrHPV infection mayminimize risk of cervical cancer development. This study aimed to compare two commercial HPV genotypingassays that may affordable for early screening in a limited-resource setting in Bandung, Indonesia. Materialsand Methods: DNA from cervical biopsies with histologically confirmed as squamous cell cervical cacinoma wereHPV genotyped by Linear Assay 1 (Roche Diagnostics, Mannheim, Germany) or Linear Assay 2 (Digene HPVGenotyping RH Test, Qiagen Gaithersburg, MD). In a subset of samples of each group, HPV genotype results werethen compared. Results: Of 28 samples genotyped by linear assay 1, 22 (78.6%) demonstrated multiple infectionswith HPV-16 and other hrHPV types 18, 45 and/or 52. In another set of 38 samples genotyped by linear assay 2,28 (68.4%) were mostly single infections by hrHPV type 16 or 18. Interestingly, 4 samples that had been testedby both kits showed discordant results. Conclusions: In a limited-resource area such as in Indonesia, countrywith a high prevalence of HPV infection a reliable cervical screening test in general population for early hrHPVdetection is needed. Geographical variation in HPV genotyping result might have impacts for HPV prevalenceand molecular epidemiology as the distribution in HPV genotypes should give clear information to assess theimpact of HPV prophylactic vaccines.     

Comparison Between Two Detection Methods for HPV16,HPV18 and P16Ink4a Biomarkers in Diagnosis of Abnormal Cervical Cytology

Background: Cervical cancer is the second most common cancer among women in many populations. While the Pap smear is a well established screening test it suffers from both false-positive and false-negative results in diagnosis of cancers and precancerous states. In this study, immunocytochemistry of the P16 biomarker and HPV-PCR were compared for their diagnostic potential. Materials and methods: In the study, we obtained pairs of specimens from 45 women with cervical dysplasia. One sample was placed in a liquid-based solution, and processed for staining of sections with antibodies to P16. HPV-PCR was performed on the other and the results obtained were analyzed by T-test using SPSS v. 15. Results: Using HPV-PCR 71% of the samples were found to be infected with either HPV 16 or HPV 18, and the rate of infection did not have a statistically significant relationship with higher grades of dysplasia (p= 0.253). In contrast, with immunocytochemistry evaluation of P16, 64% of the specimens were positive, but the percentage of positive results significantly increased with higher grades of dysplasia (p= 0.0001). Conclusion: Employment of the P16 marker as an optional test might be preferable over HPV-PCR for cervical dysplasia in our geographical region.     

MRI在宫颈癌诊断与分期中的应用价值

[目的]探讨MRI扫描在宫颈癌术前诊断、分期中的应用价值。[方法]回顾性分析67例宫颈癌患者的术前MRI平扫、动态增强表现,分析肿块影像特点,邻近组织受侵情况及远处脏器转移情况,对MRI分期、临床分期及术后病理分期进行对照。[结果]宫颈癌病灶在平扫T1WI上多呈等、低信号,在T2WI上多呈等信号或稍高信号,仅少数呈低信号,在T2WI（FS）上肿瘤呈稍高信号,仅少数呈低信号,增强扫描（VIBE）肿瘤呈明显中度（等同宫体强化）强化,部分病例轻度强化。MRI对宫颈癌的定位准确率为97.01%（65/67）,分期总准确率为86.56%（58/67）,临床分期总准确率为71.64%（48/67）,MRI对宫颈癌的分期总准确率高于临床分期总准确率（χ2=5.786,P〈0.05）。[结论]MRI对宫颈癌的定位及诊断准确率较高,可作为宫颈癌诊断的常规检查。术前分期中MRI较临床有明显优势,尤其对Ⅱb及以上期别病例,可作为中晚期宫颈癌术前评估的常规检查方法。     

The Potential Value of MRI in External-Beam Radiotherapy for Cervical Cancer

The reference standard treatment for cervical cancer is concurrent chemoradiotherapy followed by magnetic resonance imaging (MRI)-guided brachytherapy. Improvements in brachytherapy have increased local control rates, but late toxicity remains high with rates of 11% grade ≥3. The primary clinical target volume (CTV) for external-beam radiotherapy includes the cervix and uterus, which can show significant inter-fraction motion. This means that generous margins are required to cover the primary CTV, increasing the radiation dose to organs at risk and, therefore, toxicity. A number of image-guided radiotherapy techniques (IGRT) have been developed, but motion can be random and difficult to predict prior to treatment. In light of the development of integrated MRI linear accelerators, this review discusses the potential value of MRI in external-beam radiotherapy. Current solutions for managing pelvic organ motion are reviewed, including the potential for online adaptive radiotherapy. The impacts of the use of MRI in tumour delineation and in the delivery of stereotactic ablative body radiotherapy (SABR) are highlighted. The potential role and challenges of using multi parametric MRI to guide radiotherapy are also discussed.