Cervical cancer--what role for human papillomavirus?

OBJECTIVE: To review the role of human papillomavirus (HPV) as a causative agent of cancer of the cervix. DATA SOURCES, data synthesis, study selection: Medical journals, recently published text books related to cancer of the cervix and HPV and Papillomavirus Reports were examined to review the pathology of cervical cancer and its precursor lesions, its epidemiology in Australia and overseas, methods of detection of HPV (in particular molecular biology techniques used to diagnose HPV) and evidence linking HPV with genital neoplasia. CONCLUSION: While there is compelling evidence strongly linking certain HPV types with genital cancer, a causative role is yet to be proven and the aetiology is most likely multifactorial. Detection and typing of high risk genotypes of HPV in the genital tract as a diagnostic exercise to identify those women most at risk of developing genital neoplasia is not currently recommended.     

长链非编码RNA在宫颈癌发生、发展中的机制

宫颈癌是女性第二常见的恶性肿瘤,是发展中国家女性恶性肿瘤死亡的第三大主要原因,早期诊断和治疗是有效治疗宫颈癌、改善预后的关键。由于其复杂性,宫颈癌的发生、发展机制仍然是研究者亟需攻克的难题。近年来,大量研究表明长链非编码RNA（lncRNA）在肿瘤发生、发展中起着重要作用。本文围绕人乳头瘤病毒（HPV）型E6和E7癌蛋白相关机制、lncRNA性质相关机制和肿瘤发生、发展中常见信号通路相关机制,对宫颈癌机制网络中lncRNA的作用进行综述,为筛查宫颈癌早期诊断和治疗中可用的潜在标志物提供参考。     

Cervical cancer: epidemiology, prevention and the role of human papillomavirus infection

ORGANIZED SCREENING HAS CONTRIBUTED TO A DECLINE in cervical cancer incidence and mortality over the past 50 years. However, women in developing countries are yet to profit extensively from the benefits of screening programs, and recent trends show a resurgence of the disease in developed countries. The past 2 decades have witnessed substantial progress in our understanding of the natural history of cervical cancer and in major treatment advances. Human papillomavirus (HPV) infection is now recognized as the main cause of cervical cancer, the role of coexisting factors is better understood, a new cytology reporting terminology has improved diagnosis and management of precursor lesions, and specific treatment protocols have increased survival among patients with early or advanced disease. Current research has focused on the determinants of infection with oncogenic HPV types, the assessment of prophylactic and therapeutic vaccines and the development of screening strategies incorporating HPV testing and other methods as adjunct to cytology. These are fundamental stepping stones for the implementation of effective public health programs aimed at the control of cervical cancer.     

Human papillomavirus screening and cervical cancer prevention

Infection with one of several types of human papillomavirus (HPV) appears to be a necessary first step in the development of invasive cervical cancer. We cannot currently treat HPV infections; thus, the role of HPV testing is to identify women with precancerous lesions that can be removed and, in so doing, prevent progression to invasive carcinoma. Although HPV testing may help to identify women at risk of cervical cancer who might be missed by other screening tests, it is inherently nonspecific at identifying those who would otherwise develop cervical cancer. In order to avoid overtreatment of women with minor lesions with little potential for progression, HPV testing needs to be repeated or combined with Pap smears. Protocols for HPV screening have yet to be properly evaluated. Here we consider several possible applications of HPV testing in the prevention of cervical cancer. The most immediate role is as a secondary test in women with minor cytological abnormalities. Appropriate use of HPV testing as a primary screening tool depends on the setting. In a developed country without an organized screening program, HPV testing might be used in addition to Pap smears in women age 35 and over to increase sensitivity. Within an organized screening program, HPV testing might be used in combination with Pap testing, but with extended screening intervals so as to obtain the maximum advantage to women without unduly increasing costs. Where resources are strictly limited, an attractive option would be to perform visual inspection of the cervix after application of dilute acetic acid using a low threshold for referral, and to test for HPV only on those with abnormal looking lesions.     

Is Routine Human Papillomavirus Vaccination an Option for Ghana?

Cervical cancer remains an important public health problem in developing countries where over 80% of the global burden occurs annually but screening has been ineffective. In a polygamous country like Ghana with a high incidence of cervical cancer but no national screening program, the Human Papilloma Virus (HPV) vaccine presents a unique opportunity to reduce the burden of HPV infection and cervical cancer in Ghanaian women. The evidence so far indicates that the vaccines are safe and efficacious. Although routine HPV vaccination of girls raises several religious, political, socioeconomic and ethical challenges, the emphasis of this paper will be on addressing the ethical challenges using the principles of autonomy, beneficence, non-maleficence and justice as a framework. Parental autonomy can be preserved with judicious exemptions for those who decline the vaccine on religious and philosophical grounds. This promotes public health without trampling parental authority. Routine HPV vaccination confers several benefits to individuals and society by preventing HPV infection. Instead of causing harm; it reduces harm by preventing the development of about 70% of cervical cancers and removing the negative physical and psychological impact of a cervical cancer diagnosis. It also has the potential to reduce the disparities in cervical cancer rates and its cost effectiveness will ensure considerable cost savings in terms of the money spent on diagnosis and treatment. Consequently, the HPV vaccine is an important public health landmark and achievement in women's health that must be heralded, especially in developing countries where the bulk of the disease and death occur.     

应用荧光定量聚合酶链方法检测宫颈组织中人乳头瘤病毒16E6基因

目的　建立荧光定量聚合酶链 (FQ PCR)方法检测宫颈细胞中人乳头瘤病毒 16型(HPV16 )E6基因的方法。方法　以 2 2 0例新疆妇女宫颈不同病变组织DNA作为样本 ,人乳头瘤病毒 16型 (新疆株 )E6基因 (HPV16E6 ,AF32 785 1)作为扩增的靶基因 ,同时以人 β 肌动蛋白基因片段作为内参照 ,借助于设计的目的基因引物 ,两个特异的荧光探针 ,在筛选的FQ PCR优化反应体系中 ,同时对两个基因片段进行扩增 ,得到HPV16E6的相对含量。结果　对 β 肌动蛋白阳性的宫颈不同病变组织中HPV16E6阳性率及其相对含量进行统计分析 ,新疆妇女宫颈脱落细胞标本 96例中 ,HPV16E6阳性 3例 (3 3% ) ;宫颈癌蜡块组织 5 9例中HPV16E6阳性 4 9例 (83 0 % ) ;宫颈上皮内瘤变 (CIN)蜡块组织 6 5例中 ,HPV16E6阳性 2 8例 (75 7% ) ;宫颈炎蜡块组织 33例 ,HPV16E6阳性 2 8例 (93 3% )。HPV16E6的相对含量随病情加重呈上升趋势 ,二者呈显著正相关 ,相关系数为 0 83。结论　建立的FQ PCR检测宫颈不同病变组织内HPV16E6基因的方法 ,能反映单位细胞人乳头瘤病毒的复制情况 ,筛查宫颈癌患者 ,并可能应用于宫颈癌的风险评估和疗效观察。     

高危型人乳头瘤病毒联合宫颈液基薄层细胞学检测在宫颈上皮内瘤变筛查中的应用价值

背景　据2018年全球数据统计,每年约有56万宫颈癌新发病例,宫颈癌在发展中国家的病死率尚居高位。某些欠发达地区无法满足全面开展宫颈上皮内瘤变筛查工作的需要,单项检测项目漏检风险较大。目的　探讨通过第三代杂交捕获定量分型（DH3）技术检测高危型人乳头瘤病毒（HPV）联合宫颈液基薄层细胞检测（TCT）在宫颈上皮内瘤变筛查中的应用价值。方法　选择2020年1-6月于包头医学院第一附属医院进行宫颈筛查的女性患者1 620例作为研究对象,使用DH3技术对患者进行14种HPV型别检测;依据伯塞斯达系统（TBS）宫颈细胞学分类法对TCT结果进行判读;以宫颈组织病理学检查为金标准,对结果进行统计分析。结果　在1 620例患者中,HPV检测阳性者619例,阴性者1 001例;TCT阳性者449例,阴性者1 171例;HPV检测联合TCT阳性者205例,阴性者1 415例;病理学检查阳性者187例,阴性者1 433例。HPV检测联合TCT对宫颈上皮内瘤变筛查的灵敏度（96.79%）、特异度（98.32%）、阳性预测值（88.29%）和阴性预测值（99.56%）均高于HPV检测（81.28%、67.41%、24.56%和96.50%）和TCT（75.40%、78.51%、31.40%和96.07%）。结论　HPV检测联合TCT对宫颈上皮内瘤变筛查的灵敏度、特异度、阳性预测值和阴性预测值均高于单项检测,HPV检测联合TCT筛查宫颈上皮内瘤变可以降低单项检查的误诊率、漏诊率,具有较高的临床应用价值。     

Epidemiology of cancer of the cervix: global and national perspective

Cancer of the uterine cervix is one of the leading causes of cancer death among women worldwide. The estimated new cancer cervix cases per year is 500,000 of which 79% occur in the developing countries. Cancer cervix occupies either the top rank or second among cancers in women in the developing countries, whereas in the affluent countries cancer cervix does not even find a place in the top 5 leading cancers in women. The truncated rate (TR) in the age group 35-64 years in Chennai, India, is even higher (99.1/100,000; 1982-95) than rate reported from Cali, Colombia (77.4/100,000, 1987-91). The cervical cancer burden in India alone is estimated as 100,000 in 2001 AD. The differential pattern of cervical cancer and the wide variation in incidence are possibly related to environmental differences. Aetiologic association and possible risk factors for cervical carcinoma have been extensively studied. The factors are: Sexual and reproductive factors, socio-economic factors (education and income), viruses e.g., herpes simplex virus (HSV), human papillomavirus (HPV), human immunodeficiency virus (HIV) in cervical carcinogenesis and other factors like smoking, diet, oral contraceptives, hormones, etc. The accumulated evidence suggests that cervical cancer is preventable and is highly suitable for primary prevention. Sexual hygiene, use of barrier contraceptives and ritual circumcision can undoubtedly reduce cervical cancer incidence. Education, cervical cancer screening of high risk groups and improvement in socio-economic status can reduce cervical cancer morbidity and mortality significantly.     

Role of VIA in cervical cancer screening in low-resource countries

Cervical cancer is one of the few highly preventable cancers. The early detection and removal of precancerous cervical lesions effectively abolish the development of invasive cervical cancer. The Pap test has been the standard screening test in the Western world for the last five decades. Visual inspection of cervix with acetic acid (VIA) is currently more popular method of cervical cancer of screening test in low resource countries. Cervical cancer incidence and mortality have been reduced dramatically as a result of successful screening in many countries. Cancer cervix can be prevented through both primary prevention using human papilloma virus (HPV) vaccine and early detection using screening techniques. Several screening modalities are now available for early detection of cervical cancer and its precursor lesions. They all differ with regard to their test characteristics, feasibility and economic considerations. This review has different aspects of these screening modalities and provides different options considering mass application. In developed countries, Pap smear cytology is used for cervical cancer screening. But in low-resource country, like Bangladesh, it is too expensive and is not feasible. VIA, a non-cytological test is a simple and inexpensive test which can be provided by trained paramedical personnel with a short training. So VIA can be done in low-resource countries for screening of cervical cancer as an alternative to Pap smear cytology.     

宫颈癌流行病学概况

宫颈癌在全球妇女恶性肿瘤中居第二位,发展中国家发病率较高,且有明显的地理差别,不同年龄、职业、种族,发病率也存在差异.其危险因素主要有行为危险因素、生物学因素及遗传易感性,高危型HPV感染做为宫颈癌的首要病因已得到肯定.     

Low cost methods for secondary prevention of cervical cancer in developing countries

BACKGROUND: Cervical cancer is both a preventable and a curable disease- preventable because the pre-invasive stage can be detected by screening and curable because the very early stage can be cured. It is the commonest genital cancer among females in Nigeria. The incidence and mortality from this disease in developing countries is very high. This is due to the unavailability of organised screening programmes. To address this problem, effective and practical alternatives to cytology are being investigated in many studies. OBJECTIVE: To examine the strengths and limitations of new methods currently undergoing evaluation for secondary prevention of cervical cancer in developing countries. MATERIAL AND METHODS: We conducted a computerised literature search for published articles. Mesh phrases used for the search were cervical cancer screening, cervical cancer screening in developing countries, cervical cancer screening- new techniques. Hand searches of journals and the proceedings of major conferences were also done. RESULTS: The visual tests for screening for cervical cancer was found to be highly sensitive and can be performed by not only physician but also other trained health care providers. The "single visit approach" to prevention of cervical cancer also referred to as "see and treat" has been tried in some countries in Asia and Africa and found to be effective and acceptable to women and their partners. CONCLUSION: Several studies conducted in many developing countries have shown that low cost methods for cervical cancer prevention do have a place in reducing the incidence of this deadly disease.     

人乳头状瘤病毒感染及端粒酶hTERT表达与宫颈癌关系的研究进展

人乳头状瘤病毒(HPV)感染和人子宫颈癌的发生密切相关,HPV致癌作用的主要基因为E6、E7.E6蛋白能诱导端粒酶的表达,其机制是激活了端粒酶催化亚基hTERT的转录活性.端粒酶激活是HPV感染后导致宫颈上皮瘤变和宫颈癌发生的关键性步骤.现就HPV感染及端粒酶hTERT在宫颈癌形成中的协同作用进行综述.     

Detection of human papillomavirus in women attending Pap?cervical screening camp at a peripheral hospital of North-Eastern India

Human papillomavirus (HPV) associated cervical cancer is the leading cause of deaths in India. However, cytological/HPV screening may result in early detection of cervical cancer, resulting in early treatment and reduced mortality. Although reports related to general population is available, data on HPV prevalence among women attending AFMS health care facilities is scarce. Cervical samples were collected for cytological staining by Pap test and molecular detection by PCR, genotyping by HPV specific primers and sequencing. Apart from finding of atypical cells of undetermined significance (ASCUS) in one subject, no evidence of malignancy was observed. A high prevalence of HPV was found in this study group, which was intermediate between previous reports from general population and cervical cancer patients. All the subjects had infection of high risk HPV type16. HPV prevalence was found similar between different age groups. Although, none of the study subjects had malignant changes, but due to high prevalence of high risk HPV infection and other associated risk factors, these subjects might be at an elevated risk of developing cervical cancer. Regular follow-up of these patients who were detected HPV positive are required to screen for cervical malignancy.     

Chimeric virus-like particles of the human papillomavirus type 16 (HPV 16) as a prophylactic and therapeutic vaccine

Infection by certain human papillomaviruses (HPV), most notably HPV types 16 and 18, is the major risk factor for cervical cancer. Worldwide, this disease represents the second most frequent malignant tumor in women; thus, there is urgent need for efficient therapy and prevention. The natural history of cervical cancer and its precursors (cervical intraepithelial neoplasias), as well as animal experiments, strongly suggest that the immune system controls both the primary infection (by neutralizing antibodies directed against the major structural protein L1) and the progression of the disease (via cytotoxic T cells specific for the viral oncoproteins expressed in transformed cells, e.g., E7). By the expression of an HPV 16 L1E7 fusion protein, we have generated chimeric virus-like particles (CVLP). Immunization of mice with CVLPs induces neutralizing antibodies directed against L1 virus-like particles (devoid of the E7 portion) and E7-specific T cells as measured in vitro. Vaccinated animals are protected against tumor growth following inoculation of syngeneic HPV 16-transformed cells. In addition, we observed a therapeutic effect of vaccination on pre-existing tumors. This data allowed us to conclude that CVLPs are suitable for prevention and therapy of HPV infection. A vaccine based on HPV 16 L1E7 CVLPs is currently under development.     

宫颈癌组织中HPV16 E6、E7蛋白水平与患者临床病理特征及预后的关系

目的 探究宫颈癌组织中16型人乳头瘤病毒E6蛋白（human papilloma virus type 16 E6 protein,HPV16 E6）、16型人乳头瘤病毒E7蛋白（human papilloma virus type 16 E6 protein,HPV16 E7）水平与患者临床病理特征及预后的关系。 方法 选取行宫颈癌根治术87例患者的肿瘤组织、癌旁组织、正常宫颈组织标本进行研究,采用免疫组织化学法检测组织中HPV16 E6、HPV16 E7蛋白表达情况,并结合患者临床病理特征进行分析,采用Kaplan-Meier生存曲线比较患者3年生存情况,采用COX回归分析各项因素对患者预后的影响。 结果 免疫组化结果显示肿瘤组织中HPV16 E6、HPV16 E7阳性率高于癌旁组织和正常组织（P＜0.05）; HPV16 E6及HPV16 E7蛋白阳性表达患者3年生存率低于阴性表达患者（P＜0.05）;多因素分析显示HPV16 E6、HPV16 E7阳性是宫颈癌患者预后不良的独立危险因素（P＜0.05）。 结论 HPV16 E6、HPV16 E7蛋白在宫颈癌组织中阳性表达,与患者临床病理特征和预后相关,可能作为治疗宫颈癌的新靶点发挥作用。     

从“治未病”思想探讨中医药防治HPV相关宫颈癌的研究意义

宫颈癌是发生在全球妇女中仅次于乳腺癌的第2个常见的恶性肿瘤。人乳头状瘤样病毒（HPV）感染是宫颈癌发生最主要的危险因素。宫颈组织上皮内瘤病（CIN）是宫颈癌发展的重要阶段,因而早期诊断和治疗CIN非常必要。中医药防治HPV相关宫颈癌有其应用简便、价格低廉、有效安全等优势,符合中医“治未病”的思想。由此推理,中医药防治HPV相关宫颈癌有着广阔前景,值得我们深入研究。     

宫颈癌组织中HPV16 E6基因的检测及其意义

目的：探讨宫颈癌组织中人乳头状瘤病毒16型(HPV16)E6基因的检测及其意义。方法：运用PCR方法扩增HPV16E6／E7基因，分子克隆技术进行基因的克隆后进一步测定基因序列，宫颈炎和宫颈癌的确诊依赖于病理学方法。结果宫颈癌组织中HPV16E6基因的检出率为45％，显著高于宫颈炎组织中5％的检出率，两者有统计学差异。HPV16E7基因的检出率在两者之间没有显著性差异。结论：HPV16E6基因在宫颈癌的发病中起到重要的作用。宫颈组织中HPV16E6基因的检测有望成为宫颈癌筛查的新手段。     

宫颈癌癌前病变中人乳头状瘤病毒16整合状态的检测

目的　探讨宫颈癌癌前病变中人乳头状瘤病毒(HPV)16DNA整合入宿主基因组的发生情况。方法　选取 108例细胞学为宫颈癌癌前病变的患者,应用多重聚合酶链反应 (PCR)同时检测液基细胞标本中的HPV16L1、E_2和E_6基因。采用通用引物GP_(5+) /GP_(6+)扩增HPVL1基因保守区的一个长 150bp的片断,以检测HPV的存在。E_2PCR引物目标是HPV整合时最常缺失的E_2开放阅读框(ORF)的特殊区域,E_6引物目标是E6ORF。在游离型中,E_2、E_6拷贝数比例相等;在整合型中,E_2缺失;在游离、整合的混合型中,E2的拷贝数少于E_6。对E_2、E_6的PCR产物凝胶电泳条带的面积灰度值进行半定量分析,从而确定HPV16的整合状态。结果　HPV感染者 62例 (57. 41% );HPV16感染者 32例 ( 29. 63% ),其中 15例 ( 46 .88% )为纯游离型; 13例 ( 40 .62% )为混合型; 4例(12. 50% )为纯整合型。HPV16DNA整合和 /或混合型的比例随宫颈病变级别升高而增加,不同病变之间差异有统计学意义(P<0 .01)。结论　HPV16整合入宿主基因组在部分宫颈上皮内瘤变中即已发生。多重PCR同时检测HPVL1、HPV16E_2、E_6基因以及E_2 /E_6比值,是一种在宫颈细胞学标本中同时检测HPV感染、HPV16感染和HPV16整合状态的简便方法。它可以作为细胞学筛查的一种补充手段,以发现向宫颈高     

深圳女性子宫颈人乳头瘤病毒感染型别分布情况

目的 了解深圳市女性子宫颈人乳头瘤病毒（human papillomavirus, HPV）感染及基因亚型分布情况。方法 以深圳地区2017年1—9月参与子宫颈癌HPV筛查女性为研究对象,分析其中结果阳性并进行HPV基因分型检测的女性HPV感染亚型分布,采用χ²检验和Fisher确切概率法进行组间比较。结果 2017年1—9月,深圳地区参与子宫颈癌筛查的妇女HPV感染率为10.3%（10 328/100 222）,其中5 258例HPV感染者纳入型别分布分析,中位年龄为36岁（P₂₅~P₇₅：31~44）,汉族占99.6%（5 238例）,已婚者占96.8%（5 090例）,单一型别感染者占78.7%（4 139例）,高危型HPV感染者占94.3%（4 960例）。在4 960例高危型HPV感染者中,HPV52、HPV16、HPV58、HPV51和HPV18为感染最多前5种亚型,分别占26.1%、17.4%、14.7%、8.9%和8.4%。在298例低危型HPV感染者中,HPV6、HPV43、HPV11、HPV42和HPV44为感染最多前5种亚型,分别占30.5%、20.8%、20.1%、20.1%和11.7%。高危型HPV感染率在不同年龄、民族、婚姻状况、职业、筛查形式和医保类型的HPV阳性者的分布差异均无统计学意义（P>0.05）。结论 深圳地区女性子宫颈HPV感染以单一型为主,HPV52是最常见的高危感染亚型。     

成都地区女性患者对宫颈癌筛查和HPV疫苗认知调查分析

目的 了解女性对宫颈癌筛查和预防性高危型人乳头瘤病毒(human papilloma virus,HPV)疫苗认知和接受度,分析相关影响因素.方法 选取695例门诊女性患者进行调查,对调查数据进行统计分析.结果 44.32％(308/695)女性知道宫颈癌筛查,43.73％(297/695)女性曾接受过宫颈癌筛查,17.70％(123/695)的女性知道HPV疫苗,48.00％(59/123)的女性愿意接种HPV疫苗.电视、网络是获取信息的主要途径,年龄、文化程度、对宫颈癌筛查的认知是影响HPV疫苗认知和接受度的重要因素.结论 女性对宫颈癌筛查的认知和接受度较高,对HPV疫苗认知率低,但接受度高,加强健康宣教和预防宫颈癌知识的宣传,推进宫颈癌防控工作的实施.