HPV与肛门肿瘤

人乳头状瘤病毒（HPV）感染作为一种重要致癌因素越来越受到广泛的重视，在不同类型肿瘤中的相关研究也竞相展开。以往的流行病学证据显示肛门肿瘤的发生与HPV高危亚型的感染相关，HPV检测方法的标化及前瞻性临床实验的开展将有助于进一步阐明肛门部位HPV感染的自然史以及与肛门癌发生发展的关系。     

最新进展

正HPV疫苗预防肛门HPV感染和肛门上皮内瘤变背景近些年来在男、女性人群尤其是在男同性恋人群中,肛门肿瘤的发病率大大增加。肛门肿瘤是由高度(2、3级)肛门上皮内瘤变发展而来,而后者与肛门感染人乳头瘤病毒HPV(主要是HPV16、18型)密切相关。本研究旨在探讨4价HPV(qHPV)疫苗应用于男同性恋人群后对于HPV-6、HPV-11、     

人乳头状瘤病毒感染对头颈部肿瘤的影响

高危型人乳头状瘤病毒(HPV)感染导致的恶性肿瘤包括宫颈癌、肛门癌、阴茎癌、外阴癌、阴道癌和头颈部肿瘤等, 其中头颈部肿瘤的疾病负担仅次于宫颈癌。头颈部肿瘤多源于鳞状上皮细胞的恶性病变, 主要包括口腔癌、咽癌(包括鼻咽癌、口咽癌和下咽癌)和喉癌。头颈部肿瘤的主要危险因素是吸烟、频繁饮酒和HPV感染。近年来, 全球HPV相关头颈部肿瘤发病率处于上升趋势, 且在高收入国家中尤为显著。中国HPV相关头颈部肿瘤的疾病负担和变化趋势尚未明确, 一些小样本单中心的研究提示了可能存在的高HPV感染率和上升趋势, 但研究间存在HPV检测方法学的不同和地区差异性。头颈部肿瘤部位中已证实由HPV感染导致的是口咽癌, HPV与其他部位的关系尚未明确, 相关研究较为匮乏。文章将从HPV感染与头颈部肿瘤的关系研究入手, 比较全球研究和中国研究的头颈部肿瘤中HPV感染的差异, 深入探讨HPV感染与不同类别头颈部肿瘤之间的关系, 旨在总结目前最新的研究进展, 以期深入推进相关研究。     

人乳头状瘤病毒16变异体研究进展

人乳头瘤病毒(HPV)16与多种肿瘤的发生相关,流行病学上揭示了其变异体的分布具有地域性和种族特性,并在病毒持续感染和疾病演变中发挥重要作用,HPV16型变异体研究是HPV及相关肿瘤研究中的重要领域.     

人乳头状瘤病毒16变异体研究进展

人乳头瘤病毒(HPV)16与多种肿瘤的发生相关,流行病学上揭示了其变异体的分布具有地域性和种族特性,并在病毒持续感染和疾病演变中发挥重要作用,HPV16型变异体研究是HPV及相关肿瘤研究中的重要领域.     

人乳头状瘤病毒16变异体研究进展

人乳头瘤病毒(HPV)16与多种肿瘤的发生相关,流行病学上揭示了其变异体的分布具有地域性和种族特性,并在病毒持续感染和疾病演变中发挥重要作用,HPV16型变异体研究是HPV及相关肿瘤研究中的重要领域.     

口腔HPV感染与口咽癌发生的相关性及临床意义

吸烟、饮酒是口咽癌已知的常见病因.近年来,宫颈癌病因学研究取得了突破性进展,证实了高危型的人乳头瘤病毒(HPV)感染是宫颈癌发生的必要条件.新近的研究表明,感染有转录活性的HPV的头颈癌,其基因表达谱完全不同于没有感染HPV的肿瘤,表明HPV感染在头颈鳞癌的形成过程中发挥了重要的作用.本文就口腔HPV感染与口咽癌发生的相关性及临床意义予以综述.     

猪肉摄入量与人类乳头瘤病毒相关性疾病

人乳头瘤病毒(HPV)同肛门与生殖器癌的发生相关。然而,外界环境因素对于人乳头瘤病毒诱导湿疣的恶性转变似乎是必须的。在人类可能涉及到饮食成分,因为维生素A、C和叶酸的缺乏似乎与宫颈肿瘤的发生有关。作者举一例重度湿疣病人(一种HPV性疾病)随食谱的改变湿疣消退。猪肉的摄入量与宫颈痛(一种HPV性疾病)的发生呈国际相关     

HPV感染与非宫颈鳞状上皮细胞癌相关性的研究进展

目的:总结国内外HPV感染与非宫颈鳞状上皮细胞癌的相关性研究进展,探讨HPV可能的致癌作用,为非宫颈鳞状上皮细胞癌的防治提供理论依据.方法:应用PubMed及CNKI期刊全文数据库检索系统,以“HPV、鳞状上皮细胞癌”等为关键词,检索2005-01-2011-06的相关文献,共检索到英文文献1 134条.纳入标准:1)HPV的一般特性;2)HPV的致瘤性;3)HPV与鳞状上皮细胞癌发生、发展的关系.根据纳入标准,符合分析的文献49篇.结果:HPV感染与头颈部、皮肤、肺部鳞癌密切相关,与上消化道鳞癌的形成有一定相关性,与下消化道鳞癌的形成关系尚待进一步研究.HPV感染在导致各部位鳞癌发生上可能有着不同的基因作用机制,已证实与HPV感染相关的各部位鳞癌中HPV阳性者均发现有着更好的治疗效果.结论:HPV感染与非宫颈部位鳞癌的形成密切相关.但各部位鳞癌发生与相关HPV感染的亚型并非一致,仍需不同地区进一步大样本检测结果.     

肺癌与人乳头状瘤病毒感染和胰岛素样生长因子Ⅱ蛋白表达的相关性及其临床意义

目的:研究肺癌发生、发展中人乳头状瘤病毒(human papillomavirus, HPV)感染的病因学意义以及胰岛素样生长因子Ⅱ(insulin-like growth factor-Ⅱ, IGF-Ⅱ)蛋白的表达,并探讨肺癌发生与这2者之间的相关性.方法:采用PCR和免疫组织化学SP法分别检测68例肺癌组织和12例肺良性病变组织中HPV16/18型DNA﹑高危广谱型HPVE6/E7原癌蛋白和IGF-Ⅱ蛋白的表达水平.结果:肺癌组织的HPV阳性检出率为44.1%,高于肺良性病变组织的8.3%,差异有统计学意义(P＜0.05).HPV感染仅与肿瘤分化程度相关.IGF-Ⅱ蛋白在肺癌组织中的表达水平明显高于肺良性病变组织,且与肿瘤分化程度﹑淋巴结转移和临床分期相关(P<0.05).肺癌组织HPV阳性组与阴性组IGF-Ⅱ蛋白的表达水平差异有统计学意义(P<0.05),HPV阳性组中IGF-Ⅱ蛋白的表达水平较高.结论:高危HPV16/18型感染在肺癌的发生中具有重要的病因学意义,并可能通过整合的HPVE6/E7原癌蛋白促使有丝分裂原IGF-Ⅱ高表达,从而在肺癌的发生、发展中发挥重要作用.     

Anal cancer: an overview

Anal cancer is a rare tumor with an incidence that has been rising over the last 25 years. The disease was once thought to develop as a result of chronic irritation, but it is now known that this is not the case. Multiple risk factors, including human papillomavirus (HPV) infection, anoreceptive intercourse, cigarette smoking, and immunosuppression, have been identified. HIV infection is also associated with anal cancer; there is a higher incidence in HIV-positive patients but the direct relationship between HIV and anal cancer has been difficult to separate from the prevalence of HPV in this population. HIV infection is also associated with anal cancer; there are increasing numbers of HIV-positive patients being diagnosed with the disease. Treatment of anal cancer prior to the 1970s involved abdominoperineal resection, but the standard of care is now concurrent chemoradiation therapy, with surgery reserved for those patients with residual disease. We present a case of anal cancer followed by a general discussion of both risk factors and treatment.     

Plasma micronutrients and the acquisition and clearance of anal human papillomavirus infection: the Hawaii HPV cohort study

Anal human papillomavirus (HPV) infection is common among women and the cause of most anal malignancies. The incidence of anal cancer has been increasing among U.S. women, yet few cofactors for the natural history of anal HPV infection have been identified. We examined the hypothesis that plasma carotenoid, retinol, and tocopherol concentrations are associated with the acquisition and clearance of anal HPV infection in a cohort of 279 Hawaiian residents followed at 4-month intervals for a mean duration of 16 months. At each visit, interviews were conducted and biological specimens were obtained, including anal cell specimens for HPV DNA detection and genotyping, and a fasting blood sample to measure 27 micronutrients. Cohort participants acquired 189 anal HPV infections, 113 of which cleared during the study period. The most frequently acquired HPV genotypes were HPV-52, -53, -84, and -16. Women in the highest quartile of trans-zeaxanthin, trans -anhydro-lutein, and trans-, cis-, and total β-carotene had significant 43% to 50% reduction in the risk of acquisition of any HPV infection compared with women in the lowest quartile. Few associations were observed between micronutrient levels and clearance of transient (≤ 150 days) anal HPV infections. However, clearance of persistent (> 150 days) infections was associated with higher levels of β-tocopherol + γ-tocopherol and lower levels of carotenoids and retinol. Our findings suggest that several carotenoids can reduce the risk and clearance of anal HPV infections that contribute to anal cancer.     

Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions

A systematic review was conducted of HPV type distribution in anal cancer and anal high‐grade and low‐grade squamous intraepithelial lesions (HSIL and LSIL). A Medline search of studies using PCR or hybrid capture for HPV DNA detection was completed. A total of 1,824 cases were included: 992 invasive anal cancers, 472 HSIL cases and 360 LSIL cases. Crude HPV prevalence in anal cancer, HSIL, and LSIL was 71, 91 and 88%, respectively. HPV16/18 prevalence was 72% in invasive anal cancer, 69% in HSIL and 27% in LSIL. The HPV 16 and/or 18 prevalence in invasive anal cancer cases was similar to that reported in invasive cervical cancer. If ongoing clinical trials show efficacy in preventing anal HPV infection and associated anal lesions, prophylactic HPV vaccines may play an important role for the primary prevention of these cancers in both genders. © 2008 Wiley‐Liss, Inc.     

Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer.

Forty anal paraffin-embedded tissue specimens from 24 subjects were studied for the presence of human papillomavirus (HPV) types 6, 11, 16, 18, 31, and 33, herpes simplex virus (HSV), Epstein-Barr virus, and cytomegalovirus DNA by using the polymerase chain reaction. These tissues ranged from histologically normal to invasive squamous cell carcinoma. HPV DNA was detected in the invasive anal cancer tissues of 11 of 13 subjects. HPV types were segregated by histopathological severity, with HPV 16 associated exclusively with high grade anal intraepithelial neoplasia and invasive cancer. HPV types 6 and 11 were associated with condyloma and low grade anal intraepithelial neoplasia. HPV DNA in situ hybridization studies confirmed the presence of HPV DNA in the invasive cancer tissues of 6 of 12 subjects. HPV DNA in these tissues was highly focal and primarily associated with invasive cell nests that demonstrated the greatest degree of squamous differentiation. HSV DNA was detected only in association with advanced disease, being found in the cancer tissues of 5 of 13 subjects, and in 3 of 4 subjects with high grade anal intraepithelial neoplasia, but was not detected by in situ hybridization. Epstein-Barr virus and cytomegalovirus DNA were not detected in the 40 tissue specimens. We conclude that HPV infection may play an important role in the pathogenesis of anal cancer. The association between HSV infection and high grade anal disease suggests that HSV infection may also play a role in disease progression.     

EUROGIN 2014 roadmap: Differences in human papillomavirus infection natural history,transmission and human papillomavirus‐related cancer incidence by gender and anatomic site of infection

Human papillomaviruses (HPVs) cause cancer at multiple anatomic sites in men and women, including cervical, oropharyngeal, anal, vulvar and vaginal cancers in women and oropharyngeal, anal and penile cancers in men. In this EUROGIN 2014 roadmap, differences in HPV‐related cancer and infection burden by gender and anatomic site are reviewed. The proportion of cancers attributable to HPV varies by anatomic site, with nearly 100% of cervical, 88% of anal and <50% of lower genital tract and oropharyngeal cancers attributable to HPV, depending on world region and prevalence of tobacco use. Often, mirroring cancer incidence rates, HPV prevalence and infection natural history varies by gender and anatomic site of infection. Oral HPV infection is rare and significantly differs by gender; yet, HPV‐related cancer incidence at this site is several‐fold higher than at either the anal canal or the penile epithelium. HPV seroprevalence is significantly higher among women compared to men, likely explaining the differences in age‐specific HPV prevalence and incidence patterns observed by gender. Correspondingly, among heterosexual partners, HPV transmission appears higher from women to men. More research is needed to characterize HPV natural history at each anatomic site where HPV causes cancer in men and women, information that is critical to inform the basic science of HPV natural history and the development of future infection and cancer prevention efforts.     

EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease

The EUROGIN 2011 roadmap reviews the current burden of human papillomavirus (HPV)-related morbidity, as well as the evidence and potential practice recommendations regarding primary and secondary prevention and treatment of cancers and other disease associated with HPV infection. HPV infection causes ～600,000 cases of cancer of the cervix, vulva, vagina, anus and oropharynx annually, as well as benign diseases such as genital warts and recurrent respiratory papillomatosis. Whereas the incidence of cervical cancer has been decreasing over recent decades, the incidence of anal and oropharyngeal carcinoma, for which there are no effective screening programs, has been rising over the last couple of decades. Randomized trials have demonstrated improved efficacy of HPV-based compared to cytology-based cervical cancer screening. Defining the best algorithms to triage HPV-positive women, age ranges and screening intervals are priorities for pooled analyses and further research, whereas feasibility questions can be addressed through screening programs. HPV vaccination will reduce the burden of cervical precancer and probably also of invasive cervical and other HPV-related disease in women. Recent trials demonstrated that prophylactic vaccination also protects against anogenital HPV infection, anogenital intraepithelial lesions and warts associated with vaccine types, in males; and anal HPV infection and anal intraepithelial neoplasia in MSM. HPV-related oropharyngeal cancer could be treated less aggressively because of better survival compared to cancers of the oropharynx unrelated to HPV. Key findings in the field of cervical cancer prevention should now be translated in cost-effective strategies, following an organized approach integrating primary and secondary prevention, according to scientific evidence but adapted to the local situation with particular attention to regions with the highest burden of disease.     

Human papillomavirus infection as a risk factor for anal and perianal skin cancer in a prospective study

Human papillomavirus has emerged as the leading infectious cause of cervical and other anogenital cancers. We have studied the relation between human papillomavirus infection and the subsequent risk of anal and perianal skin cancer. A case-cohort study within two large Nordic serum banks to which about 760 000 individuals had donated serum samples was performed. Subjects who developed anal and perianal skin cancer during follow up (median time of 10 years) were identified by registry linkage with the nationwide cancer registries in Finland and Norway. Twenty-eight cases and 1500 controls were analysed for the presence of IgG antibodies to HPV 16, 18, 33 or 73, and odds ratios of developing anal and perianal skin cancer were calculated. There was an increased risk of developing anal and perianal skin cancer among subjects seropositive for HPV 16 (OR=3.0; 95%CI=1.1-8.2) and HPV 18 (OR=4.4; 95%CI=1.1-17). The highest risks were seen for HPV 16 seropositive patients above the age of 45 years at serum sampling and for patients with a lag time of less than 10 years. This study provides prospective epidemiological evidence of an association between infection with HPV 16 and 18 and anal and perianal skin cancer.     

Antibody responses following incident anal and penile infection with human papillomavirus in teenage men who have sex with men

Men who have sex with men (MSM) are at risk for human papillomavirus (HPV)‐related anal cancer. Few data exist on antibody responses following incident anogenital infection with HPV in teenage MSM. A cohort of 200 MSM aged 16–20 years from Melbourne, Australia were assessed at baseline, 3, 6 and 12 months. At each visit anal and penile swabs were collected for HPV DNA and serum for HPV antibodies for genotypes 6, 11, 16 and 18 (Merck's Multiplex Assays using Luminex). The main outcome, seroconversion, was defined as the detection of HPV antibodies following a negative antibody result for the same HPV type at baseline. The seroincidence rates for HPV types 6, 11, 16 and 18 were: 19 (95% CI 12–26), 7 (3–12), 4 (1–8) and 6 (3–11) per 100 person‐years, respectively. Men who experienced incident anal HPV infections from types 6/11 were significantly more likely to develop serum antibodies to the same HPV type(s) than those who experienced incident anal infections from types 16/18 [73 vs. 18%, odds ratio (OR) = 15, 95% CI: 2–118]. The median time between incident anal HPV infection and seroconversion for HPV 6, 11, 16 and 18 was: 91, 38, 161 and 182 days, respectively. Antibody responses against HPV types 6/11 were significantly more likely to occur following incident anal compared with incident penile infection with HPV types 6/11 (OR = 6, 95% CI: 2–21). The likelihood of antibody responses following anogenital HPV infections depends on the HPV type and site of infection.     

Human Papillomavirus Infection and Anogenital Neoplasia in Human Immunodeficiency Virus-Positive Men and Women

Human immunodeficiency virus (HIV)-positive women have a higher prevalenceof human papillomavirus (HPV) infection in the cervix and anus,as well as squamous intraepithelial lesions (SILs) at thesesites, than do HIV-negative women matched for age and HIV riskfactors. Similarly, HIV-positive homosexual or bisexual men havea higher prevalence of anal HPV infection and anal SIL than doHIV-negative homosexual or bisexual men. In HIV-positive individuals,the prevalence of HPV infection, the proportion infected withmultiple HPV types, and the prevalence of anogenital SILs increasewith decreasing CD4 count. This situation may reflect loss ofsystemic immune response to HPV antigens or local HPV-HIV interactionsat the tissue or cellular level. Despite the high levels ofanogenital SILs, to date, there has not been a significant increasein reported cases of invasive anogenital cancer in HIV-positiveindividuals. However, several years may be required for SILto progress to invasive cancer, and the advent of newer therapiesfor HIV that are expected to prolong survival may paradoxicallyincrease the risk of progression to cancer in individuals withSILs if these lesions do not regress spontaneously and remainuntreated.