Scandinavian Journal of Clinical and Laboratory Investigation

ISSN: 0036-5513 (Print) 1502-7686 (Online) Journal homepage: http://www.tandfonline.com/loi/iclb20

HPV and cervical cancer Karl Ulrich Petry To cite this article: Karl Ulrich Petry (2014) HPV and cervical cancer, Scandinavian Journal of Clinical and Laboratory Investigation, 74:sup244, 59-62, DOI: 10.3109/00365513.2014.936683 To link to this article: http://dx.doi.org/10.3109/00365513.2014.936683

Published online: 01 Aug 2014.

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Scandinavian Journal of Clinical & Laboratory Investigation, 2014; 74(Suppl 244): 59–62

ORIGINAL ARTICLE

HPV and cervical cancer

KARL ULRICH PETRY

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Department of Gynaecology and Obstetrics, Klinikum Wolfsburg, Wolfsburg, Germany Abstract In recent analyses of the global burden of cancer among women, cervical cancer ranked second to breast cancer. Numbers of new cervical cancer cases are increasing constantly although this tumor is one of the best preventable malignancies of all relevant human cancers. The genesis of cervical cancer depends essentially on an infection of the uterine cervix with human papillomavirus (HPV) that needs to persist for many years and decades. Oncogenic cell transformation occurs almost exclusively in a discrete cell population at the squamous columnar junction (SCJ). These peculiarities enable primary prevention with HPV-vaccination as well as secondary prevention by detecting and treating true precursor lesions. The actual screening program with annual cytology smears is already effective but results in a high number of false positive results and unnecessary treatments. Based on a good understanding of the etiology and high evidence from large randomized controlled trials a significant improvement in the prevention of cervical cancer by shifting to HPV screening in women aged 30 years or older is feasible. This would result in a further reduction of new cancer cases by 70–80 % with less screening examinations and interventions when well-defined patient pathways are followed and colposcopy in accordance with international quality standards is used as the gold standard for the minimal invasive management of abnormal findings. HPV vaccination prevents the development of approximately 80 % of true precursors and should have a similar impact on the incidence of cervical cancer. A combination of HPV vaccination and screening could almost eradicate cervical cancer and reduce the burden of other tumors and diseases related to HPV. Key Words: Vaccination, human papilloma virus, screening

Introduction Although the incidence of cancer of the uterine cervix is declining in industrial countries since the implementation of national screening programs in the 1960s and 1970s, it is still ranked second to breast cancer in disability-adjusted life-years (DALYs) in a global survey of all malignancies among women in the year 2008 [1]. Without intensified preventive programs the number of 530,000 new cases of cervical cancer per year in 2008 is estimated to increase by 80 % until the year 2020 [2,3]. At the time of the diagnosis of cervical cancer patients are on average 50 years old, younger than for any other carcinoma. No other cancer offers as good a means for primary and secondary prevention as cervical cancer. The reason for an available effective protection from this malignancy by vaccination as well as by screening programs is its slow and monocausal genesis. Apart from very rare exceptions, cervical cancer is the accidental endpoint of persisting infections with certain types of human papillomavirus (HPV). The

complete genesis from the initial HPV-infection to persistent infection with cellular transformation to precancer and finally invasive cancer seems to need decades in most cases with a minimal latency time of approximately 7 years [4,5]. The development of high-grade precursors and cervical cancer seems to depend almost exclusively on the infection of a discrete cell population located at the squamo-columnar junction (SCJ) at the border between ecto- and endocervix. The high susceptibility of these cells for an HPV-induced oncogenic cell transformation explains why cervical cancer is so much more common compared with primary cancers of the vagina although the exposure to HPV is identical for vagina and cervix [6]. Human papillomaviruses encompass more than 120 different types that may infect human skin and mucosa. Only 13–15 of these are found in cervical cancers and other malignancies and are called ‘high risk’ HPV (HPV-HR). HPV 16 is the most important HPV-HR-type; it is linked to approximately

Correspondence: Karl U. Petry, Klinikum Wolfsburg, Department of Gynaecology and Obstetrics, Sauerbruchstr. 7, D-38440 Wolfsburg, Germany. E-mail: [email protected] ISSN 0036-5513 print/ISSN 1502-7686 online © 2014 Informa Healthcare DOI: 10.3109/00365513.2014.936683

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Prevalence, percent (%)

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-21 5-26 0-34 5-39 0-44 5-49 0-54 5-59 0-64 5-69 0-74 4 6 7 5 5 4 6 2 3 3

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Age groups

Figure 1. Prevalence of high-risk HPV in different age groups in Wolfsburg, according to the analyses of an epidemiological study (WOLVES) and a screening project (WOLPHSCREEN) with a total of more than 22,000 participants.

50 % of cervical cancers worldwide. HPV 18 ranks second, HPV 16 and 18 are associated with two thirds of all cervical cancers as well as subsets of cancers of the vulva, vagina, penis, anus, oropharynx and skin. Papillomavirus particles have a small diameter of 55 nm and contain a double-stranded DNA genome with 7200–8000 base pairs. The viral capsid consists of 72 capsomeres that are built of two capsid proteins, L1 as the major and L2 as the minor protein. The regulation of viral gene expression is complex and controlled by viral and cellular transcription factors. HPV-HR differs from other HPV types by oncogenic properties of two proteins

E6 and E7 that may interfere with cell regulation and differentiation. Infection of the uterine cervix with HPV is very common, especially in women in their early 20s. Even when infections with low copy numbers are excluded, the prevalence of HPV-HR ranges between 23 and 25 % in 20–26 y old women in Germany with an estimated life risk of 60–80 % [7]. Most infections will clear spontaneously and only a minority will finally persist for many years and decades. Therefore, HPV-HR prevalence rates decline with increasing age. Figure 1 shows the age-dependent prevalence of HPV-HR observed in Wolfsburg in an epidemiological cohort study in young women and an HPV screening pilot project in women 30 years or older. Figure 2 summarizes the four most crucial steps and identified co-factors for the genesis from the initial permissive HPV infection to persistent transforming infection with the development of true precursors (CIN3) that will progress to cancer in more than 30 % of cases. Primary prevention of cervical cancer The major capsid protein L1 will self-assemble to empty ‘virus-like particles’ (VLPs) that are highly immunogenic when injected intramuscularly. This new approach has been used successfully for the development of HPV16/18 and HPV 6/11/16/18 vaccines that have been licensed since 2006 in most countries. These two vaccines have shown to date very high efficacy against the predefined endpoint lesions (HPV 16 or 18 related cervical intraepithelial

Age, STD Persistent HPV-Infection Immunedeficiency CIN 1, CIN 2 HPV-Type Multi-Parity 10-60 % 10-25 % Smoking

HPV-Infection

HPV-Type + load Oral contraceptives Immunedeficiency Age, Parity Smoking

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Integration of HPV-DNA Genetical Factors?

Number of partners

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32-51 %

> 7 years for complete car cinogenesis

Cervical Cancer

Deutsches Ärzteblatt (2006) 103:2946 Revised 10/2013 Figure 2. A model of the genesis of cervical cancer, illustrating the distinct steps from transient HPV infection to cervical cancer including co-factors.

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HPV and cervical cancer neoplasia of grade 2 or more [CIN2⫹]), adequate safety and tolerability profiles, high immunogenicity, long term duration of protection in the range of 8–10 years, and strong indications of its ability to induce immune memory. Interestingly, some degree of cross protection against CIN 2 ⫹ related to other HPV-HR types (HPV 31, HPV 33 and HPV 45) has been documented [8]. The global estimates of the protection against cervical cancer of the currently available vaccines in properly vaccinated populations range from 75–80 % related to additional non-vaccine HPV type cross-protection. The latter however still requires some additional evaluation. None of the vaccines has shown therapeutic activity. Finally, it is important to note that these estimates show little geographical variation, thus these vaccines should be considered of global validity. Data from Australia showed a steep decline of new cases of genital warts in young women and with some delay even in young men following the introduction of HPV 6/11/16/18 vaccination of girls. A similar drop in high-grade cytology results was observed in young women which is most likely explained by the prevention of HPV 16/18 associated CIN 2⫹ [9]. Secondary prevention of cervical cancer The mechanism of secondary cervical cancer prevention is based on the detection of precursor lesions that are excised surgically. Hereby the natural cycle of carcinogenesis is interrupted and development of cervical cancer is prevented actively. In case of complete excision of precancer and all SCJ cells the subsequent risk for invasive cervical cancer is neglectably low [10]. In most industrial countries that introduced cytology-based prevention programs, a significant reduction of incidence and mortality from cervical cancer could be observed, while rates did not change in countries without such programs. Without screening the life-risk for cervical cancer ranges between 3 and 5 % [11], in some regions may reach even 6.5 % [2], while it was 0.9 % for Germany in the year 2004 according to ‘Robert Koch Institut’ cancer registry. Therefore, it can be concluded that the current screening concept prevents up to 2000 new cases of cervical cancer per month in Germany. Because of the causal role of HPV in the genesis of cervical cancer, HPV testing has appeared to be a potential screening test since the 1990s. A negative HPV test should exclude any risk for cervical cancer for many years. The publication of six randomized controlled trials (RCTs) with more than 250,000 participants and up to 8 years follow-up as well as a number of high quality cohort studies found that HPV screening results in a significantly better detection rate of high-grade precursors than Pap smear-based screening [12]. A meta-analysis of four of the six RCTs that included more than

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176,000 participants with a subtle follow-up including data of all national cancer registries was published in The Lancet and proved a significantly improved prevention of invasive cervical cancer with HPV screening reaching level I evidence [13]. This real life observation with a reduction of the cumulative cervical cancer incidence from 93.6 to 46.7 per 100,000 participants corresponds to a ‘Number needed to screen’ of 2100 as an extra benefit of HPV screening in addition to the cancer prevention achieved with cytology. As HPV infections are very common below the age of 30 y and most of these infections will be selflimiting, HPV-screening in this age-group would result in a high rate of meaningless positive results. Therefore, the consensus is that HPV screening should start at age 30 with intervals of 5 years for HPV-negative women. The German pilot project presented below confirms that HPV screening shows very few side effects with this program. In organized programs women with abnormal findings are transferred directly to colposcopy in case of high risk findings. Colposcopy allows visualizing the SCJ as the place of origin of precancer and cancer. This strategy avoids overtreatment and was costeffective in RCTs [14]. Recently colposcopy experienced a transformation from medical art to a standardized and evidence-based medical method. The management of abnormal screening results, histological assessment and, if necessary, minimal invasive therapies should be performed in specialized colposcopy clinics. The responsible colposcopists should have undergone intense training in colposcopy and fulfill the quality parameters defined by the European Federation for Colposcopy (EFC) [15]. In February 2006 in Wolfsburg the health insurance company Deutsche BKK started a pilot project that incorporates all of the elements of a modern HPV screening as highlighted in the present article. All female members aged 30 years or older were offered a prevention program with cytology and HPV testing at 5-year intervals. A contract between Deutsche BKK, Klinikum Wolfsburg and participating gynecologists in private practice defined precisely the management of abnormal screening results. Participants’ data and screening results were stored in a central data base at Klinikum Wolfsburg and used to monitor compliance with patient pathways. In case of abnormal findings, patients will be transferred for colposcopy either immediately (abnormal cytology and positive HPV test) or in cases of persisting abnormal findings (abnormal cytology or positive HPV test) after 6–12 months. Members who did not take part in the program after 2 years received an invitation letter. After 5 years the compliance with the program was excellent (91–95 %), only 3.8 % of the participants had to be transferred for colposcopy, while

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detection of CIN3 and invasive cancers was improved substantially, 95 of 172 CIN3/CA-cases were diagnosed in women with normal screening cytology. All cancers and 139/152 CIN3 were diagnosed at first colposcopy. The rate of surgical treatments of women with less than CIN2 which is perceived as an adverse event of screening was much lower than 15 %, the value defined by EFC for good patient management. In conclusion, the pilot project confirmed a high acceptance of participants and gynecologists with a structured cervical cancer prevention program with defined patient pathways, central quality assessment, HPV testing and extended intervals [16]. Questions and answers Q (Gronowski): Are there programs by organizations like WHO or the Bill Gates Foundation making efforts to perform HPV vaccination in developing countries? A (Petry): There are programs in East Africa certainly in Tanzania and Rwanda and some other countries provided by different organizations and these are successful. Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper. References [1] Soerjomataram I, Lortet-Tieulent J, Parkin DM, et al. Global burden of cancer in 2008: a systematic analysis of disability-adjusted life-years in 12 world regions. Lancet 2012;380:1840–50. [2] Arbyn M, Castellsague X, de Sanjosé S, et al. Worldwide burden of cervical cancer in 2008. Ann Oncol 2011;22: 2675–82. [3] Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine 2006;24(Suppl. 3):S3/11–25. [4] Hildesheim A, Hadjmichael O, Schwartz P, et al. Risk factors for rapid onset cervical cancer. Am J Obstet Gynecol 1999; 180:571–7.

[5] Liebrich C, Brummer O, Von WR, et al. Primary cervical cancer truly negative for high-risk human papillomavirus is a rare but distinct entity that can affect virgins and young adolescents. Eur J Gynaecol Oncol 2009;30:45–8. [6] Herfs M, Yamamoto Y, Laury A, et al. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc Natl Acad Sci USA 2012;109: 10516–21. [7] Petry KU, Luyten A, Justus A, et al. Prevalence of high-risk HPV types and associated genital diseases in women born in 1988/89 or 1983/84 – results of WOLVES, a populationbased epidemiological study in Wolfsburg, Germany. BMC Infect Dis 2013;13:135–46. [8] Wheeler CM, Castellsague X, Garland SM, et al. Crossprotective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by nonvaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2012;13:100–10. [9] Brotherton JM, Fridman M, May CL, et al. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet 2011;377: 2085–92. [10] Kocken M, Helmerhorst TJ, Berkhof J, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol 2011;12:441–50. [11] Siebert U, Sroczynski G, Hillemanns P, et al. The German cervical cancer screening model: development and validation of a decision-analytic model for cervical cancer screening in Germany. Eur J Public Health 2006;16: 185–92. [12] Arbyn M, Ronco G, Anttila A, et al. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine 2012;30(Suppl. 5):F88–99. [13] Ronco G, Dillner J, Elfstrom KM, et al. Efficacy of HPVbased screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014;383:524–32. [14] TOMBOLA group: Options for managing low grade cervical abnormalities detected at screening: cost effectiveness study. BMJ 2009;339:b2549. doi: 10.1136/bmj.b2549 Accessed 12 May 2014 from: http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC2718086/ [15] Moss EL, Arbyn M, Dollery E, et al. European Federation of Colposcopy quality standards Delphi consultation. Eur J Obstet Gynecol Reprod Biol 2013;170:255–8. [16] Luyten A, Scherbring S, Reinecke-Luthge A, et al. Riskadapted primary HPV cervical cancer screening project in Wolfsburg, Germany – experience over 3 years. J Clin Virol 2009;46(Suppl. 3):S5–10.

HPV and cervical cancer.

In recent analyses of the global burden of cancer among women, cervical cancer ranked second to breast cancer. Numbers of new cervical cancer cases ar...
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