Elsevier

The Lancet

Volume 370, Issue 9590, 8–14 September 2007, Pages 890-907
The Lancet

Seminar
Human papillomavirus and cervical cancer

https://doi.org/10.1016/S0140-6736(07)61416-0Get rights and content

Summary

Cervical cancer is the second most common cancer in women worldwide, and knowledge regarding its cause and pathogenesis is expanding rapidly. Persistent infection with one of about 15 genotypes of carcinogenic human papillomavirus (HPV) causes almost all cases. There are four major steps in cervical cancer development: infection of metaplastic epithelium at the cervical transformation zone, viral persistence, progression of persistently infected epithelium to cervical precancer, and invasion through the basement membrane of the epithelium. Infection is extremely common in young women in their first decade of sexual activity. Persistent infections and precancer are established, typically within 5–10 years, from less than 10% of new infections. Invasive cancer arises over many years, even decades, in a minority of women with precancer, with a peak or plateau in risk at about 35–55 years of age. Each genotype of HPV acts as an independent infection, with differing carcinogenic risks linked to evolutionary species. Our understanding has led to improved prevention and clinical management strategies, including improved screening tests and vaccines. The new HPV-oriented model of cervical carcinogenesis should gradually replace older morphological models based only on cytology and histology. If applied wisely, HPV-related technology can minimise the incidence of cervical cancer, and the morbidity and mortality it causes, even in low-resource settings.

Section snippets

Burden of cervical cancer

There were about 500 000 incident cases of and 275 000 deaths due to cervical cancer worldwide in 2002, equivalent to about a tenth of all deaths in women due to cancer.1 The burden of cervical cancer is disproportionately high (>80%) in the developing world.2 Not only is cervical cancer the most prevalent and important cancer in women in several developing countries, but also the societal importance of the disease is accentuated even further by the young average age at death, often when women

The cervical transformation zone

Cervical cancer usually arises from a ring of mucosa called the cervical transformation zone (figure 1). For reasons that we do not understand, persistent HPV infections cause cancers mainly at the transformation zones between different kinds of epithelium (eg, cervix, anus, and oropharynx).2 Illustrating the importance of the transformation zone, cancer-associated (carcinogenic) HPV infections are equally common in cervical and vaginal specimens;5 however, cervical cancer is the second most

Histopathology

In poorly screened populations, squamous cell carcinomas constitute most cases of cervical cancer. In regions with good cervical cancer screening programmes, the proportion of adenocarcinomas is increased (15–20%) compared with unscreened populations, presumably because they arise from the poorly sampled glands of the canal or from poorly recognised precursor lesions.11 Beyond the relative increase, absolute rates of cervical adenocarcinomas are thought to have increased in various countries

Basics of HPV virology

Papilloma (wart) viruses have co-evolved with animal hosts over millions of years and the life cycle of each genotype of HPV is tied closely to the differentiation of its specific epithelial target (eg, sole of foot, non-genital skin, anogenital skin, anogenital/oropharyngeal mucosa).16 The relations between HPV genotypes can be expressed in the form of phylogenetic trees based on DNA sequence and protein homologies, which serve as unifying tools in understanding HPV classification and

Development of cervical cancer

Cervical cancer arises via a series of four steps—HPV transmission, viral persistence, progression of a clone of persistently infected cells to precancer, and invasion—that can be reproducibly distinguished and which provide a rational starting point for any discussion of optimum prevention efforts (figure 3). Backward steps occur also, namely clearance of HPV infection and the less frequent regression of precancer to normality. The molecular virology underlying HPV persistence, progression,

Risk as a guiding principle of prevention strategies

The steps in cervical cancer pathogenesis can guide prevention and management. Short-term risk of CIN3 is a scientifically valid, ethically justified surrogate for long-term cancer risk, and can be estimated in prospective studies and clinical trials. To base clinical decisions on knowledge of risk of such lesions makes sense; the clinical response should be uniform irrespective of what clinical test is used to define risk85 (panel 1). For example, finding HPV16 on an HPV DNA test conveys

Treatment of cervical precancer and invasive cancer

The effect of behavioural factors on the clearance of HPV or precancer is poorly understood. However, consideration of smoking is always important for reasons of public health. There is some evidence that smoking cessation promotes resolution of HPV-induced cytopathology.149 Genotoxic smoke constituents are secreted at high levels into the cervical mucus.150 Enhancement of cellular immunity is also probably involved. In any case, it makes sense to encourage women with precancerous screening

Fitting prevention strategies into available resources and existing programmes

New cervical cancer prevention methods must be introduced with consideration of added value and added cost. Otherwise, the rich could easily be over-treated, while the poor at higher risk are neglected. For example, the addition of HPV testing to cytology for screening, if repeated every year, cannot be cost effective and will lead to excessive interventions.162 Similarly, new preventive vaccines, if adopted with high acceptance, rationally must lead to less frequent screening to be cost

Future directions

There are a number of important, active research topics that will soon affect clinical management of cervical HPV and precancer: the average risk and timing of clearance versus persistence of each type of HPV; the risk and timing of diagnosis of precancer given persistence of each of the types; the effect, if any, of age at infection on these rates of clearance, persistence, and progression; the risk, if any, of occasional re-appearance of an HPV type via reinfection or latency, if such a state

Conclusions

Much of the cervical cancer problem can be solved with existing or soon-to-be available technology, sufficient will, and modest resources. There is an enlarging repertoire of options for cervical cancer prevention for regions with varying needs and values, based on innovative technology and clear understanding of cervical carcinogenesis. Because of the importance of the problem and the feasibility of ameliorating it, we hope to see a major decrease in the numbers of women affected with this

Search strategy and selection criteria

We searched the Cochrane Library (2000–07) and Medline (1980–2007) with the terms “human papillomavirus”, “HPV”, “CIN”, “cervix cancer”, “cervical carcinoma”, “cervical neoplasia”, “cervix cancer”, “cervix carcinoma”, and “cervix neoplasia”. We largely selected publications from the past 5 years, but chose some commonly referenced, important older publications. Review articles and book chapters are cited to provide readers with additional details and references. Our reference list was

References (172)

  • AN Burchell et al.

    Chapter 6: epidemiology and transmission dynamics of genital HPV infection

    Vaccine

    (2006)
  • SR Pagliusi et al.

    Chapter 23: International standard reagents for harmonization of HPV serology and DNA assays–an update

    Vaccine

    (2006)
  • AB Moscicki et al.

    Regression of low-grade squamous intra-epithelial lesions in young women

    Lancet

    (2004)
  • WK Kinney et al.

    Where's the high-grade cervical neoplasia? The importance of minimally abnormal Papanicolaou diagnoses

    Obstet Gynecol

    (1998)
  • RJ Kurman et al.

    Analysis of individual human papillomavirus types in cervical neoplasia: a possible role for type 18 in rapid progression

    Am J Obstet Gynecol

    (1988)
  • M Stanley

    Immune responses to human papillomavirus

    Vaccine

    (2006)
  • CB Woodman et al.

    Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study

    Lancet

    (2001)
  • AT Lorincz et al.

    Viral load of human papillomavirus and risk of CIN3 or cervical cancer

    Lancet

    (2002)
  • N Ylitalo et al.

    Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study

    Lancet

    (2000)
  • AM Josefsson et al.

    Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case-control study

    Lancet

    (2000)
  • JS Smith et al.

    Cervical cancer and use of hormonal contraceptives: a systematic review

    Lancet

    (2003)
  • JM Palefsky et al.

    Chapter 16: HPV vaccines in immunocompromised women and men

    Vaccine

    (2006)
  • J Peto et al.

    The cervical cancer epidemic that screening has prevented in the UK

    Lancet

    (2004)
  • LJ Kinlen et al.

    Women with positive cervical smears but without surgical intervention. A follow-up study

    Lancet

    (1978)
  • S Inglis et al.

    Chapter 11: HPV vaccines: commercial research & development

    Vaccine

    (2006)
  • EA Joura et al.

    Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials

    Lancet

    (2007)
  • J Paavonen et al.

    Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial

    Lancet

    (2007)
  • AT Newall et al.

    Cost-effectiveness analyses of human papillomavirus vaccination

    Lancet Infect Dis

    (2007)
  • DM Parkin et al.

    Global cancer statistics, 2002

    CA Cancer J Clin

    (2005)
  • PE Castle et al.

    A population-based study of vaginal human papillomavirus infection in hysterectomized women

    J Infect Dis

    (2004)
  • PE Castle et al.

    Age-related changes of the cervix influence human papillomavirus type distribution

    Cancer Res

    (2006)
  • SP Dobbs et al.

    Does histological incomplete excision of cervical intraepithelial neoplasia following large loop excision of transformation zone increase recurrence rates? A six year cytological follow up

    BJOG

    (2000)
  • A Berrington de Gonzalez et al.

    Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8 097 women with squamous cell carcinoma and 1 374 women with adenocarcinoma from 12 epidemiological studies

    Int J Cancer

    (2007)
  • ME Sherman et al.

    Mortality trends for cervical squamous and adenocarcinoma in the United States. Relation to incidence and survival

    Cancer

    (2005)
  • F Bray et al.

    Incidence trends of adenocarcinoma of the cervix in 13 European countries

    Cancer Epidemiol Biomarkers Prev

    (2005)
  • A Berrington de Gonzalez et al.

    Comparison of risk factors for squamous cell and adenocarcinomas of the cervix: a meta-analysis

    Br J Cancer

    (2004)
  • JS Smith et al.

    Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update

    Int J Cancer

    (2007)
  • D Solomon et al.

    The 2001 Bethesda system: terminology for reporting results of cervical cytology

    JAMA

    (2002)
  • M Wells et al.

    Epithelial tumours

  • J Doorbar

    Molecular biology of human papillomavirus infection and cervical cancer

    Clin Sci (Lond)

    (2006)
  • K Munger et al.

    Biological activities and molecular targets of the human papillomavirus E7 oncoprotein

    Oncogene

    (2001)
  • F Mantovani et al.

    The human papillomavirus E6 protein and its contribution to malignant progression

    Oncogene

    (2001)
  • M Schiffman et al.

    The promise of global cervical-cancer prevention

    N Engl J Med

    (2005)
  • MH Stoler et al.

    Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study

    JAMA

    (2001)
  • JN Roberts et al.

    Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan

    Nat Med

    (2007)
  • F Mendez et al.

    Cervical coinfection with human papillomavirus (HPV) types and possible implications for the prevention of cervical cancer by HPV vaccines

    J Infect Dis

    (2005)
  • M Plummer et al.

    A 2-year prospective study of HPV persistence among women with ASCUS or LSIL cytology

    J Infect Dis

    (2007)
  • R Herrero et al.

    Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica

    J Infect Dis

    (2005)
  • X Castellsague et al.

    Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners

    N Engl J Med

    (2002)
  • RL Winer et al.

    Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students

    Am J Epidemiol

    (2003)
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