Elsevier

The Lancet

Volume 382, Issue 9895, 7–13 September 2013, Pages 889-899
The Lancet

Seminar
Human papillomavirus and cervical cancer

https://doi.org/10.1016/S0140-6736(13)60022-7Get rights and content

Summary

Cervical cancer is caused by human papillomavirus infection. Most human papillomavirus infection is harmless and clears spontaneously but persistent infection with high-risk human papillomavirus (especially type 16) can cause cancer of the cervix, vulva, vagina, anus, penis, and oropharynx. The virus exclusively infects epithelium and produces new viral particles only in fully mature epithelial cells. Human papillomavirus disrupts normal cell-cycle control, promoting uncontrolled cell division and the accumulation of genetic damage. Two effective prophylactic vaccines composed of human papillomavirus type 16 and 18, and human papillomavirus type 16, 18, 6, and 11 virus-like particles have been introduced in many developed countries as a primary prevention strategy. Human papillomavirus testing is clinically valuable for secondary prevention in triaging low-grade cytology and as a test of cure after treatment. More sensitive than cytology, primary screening by human papillomavirus testing could enable screening intervals to be extended. If these prevention strategies can be implemented in developing countries, many thousands of lives could be saved.

Introduction

One of the most important scientific discoveries of the past 30 years is the causal link between human papillomavirus infection of the cervix and cervical cancer. This finding resulted from the original seminal findings by Harald zur Hausen and his group, that human papillomavirus 16 can be detected in cervical cancer tissue, and was followed by an enormous worldwide effort involving epidemiologists, molecular biologists, vaccinologists, and clinicians culminating in the development of effective prophylactic vaccines for human papillomavirus, which have the means to prevent 70–80% of cervical cancer. zur Hausen was awarded the Nobel Prize in Physiology or Medicine in 2008, in recognition of his discovery.

Human papillomavirus belongs to the papillomavirus family of viruses, which have a diverse range of hosts in both animals and man. The family has an agreed taxonomy that is based on genome sequence homology, biological function, and pathological effect.1 More than 100 types of human papillomavirus have been identified, including 13 high-risk types, which are responsible for cervical neoplasias and other anogenital and oropharyngeal cancers.

We review the worldwide epidemiology and natural history of cervical human papillomavirus infection, the virus's lifecycle, and the process of viral oncogenesis. We then discuss how the unique relationship between human papillomavirus and cervical cancer has been exploited for primary (prophylactic vaccines) and secondary (screening) prevention.

Section snippets

Epidemiology

Human papillomavirus infection is the most common sexually transmitted infection worldwide and most sexually active individuals of both sexes will acquire it at some point during their life.2 On the basis of a meta-analysis3 of 1 million women with normal cervical cytology, around 291 million women worldwide are estimated to have human papillomavirus infection of the cervix at a given point, corresponding to an average prevalence of 10·4%, though prevalence is higher in women younger than 25

The viral lifecycle

Human papillomavirus infects only epithelial cells and depends on the differentiation pathway of epithelial cells to complete its lifecycle.26 Human papillomavirus infects cells in the basal layer of the epithelium, probably via microabrasions in the epithelial surface. It capitalises on the lateral extension of basal cells that accompanies wound healing to gain entry to the cell. Infectious internalisation takes several hours, after which viral DNA is released from the capsid and transported

Prophylactic vaccines

Understanding of the ubiquitous role of human papillomavirus infection in all CIN and cervical cancer combined with an understanding of human papillomavirus natural history has led to the development of the first prophylactic cancer vaccines. These vaccines contain human papillomavirus L1 self-assembling virus-like particles (figure 3), which induce strong neutralising antibody responses against human papillomavirus infection.60 These antibodies are thought to block the human papillomavirus

Human papillomavirus testing in cervical screening

Because of its crucial causal role and the need for continued expression to maintain the disease phenotype, human papillomavirus can be used as a biomarker of cervical cancer and precancer. Randomised trials88, 89, 90 have shown that human papillomavirus DNA testing provides greater sensitivity than does cytology for detection of CIN. Human papillomavirus testing is more reproducible with less subjective analytical characteristics,91 and users need less training and expertise. The major

The role of human papillomavirus testing

Atypical cytology of unknown significance or borderline cytology are associated with underlying CIN2 or worse in roughly 10% of cases. In atypical cytology of unknown significance or borderline cytology, about 60% test positive for high-risk human papillomavirus, which enables human papillomavirus testing to identify those at very low risk (human papillomavirus negative), who can be routinely recalled at standard screening intervals, whereas a human papillomavirus positive result warrants

Conclusion

Human papillomavirus is a well-established cancer-causing infectious agent that is almost exclusively sexually transmitted and has increased in prevalence in many parts of the world during the past few decades.10, 105 Only comprehensive cervical screening programmes have avoided a corresponding epidemic of cervical cancer.105 Thus, economic improvements in developing countries will not be sufficient to overcome the present international disparities in cervical cancer burden unless human

Search strategy and selection criteria

We searched the Cochrane Library and PubMed for relevant randomised trials and other high-quality studies (eg, systematic reviews, meta-analyses) between Jan 1, 2000, and July 1, 2012, for the terms “HPV”, “human papillomavirus”, “HPV vaccination”, “cervical cancer”, “cervical carcinoma”, “cervical neoplasia”, and “cervical carcinogenesis”. Widely cited older publications that we judged to have remained important references were also included. References from relevant articles identified by our

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