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
SeminarHuman papillomavirus and cervical cancer
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
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