Aetiology
A number of different risk factors have been identified for cervical cancer and its precursors and these include smoking, early age at first intercourse, nutritional deficiency, chlamydial infection, multiple sexual partners, multiple pregnancies, and long-term use of oral contraceptives (2-6).
However, the fundamental and sine qua non causative agent is the persistence of oncogenic human papillomavirus (HPV) in the epithelium of the transformation zone (TZ) and/or adjacent glandular epithelium. The relationship between oncogenic HPV and cervical precancer appears at first paradoxical. Cervical cancer is always associated with oncogenic HPV but oncogenic HPV is a normal and usually transient infection that most normal sexually active women will encounter in early reproductive life. Current thinking is that the oncogenic HPV virus gains entry to the cervical epithelium at the new squamocolumnar junction, possibly associated with minor abrasions and that this allows the virus to access reserve cells underneath the single layer of columnar epithelium.Screening tests
Systematic high coverage and quality-assured population screening for precursors to cervical cancer is highly effective. This is not surprising given the conditions for an ideal screening test (7) apply very precisely to cervical cancer. The disease has a long precan- cerous phase, effective screening tests are available and are easily performed, and the disease is common enough to justify the expense of population screening, even in low- and middle-income countries (LMIC) (8). There are effective and low-morbidity preventive treatments of proven value for screen-positive women. Finally, vaccination is available and effective. Cervical cancer really shouldn't exist.
A positive diagnostic test result reveals an abnormality. Advice about management is usually accepted willingly.
When a woman receives an abnormal screening test result, the expectations and fears that she carries are quite different. Cervical screening tests, whether visual inspection, cervical cytology, or HPV tests, do not give a diagnosis, rather they modify the risk for an individual of developing cervical cancer. The progression to precancer and cancer is slow and is a very uncommon outcome for screen-positive women. The threshold of abnormality at which the risk of cancer outweighs any disadvantage of treatment varies according to patient characteristics and local service considerations. Most clinical guideline documents advise treatment at the high-grade squamous intraepithelial lesion level (HSIL or cervical intraepithelial neoplasia (CIN) 2-3). However, in many countries with established screening programmes, and where low rates of default to follow-up exist, the threshold for treatment may be higher, especially in young women with moderate intraepithelial neoplasia (HSIL-CIN2).But current screening tests for cervical precancer are neither completely sensitive nor absolutely specific. Oncogenic or high- risk HPV testing is highly sensitive but has poor specificity. Cytology is far more specific but less sensitive (9, 10) and has to be performed relatively frequently. The long natural history of cervical cancer is forgiving of the relatively poor sensitivity of cytology. Molecular biomarkers may soon prove to be cost-effective secondary screening tests.
Visual inspection with acetic acid (VIA) is now the de facto primary screening method in many LMICs. Also, a policy of screen and treat is gaining popularity as an efficient method of reaching large numbers of women as a once in a lifetime event. However, the specificity of VIA is poor (11). Overtreatment of the majority of VIApositive women is perceived by many as less of a problem.
VIA (or visual inspection with Lugol's iodine) is inexpensive, simple, and can be carried out by primary care staff trained in a relatively short time.
They provide immediate results and may be performed in hospital clinics or in the community. The sensitivity as well as the specificity of visual inspection techniques are highly variable and very reliant on quality-assured training and retraining (12, 13). Of course, these methods only assess the ectocervix and will miss endocervical lesions with consequent poorer performance| Population | Incidence | Mortality | Prevalance | ||
| I Number | ASR (W) | I Number | ASR (W) | 5-year | |
| World | 527624 | 14.0 | |||
| More developed regions | 83,078 | 9.9 | 35,495 | 3.3 | 288,967 |
| Less developed regions | 444,546 | 15.7 | 230,158 | 8.1 | 1,258,194 |
Source data from Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, IARC CancerBase No. 11. IaRc; 2013. Available at: http://globocan.iarc.fr.
in older women. Finally, visual inspection is very unlikely to detect glandular intraepithelial lesions.
HPV DNA testing will probably replace or complement cytology as the primary screening tool in many developed countries for women over 30 years of age (14, 15). Because of the absolute relationship between oncogenic HPV and cervical cancer, its negative predictive value is very high. There are essentially three realms where HPV testing is of proven clinical utility: as a screening tool in women over 30 years, as a triage tool for low-grade abnormalities, and as a follow-up tool for women who have been treated for squamous cervical precancer.
Oncogenic HPV testing as the primary screening tool
Sankaranarayanan and colleagues (16) first demonstrated in a large cluster randomized controlled trial that a single round of HPV testing was superior to cytology or VIA or no screening in reducing the incidence of advanced cervical cancer and of cervical cancer mortality. Four randomized controlled trials of HPV screening versus routine cytological screening in Europe have been undertaken. In these studies, a total of 176,464 women aged 20-64 years were randomly assigned to HPV-b ased (experimental arm) or cytology-based (control arm) screening in Sweden, the Netherlands, England, and Italy (15). The authors conclude in their summary that ‘HPV-based screening provides 60-70% greater protection against invasive cervical carcinomas compared with cytology. Data from large-scale randomized trials support the initiation of HPV-based screening from age 30 years and extension of screening intervals to at least 5 years’. The results of this overview are very convincing.