One of the purposes of epidemiological studies is to estab-lish disease causation by comparing disease frequency with the prevalence of suspected risk factors in the envi-ronment. There are several ways of doing this.
Geographical comparisons look for an association between the distribution of a disease and the presence of suspected risk factors. Cervical cancer incidence and mortality is rela-tively high in developing countries. Although there are many potential factors at play, the link is thought to be a greater exposure to environmental carcinogens (e.g. HPV, cigarette smoking) and the lack of organized cervical screening.
Time trends are retrospective studies which look for a cor-relation between trends in disease incidence and trends in environmental factors or ways of life. For instance, succes-sive rises and falls in mortality from cervical cancer have been related to varying levels of sexual promiscuity.
Migrant studies compare disease rates in migrants with those in natives to help discriminate genetic from
environmental causes of disease. For example, Japanese migrants in USA have lower incidence of stomach cancer than native Japanese. This strongly indicates an environ-mental cause of the disease.
Longitudinal studies are different from time trend studies in that they are prospective, that is, they follow subjects over time whilst monitoring risk factors and health outcomes.
Case-control studies compare cases (people with the dis-ease under consideration) with controls (people without the disease) with respect to exposure to suspected causa-tive factors. Differences in the level of exposure between the two groups might indicate causation but this needs to be proved using sound statistical techniques.
An important problem with any type of epidemiological study is that people differ in all kinds of ways, not just in their exposure to the factors being investigated. If an unsus-pected factor is at play and is independently affecting the risk of disease then it is said to be a confounding variable.
5.1 CERVICAL CANCER EPIDEMIOLOGY 111111
Squamous cell carcinoma is associated with the more common HPV type 16, whereas ade-nocarcinoma is more closely associated with type 18. Many of the traditionally quoted risk factors for cervical cancer (such as number of sexual partners, age at first sexual intercourse and the sexual behaviour of the male partner) are simply markers of infection with high-risk HPV. That is not to say that other factors are not involved in the development of cervical can-cer. Cofactors for cervical cancer include smoking, immunosuppression, hormones, and host genetics. An in-depth discussion of these other influences is outside the scope of this book.
Key Points Key Points
Collectively, HPV types 16 and 18 are responsible for approximately 70% of cases of squamous cell carcinoma of the cervix.
Figure 5.1 illustrates the mechanism by which HPV causes cervical cancer. Briefly, the virus makes contact with the basal epithelial cells of the cervical epithelium, presumably via a break in the overlying epithelial layers. Next, the protein coat of the virus (i.e. the capsid) is shed and viral DNA enters one or more basal cells. At this stage viral DNA remains in episomal form (i.e. separate from host cell DNA) and replicates in tandem with host cell DNA. This stage of infection is known as the latent phase—no new viral particles are produced and there are no clinical or cytological manifestations.
Key Points Key Points
HPV is one of those viruses whose life cycle involves a latent phase and a productive phase. Viral latency is the stage during a virus’s life cycle during which there is no virus production and the viral genome remains dormant. However, the virus can reactivate and begin producing large amounts of viral progeny at any time, and this is called the productive phase of the infection.
Importantly, most latent infections resolve but a small proportion progress to a productive phase, in which viral DNA replication occurs independently of host DNA. Virus assembly is completed in the intermediate and superficial layers of squamous epithelium and the charac-teristic cytopathic effect, known as koilocytosis, is produced.
Some women with productive HPV infections, but by no means all, then develop cervical intraepithelial neoplasia (CIN). Many cases of CIN spontaneously resolve or will remain as stable lesions for many years, but those that do not will progress to invasive cancer if left untreated. At this stage the virus is said to have induced malignant transformation in the infected cells.
Although much research remains to be done, the most important event in malignant trans-formation appears to be the integration of HPV DNA into cellular DNA. The interaction disrupts important genes involved in the control of cell growth, resulting in the loss of the normal constraints to cell proliferation. The end result is malignant tumour formation (cancer).
Throughout the latent and productive phases of the HPV life cycle there is an important but incompletely understood interaction between HPV and various cofactors, such as host immune status, cigarette smoke, and possibly other environmental carcinogens.
Cofactor
An agent or a condition, other than the main causative factor, that affects the risk of developing a disease. For instance, while smoking on its own is unlikely to cause cervical cancer, it increases the risk that HPV infection will do so.
Cross reference Chapter 4.
Malignant transformation This is the process by which a normal cell becomes a cancer cell.
Viral integration
This is the insertion of viral DNA into host cell DNA.
Carcinogen
A substance or agent that causes cancer.
Invasive carcinoma Basal epithelial cells
HPV particles
Break in epithelium
Latent HPV infection
Episomal viral DNA Key
Productive HPV
infection and CIN1 New viral particles Koilocytosis
Key CIN2 / CIN3
FIGURE 5.1
The life cycle of HPV and its association with cervical neoplasia.
Key Points Key Points
Only a small proportion of HPV infections of the cervix ultimately progress to invasive cancer. Most are cleared spontaneously by the woman’s immune system.
5.2 SQUAMOUS NEOPL ASIA OF THE CERVIX 113113
Now that the link between cervical cancer, high-risk HPV infection, and molecular control of the cell cycle is firmly established, it is perhaps not surprising that HPV-related technology is rapidly becoming a new industry. HPV vaccines have been developed with the expectation that mass vaccination programmes will reduce the global burden of HPV-related disease, including cervi-cal cancer. New molecular tests are being investigated as adjuncts to, or even replacements for, cytology and histology. As well as HPV testing, tests for the altered expression of cell cycle con-trol genes or their associated proteins are exciting opportunities to be exploited in the diagnostic laboratory of the near future. You will read more about this brave new world in Chapter 13.
For now we will concentrate on the histology and cytology of cervical cancer and its precursors.
SELF-CHECK 5.1
A ‘successful’ HPV infection depends upon virus particles making contact with basal epithelial cells or reserve cells. Can you think of possible ways in which the virus can penetrate the pro-tective stratifi ed squamous epithelium in the cervix?
5.2 Squamous neoplasia of the cervix
The knowledge that invasive squamous cell carcinoma of the cervix is preceded by detecta-ble precancerous changes in cervical epithelium is the basis for the existence of cervical screen-ing programmes. Cervical intraepithelial neoplasia (CIN) is the name given to the precancerous lesion of cervical squamous epithelium. It develops over several years and regular cervical screening has been the mainstay of its early detection in the UK for over five decades.
To understand why cervical screening can be so successful you will need to know about the histology, natural history, and cytology of CIN. This is what we will deal with next.
Cross reference Chapter 13.
Cross reference Chapter 4.