About this chapter
This chapter is based on the following WHO guidelines:
Cervical cancer screening in developing countries: report of a WHO consultation. Geneva: WHO; 2002. (http://whqlibdoc.who.int/publications/2002/9241545720.pdf).
WHO guidance note: comprehensive cervical cancer prevention and control: a healthier future for girls and women. Geneva: WHO; 2013. (http://apps.who.int/iris/bitstream/10665/78128/3/9789241505147_eng.pdf).
Other articles and publications on which the chapter is based can be found under Further reading, at the end of the chapter.
This chapter has three sections. Section 1.1, Why focus on cervical cancer?, summarizes global statistics and the large disparities within and between countries in the rates of new cases diagnosed (incidence) and deaths recorded (mortality) each year. This information illustrates the burden that cervical cancer places on women and on health services, and the reasons why universal access to preventive services is of the utmost importance.
Section 1.2, Female pelvic anatomy and physiology, illustrates women's pelvic anatomy and describes the changes to the cervix that take place across the lifespan, from infancy to postmenopause. It also explains how these changes relate to cervical cancer prevention. Basic knowledge of women's reproductive anatomy gives health-care providers helpful tools for communicating with women, families and communities about cervical cancer prevention services (see Chapter 3).
Section 1.3, Natural history of cancer of the cervix, provides information on the very slow progression of changes caused by persistent HPV infection. Health-care providers need to understand these sequential changes to be able to explain to the community why we have the opportunity to prevent most cervical cancer from occurring, and thus avoid the suffering and premature deaths that it causes.
1.3. Natural history of cancer of the cervix
1.3.1. What is cancer?
Cancer is a term used for the malignant, autonomous and uncontrolled growth of cells and tissues. Such growth forms tumours, which may invade the tissues around the cancer and cause new growths similar to the original cancer in distant parts of the body, called metastases. As cancer grows, it destroys normal tissues and competes for nutrients and oxygen.
1.3.2. What is cervical cancer?
Persistent infection with cancer-causing HPV types is the cause of most cervical cancer. Ninety per cent of cervical cancers are squamous cell cancers and initiate in the transformation zone of the ectocervix; the other 10% are adenocarcinomas, which arise in the glandular columnar layer of the endocervix.
As stated in section 1.1 of this chapter, cervical cancer is preventable by vaccinating young girls against the human papillomaviruses that cause it and by screening for and treating precancerous lesions in women, since these lesions precede cancer by many years. In addition, if detected early and treated, cervical cancer can still be cured.
1.3.3. What is cervical pre-cancer?
Cervical pre-cancer is a distinct change in the epithelial cells of the transformation zone of the cervix; the cells begin developing in an abnormal fashion in the presence of persistent or long-term HPV infection.
With the majority of cancers, even if they have a precursor stage, it is too short to be noticed and not amenable to easy diagnosis and treatment. Cervical cancer is one of the very few cancers where a precursor stage (pre-cancer) lasts many years before becoming invasive cancer, providing ample opportunity for detection and treatment.
Unfortunately, although preventable, there are still large numbers of women who die of cervical cancer in many countries (see section 1.1). This is because they lack access to services for prevention and treatment – a problem that may be caused by many factors, such as barriers that limit their access to services (e.g. hours of operation, distance, lack of transportation) as well as prevailing cultural and gender barriers. In most cases, though, the overarching cause is poverty.
1.3.4. HPV infection and cofactors that facilitate persistent infections
The primary cause of cervical pre-cancer and squamous cervical cancer is symptom-free, persistent or chronic infection with one or more of the high-risk (cancer-causing or oncogenic) types of HPV. HPV is the most common sexually transmitted infection.
Of the more than 100 numbered types of HPV, most of them are not associated with cervical cancer. Seven out of 10 (70%) of all cervical cancer cases reported throughout the world are caused by only two types of HPV: 16 and 18. Another four high-risk HPV types − 31, 33, 45 and 58 – are less commonly found to be associated with cervical cancer, with particular types being more prevalent than others in certain geographical areas.
Two low-risk types of HPV (6 and 11) do not cause cervical cancer but are the cause of most genital warts or condylomas.
Almost all women and men are infected with HPV shortly after initiating sexual activity. Penetration of the vagina by the penis does not have to occur because the virus can be transmitted by skin-to-skin contact of the genital areas near the penis and vagina.
As in women, HPV infections in men are also commonly without symptoms and most infections are short-lived. Men can develop cancer of the anus; this is most commonly associated with HPV type 16, and is more common in men who have sex with men. As in women, HPV types 6 and 11 cause the majority of male genital warts.
In women, during puberty and pregnancy, the transformation zone on the ectocervix is enlarged. Exposure to HPV at these times may facilitate infection and may explain the associations between squamous cell cervical cancer and early sexual activity, young age at first birth, and a history of multiple pregnancies. Behaviours that can also increase the risk of HPV infection (and thus cervical cancer) include having multiple partners, and having partners with multiple partners.
While infection with a high-risk HPV type is the underlying cause of almost all cases of cervical cancer, it is NOT the case that these infections almost always cause cancer. In fact, most women infected with high-risk HPV do not develop cancer because most infections, regardless of HPV type, are short-lived; the body eliminates them spontaneously in less than two years. Infection with high-risk HPV only persists (becomes chronic) in a small percentage of women, and only a small percentage of these chronic infections can progress to pre-cancer; of these, even fewer will progress to invasive cancer. Thus, it is estimated that no more than 2% of all women in low-resource countries will develop cervical cancer during their lifetimes.
The conditions (cofactors) that may lead HPV infection to persist and progress to cancer are not well understood, but the following risk factors probably play a role:
HPV type – its oncogenicity or cancer-causing strength;
immune status – people who are immunocompromised, such as those living with HIV, are more likely to have persistent HPV infections and a more rapid progression to pre-cancer and cancer;
coinfection with other sexually transmitted agents, such as those that cause herpes simplex, chlamydia and gonorrhoea;
parity (number of babies born) and young age at first birth;
tobacco smoking;
use of oral contraceptives for over five years.
The last cofactor, use of oral contraceptives (OCs) for over five years, is the weakest. This was studied extensively by a WHO expert group, which concluded that the great benefits conferred by use of a very effective contraceptive method for preventing unplanned and unwanted pregnancies (with consequent prevention of morbidity and mortality associated with these pregnancies) far outweigh the extremely small potential for an increased risk of cervical cancer that may result from OC use. Thus, it is not in the woman's interest to discourage or prevent her from using OCs. All that is needed is for these women, like all other women, to be screened for cervical cancer.
1.3.5. The development of pre-cancer
After entering cervical epithelial cells, high-risk HPV infection interferes with their normal functions, leading to changes characteristic of pre-cancer (also called dysplasia). See Annex 4 for terminology.
depicts the timeline of the progression from a normal (uninfected) cervix to HPV-infected cervix to pre-cancer and invasive cancer. Note that changes occur in both directions because a large proportion of HPV-infected cells return to a normal state and a large proportion of cervical pre-cancers do not become cancer.
The timeline and natural history of cervical pre-cancer and cancer development. Source: reproduced by permission of the first author from
SchiffmanMCastlePEThe promise of global cervical-cancer preventionN Engl J Med2005353202101416291978.
illustrates normal cervical squamous epithelium on the left and progressively thicker layers of new abnormal small cells involving the epithelium in the large intermediate section. As this section in the middle involves more and more of the thickness of the normal epithelium, the epithelium is considered to have mild, then moderate, and finally severe pre-cancer. This sequence leads to invasive cancer if the abnormal cells invade the bottom layer of the epithelium (basement membrane), as shown on the right of the figure.
Progress from normal epithelium to invasive cancer.
1.3.6. Routes taken by invasive cancer through the body as it progresses
There are four, usually sequential, routes through which invasive cancer progresses.
Within the cervix: Spread occurs from a tiny focus of microinvasive cancer until it involves the entire cervix, which can enlarge to 8 cm or more in diameter. The cancer can be ulcerating, exophytic (growing outwards) or infiltrating (invading inwards).
To adjacent structures: Direct spread in all directions is possible – downwards to the vagina, upwards into the uterus, sideways into the tissues supporting the uterus in the pelvis and the ureters, backwards to the rectum, and forwards to the bladder.
Lymphatic: Spread to pelvic lymph nodes occurs in 15% of cases when the cancer is still confined to the cervix, and increases as the cancer spreads. Lymph-node metastases are at first confined to the pelvis and are later found in the chain of nodes along the aorta, eventually reaching the space above the collarbone (supraclavicular fossa). The lymph nodes, once invaded with cancer, are enlarged and, if close to the skin, can be palpated. For example, if the cancer has advanced into the lower third of the vagina, the groin nodes may become involved and will be palpably enlarged, and the supracervical nodes will also feel noticeably enlarged.
Distant metastases through the bloodstream and lymph channels. Cervical cancer cells may spread through the blood stream and lymphatic system to develop distant metastases in the liver, bone, lung and brain.
While invasive cancer initially remains confined within the pelvic area, many cases can still be cured with appropriate treatment. If left untreated, however, cervical cancer progresses in a predictable manner and will almost always lead to death (see Chapter 6 for information on diagnosis and treatment of invasive cervical cancer).
1.3.7. Cervical cancer and human immunodeficiency virus (HIV) infection
Cervical cancer is a defining illness of acquired immunodeficiency syndrome (AIDS)1 in patients with HIV.
Women living with HIV and other immunocompromised women have a higher prevalence of HPV (the risk of infection increases with the degree of immunosuppression) and a higher prevalence of persistent HPV infection and infection with multiple high-risk HPV types.
This increased susceptibility to HPV infection leads to:
a greater risk of pre-cancer and cancer at younger ages, which increases with the degree of immunosuppression;
an increased risk of developing invasive disease up to 10 years earlier than in women not infected with HIV; and
more frequent presentation with advanced disease with smaller chance of survival for five years.
The above points strongly suggest the need to develop specific vaccination, screening and treatment protocols for women living with HIV and for all women living in countries or regions with a high prevalence of HIV. Existing protocols are based on experience, and studies are ongoing to determine whether or not these protocols include the best possible practices. For information specific to women living with HIV, see Chapter 5, sections 5.2.5 and 5.4.6; Chapter 6, section 6.6.2; and Annex 9.