1.1.1. Reasons to focus on cervical cancer

The reasons to focus on cervical cancer include:

• Worldwide, 266 000 women die of cervical cancer each year. It is the leading cause of cancer deaths in Eastern and Central Africa.
• The majority of these deaths can be prevented through universal access to comprehensive cervical cancer prevention and control programmes, which have the potential to reach all girls with human papillomavirus (HPV) vaccination and all women who are at risk with screening and treatment for pre-cancer.
• We know what causes cervical cancer: almost all cases are caused by a persistent (very long-lasting) infection with one or more of the “high-risk” (or oncogenic) types of HPV.
• We understand the natural history of HPV infection and the very slow progression of the disease in immunocompetent women, from normal (healthy) to pre-cancer, to invasive cancer, which is potentially fatal.
• The 10- to 20-year lag between pre-cancer and cancer offers ample opportunity to screen, detect and treat pre-cancer and avoid its progression to cancer. However, immunocompromised women (e.g. those living with HIV) progress more frequently and more quickly to pre-cancer and cancer.
• There are several available and affordable tests that can effectively detect pre-cancer, as well as several affordable treatment options.
• HPV vaccines are now available; if given to all girls before they are sexually active, they can prevent a large portion of cervical cancer.
• Until there is universal access to cervical cancer prevention and control programmes, which will require addressing present inequities, the large disparities in incidence rates and mortality rates that exist in different settings will continue to be ample evidence of lack of comprehensive and effective services.

1.1.2. Global epidemiology of cervical cancer

Epidemiology is the study of the distribution and determinants of health-related states or events (including disease), and the application of this study to the control of diseases and other health problems.

a. Numbers and comparisons between countries

Cervical cancer is the most common cancer among women in 45 countries of the world, and it kills more women than any other form of cancer in 55 countries. These include many countries in sub-Saharan Africa, many in Asia (including India), and some Central and South American countries. The maps in Figures 1.1 and 1.2 illustrate global differences in incidence and mortality rates between countries and regions of the world. These maps do not include the wide disparities in incidence and mortality between areas within specific countries, which are related to socioeconomic and geographic variation, gender bias and culturally determined factors that can all severely restrict access to preventive services among some groups of women.

Figure 1.1

Estimated cervical cancer incidence worldwide, 2012. Source: International Agency for Research on Cancer (IARC) World Health Organization (WHO)GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012: cancer fact sheets: (more...)

Figure 1.2

Estimated cervical cancer mortality worldwide, 2012. Source: International Agency for Research on Cancer (IARC) World Health Organization (WHO)GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012: cancer fact sheets: (more...)

Further, the following data clearly illustrate the great differences found between women living in high-income versus low- to middle-income countries:

• In 2012, 528 000 new cases of cervical cancer were diagnosed worldwide; of these, a large majority, about 85% occurred in less developed regions.
• In the same year, 266 000 women died of cervical cancer worldwide; almost 9 out of every 10 of these, or 231 000 women in total, lived and died in low- to middle-income countries. In contrast, 35 000, or just 1 out of every 10 of these women, lived and died in high-income countries.

The main reason for these disparities is the relative lack of effective prevention and early detection and treatment programmes, and the lack of equal access to such programmes. Without these interventions, cervical cancer is usually only detected when it is already at an advanced stage so that it is too late for effective treatment, and therefore mortality is high.

1.2.1. Why understanding female genital anatomy is important

An understanding of the anatomy of the female pelvic structures will help health-care providers involved in cervical cancer programmes to:

• perform their tasks, including community education, screening, diagnosis and treatment of pre-cancer;
• refer women who have lesions that cannot be managed at the provider's level to appropriate higher-level facilities;
• interpret laboratory and treatment procedure reports and clinical recommendations received from providers at higher levels of the health-care system;
• educate and provide one-on-one counselling to each patient (and her family if she requests this) about her condition and the plan for her follow-up care; and
• communicate effectively with providers at all levels of care, including community health workers and tertiary-level referral providers.

See Introduction for descriptions of the different levels of health-care services and the providers at each level.

1.2.2. Identification of the external and internal organs

a. The external organs

The external organs include those visible with the naked eye and those visible using a speculum. Figure 1.3 shows the area seen when a woman of reproductive age spreads her legs. This includes the vulva (the area between the upper border in figure and the level of the Bartholin glands), the perineum and the anus. The vulva comprises the vaginal opening (introitus), which, with nearby structures, is protected by the major and minor labia. The clitoris is a small and very sensitive organ that enhances sexual pleasure. The urinary opening (urethra) is a very small opening above the introitus. The perineum is the area between the vaginal opening and the anus. Bartholin glands produce clear mucus which lubricate the introitus when a woman is sexually stimulated.

Figure 1.3

Female external genitalia.

b. The internal organs

The organs inside the pelvis are not visible except when exposed by an incision or laparoscopy. As shown in Figure 1.4, the urinary bladder and urethra are behind the pubic bone and in front of the vagina and cervix. The body of the uterus is above the cervix and the bottom of the colon and rectum are behind the genital structures. The uterus is held in place by thickenings or ligaments in the lining of the abdomen (peritoneum). The ureters (thin tubes that carry urine from the kidneys to the bladder) are on either side of the uterus but are not shown in these figures.

Figure 1.4

Front and side views of female internal organs.

1.2.3. Brief description of the pelvic organs

b. Cervix

The cervix is the lower third of the uterus. In a non-pregnant woman of fertile age, it measures approximately 3 cm in length and 2.5 cm in diameter. The lower part of the cervix (ectocervix) lies within the vagina and is visible with a speculum; the upper two thirds of the cervix (endocervix) lies above the vagina and is not visible. Most cervical cancers originate in the area where the endocervix and ectocervix join. Figure 1.5 shows the uterus and the relative size of the cervix as part of the uterus in a woman of reproductive age.

Figure 1.5

Uterus and cervix of a woman of reproductive age.

The cervix is composed of dense fibro-muscular tissue. The cervical canal runs through the centre of the cervix from the internal os (the opening at the entrance to the cavity of the uterus) to the external os (the opening in the cervix seen with a speculum).

Figure 1.6 is a slightly enlarged photograph of the cervix as seen with a speculum in place. It shows the slightly irregular opening to the cervical canal, or external os, in a woman of reproductive age who has not had any vaginal deliveries. In a woman who has had one or more deliveries, the os would look like a wide, mouth-like, irregular slit. In this figure, the darker area surrounding the os is an extension of the columnar epithelium lining the canal; the lighter area around it is composed of stratified squamous epithelium extending from the vagina. The line where the two epithelia join is the squamocolumnar junction (SCJ).

Figure 1.6

Cervix.

Please see later sections for a more detailed description of the cervical epithelia and normal changes that occur during the reproductive years (section 1.2.4), and for a description of the changes in the appearance of the cervix across a woman's lifespan (section 1.2.5). Those sections serve as an important preamble to section 1.3: Natural history of cancer of the cervix.

1.2.4. The cervical epithelia and normal changes during the reproductive years

a. Description of the cervical epithelia

The surface of the cervix is lined by two types of epithelium, which is the lining that is found on skin and inside hollow organs. The ectocervix is covered by the strong, protective, stratified (multi-layered) squamous epithelium, which is a continuation of the vaginal covering. The canal is covered by a single layer of tall columnar cells – the columnar epithelium – which lines the cervical canal (see Figures 1.7 and 1.8).

Figure 1.7

The normal cervix. Source: BlumenthalPDMcIntoshNCervical cancer prevention guidelines for low-resource settings Baltimore (MD) Jhpiego2005.

Figure 1.8

The two types of cervical epithelium and the squamocolumnar junction (SCJ). Source: Adapted with permission from SellorsJWSankaranarayananRColposcopy and treatment of cervical intraepithelial neoplasia: a beginners' manual Lyon International Agency for (more...)

The stratified squamous epithelium, as shown in Figure 1.8, consists of a plump, deep layer topped by multiple layers of increasingly tile-like, flatter cells.

The columnar epithelium, a single layer of tall cells, lines the cervical canal and extends outwards to a variable portion of the ectocervix. It is much thinner and more fragile than the squamous epithelium of the ectocervix and contains multiple glands that lubricate the canal.

The squamocolumnar junction (SCJ) is where the two types of epithelia meet. The SCJ is seen in Figure 1.8 as a sharp line with a step caused by the different thicknesses of the two epithelia. The location of the SCJ varies with a woman's age, hormonal status, history of birth trauma, pregnancy status and use of oral contraceptives.

b. Normal changes in the cervical epithelia during a woman's reproductive years

When exposed to the acidic environment of the vagina, the more fragile columnar epithelium that extends out from the cervical canal onto the face of the cervix is replaced by more sturdy squamous epithelium. This normal replacement process is termed squamous metaplasia; it gives rise to a second SCJ. The area of variable size between the original and the new SCJs is the transformation zone.

As we will describe in the next section of this chapter, on the natural history of cancer of the cervix (section 1.3), the cells of the transformation zone are particularly vulnerable to HPV infection and it is here that most squamous cell carcinoma develops.

Figure 1.9 depicts the face of the cervix of a woman who has had one or more vaginal births. It shows the normal changes that now include the squamous metaplastic epithelium, the transformation zone and both SCJs.

Figure 1.9

The transformation zone of the cervix of a parous woman of reproductive age. Source: Reproduced with permission from SellorsJWSankaranarayananRColposcopy and treatment of cervical intraepithelial neoplasia: a beginners' manual Lyon International Agency (more...)

1.2.5. Normal changes in the appearance of the cervix as a woman ages

In addition to the epithelial changes on the cervix described in section 1.2.4, the appearance of the cervix also undergoes striking changes from birth to postmenopause. Figure 1.10 is composed of schematic drawings showing these age-induced changes in the cervix, although it should be noted that in real life the appearance and demarcation of a woman's cervix at different life-stages is not quite as neat as shown.

Figure 1.10

Appearance of the cervix across a woman's lifespan. SCJ: squamocolumnar junction. Source: Drawing by August Burns; adapted with permission from SellorsJWSankaranarayananRColposcopy and treatment of cervical intraepithelial neoplasia: a beginners' manual Lyon International (more...)

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.

Figure 1.11 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.

Figure 1.11

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.

Figure 1.12 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.

Figure 1.12

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.

1. 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).
2. 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.
3. 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.
4. 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.