CANCER OF THE CERVIX AND ITS PREVENTION: STILL A PUBLIC HEALTH CONCERN:
High lights for both Developed and Developing Countries:
-Definition of Cancer of the cervix.
-What causes cancer of the cervix?
2) The magnitude of cancer of the cervix, its distribution and determinants.
3) Factors associated with cancer of the cervix high lighted.
4) Signs and symptoms of cancer of the cervix.
5) Common complications of cancer of the cervix.
6) Prevention of cancer of the cervix. The Role of Human Papilloma Virus Vaccine and cancer cervix screening programs is mentioned.
7) The magnitude of cancer of the cervix, its distribution and determinants.
8) Comparison of the developed and developing countries.
- The regions to be considered:
9) What has been done well and where are the bottle necks.
10) Successful Cancer cervix screening Programs to learn from.
11) The way forward for countries with a big disease burden to reduce the problem basing on lessons learnt from other countries successes and failures.
12) References and additional information.
Cervical cancer refers to the malignant condition of the cervix (the mouth of the uterus/womb). Despite the known pre-invasive and implementation of cervical screening programs, cervical cancer has remained a major health problem especially in the developing world (1).
The exact cause of cancer of the cervix is not clearly defined but high risk human papilloma virus subtypes are the major ones incriminated (1-5). Human papilloma virus (HPV) is sexually transmitted and thus the linkage between cancer of the cervix and sexually transmitted infections. HPV infects the cells of the cervix and may result into precancerous lesions and invasive cancer (6, 7) The positive rate of high risk HPV increases as the severity of cervical squamous intra-epithelial lesion increases (1,8) The high risk HPV types include 16,18, 31,33 and 35). Most cervical cancers (approximately 80%) are squamous cell carcinomas, with adenocarcinomas and mixed types (adenocarcinomas) accounting for most of the remainder. However the relative and absolute frequencies of adenocarcinomas are rising worldwide, particularly among younger women for reasons that are poorly understood. There may be an association between cancer of the cervix and HIV/AIDS (1, 9).
Who is at risk of developing cancer of the cervix?
Basically every woman who has ever been sexually active can develop cancer of the cervix. Higher rates of cervical cancer have been seen in those at risk of sexually transmitted infections like those with multiple sex partners, having un protected sex before age of 18yrs, presence of other sexually transmitted infections like herpes simplex and Human Immune deficiency Virus infection (HIV) (6,7). The developing countries accounted for 370,000 out of 466000 cases of cervical cancer that were estimated to have occurred in world in the year 2000 (7, 10).Cervical cancer is an important public health problem among adult women in developing countries in South and Central America, Sub Saharan Africa and South Asia and South East Asia where it’s the most common or second commonest cancer among women. About 231,000 or more deaths occur due to cancer of the cervix world wide. More than 80% of those deaths occur in the developing countries (10, 11). A conservative estimate of the global prevalence (based on the number of patients still alive 5 years after the diagnosis) suggests that each year they are 1.4 million cases of clinically diagnosed recognized cancer. It is also likely that 3 to 7 million women worldwide may have high grade dysplasia (pre-cancer lesion). Cancer of the cervix is most common among poor communities with limited facilities for screening for cancer of the cervix (11). Other factors that are associated with cancer of the cervix are low educational status, lack of knowledge about screening, high parity and presence of other sexually transmitted infections like Herpes simplex Virus.
Some developing countries that have data on cancer incidence and / or mortality have registered either a stable or slowly declining trend in cervical cancer incidence, most likely due to sociodemographic changes rather than to early detection/ prevention efforts (12).On the other hand, some regions in sub Saharan Africa have registered an increased incidence in the recent years (13). Despite the declining trends in incidence observed in some regions, the total burden of cancer is rising in developing countries mostly due to increasing populations.
In the developed countries, initiation and sustenance of cervical screening programs involving screening of sexually active women annually, or once in every 2-5 years, have resulted in large declines in cervical cancer incidence and mortality over the last 40-50 years (14-17).
Other factors thought to be associated with Cancer of the cervix:
Marital and sexual factors:
The epidemiologists have noted that risk of cervical cancer is strongly influenced by sexual behavior. This has led to discovery of the role of HPV infection. Studies have shown increased risk due to marriage at young age, onset of regular sex at an early age <20yrs, multiple lifetime number of sexual partners (18). These risk factors remain significant especially among those women without apparent human papilloma virus infection (HPV). Frequency of intercourse has not been found to be a risk factor after accounting for the effects of number of sexual partners.
The role of the male sexual partner:
In most studies, the husbands of the cervical cancer patients were found to report more sexual partners, history of various genital infections like venereal warts, gonorrhea and herpes simplex genitalis compared to husbands of control subjects. Frequent use of condoms was associated with a lower risk for cancer of the cervix (19).
Gynecological and obstetric events:
Multiparity with short intervals between pregnancies (<2 yrs) has been consistently shown to increase the risk of SIL (squamous intra-epithelial lesion) and cervical cancer (2). The prevalence of HPV is not increased in multiparous women, thus multiparity could thus be an independent factor. There is little evidence to show that the risk of cervical cancer is affected by age at menarche and menopause, characteristics of menses or personal hygiene (20).
Recent research is showing that long-term users of oral contraceptives are at excess risk for cervical cancer, even after adjusting for sexual and social factors. The risk may be stronger for adenocarcinoma than squamous cell neoplasm (20).This could possibly explain the surveys showing increasing rates of cervical adenocarcinoma among young women. Some studies found an elevated risk among HPV positive women who used oral contraceptives (19, 20). It’s presumed that oral contraceptives promote the activity of HPV infection. Such findings pose challenges to Health in other areas like family planning, where oral contraceptive use is one of the best methods to prevent pregnancy. There is need for more research in that area. Regular users of barrier methods of contraception (condom or diaphragm) have been found to have lower risk of cervical cancer (21).
Although some reports suggest that a familial tendency does exist, but there is still little attention to it (22). Whether this tendency reflects environmental or genetic factors is unknown.
Micronutrients (e.g. carotenoids, vitamin C and folate) are thought to have a protective effect to cervical cancer by promoting the regression of low grade squamous intra-epithelial lesion (SIL). Some components of fruits and vegetables have been suggested to be protective too (23).
Some case control studies and a cohort investigation have demonstrated increased risk of cervical cancer and SIL among smokers even after controlling for most other risk factors. However, the smoking effect is restricted to squamous cell carcinoma and not among other histological types (24). Smoking is strongly associated with high risk of cervical HPV infection because of correlation between smoking and sexual behavior (25).Therefore, HPV status can confound studies of smoking and cervical cancer.
Infections other than HPV:
may not be the only agent involved in causation of cervical cancer. Of the
other agents examined, most attention has been focused on herpes simplex virus
type 2 (HSV-2) and Chlamydia which have
been shown to increase the risk (26).
One of the studies conducted in
Signs and symptoms of cancer of the cervix:
are commonly 30 years and above. In some developing countries like
-Post coital per vaginal bleeding,
-Abnormal per vaginal discharge which tends to be foul smelling.
-Lower abdominal pain and backache are symptoms for advanced disease due to infiltration of the cancer to involve nerves of the sacral plexus
- Leakage of urine or stool incontinence may occur when the cancer has advanced to stage 4 disease to involve the urinary bladder and rectum respectively (refer to some of the quoted text books for details about staging of the cancer and management0.
NB: It is very important to do a vaginal and speculum examination to be able to look at the cervix. It’s important to have a good source of light when looking at the cervix.
The fact that cancer cervix is asymptomatic in the early stages can partly explain why most patients have advanced disease at the time of diagnosis especially in countries where the screening services are very rare.
The other problem is that the symptoms for cancer of the cervix mimic infections like vaginitis and pelvic inflammatory disease. It is thus common to get someone with cancer cervix receiving treatment for pelvic inflammatory disease in the hands of general practioners (personal experience). Some patients end up buying medicines from the counter attempting to manage menstrual problems without going for a proper check up. All these factors coupled with poverty, ignorance and lack of nearby services impact on cancer cervix prevention and management.
Complications of Cancer of the cervix:
The common ones include:
- Severe anemia as a result of severe or chronic on and off bleeding from the cervix
- Kidney complications and later kidney failure (Renal failure with hydronephrosis) due to obstruction of the ureters by the infiltrating cancer which continues to spread to the pelvic walls.
- The lymphatic drainage gets blocked too and leads to swelling of the lower limbs (lymphoedema).
- Vesico vaginal fistula (communication between the urinary bladder and vagina) and rectal vaginal fistula (communication between rectum and vagina).
- Severe pain as a result of infiltration of the sacral nerves.
- Mortality is commonly due to anemia and Uremia (due to kidney failure).
PREVENTION OF CANCER OF THE CERVIX:
1) Human Papilloma Virus Vaccine:
Plans are currently in advanced stages about development of a vaccine against the human papillomavirus. That will go a long way in helping prevention of cancer of the cervix. The Medical College of Georgia is a site for the first international study of the vaccine that protects against four strains (6, 11, 16 and 18) of human papilloma virus in men age16-23.Dr Daron G Ferris (the Principal investigator) says. If we do a good job and vaccinate men as well, then it’s less likely that women are going to be at risk.”
2) Screening Programs as a means to prevent cancer of the cervix:
-The aim of these programs is to detect precancerous lesions and treat them before they progress to invasive cancer.
Cancer cervix is one of the few preventable cancers since it has a clear pre-cancer stage. Despite that, it’s still a major public health problem. Regular cytology screening programmes either organized or opportunistic have led to large decline in cervical cancer incidence and mortality in the developed countries. In contrast, cervical cancer remains largely uncontrolled in high risk developing countries because of ineffective or no screening.
Substantial costs are involved in providing the
infrastructure, manpower, consumables, follow-up and surveillance for both
organized and opportunistic screening programs for cervical cancer. Owing to
their limited health resources, developing countries cannot afford the models
of frequently repeated screening of women over wide ranges that are used in the
developed countries (11). Many low
income developing countries, including most in sub-Saharan
Low or middle income countries intending to start a screening program should start with a limited geographical area before considering expansion. It is more realistic and effective to target the screening on high risk women once or twice in their life time using a highly sensitive test, with emphasis on high coverage (>80%) of the targeted population (11). The sensitivity and specificity of the values that are reported for various screening tests correspond to the detection of high grade lesions (cervical intraepithelial neoplasia II and III) and invasive cancer. All these efforts to organize an effective screening program in these countries need adequate financial resources to develop the infrastructure, train the needed manpower and elaborate surveillance mechanisms for screening, investigating, treating and follow up the targeted women. The findings from existing research on the various screening approaches carried out in developing countries and from the available managerial guidelines should be taken into account when reorganizing existing programs and when considering new screening initiatives.
Cervical Screening World wide:
Cervical cancer prevention efforts worldwide have focused on screening sexually active women using cytology smears and treating precancerous lesions. It is thought that cancer of the cervix develops after dysplastic changes within the cervix. These changes tend to progress steadily from mild to moderate and finally to severe dysplasia. The progression to high grade dysplasia occurs in about 30-33% of those who develop dysplasia. The severe dyplasia may progress to cervical cancer over a period of about 10-15 years while most of the low grade dysplasias regress spontaneously (28,29).
Cytology screening has been shown to be effective in
reducing the incidence and mortality from cervical cancer in the developed
countries (14-17). The incidence of
cervical cancer can be reduced by as much as 80% if the quality, coverage and
follow up of screening are high. In most developing countries, women are
advised to have their first smear test soon after becoming sexually active and subsequently
once every 1-5 years. A number of National guidelines are currently moving
towards less frequent smear tests (once every 3-5 years) since the cervical
lesions develop fairly slowly after several years. Women with high grade
lesions of the cervix are further evaluated using colposcopy, biopsy and
subsequent treatment of confirmed lesions. The women with low grade lesions are
generally advised to return for routine follow up smears. Organized programs
with systematic call, recall and follow up showed greatest effect in
Though cervical cytology (Papanicolao Smear or PAP smear) is considered to be a very specific test for high grade precancerous lesions or cancer, its sensitivity is only moderate even if the quality of other factors is good. I.e. with good collection and spreading of cells, fixation and staining of smears, reporting by well trained technicians and cytopathologists. Cytological screening was shown to have a wide range of sensitivity to detect lesions
(30, 31). Results of meta-analyses estimated the mean sensitivity of cytological smears as 58% (probability that a positive test will detect disease) and specificity of 69% (probability that a negative test will truly imply that no disease (30). It’s possible that the observed decrease in risk of cervical cancer in the developed world may be a result of high screening frequency. Since progression to cervical cancer occurs after several years and the low grade lesions tend to regress spontaneously or may not progress, high frequency of screening would help in detection of previously missed high-grade lesion of the cervix. Current procedures that involve screening women once every 1-5yrs have considerable cost and resource implications. The limited health care budgets in most developing countries preclude initiating and sustaining such programs even in a small geographic setting (11)
Cervical cancer screening programs in the developing countries:
Cytology-based screening programs for cervical cancer have been introduced
in some developing countries, particularly in South and
Since the 1970s, there have been efforts to organize cervical cytology screening programs nationally or regionally in selected Latin American countries.
An evaluation of the cervical cytology tests provided
within the Mexican program indicated that the validity and reproducibility
varied greatly within and between the screening carried out by the MOH and the
IMSS (40). Among the CCSCs the
sensitivity to detect high-grade lesions varied from 46% to 90% and that of the
specificity from 48% to 96%. The false-negative rate varied from 10% to 54%,
with an average false-negative rate of 35%. Review of a random sample of 6011
negative smears indicated that 64.0% of the smears were of insufficient
quality. There has been no decline in mortality from cervical cancer in
An early detection program for cervical cancer was
There are no organized or opportunistic screening
programs for cervical cancer in any of the high- risk sub-Saharan African
countries. While data from
Currently, cytology smears are provided on demand in
antenatal, postnatal, gynecology, and family planning clinics in
A three-arm, prospective randomized intervention trial in South Africa is currently addressing the comparative safety, acceptability and efficacy of screening women with VIA and HPV DNA testing and immediately treating screen-positive women with cryotherapy performed by nurses in a primary health care setting. Outcome measures include reduction of high-grade cervical cancer precursors in treated versus untreated women, followed over a 12-month period.
Other countries: Cross-sectional/randomized screening intervention studies are currently ongoing in several African countries ¾ Burkina Faso, Congo (Brazzaville), Ghana, Guinea (Conakry), Kenya, Mali, Niger, and Nigeria ¾ to address the accuracy of various screening approaches such as cytology, HPV testing, VIA, and visual inspection with Lugol's iodine (VILI) as well as the detection rates associated with them.
Visual inspection-based approaches to cervical cancer
screening have been extensively investigated in
There are three large, ongoing cluster-randomized
intervention trials in
From the Ugandan experience, cervical cancer is the
commonest malignancy among women (13). Over 80% of patients diagnosed with cancer at
Mulago hospital present with advanced disease (63, 64). Cancer cervix patients
on palliative radiotherapy account for ~20 to 30% of the patients on the gynecological
wards at Mulago hospital. There are no organized screening programs in
Effective screening programs in developing countries:
To organize effective cervical cancer screening programs, developing countries will have to;
-find adequate financial resources, develop the infrastructure, train the needed manpower, and elaborate surveillance mechanisms for screening, investigating, treating, and follow-up of the targeted women.
- There is considerable discussion focused on which screening test to use ¾ cytology or alternatives to cytology, such as VIA or HPV testing ¾ or which combinations/sequence of screening tests should be used for screening in developing countries. Choosing a suitable screening test is only one aspect of a screening program.
- A more fundamental and challenging issue is the organization of the program in its totality. Whichever screening test is to be used, the challenges in organizing a screening program are more or less the same.
- However, screening tests (e.g. cytology, HPV testing) that require additional recalls and revisits for diagnostic evaluation and treatment may pose added logistic difficulties and these may emerge as another barrier for participation in low-resource settings.
-The choice of screening test in countries/ regions that plan to initiate new programs should be based on the comparative performance characteristics of cytology and its potential alternatives such as VIA, their relative costs, technical requirements, the level of development of laboratory infrastructure, and the feasibility in a given country/region.
-A highly sensitive test should be provided. If cytology is chosen, considerable attention should be given to obtaining good quality smears, staining, and reporting so that a moderately high sensitivity to detect lesions is ensured.
- If VIA is chosen for screening, considerable attention should be given to the proper monitoring and evaluation of the program inputs and outcomes before further expansion, since VIA is still an experimental option for cervical cancer screening and it remains to be demonstrated whether VIA-based screening programs are associated with a reduction in cervical cancer incidence and mortality.
- In developing countries, existing ineffective cytology- based programs should be urgently reorganized and monitored.
Quantitative studies have shown that after two or more negative cytology smears, even screening once every 10 years yields a 64% reduction in the incidence of invasive cervical cancer, assuming 100% compliance (15, 59). Further studies based on this model indicate that once-in-a-lifetime screening may yield around 25-30% reduction in the incidence of cervical cancer (60, 61,).
To have an impact on cervical cancer incidence and mortality, efforts must be focused on the following:
1) Increasing the awareness of women about cervical cancer and preventive
health-seeking behavior; screening all women aged 35¾50 years at least once, before expanding
the services and providing repeated screening (11). In
2) Providing a screening test with high sensitivity (since women have less frequent opportunities for repeated screening);
3) Treating women with high-grade dysplasia and cancer;
4) Monitoring program inputs and evaluating the outcomes should part of the package.
5) Strengthening training of service providers on how to perform cancer cervix screening is mandatory plus to training cytopathologists and cytotechnicians to ensure quality specimens and interpretation of results.
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More information can be obtained from the following websites:
HPV Vaccine Studied For First Time In
3) Cancer screening web sit.htm. (bbc.co.uk) BBC Health Condition Screening Programmes.
4) Health Promotion Lifestyle. (http://www.patient.co.uk/showdoc/16/#can.
5)New scientist.com .Will the cancer Vaccine get to al lwomen? http://www.newscientist.com/channel/sex/mg18624954.500.
7)http://www.fpahealth.org.au/news/20021128_papvirus.html: Human Papilloma Virus(HPV) Vaccine.
8)The interested reader is referred to common text books about details of examination of a patient with cancer of the cervix and for details about staging of the cancer and management).
NB To read about Programmes that have worked: Most of the section on Cervical Cancer Screening from developing countries is from a “WHO Bulletin” where I found good information regarding experience from developing countries”.