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Cervical cancer in developing countries

Cervical cancer information

Milena Alec, Pierre Vassilakos

Cervical cancer is globally the third most common cancer, and the fourth cause of cancer-related mortality among women worldwide (1). In 2008, the global burden of disease was estimated at 530’000 new cases. More than 85% of the cases occurred in developing countries, where it accounts for 13% of all female cancers (1,2). Cervical cancer is also the fourth most lethal cancer in women worldwide (266,000 deaths) and the third cause of cancer-related death in developing countries (230,158 deaths) (3). It is therefore a matter of public health, as it affects women within the reproductive age groups.

There is a high disparity for cervical cancer between higher and lower income regions. It is primarily due to the difficulty in implementing cytology-based screening programs. The most common screening test in developed countries is currently the Papanicolaou test or Pap smear. Unfortunately, it requires qualified pathologists to evaluate the results, thus rendering it difficult and expensive to implement in developing countries. Moreover, cytology even if done in optimal conditions is limited to its sensitivity. To be efficient, the test has to be repeated frequently, a prerequisite impracticable in low resource settings.

Visual inspection with acetic acid (VIA) is an alternative strategy that combines “screen and treat” on a single visit. Different health-care workers such as physicians, nurses, midwives and technicians can perform VIA. VIA eventually associated with visual inspection with lugol iodine (VILI), is recommended by the Alliance for Cervical Cancer Prevention (ACCP) (4) for cervical cancer screening in low-income countries. To begin with it requires minimal infrastructure. It is also simple and inexpensive. In the next place, if abnormal acetowhite lesions are observed, the patient can be treated immediately, obviating the need for histology. However, because VIA relies on subjective visual interpretation, its accuracy may vary widely. The large variability in the detection rate of the cancer and its precursors may be a major drawback in the implementation of this approach (5,6).

Therefore, it is not only crucial to define suspicious lesions with consistent criteria but also to train the care providers to correctly implement these criteria. Only consistent training, quality control and experience will improve effectiveness and decrease the intra- and inter-observer variability of VIA. Nevertheless, such training sessions are difficult to organize regularly in developing countries.

Progress in telecommunication, computer technology and high resolution video imaging devices, offers the possibility to deliver medical services to patients located in rural areas and areas with poor medical services. Nowadays, the digital camera incorporated in a cellular phone produces high resolution images, that can be magnified and used to perform an examination of the cervix. This could potentially improve the performance of VIA.

The main objective of this site is to develop an e-Learning platform for VIA using smartphone images, in order to strengthen the screening capacity of cervical disease by health professionals, especially in countries with limited resources and treatment. Specific objectives include basic knowledge of:

  • Human papillomavirus and cervical cancer
  • Cervical cancer prevention
  • Cervical cancer treatment

Human papillomavirus and cervical cancer

Human papillomavirus (HPV) are small, non-enveloped DNA viruses that cause most common viral infections of the reproductive tract. Different HPV types target different epithelia and at least forty types infect the human genital tract. Of these forty, twelve are frequently found in cervical cancers and are therefore considered as high-risk types. Persistent infection with a high-risk HPV (HR-HPV) is the single and most important risk factor for progression to precancer and cancer (7). Approximately 70% of cancers and 54% of precancers are attributable to HR-HPV types 16/18. The other HR-HPV types are 33, 45, 31, 58, 52, 35, 59, 51, 56, 39 and 68 in descending order in the world-wide distribution, though there are geographical variations (8).

It is substantial to emphasize that only a minority of women with persistent high-risk infections develop precancer. The rate at which precancer evolves to an invasive cancer is usually slow, measured in years, even decades. For this reason cancer incidence in young women is normally low.

Most sexually active women and men will be infected at some point in their lives and some may be repeatedly infected. Approximately half of the carcinogenic HPV infections are resolved within six months of the exposure (9). Less than 10% become persistent and are still detectable after two years. Sexually inactive women rarely develop cervical cancer, whereas early sexual activity with multiple sexual partners increases the risk of developing cervical cancer.

Persistence of infection is necessary for progression to cancer and as the probability of clearance decreases with time from exposure, the risk of invasion increases. For malignant transformation however, viral DNA integration into the host genome is almost always necessary. The critical molecules in viral replication are E6 and E7, which functionally inactivate the products of two important tumor suppressor genes, p53 and pRb, respectively. Both E6 and E7 oncoproteins induce proliferation, immortalization, and malignant transformation of the infected cells (10).

Cervical cancer precursor lesions are histologically called cervical intraepithelial neoplasia (CIN), or dysplasia. CIN is ranked histologically according to the degree of dysplasia. CIN 1 beeing a mild dysplasia, CIN 2 a moderate one and CIN 3 beeing a severe dysplasia). The proportion of the thickness of the epithelium showing undifferentiated cells is used for grading CIN (11).

CIN1 signs generally transient infections, caused by both high- and low-risk HPV types. Most of them regress to normal in a relatively short period of time or they don’t progress further to higher grades. The abnormal undifferentiated cells are confined to deeper layers, the lower third of the epithelium. Mitotic figures are rare. CIN2 is characterized by dysplastic cellular changes mostly restricted to the lower two-thirds of the epithelium, with more apparent nuclear abnormalities than in CIN 1. Mitotic figures may be seen throughout the lower half of the epithelium. The majority of CIN2 regress. In CIN3, or carcinoma in situ, differentiation and stratification may be totally absent or only present in the superficial quarter of the epithelium with numerous mitotic figures. Nuclear abnormalities extend throughout the thickness of the epithelium. Many mitotic figures have abnormal forms. CIN3 is considered as the immediate precursor of invasive cancer and should always be treated due to the high risk of progression.

A further categorization, the Bethesda system (12) is based on cytologic (Pap test) findings such as atypical squamous cells of undetermined significance (ASCUS), and a dichotomous division of cervical cancer precursors called Squamous Intraepithelial Lesions (SIL). Low-grade squamous intraepithelial lesions (LSIL) corresponds to CIN1 cytologic atypia and high-grade squamous intraepithelial lesions (HSIL) to CIN 2 and 3. The aim of the Bethesda System is to promote a more effective communication of cervical cytology results from the laboratory to the clinicians. The dichotomous division of SIL reflects substantial virological, molecular and clinical evidence that LSIL is generally a transient infection, while HSIL is more often associated with HPV persistence and a higher risk of progression.

Invasive cancer can come from either the squamous or the glandular cells. Most of the cervical cancers originate in the squamous component of the cervix. In the very early phase of invasion, cancer may not be associated with obvious signs and symptoms, and is therefor known as a preclinical invasive cancer. As the stromal invasion progresses, the disease becomes clinically obvious, showing several growth patterns which are visible on speculum examination. Early lesions may present as a rough, reddish, granular area that bleeds to the touch. More advanced cancers may present a proliferating, bulging, mushroom- or cauliflower-like growth with possible bleeding and foul-smelling discharges. Occasionally they may present a modest surface growth, resulting in a grossly enlarged and irregular cervix with a rough, granular surface.

Cervical cancer prevention

The well-defined premalignant phase and the fact that the cervix is easily accessible for sampling and treatment, makes cervical cancer particularly amenable for screening. During the last 50 years, large parts of the world were covered by screening programs based on Pap smear. Most of them have demonstrated a reduced cervical cancer incidence and mortality, undoubtedly due to these programs. Nevertheless there are considerable barriers in low- and middle income countries, to introduce the necessary infrastructure and quality control systems for screening facilities. Therefore, such programs have been difficult to establish in these countries that consequently greatly suffer from cervical cancer burden.

Prophylactic HPV vaccines may eventually provide an optimal solution for prevention of cervical cancer in developing countries. Since most women are infected during their first intercourse, women should optimally be vaccinated before their sexual debut. As these vaccines do not treat preexisting HPV infections and precancerous conditions, screening will still be necessary for the generations of unvaccinated women. In addition, vaccinated cohorts continue to undergo regular cervical screening since the vaccines do not protect against all the oncogenic genotypes of the virus.

Several screening alternatives have been proposed for areas with limited resources. Among these, the direct inspection of the cervix using Acetic Acid (VIA), involves the application to the cervix of 5% diluted acetic acid (vinegar), making the dysplastic epithelium turn white (acetowhitening).

The main advantages of this technique are that unlike conventional cytology, it is of low cost, easy to perform and does not need specialized laboratory. The results of the test are obtained almost immediately facilitating same-day screen and management.

However VIA is controversial because of concerns over its reproducibility and accuracy.

Another alternative may be HPV testing as primary screening test. The cost of HPV testing has considerably decreased and recent developments suggest that HPV testing might be performed in non-sophisticated laboratories with results available within a few hours. In addition HPV testing offers the advantage of being performed by the patient herself with results as reliable as those of sampling performed by a health care professional and, with a higher sensitivity than a cytology-based screening. Since HPV testing has a mediocre specificity and positive predictive value, a triage involving visual inspection of the cervix after application of acetic acid (VIA) for women testing HPV positive could be beneficial for further management.


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