The European average 5-year age-standardised relative survival for cervical cancer diagnosed in the period 1990–1994 and followed up to 1999 was 62.1%³¹. In sweden, Netherlands and Norway 5-year age-standardised relative survival was significantly higher than the European mean, while Poland, Estonia and Portugal had the poorest survival for cervical cancer. In Portugal (estimates from the southern region) had particularly low survival for cervical cancer (55.6%)³² . The relative survival of patients with cervical cancer increased by 3%, from the cases diagnosed in the period 1978-1989 [EUROCARE-2³³] to the period 1994-1999 [EUROCARE-4²⁶]. The main determinant of cervical cancer prognosis remained the stage at diagnosis and this modest increase in survival rate has been interpreted as being due mainly to earlier diagnosis³² .

Cervical cancer mortality

A declining trend in cervical cancer mortality is clearly observed, in developed countries where mainly cervical cytology programme exist. In European Union countries, from1993 to 2001,a gradual decrease was observed in age-standardised mortality rate, from 3.4 per 100,000 women in 1993 to 2.8 per 100,000 (World population reference)¹. However, in less developed countries, this trend follows the opposite direction. In south Africa, for example, age-standardised mortality rate increased from 9.9 per 100,000 in 1993 to 13.3 per 100,000 in 2005¹.

Burden of cervical cancer in Portugal

Portugal presents the highest rates of cervical cancer in Western Europe, with an incidence rate of 14.8 per 100,000 women and a mortality rate of 4.9 per 100,000 women in 2001, being the fifth most common cancer among women³⁴. Approximately 780 new cases occur and 260 women die every year³⁴ .

Relative 5-year survival in the south of Portugal was 60%, the fourth lowest among other European countries represented in the recent publication of the Registo Oncológico Regional da Região Sul (ROR-Sul)³⁵ .

Incidence of cervical cancer in Portugal

Cervical cancer incidence rates are available from three population-based Regional Cancer Registries, namely the Registo Oncológico Regional da Região Norte (RORENO), covering the Northern region (3.5 million inhabitants), ROR-Centro, covering the Central region of the country (1.7 million inhabitants), and ROR-sul, which covers the south and the Madeira islands (4.2 million inhabitants)³⁶ .

The data made available by the ROR-sul does not allow a sound interpretation of the variation of incidence over the years and in the northern region no descending trend is observed in the most recent years.

For the region covered by ROR-Centro, data is available for both invasive and in situ cervical cancer, with similar trends since 2000.

Survival of cervical cancer patients in Portugal

In women aged between 25 and 79 years mortality from cervical cancer has remained stable between 1980 and 2005 (annual percent change=0.0%, 95%CI: -0.5 to 0.5). The variation was 2.0%/year (95% CI: 0.8 to 3.2) in the age-group 25-44 years, 0.7%/year (95% CI: -0.3 to 1.7) in women aged between 45 and 54 years, 0.4%/year (95% CI:1.4-0.6) in the age-group 54-64 years and -1.6%/ year (95%CI: -2.4 to -0.7%) in the age-group 6579 years⁷⁷ .

Risk factors for cervical cancer

Epidemiological studies conducted over the past 4 decades have consistently shown that cervical cancer risk is strongly influenced by sexual behaviour: multiple sexual partners, early age at first sexual intercourse, and sexual habits of male partners^79,80. Evidence on the causal role of some HPV infections, a sexually transmitted, in the development of cervical cancer are provided by epidemiological studies, supported by molecular technology⁷. thus, early age at first intercourse and multiple sex partners are associated with a higher risk of HPV infection indirectly increasing the risk of cervical cancer⁸¹. Case-control studies, case series, and prevalence surveys have unequivocally shown that HPV-DNA can be detected in 95-100% of cases, compared with a prevalence of 5-20% in cervical specimens from a women identified as suitable epidemiological controls¹⁵ and infection with a high-risk HPV type is now considered a necessary cause, though not sufficient, for cervical cancer. Factors such as the number of full-term pregnancies, tobacco smoking and long-term use of hormonal contraceptives may contribute to the progression from cervical HPV infection to cancer⁸² .

HPV and cervical cancer

Virtually all cases of cervical cancer result from a history of persistent infection with HPV pertaining to a “high risk” subset of this family of viruses⁸⁹. The contribution of HPV DNA in high-grade squamous intraepithelial lesions (morphological precursors of invasive cervical cancer), as indicated by cross-sectional studies of the natural history of cervical cancer, is estimated to be over 85%⁹⁰ .

The strength of the association between infection of the cervix with high-risk types of HPV and invasive cervical cancer is almost unprecedented in cancer epidemiology, with odds ratios (OR) over 50 in most studies^91,92.

HPV types are stratified into low-, intermediate-, and high-risk categories based on the strength of the association between infection and the occurrence of high-grade and invasive lesions. More than 100 different HPV types have been described, of which approximately 40 types infect the anogenital tract⁹³ . Among this, about 15 types (HPV-16,-18,-31,-33,35,-39,-45,-51,-52,-56,-58,-59,-68,-73, and -82) are now considered to be of high-oncogenic-risk (HRHPV)⁹². The predominant low-risk types (HPV 6 and 11)^{94, 95} cause 90% of genital warts (condyloma acuminata). The most prevalent high-risk types (HPV 16 and 18) cause 70% of cervical cancer and cervical intra-epithelial neoplasia (CIN) and a reconsidered the most oncogenic viruses worldwide⁹³ .

Human papillomavirus type 16 is the most common high-risk type, accounting for more than half (56%) of all cervical cancers⁹¹ .

It has now been established, based on both molecular and epidemiologic evidence, that HPV can cause high-grade cervical intraepithelial neoplasia and invasive cervical cancer, being a major discovery in human cancer aetiology⁹⁶. the evidence is consistent worldwide and implies both the squamous Cell Carcinomas (SCC), the adenocarcinomas and the vast majority (i.e. > 95%) of the immediate precursors, namely High grade squamous Intraepithelial lesions (HSLL)/Cervical Intraepithelial Neoplasia 3 (CIN3)/Carcinoma insitu⁹⁷ .

It is not yet clear how aging affects HPV prevalence in different populations worldwide. Many studies have reported that the highest prevalence occurs in women under 25, with a progressive linear decline after the age of 25, remaining below 5% after the age of 55 ^98,99.

Other risk factors for cervical cancer

Several factors may influence whether a woman with precancerous lesions develops cervical cancer or not, such as the use of tobacco^{81, 100}, an impaired immune system, hormonal factors, the use of hormonal contraceptives, early age at first birth, high parity^{8, 81, 101} and Clamydia trachomatis infections¹⁰² . The effects of smoking have been studied in many case-control studies which found moderate and statistically significant associations with cervical cancer, after adjustment for the strong effects of HPV^{103, 104}. Nicotine have been detected in the cervical mucus of smokers, strengthening the hypothesis of a synergistic action between cigarette smoking and the development of HSIL and cervical cancer¹⁰⁵ . A linear dose-response relationship between cervical cancer and the use of hormonal contraceptives is showed in a recent meta-analysis.the relative risk of cervical cancer increased with increasing duration of oral contraceptive, being with the use of oral contraceptive approximately less than 5 years, 5-9 years and 10 years or longer, respectively,1.1(95%CI1.1-1.2),1.6(1.41.7) and 2.2 (1.9-2.4)¹⁰¹ .

High parity is a consistent risk factor for cervical cancer and has been found consistently in most case-control studies to be associated with both cervical cancer and carcinoma in situ. In the International Agency for Research on Cancer (IARC) multicentric study, the OR for cervical cancer in women with seven or more full-term pregnancies was fourfold higher than in nulliparous women, and the risk increased linearly with increasing number of full-term pregnancies¹⁰⁶ . The evidence on the role of lifestyles related to diet or physical activity in cervical carcinogenesis is too limited to conclude that any aspect of food, nutrition, and physical activity directly modifies the risk of this cancer¹⁰⁷ .

HPV vaccination

Ninety-five percent of all cervical cancers are at tributable to HPV infection in the general populatio¹⁰⁸ . The diseases produced by the oncogenic genotypes of HPV have the potential to be eradicated¹⁰⁹.thus, primary prevention of cervical cancer can be achieved through prevention and control of genital infection with oncogenic HPV types¹¹⁰ .

Recently, prophylactic vaccines have become commercially available, that are based on the recombinant expression and self-assembly of the major capsid protein, l1, into virus-like particles (VLPs) that resemble the outer capsid of the whole virus¹¹¹ .

A quadrivalent HPV 16/18/6/11 vaccine was the first to be approved for use in adolescent and young women ages 9 to 26 years for the prevention of cervical cancer (HPV 16 and 18) and genital warts (HPV 6 and 11), as well as vulvar and vaginal precancerous lesions. It is administered as a 0,5 ml intramuscular injection in a three-dose immunization protocol (2 and 6 months after the first dose)¹¹² .

A bivalent HPV 16/18 virus-like particles (VLP) vaccine is also available as a 0,5 ml intramuscular injection in a three-dose immunization protocol at 1 and 6 months after the first dose¹¹² .

Bivalent vaccines as well as quadrivalent vaccines have been demonstrated to be safe, immunogenic and effective against type-specific HPV infection^10,113.

In women who have no evidence of exposure or infection with the HPV genotypes that are present in the vaccine, both vaccines show very high efficacy, with over 90% reduction in persistent infection and greater than 98% reduction in high-grade cervical lesions^{102, 114, 115}. Human Papillomavirus vaccines are efficacious in all age groups within the 15-26 years range¹¹⁶ .

The progressive development of primary prevention strategies should coexist with secondary prevention of cervical cancer, by means of redesigned screening programs, because vaccination is for pre-exposure prophylaxis; most women will continue to rely on screening¹¹⁷ .

Screening and vaccination, adopted in synergy, have the potential to significantly reduce cervical cancer globally. However, in an era of strained health care budgets, even resource-rich countries will have difficulty to support the extra costs of vaccination without some level of re-structuring of their screening programmes¹¹⁸ .

Vaccination plus screening should, in theory, prevent almost 100% of cervical cancers, but this could only apply in countries with organized screening programmes, allowing, ensuring an equal coverage fall population groups¹¹⁶ .

The gradual extension of vaccination will progressively reduce the costs of the diagnosis and treatment of lesions detected by screening of vaccinated cohorts¹⁰⁹ . At the beginning of 2008, HPV vaccination had not been implemented in all countries of the European Union. CzechRepublic, France, Germany, Greece and Italy had implemented HPV vaccine in the national immunization programme since 2007 and the target populationis, respectively, 12-15,14-25,12-17,12-15 years. In 2008, Luxembourg, Portugal, Spain and United Kingdom introduced the vaccine in the national immunization programme for girls with 12-18, 13, 12 and 12-13years respectively².

Cervical cancer screening

Cervical cancer is both preventable and curable and is the malignant neoplasic disease for which public health prevention initiatives have had the greatest success¹¹⁹ .

Precancerous changes in cervical tissue can persist for years. However, if they are identified and successfully treated early, the lesions will not develop into cervical cancer. Thus, screening women for precancerous changes and treating tissue abnormalities seems to protect women from developing cervical cancer, ultimately decreasing its mortality¹¹⁹ .

Screening methods

Cervical cancer screening started with the introduction of Papanicolaou test into developed countries and it is largely responsible to the remarkable success achieved in cervical cancer prevention. The cervical cytology is a laboratory test Developed in the 1940s to detect abnormal cell changes and screening with this method is still considered an integral part of women’s preventive health care in many settings¹²⁰ .

In most routine settings, cervical cytology has a wide range in sensivity in detecting cervical neoplasia. In reviews of several studies the sensivity to detect high-grade CIN lesions ranged from 47-62% and the specificity from 91-96%^121-123. In studies in developing countries the sensivity of cervical cytology ranged from 31 to 78 percent and the specific from 91-96%¹²⁴.This low sensivity has been attributed to a combination of poor sample collection (5%-10% of all slides), incorrect slide preparation and laboratory interpretation errors^{121, 125}. False-negative results occur even in optimized screening programs and cannot be entirely eliminated¹²⁶ .

However, conventional cervical cytology test screening has the potential to reduce the risk of developing cervical cancer by 60% to 90% within three years¹²⁷ , and reduction in cervical cancer incidence and mortality in the US and other developed countries has been accomplished despite the relatively low sensivity of conventional cytology¹²³ .

In England, invasive cervical cancer incidence and mortality rates decreased by approximately 50% from 1988 to 1997, after the introduction of an organised screening program. A similar trend was observed in Norway immediately after the introduction of a national cancer cytology program (cervical cytology test) in 1995¹²⁷. The extent of this decrease is not generally verified in countries where screening is population-based¹⁵ .

Liquid-based cytology (LBC) was developed primarily to improve the quality of cervical samples^{128, 129}.This process aims to potentially reduce two important deficiencies observed in conventional cytology: the relatively small and potentially non-representative sample of cells and the effect of other material, including mucous, blood, and other non-cervical cells, on the readability of theslide¹²⁴. As LBC is more expensive than conventional cytology and requires additional instrumentation, it may not be feasible to implement LBC in low-resource settings¹²⁴ .

Testing cervical specimens for DNA of oncogenic (high-risk) types of human papillomavirus (HPV) has entered clinical practice, but this test is used mainly to triage for colposcopy those women with cervical cytology tests categorized as “atypical squamous cells of undetermined significance” (ASCUS)^{130, 131}. HPV testing is more sensitive than cervical cytology testing for identifying cervical cancer and its precursors in population screening.this test is already being incorporated into some screening programs, generally in addition to existing Pap smear screening^132-135. HPV testing combined with conventional cytology is more sensitive, yet less specific than cytology alone for both the management of ASCUS¹³⁶ and in primary screening^{137, 138}.

Although cervical cancer screening, primarily with the cervical cytology smear test, has reduced the incidence of this cancer in industrialized countries, cervical cancer remains the second most common cause of death from cancer in women worldwide, because the developing world has lacked resources to implement widespread, high-quality screening programmes. Countries with low-resource settings perform others screening tests, as visual inspection with acetic acid (VIA) or with lugol’s iodine (VIII), also known as schiller’s test. Visual inspection with acetic acid involves swabbing the cervix with an acetic acid and precancerous cells turn white temporally. Applying iodine to the cervix makes precancerous lesions appear well defined, thick, with yellow or brown shaded areas. Recent data show that visual screening with lugol’s iodine may have higher accuracy than screening with acetic acid¹³⁹. Although adequate training of health providers is required, these tests comprise important advantages because of the relatively simple application, low-cost and rely on little infrastructure¹³⁹ .

Organised versus opportunistic cervical cancer screening

Organised cervical cancer screening accelerated the decline in cervical cancer incidence, in comparison with the trend in areas relying on opportunistic screening¹⁴⁰ . The term “organised screening programme” is used for screening programmes organised at national or regional level, with an explicit policy, a team responsible for organisation and for health care and a structure for quality assurance¹⁴¹. Organised programmes comprise personal invitation to screening to all women in the target age groups at regular time intervals, and all services are provided free of charge¹⁹. On the other hand, the term “opportunistic screening” refers to cervical cytology testing in asymptomatic women following a recommendation made during a routine medical consultation or a consultation for an unrelated condition for example, on the basis of a possibly increased risk for developing cancer or by self-referral¹⁴¹, outside the schedule of an organised programme. Organised screening provides an equitable distribution of benefits to all women¹¹⁹. Strategies must incorporate the needs and perceptions of socially disadvantaged women, and increase their access to screening. It is of extreme importance to provide good quality screening and treatment services that reach women who are at risk¹⁴² .

A good and organized prevention program for cervical cancer must reach a high proportion of women at risk of the disease, also covering the high-risk groups, effectively test these women, treat or manage those who test positive, ensure they are followed-up, monitor and evaluate program impact¹⁴³ .

There is strong evidence that well-organised screening with cytology can reduce the incidence and mortality up to 80%¹⁵. Besides reducing incidence and mortality, increased participation in screening for cervical cancer would also reduce demand for services, thereby reducing the waiting times for cancer services. In countries where wide cervical cancer screening coverage has been achieved cervical cancer incidence and death rates have fallen by more than 50%, being proved as a model for successful cancer prevention.

In the Nordic countries, following the introduction of nationwide screening in the 1960´s, cumulative mortality rates of cervical cancer showed a falling trend. Iceland had observed the greatest fall (84% from 1965 to 1982)¹⁴⁴. In Finland age-standardised (world standard population) mortality rates decreased over 80% from the level of 7.0 deaths per 100,000 women in early 1960s to 1.2 deaths per 100,000 women in the 1990’s^{22, 145}. In Sweden and Denmark the decline was 34% and 27% between 1965 and 1982, respectively. In Norway, after the introduction of a national cervical cancer cytology program in 1995, age-standardised (World standard population) mortality rates decreased from the level of 3.0 deaths per 100,000 women in 1995 to 1.9 deaths per 100,000 women in 2006²² .

In England after the introduction of an organized screening program in 1988, the cervical cancer incidence and mortality decreased around 50 from 1988 to 1997¹²⁷ .

In Turin, Italy, a decrease of 20%, from 1992 to 1998, on fully invasive cervical cancer incidence was observed after the introduction of an organised programme in an area where opportunistic screening was previously conducted¹⁴⁶ .

Cancer screening in europe

In most European countries cervical cancer screening started as an opportunistic activity, and it is still predominant in most European countries. Despite the relatively good level of resources, few national well-organised and documented programs are implemented¹⁴⁷. A recent report on the state of the art of cancer control structures in European Union countries, Iceland, Norway and Switzerland shows that 8 countries have no organised programs (Bulgaria, Cyprus, Germany, Greece, Latvia, Luxembourg, Malta and Switzerland). Among the remaining, 14 have programmes with national coverage. Participation rate ranges between 10% and 80%, approximately. In Austria, Belgium, France Ireland, Italy, Portugal, Romania and Spain, organised programmes were implemented, but not with national coverage. A heterogeneity of age target population and in screening interval (years) is also observed. The Papanicolaou test is the most frequently used test^2,148.

The first countries with organised programme were Finland in 1963, now presenting a national coverage of 97.5%, and a proportion of participation of 71%, followed by sweden with a 70% participation and 100% of national coverage and by Austria with a regional organised programme launched in 1970 with a participation of 75% of women aged between 20 and 49 years and 50% of women aged 50-69 years².

European guidelines recommend three to five years screening intervals. the most commonly recommended interval between normal cytological tests is three years¹⁵. The interval of screening varies among European countries, most of them having programmes with three-year intervals between screening tests, except for Estonia, Finland, Neverthlands and Romania that use five years as interval. Sweden and United Kingdom perform 3/5 years screening intervals².

Cervical cancer screening in Portugal

Cervical cancer screening in Portugal has been predominantly opportunistic and its practice has increased, especially since the early 1990s, mainly by indication from general practitioner or by demand¹⁴⁹. Population screening programs on a national scale do not exist. Never the less, there are regional organised programs in the Central Region of Portugal, since 1990, in the region of Alentejo, since early 2008, and recently (February2009) in the North region of the country. The screening Programme of the Central Region of Portugal is performed by the general practitioners. the cytological smears are collected in the Health Centres and sent to the cytopathology laboratory of the Coimbra Cancer Institute¹⁴⁹ .

The programme being conducted in Alentejo uses liquid based cytology. According to the Administração Regional de Saúde do Alentejo, more than 13,500 women were screened since January 2008¹⁵⁰ .

In the North the cervical cancer screening programme began initially with a pilot phase in Centro de Saúde do Castelo da Maia (February 2009) using the liquid based cytology preceded by HPV testing as methods of screening. This screening programme aims to screen at least 70% of the eligible population²⁰ .

Conclusion

The epidemiology of cervical cancer worldwide is strongly influenced by the existence of effective screening programmes. Cervical cancer incidence and mortality rates have decreased in countries with effective programmes. Furthermore, high incidence and mortality rates are observed in developing countries, which lack nationwide prevention programmes.the removal of incident cases through detection and treatment of pre-malignant lesions and the diagnosis of invasive lesions, at earlier and more curable stages, provide an opportunity to prevent or delay progression to invasive cancer, leading to a reduction in mortality from cancer of the cervix. The identification of oncogenic HPV infections as a necessary cause of cervical cancer has provided new directions for research and two HPV vaccines have been developed. However, early detection will remain the key-element in reducing cervical cancer since vaccination is presently only indicated for pre-exposure prophylaxis and, thus, most women will continue to rely on screening. Primary and secondary prevention strategies should coexist in order to maximize the decrease in cervical cancer incidence and mortality.

References