Open Journal Systems

Received: October 22^nd 2014

Accepted: May 15^th 2015

CURRENT THEMES

Epidemiological overview of uterine cervical cancer

Dulce M. Hernández-Hernández,^a Teresa Apresa-García,^b Rosa Ma. Patlán-Pérez^c

^aDivisión de Mejora a la Gestión de los Servicios de Salud, Coordinación de Políticas en Salud, Unidad de Educación, Investigación y Políticas de Salud

^bUnidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI

^cServicio de Ginecología Oncológica, Hospital de Ginecoobstetricia 3A, Centro Médico Nacional La Raza

Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: Dulce M. Hernández Hernández

Telephone: 5726 1700, extensión 15647

Email: dulce.hernandez@imss.gob.mx

The World Health Organization (WHO) reported more than 6 million cases of cancer worldwide in women during 2008; 57.2 % of those cases occurred in less developed countries. Cervical cancer (CC) ranks third in the world in all cancers affecting women, with an estimated of 530 000 new cases. CC has multiple causes and it arises by the association of various risk factors. The main factor is related to the human papillomavirus infection (HPV), which acts as a necessary but not sufficient cause. Also, the interaction with other cofactors has an impact on the development and severity of this neoplasm. Survival is related to the timeliness of care and, therefore, to more access to health services. CC is a neoplasm considered a preventable cancer; thus, it is possible to save more than 150 000 lives by 2030 if control measures are applied with opportunity. The aim of this work is to review the CC in different geographical areas and to make an analysis of risk factors related to this neoplasm.

Keywords: Female genital neoplasms; Epidemiology; Risk factors

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Neoplastic diseases and in particular cervical cancer (CC) have been recognized worldwide as a public health problem. This has been due to their behavior with the passage of time, as in today's societies they are among the most frequent causes of morbidity and mortality, in so-called developed countries and countries in development.¹ Infection by high-risk human papillomavirus (HPV) is a necessary condition for the development of a cervical lesion, but only a fraction of precursor lesions progress to invasive cancer. This implies that the presence of additional factors are required, in addition to the viral type, to increase the chance of progression to invasive cancer.

Epidemiology

Cervical cancer is the second most common cancer with worldwide distribution occurring in the female population, with an estimated 530,232 new cases, of which approximately 86% (453,531 cases) are in developing countries. According to 2008 WHO estimates,² the standardized global rate is 15.2 x 100,000 women, just below breast cancer (38.9 x 100,000 women). The highest incidence rates for cervical cancer are reported in the regions of Africa, Southeast Asia, and the Americas, with intervals of 30.7, 24.4 and 15.3 x 100,000 women, respectively, 1.7 to 3.4 times higher compared with other geographical areas of low frequency.^1,3 (Figure 1). In Latin America, CC is the second most common cancer in women. The countries with incidence rates higher than 30 x 100,000 women are Guyana (44.7), Nicaragua (39.9), Honduras (37.8), El Salvador (37.2 x 100,000), Bolivia (36.4), Paraguay (35.0), Peru (34.5), Venezuela (31.4), and Guatemala (30.5). Only Chile and Puerto Rico have rates below 15 x 100,000 women (14.4 and 7.5, respectively). The most developed countries show significant trends toward reduction in the incidence of cases. For example, Denmark, which had a rate of 22.5 x 100,000 in 1975, decreased it by 20 points for a reported rate of 2.5 x 100,000 women in 2008. However, in less developed countries this relationship is not so obvious.

Deaths from cervical cancer rank third in cancer mortality in women worldwide, with a total of 31,712 deaths,2 representing 8.22% of deaths from malignant neoplasms, with a standardized mortality rate of 7.8 x 100,000 women. Mortality rates are consistent with reported incidence for countries in the area of ​​the Americas. The highest mortality rates, above 20 x 100,000 women, were observed in Jamaica, Guyana, and Nicaragua, while the lowest, less than 7 deaths x 100,000 women, were reported in Uruguay, Chile, and Puerto Rico (6.8, 6.6, and 2.8 respectively).⁴

In developing countries, the greater significance of cervical cancer is due to the high mortality rates reported, which are related to late diagnosis in advanced stages of the disease.^5,6

In Mexico, according to WHO (2008), the frequency of new cases of cervical cancer was 10,186, which represents a standardized global rate of 19.2 x 100,000 women; this implies a cumulative risk of 1.94 x 100 women.¹ CC is second in frequency of disease due to malignancy in women, after breast cancer (27.2 x 100,000 women), unlike Hispanic women residents in the United States, where cervical cancer has seventh place among neoplasms, while breast cancer holds the first position.⁷ 

The mortality rate in Mexico decreased approximately 2.5% per year in the nineties to about 5% per year over the last decade, with a 2008 estimate of 9.7 x 100,000 women (5061 deaths), which is still considered too high.^3,8 Regarding the insured population of the Instituto Mexicano del Seguro Social (IMSS), the health institution serving about half of the population of Mexico, it is reported that the trend in mortality continues to decline, with a rate of 13.3 deaths x 100,000 women in 2000 and 5.3 x 100,000 in 2011 (Figure 2). According to this information, in 2011 the three states with rates equal to or greater than 9.0 x 100,000 insured women were Morelos, Tamaulipas, and Quintana Roo; the national average was 5.4 x 100,000 women, and the states with the lowest global reference values ​​(< 2.0 x 100,000) were Baja California Sur and Durango (Figure 3).⁹  

Natural history of cervical cancer

According to the natural history of CC, it has been shown that it is preceded by a series of cell lesions within the endocervical epithelium. These lesions, considered premalignant, are referred to as cervical intraepithelial neoplasia (CIN) or squamous intraepithelial lesions (SIL) according to the Bethesda system. From a histological classification, SIL depends on the degree of cell lesion within the epithelium, this classification being designed to standardize the reporting system for the Pap test. It is based on the morphological description of the lesions, which identifies data suggesting HPV infection and cellular changes related to the development of cervical cancer, which were identified as atypical squamous cells of undetermined significance (ASCUS) and low- and high-grade SIL.^10,11  

In prospective studies it has been reported that low-grade SIL (LSIL) can present rates of spontaneous regression without treatment in more than 60% of patients at a median follow-up of 12-18 months. These rates can also be as high as 91% at three years of follow up. Meanwhile the risk of developing HSIL or CIN3 in women in these cohorts was 3 to 5%. On the other hand, in a meta-analysis report of the natural history of CC conducted with a total of almost 28,000 patients, the progression from HSIL to subsequent invasive cancer found a reported rate at two years of follow-up of 1.44% (0-3.95%).¹² Some authors say that it takes about ten years on average after detection of low-grade abnormalities for invasive cancer to be presented in situ.¹³ By age, peak CIN3 incidence has been reported from age 27 to 35 on average, while invasive cancer is presented at least ten years later (mean age 48 years), which makes disease progression with age evident (Figure 4).¹⁴

Risk factors

The large number of epidemiological, molecular, and experimental studies done in the search for causal associations has shown that HPV is the main etiological agent of CC.^15,16 Early studies showed a close relationship between sexual and reproductive factors with the presence of invasive CC and precursor lesions. Consistent with infectious etiology, a significant effect has been observed in women who reported having multiple sexual partners, and they were shown to have an excess risk two to 10 times higher when a greater number of partners were reported (more than 10 partners). Initiation of sexual life before age 18 was associated with excess risk is 1.5 to 5 times higher, and no linear relationship was seen; relatedly, first pregnancy under that age has a similar impact on risk. Furthermore, multiple pregnancies (more than three) significantly increase the risk even after adjusting for other sexual parameters.^17,18

HPV co-infection with other sexually transmitted infectious agents, such as Chlamydia trachomatis, herpes simplex virus type 2 (HSV-2), and human immunodeficiency virus (HIV), may create a synergistic effect that increases the chances of cellular alterations leading to the development of a neoplasm. Chlamydia trachomatis and marginally HSV-2 infection favor the entry and persistence of multiple HPV types, leading to viral integration, inhibition of apoptosis, overexpression of oncogenes E6/E7, and cell transformation.¹⁹ However, to date the viral integration mechanisms are not fully defined. Recently it has been suggested that the inflammatory process plays an important role in the development of carcinogenesis and especially HPV viral integration; it is suggested that reactive oxygen species generated during the inflammatory process can cause breaks in the DNA strand, which would allow viral integration.^20,21

The frequency of HPV infection in HIV-infected women is about 50% and reaches 75% in ages 25-34, almost four times higher than that reported in the population without risk. A higher frequency of infection is observed in this group of women associated with lower CD4 counts and higher severity of cervical lesions.²²

Among women who use oral contraceptives, the risk of cervical cancer increases with increasing duration of use (relative risk -RR- for five years or more compared with non-users, 1.9; 95% CI 1.7-2.1). The risk decreases to the same level as non-users 10 years after suspending use.²³ One study found that women using steroid sex hormones have an interactive effect dependent on a polymorphism of haptoglobin, a protein that acts in modulating the local immune response in epithelia. It is noted that carriers of the haptoglobin 1 allele and users of hormonal steroid have six-fold increased RR relative to non-carriers and non-users.²⁴

Smoking, which is not infectious agent but a chemical one, is one of the factors that has been studied significantly in association with cervical cancer. High concentrations of tobacco constituents in the cervical mucus and serum showed biological evidence in the development of CC. It has been observed that the fraction of DNA in phase S (as a measure of proliferation) was correlated with the number of cigarettes smoked and the serum level of progesterone.²⁵ In another study in Mexican women an association was seen between a CYP1A1 polymorphism (MspI) and CC, which potentiated the effect three times more in women smokers when the C/C genotype was present, compared to nonsmokers and women without this genotype. Enzymes derived CYP1A1 from play a significant role in the detoxification of aromatic hydrocarbons and aromatic amines present in the cigarette.²⁶

Human papillomavirus

Genital HPV infection is considered one of the most common sexually transmitted infections (STIs) in the world population, especially in young women, although it is also widespread among adults who have been sexually active.²⁷ Infection of the squamous epithelium of the genital tract by different HPV types is manifested in latent, subclinical, or clinical form. Clinical HPV infection is defined as any visible lesion to the epithelium or lesion that causes symptoms. Subclinical infection does not cause symptoms and can only be diagnosed using colposcopy or microscopy, while latent infection is not associated with abnormalities of the squamous epithelium and may only be detected by virology. The natural history of HPV infection shows that spontaneous resolution occurs in 90% of immunocompetent women over the course of about two years.¹⁴ The infection rate in the female population is estimated at 40% for women aged 20 to 29, and, in the general population independent of age, figures are reported at 13 to 15%,^16,17,27 figures far exceeding the number of cases of invasive cancer estimated at less than 0.01%. On the other hand, over 98% of cases of invasive cervical cancer are associated with some type of HPV. This is the main reason why it has been established that HPV infection is a necessary but not sufficient cause for development of invasive cancer.¹⁵ Other risk factors have been determined associated with both the acquisition of HPV infection and its persistence, conditions that favor the subsequent development of invasive cancer. These include viral types and subtypes, those identified as most likely to cause persistent HPV infection being 31, 16, 58, and 52. Viral load, defined as the number of HPV genomes present in cells, has been shown to correlate with disease severity. Higher levels of high-risk HPV were detected in CIN3 and invasive lesions, compared with those present in low-grade lesions.²⁸  

HPV are classified into genotypes based on the sequence of nucleic acids that make up its genome; individual HPV genotypes are defined by having open reading frames in L1, E6, and E7, differing by more than 10%. More than 170 HPV genotypes have been detected, and more than 20 have been detected in the human genital tract.²⁹ The HPV types found most frequently in precursor and malignant CC lesions are HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68, so it was considered that their presence is high-risk for development of invasive cancer. HPV 16 is the genotype most frequently found in cervical cancer at the global level (50%; 45-64%), followed by HPV 18 (14%; 6-23.4%), HPV 45 (8%; 3-13.8 %) and HPV 31 (4.5%; 1-7-2%), with variations determined by different geographical areas. In Mexico a meta-analysis study reported the following HPV frequencies depending on the type of lesion: invasive cancer, HPV 16 (63.1%), HPV 18 (8.6%), HPV 58 and HPV 31 (5%); for high-grade intraepithelial lesions (HSIL): HPV 16 (28.3%), HPV 58 (12.6%), HPV 18 (7.4%), and HPV 33 (6.5%); for low-grade intraepithelial lesions (LSIL) HPV 16 (13.1%), HPV 33 (7.4%), HPV 18 (4.2%), and HPV 58 (2.6%); while women without lesions: HPV 16 (3.4%), HPV 33 (2.1%), 18 and 58 (1.2%).³⁰

HPV 16 and HPV 18 variants have shown a differential distribution between the severities of cervical lesions in CC, most likely due to their phylogenetic differences. In Mexico the most frequently reported HPV 16 variants are HPV 16 var E (58.8%), HPV 16 var AA-a (32.3%), and HPV 16 var AA-c (8.8%). Interestingly, HPV-16 var AA-c despite its low frequency was observed only in invasive cancer.³¹

Genital HPV infection is mainly due to sexual transmission, as shown by the evidence mentioned above; however, other possible transmission mechanisms are shown due to the following observations: determination of high frequency of antibodies in children; the lack of association of HPV seropositivity with sexual activity; the presence of HPV DNA in oral cavity scrapings in children and adults; and the development of recurrent respiratory papillomatosis in children exposed to HPV 6 or 11 during birth.³² 

Genetic risk

Some epidemiological evidence shows a genetic predisposition to cervical cancer. An excess risk is reported (RR = 1.83; 95% CI, 1.77-1.88) of the biological mothers of women identified as cases (CC) having suffered from cervical cancer, while for adoptive mothers the relative risk was not significantly different from one (1.1, 0.76-1.5). The relative risk for biological sisters of cases was 1.93 (1.85-2.0), while for non-biological sisters of cases, the risk was 1.1 (0.8-1.5), which indicates a significantly increased risk for first-degree biological relatives of women with cervical cancer.³³

In developing countries, the presence of cervical cancer is also associated with factors related to poverty, such as low education, unemployment, residence in rural areas, and lack of access to health services.^17,18,28 Table I summarizes the main risk factors for HPV infection and development of cervical cancer.

Conclusions and recommendations

Cervical cancer is a malignancy of relevance to public health due to the magnitude it presents in the world with respect to morbidity and mortality, especially taking into account its high potential for prevention, to avoid mortality from this cause. In some countries, including Mexico, there has been a trend towards decreased frequency of CC. HPV infection is the main cause associated with the presence of this cancer, so preventive actions must be strengthened to achieve a lower risk of infection. Social and reproductive factors have great influence on higher probability of HPV infection. The prophylactic vaccine against infection by this virus is an alternative directed at some viral types that can decrease the risk of infection.

Tardy diagnosis has been attributed as a main cause of mortality, whose factors include, among others, barriers to healthcare access, social and cultural aspects that prevent timely detection, and request for services only at the first signs of the disease. Therefore, health services should strengthen actions aimed at health education, promote primary prevention by immunization and secondary promotion through timely detection, and have the necessary healthcare resources to meet demand in newly identified cases to help reduce mortality from this cause.

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