**4. Human papillomavirus**

• Early first sexual intercourse; the risk increases if the first sexual activity is before 21 years of age [11, 12], being approximately 1.5% when first sexual activity is at 18–20 years of age

• High-risk sexual partner, for example, a partner with multiple sexual partners or with HPV

• Squamous vulvar intraepithelial neoplasia or vaginal neoplasia (highly associated with

• Immunosuppression: VIH-positive women have consistently shown to be at an increased

• Young age at first full-term pregnancy (less than 20 years of age) and high parity are exogenous cofactors associated with an increased risk of cervical carcinoma; these factors are thought to increase the risk through the maintenance of the transformation zone on the

• Low income/socio-economic status is associated with cervical cancer; incidence and mor-

• Oral contraceptives: The data analysis of 24 epidemiologic studies [17] found that the risk of cervical cancer increases with increasing duration of oral contraceptive use (5 years or more of using oral contraceptives vs. non-users); the relative risk was 95% and it decreased after use of oral contraceptives has ceased; the same analysis estimated that 10-year use of oral contraceptives that started at 20–30 years of age increases incidence of cervical cancer

• In current smokers, a doubling in risk of developing cervical cancer has been observed, with a positive correlation with the habit intensity; nicotine and smoke derivates from tobacco discovered on cervical mucus suggest a possible biologic mechanism through immunosuppression that favor infectious agent such as HPV; tobacco smoking is associated

• Some daughters of women, especially young women, who took diethylstilbestrol during pregnancy have developed clear cell adenocarcinoma of the cervix and vagina [19, 20] • High incidence of cervical cancer is observed in Afro-Americans, Latins, and ethnic groups with low incomes and socio-economic conditions with limited access to effective screening

There is no established model for a genetic base, although population studies have found increased risk in familiar groups. In the past, it was attributed to ambient environmental

• History of sexually transmitted disease (chlamydia, genital herpes) [13, 14].

34 Cervical Cancer - Screening, Treatment and Prevention - Universal Protocols for Ultimate Control

exocervix for a prolonged time, which facilitates exposure to HPV [15].

and younger.

infection.

• Multiple sexual partners.

HPV infection) in the past.

in middle-age women

and health system [18]

**3. Genetic factors**

with squamous cervical cancer [18]

risk for high-grade cervical dysplasia. [14]

tality are higher in high-poverty communities [16].

The causal role of HPV in all common and non-common histologic types has been firmly established biologically and epidemiologically and has led to a new carcinogenic model for cervical cancer: HPV acquisition, HPV persistence, progression of pre-malignant lesion to invasive cancer [25, 26]. Human papillomavirus is acquired through sexual contact; most population prevalence reaches its peak few years after the median age of initiation of sexual intercourse.

Most HVP infections are transient, lasting no more than 1 or 2 years [27]. Persistent HPV infection for 1–2 years, especially by HPV 16 predicts development of CIN 3 (cervical intraepithelial neoplasia) or malignant changes. The probability of untreated CIN 3 transforming into an invasive cancer is 30%, although 1% of treated CIN 3 transforms into an invasive cancer [28].

There are more than 100 HPV types; high-risk types 16, 18, 31, 35, and 39 are linked to malignant transformation [29]. Type 18 infection progresses with bad prognosis based on recorded survival rates.

High-risk HPV infection may generate some of the following cell biologic alterations leading to malignant transformation. Two of the eight proteins encoded by the HPV genome, E6 and E7, accounts for most carcinogenic effects of high-risk HPV types. They promote carcinogenesis in several ways:


Progression of HPV infection to uterine cervical cancer is associated with progressive histologic changes. Cervical intraepithelial neoplasia (CIN) is a histologic change corresponding to dysplasia of cervical squamous epithelium associated with HPV infection and is considered a potential precursor of uterine cervical cancer. They are classified into three grades: CIN grade I, mild dysplasia, or abnormal cell growth confined to the basal 1/3 of the cervical epithelium; CIN grade II, moderate dysplasia confined to the basal 2/3 of the epithelium; and CIN grade 3, severe dysplasia that spans more than 2/3 of the epithelium, and may involve the full thickness.

uterine cervical cancer in Venezuela, identification of the country's most frequent HPV type, and comparison with worldwide incidence of VPH. HPV DNA sequences were associated in 52.3% of the patients, VPH 16 in 24.52%, and HPV 18 in 7.4% of their population. These results suggest the imperative need of large-scale epidemiological studies as these results do

Uterine Cervical Cancer Screening

37

http://dx.doi.org/10.5772/intechopen.72606

Screening of uterine cervix decreases the incidence and mortality of cervical cancer. Cervical cancer has two main histological types: squamous and adenocarcinoma. Screening can detect precursors and early stage for both types, and treatment of precursors can prevent the development of invasive cancer. Currently, in addition to screening, test for high-risk human papillomavirus types, which form the foundation of uterine cervical cancer pathogenesis, has been included. In view of the high incidence and mortality of cervical cancer, its significance as a global public health problem, and the difficulties involved in establishing effective screening in different regions of the world, the American Society of Oncology (ASCO), in the year 2013 [39], released a world guide for cervical screening and follow-up of positive cases, as well as guidelines for treatment for pre-malignant lesions. The main recommendation was screening for cervical pre-cancers for all women in appropriate age groups and establishing consistent minimum standards for screening considering and based on resource levels and health sys-

Based on the results of a large clinical trial in India that demonstrated that cervical cancer screening with acetic acid (vinegar) could prevent thousands of deaths each year in developing countries [39], initial visual inspection with acetic acid (vinegar) was incorporated in the

Cancer of the cervix is a highly preventable disease; low-income countries lack large-scale screening and vaccination programs against HPV. As a result, more than 85% of the world's cervical cancer diagnoses and deaths occur in less developed regions. Access to programs of detection and treatment of cervical cancer varies not only between countries but also within them. Standards were established in four different areas of health: basic, enhanced, and maximum limited. These levels correspond not only to the financial resources of a country or region, but also the strengths of the health care including personnel, infrastructure, and access

ASCO's guideline builds upon WHO's recommendations by providing a minimum set of standards across all countries based on their existing resources, and by accounting for the 2013 VIA study and other recent data. HPV DNA testing is recommended in all resource settings and VIA may be used while HPV testing becomes available. If VIA, as a primary screening, gives abnormal results, women should receive treatment. After a positive HPV DNA testing result, VIA is recommended for follow-up in basic and limited settings. For other settings, HPV genotyping and/or cytology may be used for triage. Women with abnormal triage results should receive immediate treatment in basic and limited settings, or colposcopy in

not reflect the results reported in other countries [38].

**5. Uterine cervical cancer screening**

tems infrastructure.

to health systems.

global screening guideline.

Historical data demonstrated that the majority (71–90%) of CIN 1 lesions *regress spontaneously* in contrast with persistence and progression rates for CIN 2 and CIN 3, estimated in 57 and 70% respectively [37].

There are mainly four steps implicated in the development of uterine cervical cancer:


Formal epidemiological evidence of the association between HPV and cervical cancer did not exist until the early 1990s, although molecular characterization of one of the first types of HPV in the 1980s made it possible to develop tests of hybridization to obtain fragments of HPV genes in human tissue. Using hybridization studies based on polymerase chain reaction (PCR), studies have been conducted for the identification of HPV DNA. One of the pioneer studies in Latin America was carried out by the Agency for Research of Cancer, between Colombia and Spain. The results of this study have been considered as the first evidence of the causal association between HPV and cervical cancer. Subsequently, similar studies were carried out in 9 countries (Algeria, Brazil, India, Mali, Morocco, Peru, Paraguay, Thailand, and Philippines) between 1985 and 1988 to evaluate the role of the virus of HPV in the etiology of CIN 3. The DNA was obtained by cytology and was evaluated by Virapap and PCR. In Spain, HPV prevalence based on PCR was detected in 63.2% of the cases and for controls was observed in 47%. In Colombia, HPV DNA was detected in 63.2% of the cases and in 10.5% of the controls. VPH 16 was the most predominant type of virus and showed stronger association with the development of CIN 3. HPV of unknown origin was common in positive cases (18.3% in Spain and 38.0% in Colombia [28]. In 2006, a study was carried out at the gynecologic department of the Padre Machado Hospital, in Venezuela; it included 58 patients with uterine cervical cancer. Typification of human papillomavirus by PCR for types 6, 11, 16, 18, 31,33, and 35 were performed; other variables such as age, stage, and histological type were also analyzed. The purpose of this study was typification of HPV in women with invasive uterine cervical cancer in Venezuela, identification of the country's most frequent HPV type, and comparison with worldwide incidence of VPH. HPV DNA sequences were associated in 52.3% of the patients, VPH 16 in 24.52%, and HPV 18 in 7.4% of their population. These results suggest the imperative need of large-scale epidemiological studies as these results do not reflect the results reported in other countries [38].
