**5. Uterine cervical cancer screening**

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

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

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

**1.** Oncogenic HPV infection of squamous cells in the transformation zone of the cervix, which is in the union area of the squamous epithelium of the exocervix and the endocervi-

**4.** Development of invasive carcinoma: Tumor cells in the epithelium cross the basement

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

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

**3.** Progression of persistent HPV epithelial cells infected to a pre-malignant lesion.

the full thickness.

70% respectively [37].

cal glandular epithelium.

membrane and invade the stroma.

**2.** Persistent HPV infection.

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 systems infrastructure.

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 global screening guideline.

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 to health systems.

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 all other settings. Screening is recommended for women of ages 25–65 years every 5 years and for ages 30–65 years, and if two consecutive tests are negative at 5-year intervals, then every 10 years. In the context of limited setting, screening is recommended for ages 30–49 years, every 10 years and for basic settings, for ages 30–49 years, one or more screens in a lifetime. When a precursor lesion is diagnosed, the recommended treatment includes LEEP, or ablative treatments (cryotherapy, cold coagulation) with a 12-month post-treatment follow-up for all settings. For women who are HIV positive, those who had recently given birth, and those who have undergone a hysterectomy, separate screening recommendations have been provided.

For women older than 30 years, PAP is recommended every 3 years with co-tests (PAP and HPV) every 5 years if both initial tests were negative. For women older than 30 years, HPV infection has a greater chance of being persistent; it also has uncertain clinical significance. Any other determination of HPV test increases the probability of positive results, with largest

Uterine Cervical Cancer Screening

39

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

In women older than 65 years, tests are not recommended if they meet the following criteria:

• No risk factors: No history of abnormal test; not a habitual smoker, or currently smoking; no disease related to HPV; not new couples; not immunocompromised; no exposure to

• Optimal screening: Two consecutive negative tests, co-tests, or three PAP tests in the last 20

There are some clinical conditions where increased risk of developing CIN and cervical cancer are observed, as in human immunodeficiency virus (HIV)-infected women. This conclusion is based on several trials including the study of Wright et al. [55] where the definition of cervical intraepithelial neoplasia (CIN) prevalence, validity of PAP tests, and the association of risk factors in women infected with HPV virus, demonstrated that these patients are more likely to have a persistent infection with the virus, increased rate of high grade cervical dys-

Immunosuppressed women: Patients with immunosuppressive therapy (organ /bone marrow transplants, prolonged treatment with steroids, systemic disease), infected with HIV present greater persistence of infection with minor ability to regress spontaneously and therefore, they have higher rates of cervical dysplasia and cancer. Information about immunosuppressed women are based on the results of screening women with systemic lupus erythematosus (SLE). High grade dysplasia and subtype of high-risk HPV persistence rates are significantly higher in women with SLE who receive immunosuppressive therapy, than immunosuppressed patients treated for other conditions, or patients with minor SLE receiv-

At present, for this group of patients, who are immunocompromised or HIV-infected, it is recommended to start screening at age 21, or PAP and HPV tests should be done at the age

Women with total hysterectomy, no history of CIN or cervical cancer, operated for benign pathologies have a very low risk of developing cervical cancer and need not undergo screening for cancer of the cervix [58, 59]. Women with sub-total hysterectomy probably share the same risks as patients with preserved cervix and must follow the general guidelines. For those women with hysterectomy and a history of CIN 2/3 or adenocarcinoma in situ, if the diagnosis was made prior to surgery or hysterectomy, the ACOG recommends screening at least 20 years after treatment [60]. The most recent summary of recommendations [61] includes the

number of colposcopies with uncertain results [52].

years, latest during five previous years [53, 54]

plasia, and higher risk of developing cervical cancer.

when participating in the first sexual relationship.

• No history of high grade dysplasia or more

diethylstilbestrol in utero

ing treatment [56, 57].

following:

Screening methods include Papanicolaou (PAP) test (cytology) and tests for high-risk human papillomavirus types. Cervical cancer screening detects precancerous lesions in the early stages and their treatment decreases uterine cervical cancer incidence and mortality. In the United States, PAP was adopted in 1950 and in the mid-1980s [40], the incidence of cervical cancer had decreased to 70% [41]. The benefit of screening is that it decreases mortality and the incidence of cancer of the cervix, but information provided by the PAP must be evaluated since infection can be transient and dysplasia can regress spontaneously, especially in young women [42]. Major adverse outcomes of screening are derived for furthers consequence to methods used for treatment of injuries. The effects on the reproductive system include stenosis, loss of pregnancy in the second trimester, premature births, and rupture of the membrane [43].

Most episodes of HPV infection and many cases of CIN 1 and CNI2 are transient and fail to develop into CIN 3 or cancer. Potential problems associated with positive screening tests are stigmatization of a sexually transmitted disease and inconvenience associated with additional diagnostic and treatment procedures [44]. Getting a positive test at any time of life may contribute to the perception that one is at an increased risk of cancer and a desire for more tests with the consequent possibility of another positive test, the monetary costs involving the control procedures after a positive result, and the higher cost, from the health perspective, of developing cancer [45]. Although any false-positive test has the potential to induce anxiety, quality of life test is usually not included in screening trials. As a result, the number of colposcopies related to CIN 3 and cancer has been regulated. Cervical cancer is rare in young women and adolescents and may not be prevented by cytological screening. The incidence has not changed in developed countries, but in low-income countries, it presents in earlier ages [46].

Screening in adolescents leads to an unnecessary evaluation and treatment of lesions with high potential of spontaneous regression with reproductive long-term problems. Cancer prevention programs in adolescent should focus on massive vaccination for HPV [47].

Among the 21 to 29 year-olds, screening is recommended with PAP every 3 years. For women aged 21 to 29, with two or more consecutive negative cytologic findings [48, 49], there is no evidence that supports a greater interval for detection (3 or more years). For women less than 30 years of age, HPV screening is not recommended, given high chance of transient HPV infections. Positive predictive value of these tests limits the usefulness of them as screening methods. Randomized studies have shown that HPV testing for women less than 30 years of age [48–50] results in high detection of transient infections by HPV and the women undergo unnecessary colposcopies [51].

For women older than 30 years, PAP is recommended every 3 years with co-tests (PAP and HPV) every 5 years if both initial tests were negative. For women older than 30 years, HPV infection has a greater chance of being persistent; it also has uncertain clinical significance. Any other determination of HPV test increases the probability of positive results, with largest number of colposcopies with uncertain results [52].

In women older than 65 years, tests are not recommended if they meet the following criteria:


all other settings. Screening is recommended for women of ages 25–65 years every 5 years and for ages 30–65 years, and if two consecutive tests are negative at 5-year intervals, then every 10 years. In the context of limited setting, screening is recommended for ages 30–49 years, every 10 years and for basic settings, for ages 30–49 years, one or more screens in a lifetime. When a precursor lesion is diagnosed, the recommended treatment includes LEEP, or ablative treatments (cryotherapy, cold coagulation) with a 12-month post-treatment follow-up for all settings. For women who are HIV positive, those who had recently given birth, and those who have undergone a hysterectomy, separate screening recommendations have been provided. Screening methods include Papanicolaou (PAP) test (cytology) and tests for high-risk human papillomavirus types. Cervical cancer screening detects precancerous lesions in the early stages and their treatment decreases uterine cervical cancer incidence and mortality. In the United States, PAP was adopted in 1950 and in the mid-1980s [40], the incidence of cervical cancer had decreased to 70% [41]. The benefit of screening is that it decreases mortality and the incidence of cancer of the cervix, but information provided by the PAP must be evaluated since infection can be transient and dysplasia can regress spontaneously, especially in young women [42]. Major adverse outcomes of screening are derived for furthers consequence to methods used for treatment of injuries. The effects on the reproductive system include stenosis, loss of preg-

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

nancy in the second trimester, premature births, and rupture of the membrane [43].

ages [46].

unnecessary colposcopies [51].

Most episodes of HPV infection and many cases of CIN 1 and CNI2 are transient and fail to develop into CIN 3 or cancer. Potential problems associated with positive screening tests are stigmatization of a sexually transmitted disease and inconvenience associated with additional diagnostic and treatment procedures [44]. Getting a positive test at any time of life may contribute to the perception that one is at an increased risk of cancer and a desire for more tests with the consequent possibility of another positive test, the monetary costs involving the control procedures after a positive result, and the higher cost, from the health perspective, of developing cancer [45]. Although any false-positive test has the potential to induce anxiety, quality of life test is usually not included in screening trials. As a result, the number of colposcopies related to CIN 3 and cancer has been regulated. Cervical cancer is rare in young women and adolescents and may not be prevented by cytological screening. The incidence has not changed in developed countries, but in low-income countries, it presents in earlier

Screening in adolescents leads to an unnecessary evaluation and treatment of lesions with high potential of spontaneous regression with reproductive long-term problems. Cancer pre-

Among the 21 to 29 year-olds, screening is recommended with PAP every 3 years. For women aged 21 to 29, with two or more consecutive negative cytologic findings [48, 49], there is no evidence that supports a greater interval for detection (3 or more years). For women less than 30 years of age, HPV screening is not recommended, given high chance of transient HPV infections. Positive predictive value of these tests limits the usefulness of them as screening methods. Randomized studies have shown that HPV testing for women less than 30 years of age [48–50] results in high detection of transient infections by HPV and the women undergo

vention programs in adolescent should focus on massive vaccination for HPV [47].

There are some clinical conditions where increased risk of developing CIN and cervical cancer are observed, as in human immunodeficiency virus (HIV)-infected women. This conclusion is based on several trials including the study of Wright et al. [55] where the definition of cervical intraepithelial neoplasia (CIN) prevalence, validity of PAP tests, and the association of risk factors in women infected with HPV virus, demonstrated that these patients are more likely to have a persistent infection with the virus, increased rate of high grade cervical dysplasia, and higher risk of developing cervical cancer.

Immunosuppressed women: Patients with immunosuppressive therapy (organ /bone marrow transplants, prolonged treatment with steroids, systemic disease), infected with HIV present greater persistence of infection with minor ability to regress spontaneously and therefore, they have higher rates of cervical dysplasia and cancer. Information about immunosuppressed women are based on the results of screening women with systemic lupus erythematosus (SLE). High grade dysplasia and subtype of high-risk HPV persistence rates are significantly higher in women with SLE who receive immunosuppressive therapy, than immunosuppressed patients treated for other conditions, or patients with minor SLE receiving treatment [56, 57].

At present, for this group of patients, who are immunocompromised or HIV-infected, it is recommended to start screening at age 21, or PAP and HPV tests should be done at the age when participating in the first sexual relationship.

Women with total hysterectomy, no history of CIN or cervical cancer, operated for benign pathologies have a very low risk of developing cervical cancer and need not undergo screening for cancer of the cervix [58, 59]. Women with sub-total hysterectomy probably share the same risks as patients with preserved cervix and must follow the general guidelines. For those women with hysterectomy and a history of CIN 2/3 or adenocarcinoma in situ, if the diagnosis was made prior to surgery or hysterectomy, the ACOG recommends screening at least 20 years after treatment [60]. The most recent summary of recommendations [61] includes the following:

• Start screening no sooner than age 21, regardless of the age of onset of sexual activity or other risk factors. Between 21 and 29 years of age, PAP smear must be done every 3 years. Between 30 and 65 years, co-testing (cytology more than an HPV test) every 5 years is preferable; if not possible, single cytology every 3 years is acceptable. After the age of 65 years, screening can be discontinued if previous screening has been done and found negative and not CIN 2 (+) during the previous 20 years.

[6] Sankaranarayanam R, Nene BM, Shastri SS. HPV screening for cervical cancer in rural

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[7] Parking DM, Almonte M, Bruni L, Clifford G, Curado MP. Pineus burden and trends of type-specific human papillomavirus and related disease in Latin America an Caribbean

[8] Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillovirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine in young women: A randomised doublé blind placebo-controlled multicenter phase II efficacy trial. Lancet Oncology. 2005;**6**:271-278 [9] Sankaranarayanan R. HPV vaccination: The promise & problems. India Journal of

[10] Saslow Castle PE, Cox JT, et al. American Cancer Society Guideline for human papillovirus(and its precursors. HPV) vaccine use to prevent cervical cancer. CA Cancer

[11] Wallim KL, Wiklund F, Angstrôm T, et al. Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. New England Journal

[12] Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus

[13] Committee on practice Bulletins Gynecology. Practice Bulletin No. 168: Cervical Cancer

[14] Klumb EM, Araujo ML Jr, Jesus GR, et al. Is higher prevalence of cervical intraepithelial neoplasia in women with lupus due to immunosuppession? Journal of Clinical

[15] Muñoz N, Francheschi S, Bosetti C, et al. Role of parity and human papillovirus in cervical cancer. The IARC multricentic case-control study. Lancet. 2002;**359**:1093

[16] Jemal A, Simmard EP, Dorell C, etal. Annual Report to Nation on Status of Cancer,1975-2009. Feature the burden and trends in human papillomavirus (HPV)-associated cancers and

HPV vaccination coverage levels. Journal of National Cancer Institute. 2013;**105**:17 [17] Cervical cancer screening programs I. Epidemiology and natural history of carcinoma of

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• Screening can be discontinued if there is total hysterectomy (with removal of cervix) and a history of CIN 2 (+).

These suggestions are valid for developed countries that allow the implementation of adequate screening campaigns with all the resources available. However, for developing countries with limited resources, cytology and direct visualization of the cervix with VIN are valid methods.
