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1 Background

Cervical cancer is the second most common malignancy in women worldwide, and it remains a leading cause of cancer-related death for women in developing countries. In the United States, cervical cancer is relatively uncommon. The number of cervical cancer-related deaths worldwide is 270.000 each year, with nearly 85% of those deaths occuring in resource-poor settings.1 Since the Papanicolaou (Pap) smear first published, it has become the most commonly used method to screen for cervical neoplasia. It is the medical procedure in which a sample of cells from a womans cervix is collected and smeared on a microscope slide. The cells then examined under a microscope in order to look for pre-malignant or malignant changes.3 The remarkable success in reducing the incidence of cervical cancer which highly attributable to cytologic screening tests has achieved. However, highquality cytology-based screening programs require well-trained personnel and some specialized equipment. It also has limited sensitivity, estimated at only 51%, which results in the need for additional cervical cytologic tests at regular intervals.4 Because infection with oncogenic human papillomavirus (HPV), especially types 16 and 18, has been identified as the underlying cause of cervical cancer, there is interest in the use of HPV testing as a primary screening test for cervical cancer. With currently available technology, HPV DNA testing is highly reproducible, is easily monitored, and provides an objective outcome. It is substantially more sensitive than cytologic testing in detecting high-grade cervical intraepithelial neoplasia (CIN).4 HPV DNA testing also has limitation. Its specificity is lower than cytologic testing, which means that the potential cost may be higher than just the cost of the test, because specificity tests the probability that a patient without the disease will test negative. For this reason, it can be concluded that women without disease will be more likely to test positive when HPV testing is used.4

Therefore, the most important question is whether improving sensitivity, by definition, increase the number of false positive tests will give higher benefit than using the high-specificity tool. 1.2 Aim and Purposes

The aim of this writing is to give more information about the importance of early screening for cervical cancer. Through increasing the knowledge and awareness of the community about it, it is said that the number of incidence of cervical cancer can be reduced. The benefits and costs have to be concerned in choosing the method of screening.

CHAPTER II REVIEW 2.1 Cervical Cancer The uterine cervix is the most distal portion of a womans uterus. Most of the uterus lies in the pelvis, but part of the cervical portion is located in the vagina, where it connects the uterus with the vagina. Cancer of the cervix occurs when the cells of the cervix change in a way that leads to abnormal growth and invasion of other tissues or organs of the body. Like all cancers, cancer of the cervix is much more likely to be cured if it is detected early and treated immediately.2 The epithelium of the cervix is composed of squamous epithelium that covers the exocervix and glands and columnar epithelial cells that line the endocervix. The border between the squamous and columnar epithelium is called the squamocolumnar junction, the site of ongoing squamous metaplasia believed to be most vulnerable to viral neoplastic transformation. The transformation zone is the most common location for detection of early cervical cancers.5 Early epidemiological data demonstrated correlation of sexual activity with cervical carcinoma is related to transmission of the HPV. Most HPV infections are transient, resulting in no changes or low-grade intraepithelial lesions (cervical intraepithelial neoplasia;CIN 1) that will be spontaneously cleared in most young women. Development of high-grade intraepithelial lesions will occur in a small minority of women, usually within 24 months. High-grade lesions (CIN 2/3) may progress to invasive cervical cancer if not treated. 5 The precursor lesions of the cervix persevere longer and progress more quickly in women with oncogenic HPV (especially type 16 and 18) infections than in women with non-oncogenic infections or without HPV. The presence of HPV in cervical cells gives the groundwork for HPV DNA testing.6 The natural history of cervical cancer involves reversible changes in the cervical tissue from a normal state, in which no neoplastic changes are detected in the squamous epithelium, to varying states of cellular abnormalities that

ultimately lead to cervical cancer. This sequence forms the basis on which cytologic screening for cervical cancer is based and corresponds to an underlying multistep carcinogenic process in the development of CIN.6 2.2 Conventional Pap Smear A pap smear is a cytological test designed to detect the presence of abnormal cervical cells. The procedure includes gently scraping cells from the cervix and then smearing and fixing them on a glass slide. The slides are sent to a cytology laboratory and evaluated by a well-trained cytologist determines the cell classification. Most protocols suggest that women with low-grade abnormalities return for regular follow-up smears until the abnormality either resolves or persists, warranting further investigation. Periodic screening and follow-up evaluation of women in their 30s or older is an acceptable, costeffective approach to preventing cervical cancer, assuming that the screening approach used is accurate and coverage is high.7 The specimen for pap test collected through several steps. First, the patient lie on the examination table on lithotomy position. The doctor then open the vagina by using speculum so that the walls of the vagina and cervix can be seen clearly. A sample of cells will be obtained from the cervix and endocervix using a cytobrush. The sample cells is evenly applied to a glass slide and immersed with a fixative (alcohol 95%). This sample is sent to the Pathology Center.8 The Pap smear generally is considered to be a very specific test for highgrade lesions or cancer, but only moderately sensitive. The high specificity means that cytology correctly identifies a high proportion of women who do not have highgrade lesions or cancer. The moderate sensitivity means that cytology identifies only a relatively modest proportion of women who actually do have high-grade lesions or cancer. In general, it is not possible to increase Pap smear sensitivity while maintaining high specificity.8


PCR HPV Testing HPV has been implicated as the etiologic agent in the development of cervical cancer. The lack of ability to utilize conventional viral culture methods initially made detection and diagnosis for HPV difficult until the advent of molecular methods, particularly amplification technology (such as polymerase chain reaction, PCR), which has allowed detection of low-level virus copy numbers in clinical samples. Analyses of cervical cancers from different regions of the world using PCR methods have shown oncogenic HPV DNA (i.e. HPV16 and HPV18) with consistent findings in a large number of investigations in different countries and populations.9 DNA target amplification technology is a laboratory-based procedure that duplicates DNA fragments from a target sequence of a gene, thus providing concentrated samples of a specific genetic sequence. PCR is a standard laboratory procedure which is the most commonly employed for detection and typing of HPV. The sample for the PCR test is obtained by various methods, including self-collected samples (using urine, vulvar swabs, vaginal tampons, or vaginal swabs) and samples collected by health care providers (including genital swab, vaginal lavage, cervical swab, and cervical brush specimens).10 PCR requires a cyclic, threestep reaction. Once cervical cells are collected and prepared, the sample is heated to approximately 950C. This heating will denature the DNA, resulting in two single strands. The temperature of the reaction is then decreased to 550C and HPV-specific primers bind to target DNA. The reaction is heated again to 720C and an enzyme present in the mixture catalyzes the extension of the probes and promotes the creation of two complementary strands of the targeted HPV DNA sequence.10 A master mix of chemicals, including all the necessary catalysts and enzymes required for the process, is placed into a reaction vessel, and the biochemical process is then automated in a thermocycler. With each thermal cycle, the amount of target DNA theoretically doubles. For example, within approximately one hour, 20 cycles can amplify the target a million-fold.10

CHAPTER III DISCUSSION The efficacy of cytological screening for cervical cancer depends on the possibility of modifying the course of the disease through identification of women with highdegree precursor lesions and invasive initial lesions. With this it is possible to distinguish the woman apparently not affected from the woman who could have the disease.11 Even though the efficacy of cytology screening has never been proven through randomized trials, it is generally agreed that the marked reduction in the incidence and mortality from cervical cancer before and after the introduction of screening programs in a variety of developed countries has been interpreted as strong nonexperimental support for organized cervical cancer screening programs.11 Two important parameters traditionally used to measure the validity of screening tests are sensitivity and the specificity. The sensitivity means the percentage of positive cases reported as being positive. It relates to the ability of disease detection. The specificity means the percentage of negative cases reported as being negative. It relates to the ability of disease exclusion.11 The value of the Pap test in cervical carcinoma screening is undisputed. Routine cytological screening by this method has resulted in a reduction in the cervical carcinoma mortality rate of close to 60% in women aged 30 and older. However, Pap smears are proven technically unsatisfactory. It has several limitations. First, the sample may contain an inadequate number of clearly visible cells and a repeat smear is required as soon as the cervix has recovered from the minor trauma of the previous test. It gives false negative Pap smear results for up to two third of them. Cultural barrier in carrying out gynecologic examination can also be an obstacle in getting adequate sample. In spite of optimal collection, specimen handling and screening procedures, the false negative (missed lesion) rate for a single smear is reported to be between 5 and 25%.11 Patients without a cervicovaginal abnormality (atypical squamous cells or worse) with unsatisfactory Pap smears had an incidence of squamous abnormalities during subsequent follow-up similar to that for patients with

satisfactory negative Pap smears.13 However, since the development of cervical dysplasias to carcinomas typically takes a long period, if annual screening is carried out, the chance of a lesion being missed is low.12 The other issues regarding the conventional Pap smears are the minimal requirement to establish an effective Pap smear screening. They include the well-trained Pap smear providers (including non-physicians), initial and ongoing access to supplies and equipment, linkages, including transportation, to a reliable cytology laboratory, proven systems for timely communication of test results to screened women, and effective referral systems for diagnosis and treatment.8 Pap smear results typically take days or weeks to become available, at which time women must be notified, counseled and possibly retested at some interval or referred for additional diagnostics or treatment. The cytology screening process, combined with the delays between screening, provision of test results and ultimate treatment (including necessary repeat visits), are major barriers to the success of cytology-based programs in low-resource settings.1 The Pap smear generally is considered to be a very specific test for highgrade lesions or cancer, but only moderately sensitive. A recent analysis of data from several Latin American urban centers found that conventional cytology (Pap smears) had a sensitivity of 53% (and a specificity greater than 99%) for detecting moderate to severe lesions, while a study in rural Peru found that cytology had a sensitivity of 26% (and a specificity of 99%) for detecting CIN of these grades. Such results, combined with the documented challenges of implementing and sustaining cytologybased programs have promoted the implementation of alternative screening.1 HPV DNA tests are now being developed into rapid, robust, easy-to-use formats. HPV DNA testing is more sensitive and the results more easily reproducible than cytologic screening for the detection of existent and incipient cervical precancerous conditions and cancer. As a consequence of the high sensitivity of HPV testing, a negative test for carcinogenic HPV types provides a degree and duration of reassurance not achievable by any other diagnostic method.14 One of the HPV DNA test is by PCR. The new PCR-based test offers considerable advantages for women identified as high-risk and women with unclear early-stage

cytological dysplasia. It also facilitates decision-making regarding further treatment. If the women has already had cervical intraepithelial neoplasia requiring treatment, the likelihood of her developing an invasive cervical carcinoma is consequently more than five time as high. Such aftercare examinations are a clear indication of when an HPV-PCR test is needed. A negative high-risk HPV result, for all purposes, rules out the risk of a relapse as it gives a negative predictive value of close to 100%. The HPV-PCR screening method thus provides valuable information not available from cytology alone.12 Studies indicate that women can successfully obtain self-collected vaginal specimens for use in HPV DNA detection. This has important implications for programs located where cultural and program barriers may limit acceptability of and access to vaginal examination. Self-sampling may be more acceptable to women, resulting in increased program effectiveness due to better population coverage. A Canadian study assessing the effectiveness and acceptability of different sampling methods found that self-collection was acceptable to women and showed sufficient sensitivity to warrant further evaluation.15 A cross sectional study which aims to determine the accuracy of PCR analysis for HPV DNA as a predictor of HPV-related cervical lesions was held in the University of Michigan Family Medicine. The participants were 456 sexually active women, aged 18-50 years. Of 133 eligible participants, 41 underwent colposcopy because of a positive result for HPV of the cervix by the PCR method and 92 underwent screening colposcopy with biopsy prior to knowing the HPV PCR results. Twentyfour of those screened were subsequently found to also be HPV DNA positive.16 The false-negative rate for HPV testing (by the PCR method) for precancerous lesions of the cervix was assessed, using cervical biopsy as the gold standard. Data from the women screened by colposcopically directed biopsy indicate that the falsenegative rate of PCR analysis for HPV DNA for predicting HPV-related lesions of the cervix was 0% (95% confidence interval [CI], 0 to 0.047); conversely, all women with HPV-related lesions in this low-risk population had positive PCR test results (sensitivity, 100%). However, of those without lesions, 42 (38.2%) were positive for HPV DNA by the PCR method. The predictive value of a positive HPV test was

33.3%, and the predictive value of a negative test was 100% (i.e., all women with negative HPV test results lacked cervical lesions).16 The inherent strength of the PCR-based methodology lies in its capacity to detect very small amount of HPV DNA. At the same time, strict laboratory procedures and controls are critical in reducing contamination-related false-positive findings. PCR frequently is used as a diagnostic tool in epidemiologic investigations of HPV, but the associated costs and technology requirements often are inappropriate for large screening programs.10

CHAPTER IV CONCLUSION Cervical cancer, as the second most common cause of cancer-related death in women, needs early screening and treatment. The natural history of this disease involves HPV infection and abnormal changes of the cervical cells which can lead to cancer. The early screening of cervical cancer that has been proven to be important in decreasing its incidence, based on the detection of abnormal cellular changes (by conventional Pap smear) and the presence of HPV in cervical cells (by PCR). Conventional Pap smear is said to have high specificity but lower sensitivity than PCR. Thus, it tends to increase the false-negative value, which means there is undetected lesion. Conversely, PCR testing has higher sensitivity than conventional Pap smear. This condition can increase the false-positive value, by definition, there is normal condition diagnosed with positive lesion. Sensitivity and specificity are important parameters for the evaluation of the accuracy of the screening test. However, it is important to bear in mind that the efficacy of screening is not restricted to the performance of the test used. Special emphasis must be given to the need to develop organized programs that have a systemic approach, that are well integrated into the existing health system, and which consider social, cultural, and economic aspects.







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from: Philip Zazove, Low False-Negative Rate of PCR Analysis for Detecting Human Papillomavirus-Related Cervical Lesions. Journal of Clinical Microbiology. 1998;36:2708-2713.