I. Introduction

Invasive squamous cell carcinoma of the cervix is the end stage of a process beginning with atypical transformation of cervical epithelium at the squamocolumnar junction, leading to cervical intraepithelial neoplasia (CIN) of advancing grades and eventual invasive disease (Berek et al, 2000). Cervical cancer is the second most common cancer in women throughout the world and it is the leading cause of cancer death among women in underdeveloped countries (Solar et al, 2000; Cohn de and Herzog, 2001; Naud et al, 2001).

There is convincing evidence that cytologic screening programs are effective in reducing mortality from carcinoma of the cervix. The extent of the reduction in mortality achieved is related directly to the proportion of the population that has been screened. In fact all studies worldwide show that screening for cancer not only decreases mortality but also probably does so by decreasing the incidence.

Numerous paper and lengthy discussions have focused on the optimal screening interval, unfortunately numerous recommendations during the last decade and a half have resulted in a confused public and dissatisfied professionals.

Screening decreases cervical cancer mortality by detecting pre-invasive disease and, specially at the beginning of a screening program in a previous un-screened population, by detecting prevalent cases of invasive cancer in earlier stages. Although it has not been proved in a prospective randomized study, all investigators credit screening as a major contributor to this reduction in death rate.

In contrast to the industrialized world, cancer of the cervix remains the primary cancer killer in women in third-world countries (Disia and Cresman, 2002). During the last decade there has been increasing emphasis on cervical cancer screening in both governmental health services and private medical practitioners in our country (Annual report of Tehran university of medical sciences, district cancer registry (TUMS- DCR), 1997; Behtash et al, 2003).

Cancer deaths may also be prevented by detecting disease at a stage when it is more curable. To be successful, a screening program must be directed at a suitable disease with a suitable screening test (Cole and Morrison, 1980).

A suitable disease must be one that has serious consequences, as most cancers do. Treatment must be available so that when such therapy is applied to screen- detected (preclinical) disease, it will be more effective than when applied after symptoms of the disease have appeared. Also, the preclinical phase of the disease must be long enough that the chances are good that a person will be screened.

There must also be a suitable screening test as defined by simplicity, acceptability to patients, low cost, and high validity (Berek et al, 2000).

II. Terminology in cervical cytology

George Papanicolaou devised the first system of reporting cervical cytology results and based the classification on the degree of certainty that malignant cells were present (Davey et al, 1992).

The current cytologic terminology, the Bethesda system was the result of the work of an expert panel which convened in 1988 under the auspices of the National Cancer Institute. It was revised in 1991 and again in 2001 (National Cancer Institute Workshop, 1989).

III. The cervical cytology

After the introduction of cervical cytology for cancer screening more than 50 years ago, multiple screening programs from all parts of the world have reported decreased rates of invasive cervical cancer and decreased death rates from a malignancy that had previously been the number one worldwide cause of cancer death in women(Disia and Cresman, 2002).

Despite the effectiveness of cervical cytology screening programs, there are several limitations of Papaniclaou smear screening.

A single Pap smear has a sensitivity of only about 51% (Apgar et al, 2002).

The cytologic sample should not be collected during the menstrual period. The patient should avoid vaginal medications, vaginal contraceptive or duches during the 48 hours before the appointment and intercourse is not recommended on the night before or the day of the examination(Apgar et al, 2002). From the standpoint of obtaining ideal cytology, postpartum Pap smears should not be performed until at least 6 or even 8 weeks after delivery, by which time the cervix has undergone reparative changes (Rarick and Tchabo, 1994).

If the woman is postmenopausal and previous smears have lacked endocervical cells or have demonstrated atrophy with inflammation, the cervix may be primed with 3 weeks of treatment with intravaginal estrogen cream followed by repeat cytologic sampling use of a combination of the Ayre spatula for sampling the ectocervix and a brush for sampling the endocervix has been shown to be superior to other techniques for obtaining a conventional Pap smear (Toffler et al, 1993).

The quality of the smear can be improved by using the spatula first, followed by the endocervical brush, because fewer smears will be obscured by blood (Eisenberger et al, 1997). The spatula is first placed at the cervical os, using the end the best conforms to the cervical anatomy. It is rotated 360 degrees about the circumference of the maintaining contact with the ectocervix. The sample smeared on the slide must be fixed immediately. Both slides of the spatula should be smeared on the slide. The brush is then inserted in to the os and rotated 180 degrees similarly.

The sample is unrolled onto the slide in the opposite direction from which it was collected by twirling the handle of the brush.

Based on a meta- analysis of 84 appropriately designed and conducted studies, the Agency for Health Care Policy and Research reported that conventional cytology has a specificity of 98% and a sensitivity of 51%. It has become clear the sensitivity of conventional cytology is even lower that traditionally recognized (Apgar et al, 2002).

However, even with this limited sensitivity, if three consecutive tests are negative, there is less than a 1% chance that the patient will have a cervical abnormality(Rock and Jones, 2003).

A false- negative Papanicolaou smear may result from either screening or interpretation problems. Screening problems include lesions that do not shed cells or that are not sampled by the clinician, or, sometimes, the diagnostic cells are not transferred from the spatula or collection device to the glass slide(Rock and Jones, 2003), Rarely, the slide preparation or staining is unsatisfactory. In other patients, problems with interpretation include failure to identify abnormal cells or misinterpretation of cells that are diagnosed as reactive or metaplastic when a dysplastic lesion exists. Various studies have shown the women who are diagnosed with invasive cervical cancer after a reportedly "negative" Papanicolaou smear, most often have abnormal cells on review of their slides. The diagnostic cells may be few in number or obscured by blood or inflammatory changes (Rock and Jones, 2003).

IV. Liquid-based, thin–layer cytology

To decrease the false- negative rate of cervical cytology, attempts have been made to improve both specimen collection and quality and to reduce errors of interpretation. Over the past several years, several liquid- based techniques have been approved by Food and Drug Administration in United States. Those techniques differ from the conventional method of Papaniclaou smear, once the clinician obtain a scraping of the squamo columnar junction and transformation zone, the spatula and brush are dipped and agitated in a small bottle of fixation solution to elute the cell rather than being smeared on a glass slide. Once in the lab, a machine prepares a slide containing about 40,000 representative epithelial cells in a thin layer. The slide is the stained and reviewed by the cytologist (Rock and Jones, 2003).

Liquid- based, thin -layer technology was developed to address the five major limitation posed by conventional Pap smear: failure to capture the entire specimen, inadequate fixation, random distribution of abnormal cells, obscuring elements, and technical variability in the quality of the smear.

Despite the limitations of the current data, more than 500,000 subjects have been studied, with a preponderance of data indicating a significant benefit of liquid- based, thin- layer technology in the detection of cervical cancer precancer lesions and in the improvement of specimen adequacy (Apgar et al, 2002).

Only one published study to date failed to find more squamous intraepithelial lesion in the liquid- based slides than in the conventional Pap smear, showing a nonsignificant 3% decrease in the detection of squamous intraepithelial lesions (Takahashi and Naito, 1997).

Liquid-based cytology has been shown to aid in reducing the proportion of ASCUS diagnoses, probably based on improvements in both the fixation and the quality of the slide. Also Ashfaq et al reported a signigicant improvement in the detection of adenocarcinoma of the cervix, with a 65% decrease in the false negative rate for the diagnosis of adenocarcinoma by Thin-prep over the conventional Pap smear, as well as 64% increase in the specificity of a diagnosis of AGUS or adenocarcinoma (Ashfaq et al, 1999).

Re-training of cytotechnologists on liquid-based cytology is needed because the characteristics of the cells differ from conventional cytology.

V. Computer-assisted diagnosis

These techniques have been used mostly for quality control to identify slides that have been read as normal by cytotechnology screeners but that have cellular characteristics recognized by the computer as suspicious (Duggan, 2000).

There is good evidence to suggest that computer- assisted diagnosis is even better when liquid- based, thin- layer slides are used because the background is much cleaner and there are fewer cell clumps with diagnostic cells obscuring another. Although the initial cost of a computer- based system is large, considerable saving should be realized by the around- the-clock work reduced need for cytotechnologists who could concentrate on the diagnostic evaluation of high- risk slides identified by the computer on primary screening (de Villiers, 1997). More clinical experience with these computer techniques is needed but results are promising.

VI. Human papilloma virus typing

Papilloma viruses (PV) are ubiquitous microorganisms that cause productive and/ or latent infections in a wide variety of species and tissues. To date, more than 90 types of human papilomavirus (HPV) have been detected (de Villiers, 1997).

Many of the newly discovered HPV types in the male and female anogenital tract were associated with cervical cancer and cancer precursors. The most prevalent anogenital HPV can be divided in to three groups: low, intermediate and high oncogenic risk.

Emerging technologies such as HPV vaccines (Kulasingam and Myers, 2003), HPV tests (Mandelblatt et al, 2002) and enhanced pap screening methods are leading policy markers to evaluate new guidelines for incorporating these technologies into current care practices, and to consider changes to the frequency of cervical cancer screening and management of cervical HPV- related disease (Insinga et al, 2004).

HPV testing in the past has been inaccurate and the complex laboratory techniques are not conductive to large volume clinical work. However, with the newer second- generation Hybrid Capture techniques, these problems seem to have been resolved. Current technology uses DNA hybridization and quantification by chemiluminescence reaction to identify the presence of any of 13 different, oncogenic types HPV.

Because HPV is difficult to culture one or more of three nucleic acid- based tests have been used for detecting and typing HPV in specimens: the Polymerase Chain Reaction, the Hybrid Capture II System and In Situ Hybridization (Apgar et al, 2002). Nevertheless, HPV testing is easy to perform and is a relatively inexpensive test that can be automated in the laboratory and requires no interpretation (a problem with the Papanicolaou test).

HPV testing has been shown to be 15% to 20% more sensitive than the conventional Pap smear and at least 10% more sensitive than liquid- based Pap smears while exhibiting an equivalent specificity in the relevant defined subgroups of women (Cuzick et al, 1999; Krumholz, 2000; Wright et al, 2000).

The most compelling data for clinical utility of HPV DNA testing in patient management relates to women with ASCUS Pap smears. Based on data, the immediate HPV- based triage of ASCUS would result in a sensitivity of 90% to 96% compared with 75% to 85% for the repeat Pap smear (Kuperman et al, 2000).

The Pap smear was slightly more specific than HPV DNA testing for the presence of high grade cervical disease (Apgar et al, 2002).

HPV testing does not appear to be beneficial in young women, who are known to have predominantly transient HPV infection. Thus, most HPV screening strategies call for HPV DNA testing in women older than 30 years (Clavel et al, 1999). HPV testing combined with cytology is a reasonable approach in elderly women in order to increase the screening interval to 3-5 years (Fehr and Welti, 2004).

VII. Adjunctive testing

A. Cervicography

Cervicography has been proposed as a adjunctive test that would increase the sensitivity and specificity of the Pap test in detecting precancerous and invasive cervical disease. Cervicography is not promoted as an independent or stand – alone test. In 1980, Adolf Stafl, invented a diagnostic methods, he called cervicography using an apparatus he called the cervicograph.

The procedure uses the cerviscope camera to take a color picture of the cervix after 5% acetic acid has been applied to it. The film is developed in to 35mm slides, and the resulting slide image is projected on to a screen and evaluated by an expert colposcopist. Cervigram are reported in one of four categories: negative, atypical, positive, and technically defective.

Early studies of cervicography reported a sensitivity the ranged from 89% to 92% for the detection of high- grade lesions or invasive disease, but the specificity was low. Changes on the cervigram report form have resulted in increased specificity, but at the expense of a decreased sensitivity as low as 49.2% in one study (Stafl, 1981; Tawa et al, 1988).

In several studies, cervicography has detected cervical cancer when the cervical cytology was normal(Apgar et al, 2002).

In addition to being as an adjunctive test, cervicography has been used as a valuable research tool, for chart documentation, for teaching colposcopy recognition skills, and in the testing and monitoring of colposcopic skills (Apgar et al, 2002).

B. Visual methods

1. Speculoscopy

The performance of colposcopy involves significant clinician time and financial expenditures. Colposcopy requires special training, is expensive, and is not available in the majority of clinical setting. Therefore, it has not been used during routine screening. Colposcopy is a diagnostic test, however, visual test may also be used as screening tools. The false- positive rate of a visual screening tool may appear higher if the gold standard (colposcopically directed biopsy) misses some disease (Buxton et al, 1991; Massad et al, 1996).

The appearance of intravaginal structures is improved using chemiluminescent light energy,compared with using bright room light. Visualization of the cervix and lower genital tract with speculoscopy is indicated whenever a patient is having a pap smear for cervical cancer screening. Speculoscopy is no longer used.

Speculoscopy visualizes the cervix with blue white chemiluminescent illumination and low power, portable magnification following the application of dilute acetic acid.

According to published data screening with chemiluminescence, as opposed to other light sources, imparts the overcall rate. Colposcopy is a more sensitive test than speculoscopy for very small lesions (Wertlake et al, 1997).

Speculoscopy can be effectively performed by all clinicians currently performing Pap smears, including nurse practitiones, with an improvement in screening sensitivity of 200% to 300% (Edwards et al, 1997; Wertlake et al, 1997).

The negative predictive value of the combined speculoscopy and Pap smear (Pap Sure) is more than 99% and provides that option of widened screening intervals in women who test negative.

A study comparing the conventional Pap test performed usually with Pap Sure performed biannually showed Pap Sure to be cost- effective while reducing the cervical cancer prevalence and death rate using a Markov prediction model (Taylor et al, 2000).

2. Visual inspection with acetic acid (VIA)

Papanicolaou smear has been the norm for cervical cancer screening for many years in developed countries. However, in most underdeveloped countries, screening program are not routinely available (Wesley et al, 1997; Bulmenthal et al, 2001).

VIA meets most generally agreed criteria of a good screening test (Bulmenthal et al, 2001).

In this method, at first, 3-5% acetic acid applicate on the cervix. The cervix was examined often 60 (second) under adequate light (100 w lamp).

Several studies have shown the potential value of visual inspection with acetic acid (VIA) as a screening approach in underdeveloped countries (Ghaemmaghami et al, 2004; Millogo et al, 2004).

The major concern about VIA test is its low specificity (a high false- positive rate), which means that many subjects must be recalled for colposcopy (Sankaranarayanan et al, 1997).

Advantages of VIA are easy learning, inexpensiveness, and immediate availability to assess results. Thus, VIA is likely to assume a feasible method of screening in cervical cancer in many parts of the world, especially in poorly resourced locations, where large- scale Papanicolaou smear screening is not available and establishing and maintaining the quality of screening program based on cytology is difficult. However, there is much to be learned concerning the most effective techniques for training provides (both medical and paramedical) to detect acetowhite lesions with the naked eye (Ghaemmaghami et al, 2004).

VIA decreased the number of patients lost at follow-up (Jeronimo et al, 2005)

3. Truscan (Polarprobe)

The Truscan device employs a real time approach to the detection of tissue abnormalities. The device includes a pen- shaped handpiece that is connected by a cable to a console containing a microprocessor control module and a digital signal processor. The handpiece makes contact with the cervix, emitting low- level electrical pulses and optical signals. The probe alerts the operator through the array of lights on the probe handle if proper contact is being made between the probe on the cervix. When an electrical voltage is applied to tissue and a bruptly turned off, the tissue behaves like a decaying battery, lasting for a fraction of a second. Because both the decay time and the waveform will differ among different types of tissue, the voltage decay waveform can provide a dynamic signature of the tissue that can assist in its classification.

Truscan also uses the transmission and scattering properties of electromagnetic radiation in tissue, in a process called diffuse reflectance.

By combining the electrical decay and spectroscopic information from a particular area on the cervix, Truscan is able, by means of a classification algorithm, to categorize the tissue.

Seventeen tissue types have been programmed in to the system and divided to three categories: normal, low- grade abnormality, and cancer or high grade abnormality. Truscan has a significantly better sensitivity and a lower false- positive rate than does repeat cytology (Wundermann et al, 1995; Singer, 1997; Quek, 1999).

Women experienced less anxiety, less pain and fewer after effects like bleeding and discomfort with Truscan than with the Pap smear (Campion et al, 1988).

This method have been conducted or are being conducted in several centers in different countries for data collection refine the tissue classification algorithm. A smaller- diameter handpiece is being developed to enable tissue measurements within the endocervical canal. In addition, the technology is potentially applicable to other sites in the body.

References

Annual report of Tehran university of medical sciences, district cancer registry (TUMS- DCR) (1997).

Apgar BS, Spitzer M, Brotzman GL, Ignatavicius DD (2002) Colposcopy: Principles and Practice: An Integrated Textbook and Atlas. Philadelphia, Saunders Company 3, 52-56.

Ashfaq R, Gibbons D, Vela C et al (1999) ThinPrep Pap Test. Accuracy for glandular disease. Acta Cytol 43, 81-85.

Behtash N, Mousavi A, Mohit M, Modares M et al (2003) Simple hysterectomy in the presence of invasive cervical cancer in Iran. Int J Gynecol Cancer 13, 177-181.

Berek JS, Hacker NF (2000) Epidemiology and Biostatistics, practical Gynecologic Oncology, third edition, by Lippincott Williams and Wilkins 7, 258.

Blumenthal PD, Gaffikin L, Chirenje ZM, McGrath J, Womack S, Shah K. (2001) Adjunctive testing for cervical cancer in low resource settings with visual inspection, HPV, and the Pap smear. Int J Gynaecol Obstet 72, 47-53.

Buxton EJ, Luesley DM, Shafi MI, Rollason M. (1991) Colposcopically directed punch biopsy, A potentially misleading investigation. Br J Obstet Gynecol 98, 1273-1276.

Campion MJ, Brown JR, McCance DJ, Atia W, Edwards R, Cuzick J, Singer A. (1988) Psychosexual trauma of an abnormal cervical smear. Br J Obstet Gynecol 95, 175-181.

Clavel C, Masure M, Bory JP, Putaud I, Mangeonjean C, Lorenzato M, Gabriel R, Quereux C, Birembaut P. (1999) Hybrid Capture II-based human papillomavirus detection, a sensitive test to detect in routine high-grade. Br J Cancer 80, 1306-1311.

Cohn de, Herzog TJ (2001) News innovations in cervical cancer screening. Clin Obstet Gynecol 44, 538- 49.

Cole P, Morrison A (1980) Basic issues in population screening for cancer. J Natl Cancer Inst 64, 1263-1272.

Cuzick J, Beverley E, Ho L, Terry G, Sapper H, Mielzynska I, Lorincz A, Chan WK, Krausz T, Soutter P. (1999) HPV testing in primary screening of older women. Br J Cancer 81, 554-558.

Davey DD, Nielsen ML, Rosenstock W, Kline TS (1992) Terminology and specimen adequacy in cervicovaginal cytology, the college of American pathologists Interlaboratory comparison program Experience. Arch Pothol Lab Med 116, 903-907.

de Villiers EM (1997) Papillomavirus and HPV typing. Clin Dermatol 15, 199-206.

Disia PJ, Cresman WT (2002) Preinvasive disease of the cervix, in Disaia PJ, Creasman WT, editors. Clin Gynecol Oncol. 6^th ed. St. Louis, Mosby year book 1, 1-35.

Duggan MA (2000) Papnet –assisted, primary screening of cervico vaginal smears. Eur J Gynecol Oncol 21, 35-42.

Edwards G, Rutkowski C, Palmer C (1997) Cervical cancer screening with Papanicolaou smear plus speculoscopy by nurse practitiones in a health maintenance organization. J Low Gen Tract Dis 3, 141-147.

Eisenberger D, Hernandez E, Tener T, Atkinson BF. (1997) Order of endocervical and ectocervical cytologic sampling and the quality of the Papanicolaou smear. Obstet Gynecol 90, 755-758.

Fehr MK, Welti S (2004) Human Papillomavirus testing in cervical cancer screening. Gynakol Geburtshilfliche Rundsch 44, 131-7.

Ghaemmaghami F, Behtash N, Modares Gilani M, Mousavi A, Marjani M, Moghimi R (2004) Visual inspection with acetic acid as a feasible screening test for cervical neoplasia in Iran. Int J Gynecol Cancer 14, 465-469.

Insinga R, Glass A, Glass A, Rush B (2004) Diagnosis and outcomes in cervical cancer screening, A population- based study. Am J Obstet Gynecol 191, 105-13.

Jeronimo J, Morales O, Horna J, Pariona J, Manrique J, Rubinos J, Takahashi R(2005)Visual inspection with acetic acid for cervical cancer screening outside of low-resource settings. Pan Am J Public Health 17(1),1-5.

Krumholz BA (2000) Value of Human Papillomavirus testing. Am J Obstet Gynecol 182, 479-480.

Kulasingam SL, Myers ER (2003) Potential health and economic impact of adding a Human Papillomavirus vaccine to screening programs. JAMA 290, 781-9.

Kuperman L, Krumholz BA (2000) The triage of women with ASCUS cytology using human papillomavirus DNA testing. J Lower Gen Tract Dis 4, 1-6.

Mandelblatt JS, Lawrence EF, Womack SM, Jacobson D, Yi B, H wany YT et al (2002) Benefits and costs of using HPV testing to screen for cervical cancer. JAMA 287, 2372-81.

Massad LS, Halperin CJ, Bitterman P. (1996) Correlation between colposcopically directed biopsy and cervical loop excision. Gynecol Oncol 60, 400-403.

Millogo FT, Akotionga M, Lankoande J. (2004) Cervix cancer screening in a health district (Burkina Faso) by voluntary biopsies after the application of acetic acid and lugol. Bull Soc Pathol Exot 97, 135-138.

Naud P, Matos J, Hammes L, Prolla J, Schwartsmann G, Vetorazzi J, Quadros C, Gomes T, Lemos A, D'΅vila A, Manfr½I A, Marc C, Berti C, Born C, Vettori D, Santos D, Dias E, Cislaghi G (2001) Cervical cancer screening in porto Alegre, Brazil, alternative methods for detecting cancer precursors in developing country. J Lower Genital Tract Dis 1, 24-28.

No authors listed (1989) National Cancer Institute Workshop the 1988 Bethesda system for reporting cervical/ vaginal cytological diagnoses. JAMA 262, 931-934.

Quek SC (1999) A comparative study of the polarprobe with histopathology and repeat cytology in women with abnormal referral smears. Proceedings of the British society of colposcopy and cervical pathology, Annual conference, 1999 April 8-10, Sutherland, England. Birmingham, England, British Society of Colposcopy and Cervical Pathology.

Rarick TL, Tchabo JG (1994) Timing of the postpartum Papanicoalaou smear. Obstet Gynecol 83, 761-765.

Rock JA, Jones III HW (2003) Cervical cancer precursors and their management in The Linde's Operative Gynecology, Ninth Edition by Lippincott Williams and Wilkins 45, 1351-1373.

Sankaranarayanan R, Syamalakunary B, Wesley R, et al (1997) Visual inspection as a screening test for cervical cancer control in developing countries. In, franco E, Monsonego J. eds. Developments in cervical cancer screening and prevention. Oxford, Blackwell Sciences 411, 21.

Singer A (1997) Clinical experience with the usage of the polarprobe. Proceedings of the EuROGIN third international congress, 1997 March 24- 27, Paris, France. Paris, European Research Organization on Genital infection and Neoplasia.

Solar ME, Gaffikine L, Blumenthat P (2000) Cervical cancer screening in developing countries, primary care update. Obstet Gynecol 7, 118- 23.

Stafl A (1981) Cervicography, A new method for cervical cancer detection. Am J Obstet Gynecol 139, 815.

Takahashi M, Naito M (1997) Application of the CytoRich monolayer preparation system for cervical cytology. A prelude to automated primary screening. Acta Cytol 41, 1785-1789.

Tawa K, Forsythe A, Cove JK, Saltz A, Peters HW, Watring WG. (1988) A comparison of the Papanicolaou smear and the cervigram, sensitivity, specificity, and cost analysis. Obstet Gynecol 71, 229-235.

Taylor L, Sorensen S, Ray N, Halpern MT, Harper DM (2000) Cost-effectiveness of the conventional Papanicolaou test with a new adjunct to cytological screening for squamous cell carcinoma of the uterine cervix and its precursors. Arch Fam Med 9, 713-721.

Toffler WL, Pluedeman CK, Sinclair AE, Ireland KM, Byrne BJ (1993) Comparative cytologic yield and quality of three Pap smear instruments. Clin Res Method 25, 403-407.

Wertlake PT, Francus K, Newkirk GR, Parham GP. (1997) Effectiveness of the Papanicolaou smear and speculoscopy as compared with the Papanicolaou smear alone: a community-based clinical trial. Obstet Gynecol 90, 421-427.

Wesley R, Sankaranarayanan R, Mathew B, Aysha Beegum A, Amma NS, Nair MK (1997) Evaluation of visual inspection as a screening test for cervical cancer. Br J Cancer 75, 436-440.

Wright TC Jr, Denny L, Kuhn L et al (2000) HPV DNA testing of self collected vaginal samples compared with cytologic screening to detect cervical cancer. JAMA 283, 81-6.

Wunderman I, Coppleson M, Skladnev, V, Reid BL (1995) Polarprobe, A precancer detection instrument. J Gynecol Tech 1, 105-109.

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