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2. Vagoras A. Basics of the microscopy of the genital smears / Vagoras A., Savicheva A., Hallen A, Domeika M. — Lithuania, Kaunas; Kata studio, 2001 — 42 p.
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DIAGNOSIS OF HUMAN PAPILLOMAVIRUS INFECTION IN SCREENING FOR CERVICAL CANCER
E. V. Shipitsyna, E. A. Zolotoverkhaya, E. S. Yushmanova, A. M. Savicheva (savitcheva@mail.ru)
D. O.Ott Research Institute of Obstetrics and Gynecology, St. Petersburg, Russia.
■ Ascertainment of the etiological role of human papillomavirus (HPV) in the development of cervical cancer has led to the recognition that diagnosis of HPV infection
is an important element in cervical cancer screening and prevention. A number of studies have repeatedly shown that sensitivity of HPV testing in the diagnosis of cervical intraepithelial neoplasias is superior to that of cytology. In the present article current recommendations on the use of HPV testing in cervical screening are discussed: in primary screening (in combination with cytology or alone), in management of patients with atypical squamous cells of undetermined significance (ASC-US) and in the management of patients after therapy of high-grade cervical lesions. Furthermore, a brief description of tests currently used for HPV detection and typing is presented.
■ key words: human papillomavirus, cervical cancer, screening
Introduction
According to the World Health Organization (WHO), there are about 500 000 cases of cervical cancer and 250 000 cases of lethal outcomes registered annually [13]. Up to date screening of the female population with the aim of diagnosing the disease at its early stage is considered the most effective approach to prevention of cervical cancer. Efficiency of organized screening has been confirmed in many countries: in Europe and North America mortality from cervical cancer decreased by 20 - 60 % as a result of implementing screening programs [6]. Cytological investigation of epithelial cells of the cervix has remained the basis of cervical screening for the past decades. However, it was shown that up to 30 % of cervical cancers have been developed in women who were regularly screened [10]. Because of the limited sensitivity of cytology, false negative
results are registered even in efficiently working screening programs. All this proves the necessity of searching for new screening technologies, particularly those that are based on testing for HPV.
Based on results obtained in a number of large scale studies, the following recommendations on the use of HPV tests in cervical screening were developed [5, 9, 14]:
• in primary screening in women over 30 years of age in combination with cytology or alone (this should be done foremost in countries with poorly organized cytological screening);
• in the management of women with atypical squamous cells of undetermined significance (ASC-US);
• in monitoring treatment of cervical intraepithe-lial neoplasia (CIN) of high grade (CIN 2/3). There are a number of reports from several countries in Europe, the USA and Asia suggesting the usefulness of different HPV detection techniques in screening for cervical cancer [2, 4].
HPV testing in primary cervical screening
The following findings have emerged from studies aimed at evaluating diagnostic characteristics of HPV testing as compared with cytology:
• sensitivity of HPV testing (88 - 100 %) is much superior to that of cytology (34 - 86 %);
• specificity of HPV testing (82 - 97 %) is slightly lower than that of cytology (78 - 99 %);
• sensitivity and negative predictive value of double negative (both HPV test and cytology) results are extremely high and in some investigations their meaning reached 100% [3].
A relatively low (in comparison with cytology) specificity and positive predictive value of HPV test-
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ing results from the natural history of HPV infection have been reported: in most women papillomavirus eliminates spontaneously. However, in women over 30 years the rate of transitory infection is significantly lower, which increases the diagnostic value of HPV testing in this age group. In the USA, screening with the use of HPV tests and cytology has been used as an alternative to cytological screening since 2003 in women over the age of 30 years. When both HPV tests and cytology are negative, the screening interval is 3 years. In case of negative cytological results but a positive test for oncogenic HPV types, the recommendation is to have both tests in 6 - 12 months; if one of the tests is positive, colposcopy has to be performed [14].
An important argument for using HPV testing in primary screening is that its very high sensitivity and negative predictive values enable up to 5 - 7 years increase screening interval for HPV-negative women.
Several approaches have been suggested to improve the specificity of HPV testing. One approach is to use cytology for triage of HPV-positive results. Another way of increasing specificity of HPV testing is to elucidate whether HPV infection is transitory or persistent through repeating HPV tests over a period of 6-12 months. Genotyping is considered the most efficient approach to detect persistent HPV infection as it allows differentiation of persistent infection and reinfection. High viral load is also supposedly indicative of clinically relevant infection that potentially can develop into cancer [4]. A number of molecular markers of displastic changes in the cervix aimed to improve the specificity of HPV testing have been proposed [7]. However, to be implemented in clinical practice all these markers have to be thoroughly evaluated.
HPV testing is thought to play an important role in primary screening for cervical adenocarcinomas, which is quite rare, but very aggressive neoplasias. Although the etiological role of HPV in the development of this condition is still being discussed, it has been shown that almost all cervical adenocarcino-mas contain oncogenic HPV types, mainly HPV 18 [15]. Because cytological methods of detection of atypical glandular cells are significantly restricted, introducing HPV testing into a screening program may contribute to improved detection of cervical adenocarcinomas and their precursors.
HPV testing in the management of patients with ASC-US
Clinical usefulness of HPV testing has also been proven in the triage of equivocal results of cytologi-cal investigations. Usually, in the case of ASC-US results immediate colposcopy or repeated cytologi-
cal tests are recommended; if the results of repeated cytology are the same, colposcopy is performed. A large scale study conducted in the USA to evaluate different algorithms of managing patients with ASC-US revealed that in a real clinical situation a single HPV test is able to detect almost all cervical high-grade neoplasias that can "hide" behind the diagnosis of atypia of undetermined significance (5 - 10 %). Moreover, the number of women referred to colposcopic and histological investigations is reduced by half as the frequency of HPV detection in this group of patients is approximately 50 % (for comparison, after repeated cytology/colposcopy is performed in about 70 % of the patients) [1].
HPV testing for monitoring treatment of CIN2/3
Currently, there is enormous interest in the usefulness of HPV testing for monitoring the treatment of high-grade cervical lesions. The main prerequisite for using HPV testing in the area of cervical screening is that adequate therapy of cervical lesions results in virus elimination, and a positive HPV test after treatment may be an early and accurate indicator of disease recurrence. In addition, testing for HPV DNA, in combination with cytology, reduces the number of follow-up visits for women whose both tests are negative.
In most countries where cervical screening programs are in effect, a standard algorithm of monitoring CIN 2/3 therapy includes cytological tests every 6 months during the first 2 years and then every year during the next 5 years. Efficiency analysis of HPV testing for the monitoring of CIN 2/3 treatment revealed that 84.2 % of women who were successfully treated had negative test outcomes for oncogenic HPV types after treatment, whereas only 15.8 % were positive. Respective results in women who had recurrent disease were 17.2 and 82.8 % [11].
Presently, the simultaneous use of cytological investigation and HPV testing 6 months after therapy has been proposed. It was assumed that such testing would be more reliable than cytological tests alone because the HPV DNA test has much higher sensitivity than cytology and detection of HPV DNA after treatment is strongly associated with the risk of recurrence [5].
Tests for HPV detection and typing
Tests for HPV detection and typing based on hybridization and polymerase chain reaction (PCR) were introduced into diagnostic practice more than 10 years ago. Currently, a number of tests for HPV detection and typing have been described [8]; how-
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ever, it is obvious that to be suitable for application in screening programs HPV tests have to be sensitive and specific, standardized and thoroughly validated.
For HPV detection and typing in developed countries, the following hybridization- and PCR-based commercial tests are available:
• Hybrid Capture 2 (Digene) — for detection and differentiation of 13 high-risk HPV types;
• Amplicor® Human Papilloma Virus Test (Roche) — for detection and differentiation of 13 high-risk HPV types;
• InnoLiPA HPV genotyping (Innogenetics) — for detection and differentiation of 25 HPV types;
• Linear Array HPV genotyping test (Roche) — for detection and differentiation of 37 HPV types. In addition, the following HPV tests based on
new technologies are being implemented:
• Cobas TaqMan HPV (Roche) — the test is based on real-time PCR; it enables quantitative detection of HPV DNA in cervical epithelial cells
• PreTect HPV-Proofer (NorChip) — the te;st is based on nucleic acid sequence-based amplification (NASBA) and used for identification of full-length mRNA of E6 and E7 HPV genes; its presence in clinical samples is thought to be associated with an increased risk of cervical neo-plastic progression [12]. The test is intended to detect mRNA of five oncogenic HPV types: 16, 18, 31, 33 and 45.
The high cost of these tests makes it difficult to implement them into cervical screening in Russia. Standardization and clinical validation of HPV tests produced in Russia are needed to provide an affordable alternative for use in screening cervical cancer.
Literature
1. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomised trial on the management of cytology interpretation of atypical squamous cells of undetermined significance // Am J Obstet Gynecol. — 2003. — Vol. 188. — P 1383 - 1392.
2. Effects of HPV detection in population-based screening programmes for cervical cancer: a Dutch moment / Bekkers R. L, Meijer C. J, Massuger L. F [et al.] // Gynecol Oncol. — 2006 — Vol. 100 — P. 451 - 454.
3. Human papillomavirus testing for primary cervical cancer screening / Dalstein V., Bory J., Graesslin O. [et al.] // Monsonego J (ed): Emerging issues on HPV infections: from science to practice. Basel, Karger. — 2006 — P. 103 - 119.
4. Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study // Int J Cancer. — 2003. — Vol. 106 — P. 396 - 403.
5. European Cervical Cancer Screening network // European guidelines for quality assurance in cervical screening. 2nd draft of 15 December 2003.
6. IARC WHO Press Release 151 IARC confirms efficacy of cervix cancer screening for women 25-65 in reducing mortality, 03 May 2004
7. von Knebel Doeberitz. Biomarkers in screening of cervical cancer / von Knebel Doeberitz.; Monsonego J (ed) // Emerging issues on HPV infections: from science to practice. — Basel, Karger, 2006 — P. 1- 19.
8. Molijn A. Molecular diagnosis of human papillomavirus (HPV) infections / Molijn A., Kleter B., Quint W., van Dorn L. // J Clin Virol, 2005. — Vol. 32S. — P. S43 - 51.
9. Cervical Cancer Control Priorities and new directions / Monsonego J., Bosch F. X., Coursaget P. [et al.] // Int. J. Cancer. 2004. — Vol. 108. — P. 329 -333
10. Nuovo J. New tests for cervical cancer screening / Nuovo J., Melnikow J., Howell L. P. // Am Fam Physician. — 2001. — Vol. 64. — P. 780-786. http://www.aafp.org/afp.
11. The role of HPV DNA testing in the follow-up period after treatment for CIN: a systematic review of the literature / Paraskevaidis E., Arbyn M., Sotiriadis A. [et al.] // Cancer Treat Rev. — 2004. — Vol. 30. — P. 205 - 211.
12. Direct detection of cervical carcinogenesis through mRNA / Skomedal H., Kraus I., Silva I. [et al.]; Monsonego J (ed.) //Emerging issues on HPV infections: from science to practice. — Basel, Karger, 2006. — P. 82 - 102.
13. World Health Organization (WHO). Comprehensive Cervical Cancer Control. A guide to essential practice. — Geneva: WHO, 2006.
14. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening / Wright T. C., Schiffman M., Solomon D. [et al.] // Am Coll Obstet Gynecol. — 2004. — Vol. 103. — P. 304 - 309.
15. The presence of high-risk HPV combined with specific p53 and p16INK4A expression patterns points to high-risk HPV as the main causative agent for adenocarcinoma in situ and adenocarcinoma of the cervix / Zielinski G. D., Snijders P. J., Rozendaal L. [et al.] // J. Pathol. — 2003. — Vol. 201. — P. 535 -543.
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