[dr_medvedev]

European Journal of Obstetrics & Gynecology and Reproductive Biology
Volume 121, Issue 1 , 1 July 2005, Pages 104-109

Prevalence of high-risk human papillomavirus (HR-HPV) types 16 and 18 in healthy women with cytologically negative Pap smear

Raksha Aroraa, Arunaz Kumara, Bhupesh K. Prustyb, Uma Kailashb, Swaraj Batraa and Bhudev C. Dasb, ,

aDepartment of Obstetrics and Gynecology, Lok Nayak Hospital, New Delhi, India
bDivision of Molecular Oncology, Institute of Cytology and Preventive Oncology (ICMR), Maulana Azad Medical College Campus, Bahadur Shah Zafar Marg, New Delhi, Delhi 110002, India

Abstract
Objective:

To study the prevalence of high-risk human papillomavirus (HR-HPV) types 16 and 18 in healthy women with negative Pap smears in identifying women with underlying cervical squamous intra-epithelial (SIL) lesions.
Methods:

A total of 3300 women who were attending the Gynecology OPD of Lok Nayak Hospital, one of the major government tertiary hospitals in New Delhi, were screened during a 1-year study period, and 2079 (63%) of them were found to have cytologically negative Pap smear with inflammation and the rest (37%) also had negative Pap report but without inflammation. Hundred and sixty of these sexually active women aged between 20 and 60 years were randomly selected, and were investigated by colposcopy and a guided biopsy was done wherever required. HPV types 16 and 18 DNA was detected in scraped cervical cells from all women using type-specific primers in polymerase chain reaction (PCR).
Results:

The high-risk HPV (type 16 and 18) prevalence by PCR was found to be 10% (16/160). Histopathological findings were obtained in 123 women, out of which 15 had LSIL and four had HSIL. High-risk HPV types 16/18 could be detected in nine out of these 19 (47.3%) squamous intra-epithelial lesions (p < 0.00008) which includes two out of the four women (50%) having HSIL, while only seven out of 104 (6.7%) of the subjects with normal (negative) Pap reports (p = 0.03) had infection of high-risk HPV.
Conclusion:

The results indicate that about 10% of women who show a negative Pap smear, but have inflammation are positive for high-risk HPV types 16/18 and about 15% harbor squamous intra-epithelial lesions. It is suggested that high-risk HPV detection can be utilized as an adjunct to routine cytology screening programs to identify ‘high risk’ women who have concurrently negative Pap smears but may harbor oncogenic HPV infection and/or more likely to develop CIN lesions.

Keywords: Human papillomavirus (HPV); Pap smear; Squamous intraepithelial lesions (SIL); Inflammation; Polymerase chain reaction (PCR); Cervical cancer

Corresponding author. Tel.: +91 120 2578837/2575838; fax: +91 120 2579437. Present address: I-7, Sector 39, Noida 201301, India.

[dr_medvedev]

А с тактикой не так просто... Сам ИФА сделать не проблема, хотя достаточно дорого. Но гораздо сложнее с профилактикой дисплазии. ВПЧ до сих пор не лечится эффективно. Группа женщин с 16 и 18 серотипами ВПЧ требует более пристального внимания: цитология, кольпоскопия и биопсия при необходимости раз в пол года. Мне случалось видеть инвазивную карциному шейки матки с метастазами через 2 года после постановки диагноза Д1-Д2, что расходится с мнениями авторитетных руководств. Это несомненно связано с наличием тех самых онкогенных ВПЧ.

[Light]

А кроме этой статьи Вам попадалась ещё информация об аналогичных результатах при скрининге у здоровых женщин?

[dr_medvedev]

Что-то где-то встречал. Поищу.

[Light]

Спасибо. Может быть, это этническая особенность индийских женщин?

[dr_medvedev]

Завтра постараюсь Вам ответить. Есть работы по регионам, по професииональным группам, в зависимости от сексуальной активности и т.д.

[dr_medvedev]

ПЦР на 16 и 18 типы ВПЧ более чувствителен цитологии, но менее специфичен в отношении предрака и рака.
Вот последние американские рекомендации:

"For routine cervical cancer screening of women age 30 years and older, the U.S. Food and Drug Administration has approved the use of the HPV test at the same time the Pap is done. In women younger than 30, an HPV test is typically done after the Pap, if the results are inconclusive"

Адрес сайта: [Ссылки могут видеть только зарегистрированные и активированные пользователи]
Немного неврачебный, но информативный :)

[dr_medvedev]

Вот он почти новый золотой стандарт для женщин "за 30" :)

HPV Test More Accurate Than Pap Smear

From Tracee Cornforth,Your Guide to Women's Health.
Dateline: 09/14/99

A study published in the British Journal of Cancer this week shows that testing women over 35 for the human papillomavirus (HPV) is more accurate for detecting cervical diseases than the Pap smear. Overall, the HPV test accurately identified 20% more cervical disease than the Pap smear.

The possible HPV-cervical cancer connection has been understood for sometime. However, other recent news from Britain reveals that HPV is the cause of 99.7% of all cases of cervical cancer.

The British Journal of Cancer study demonstrated the effectiveness of HPV testing in the early diagnosis of cervical disease in women over 35--the group most at risk for developing cervical cancer. The findings of this study suggest that incorporating HPV testing in cervical cancer screening could significantly reduce the number of deaths from cervical cancer.

Almost three thousand British women, participated in the study which drew women from 40 general medical practices within the UK's Hammersmith Health Authority. The women received HPV testing as well as Pap smears during their routine physicals.

After examining the results, researchers concluded that HPV testing, using the Digene Hybrid Capture II HPV Test, had a sensitivity to detect moderate or high-grade cervical disease in 95% of cases, as compared to the sensitivity of the Pap smear, which detected 79%.

According to a Digene press release, Professor Jack Cuzick who led the research said, "Virtually all cases of cervical cancer are positive for HPV. By testing for the presence of this virus, the detection of cervical disease is improved and there is the potential to save even more lives than with the current screening program in the United Kingdom. It might also be possible to safely extend the screening interval for women who are HPV negative, thus reducing the costs of cervical screening.

The Digene Hybrid Capture II HPV Test is the only test for HPV approved by the FDA in the United States as an adjunct to the Pap smear for cervical cancer screening.

Approximately 50 million Pap smears are performed annually in the United States with 3.5 million women diagnosed with ASCUS (atypical cells of undetermined significance) or borderline Pap smear results. Fifteen thousand women in the United States are diagnosed with cervical cancer each year and 5000 of these women die of the cancer. Worldwide cervical cancer affects 500,000 women annually.

[dr_medvedev]

Journal of Clinical Microbiology, April 1999, p. 1030-1034, Vol. 37, No. 4

Human Papillomavirus (HPV) DNA Copy Number Is Dependent on Grade of Cervical Disease and HPV Type
David C. Swan,1,* Ruth Ann Tucker,1 Guillermo Tortolero-Luna,2 Michele Follen Mitchell,2 Louise Wideroff,3 Elizabeth R. Unger,1 Rosane A. Nisenbaum,1 William C. Reeves,1 and Joseph P. Icenogle1

National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Services, Atlanta, Georgia 303331; Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 770302; and Division of Cancer Control and Population Science, National Cancer Institute, Bethesda, Maryland 20892-73443

Received 4 December 1998/Returned for modification 8 January 1999/Accepted 22 January 1999

The association between human papillomavirus (HPV) DNA copy number and cervical disease was investigated. Viral DNA copy number for the most common high-risk HPV types in cervical cancer (types 16, 18, 31, and 45) was determined in cervical cytobrush specimens from 149 women with high-grade cervical intraepithelial neoplasias (CIN II-CIN III), 176 with low-grade CIN (CIN I), and 270 with normal cytology. Quantitative, PCR-based fluorescent assays for each of the HPV genotypes and for the -globin gene were used. The amount of cellular DNA increased significantly with increasing disease; thus, HPV was expressed as copies per microgram of cellular DNA. The assay had a dynamic range of >107, allowing documentation for the first time of the wide range of HPV copy numbers seen in clinical specimens. Median HPV DNA copy number varied by more than 104 among the viral types. HPV16 was present in the highest copy number; over 55% of HPV16-positive samples contained more than 108 copies/µg. Median copy number for HPV16 showed dramatic increases with increasing epithelial abnormality, an effect not seen with the other HPV types. HPV16 increased from a median of 2.2 × 107 in patients with normal cytology, to 4.1 × 107 in CIN I patients, to 1.3 × 109 copies/µg in CIN II-III patients. Even when stratified by cervical disease and viral type, the range of viral DNA copies per microgram of cellular DNA was quite large, precluding setting a clinically significant cutoff value for "high" copy numbers predictive of disease. This study suggests that the clinical usefulness of HPV quantitation requires reassessment and is assay dependent.

[dr_medvedev]

Спасибо. Может быть, это этническая особенность индийских женщин?

Вот более серьезное исследование из Мексики. И по возрасту, и мультицентровое, и разные типы ВПЧ

Epidemiology of HPV infection among Mexican women with normal cervical cytology
Eduardo Lazcano-Ponce 1 *, Rolando Herrero 2, Nubia Muñoz 2, Aurelio Cruz 1, Keerti V. Shah 3, Patricia Alonso 4, Pilar Hernández 1, Jorge Salmerón 5, Mauricio Hernández 1
1Center for Population Health Research, National Institute of Public Health of Cuernavaca Morelos, Mexico
2International Agency for Research on Cancer, Lyon, France
3Department of Molecular Microbiology and Immunology, Johns Hopkins University, School of Public Health, Baltimore, MD, USA
4Cytopathology Laboratory, Autonomous National University of Mexico, Mexico General Hospital, Mexico City, D.F.
5Mexican Institute for Social Security, Cuernavaca Morelos, Mexico

email: Eduardo Lazcano-Ponce ([Ссылки могут видеть только зарегистрированные и активированные пользователи])

*Correspondence to Eduardo Lazcano-Ponce, Instituto Nacional de Salud Pública, Avenida Universidad 655, colonia Sta. Maria Ahuacatitlan, Cuernavaca, Morelos, México, C.P. 62508

Funded by:
Mexican National Council of Science and Technology; Grant Number: 212270-5 1189PM
Mexican National Institute of Public Health
International Agency for Research on Cancer; Grant Number: FIS/97/09
U.S. Public Health Services, National Institutes of Health; Grant Number: POI AI38533

Keywords
HPV; mexico; normal cytology; population-based studies.

Abstract
Cervical cancer is caused by human papillomavirus (HPV) and is the most common cancer among Mexican women, but no population-based studies have reported the prevalence and determinants of HPV infection in Mexico. A population-based study was carried out between 1996 and 1999, based on an age-stratified random sample of 1,340 women with normal cytologic diagnoses from 33 municipalities of Morelos State, Mexico. The prevalence of cervical HPV DNA was determined by reverse line blot strip assay to detect 17 cancer-associated and 10 non-cancer-associated HPV types. Two peaks of HPV DNA prevalence were observed. A first peak of 16.7% was observed in the age group under 25 years. HPV DNA prevalence declined to 3.7% in the age group 35-44 years, then increased progressively to 23% among women 65 years and older. Cancer-associated HPV types were the most common in all age groups; non-cancer-associated HPV types were rare in the young and became more common linearly with age. Twenty-four types of HPV were detected; HPV 16, HPV 53, HPV 31 and HPV 18 were the most common, but none was present in more than 1.7% of subjects. The main determinant of infection with both cancer-associated and non-cancer-associated HPV types was the number of sexual partners in all age groups. Less-educated women were at an increased risk of infection with cancer-associated but not with non-cancer-associated HPV types; low socioeconomic status was associated with detection of non-cancer-associated HPV types. Among young women an increasing number of pregnancies was associated with lower HPV detection and among older women low socioeconomic status was related to increased HPV detection, particularly for the age group 35-54 years. Among women with cancer-associated HPV types, there was a higher intensity of polymerase chain reaction signal in younger than in older age groups (p < 0.001). We present additional evidence for the sexually transmitted nature of HPV infection, regardless of age group and HPV type. We confirm previous findings of a second peak of high-risk HPV infections in postmenopausal women, in this case with a clear predominance of cancer-associated HPV types. In populations with this pattern, which can be related to reactivation of latent HPV infections or high previous exposure in older women, screening with HPV testing can have a reduced specificity among older women if proper cut-off points for HPV positivity are not used. Longitudinal studies of immune responses to HPV infection in different age groups are warranted. © 2001 Wiley-Liss, Inc.

[Light]

Большое спасибо за информацию.
Всё это весьма серьезно и тревожно.
Ведутся ли, в свете этих результатов, исследования в Европе, США? - может, зарубежные коллеги подскажут?
Такое положение дел, очевидно, требует нового алгоритма профилактических гинекологических наблюдений?

[AlexT]

Была у нас в свое время такая вот дискуссия про ВПЧ:[Ссылки могут видеть только зарегистрированные и активированные пользователи] F1

[E.E. Studentsov]

Большое спасибо за информацию.
Всё это весьма серьезно и тревожно.
Ведутся ли, в свете этих результатов, исследования в Европе, США? - может, зарубежные коллеги подскажут?
Такое положение дел, очевидно, требует нового алгоритма профилактических гинекологических наблюдений?
Уважаемая Ольга Юрьевна,

Исследования ведутся со страшной силой. Новое заседание ASCCP по цервикальной патологии намечено на 2006 год. Возможно в существующие рекомендации будут внесены некоторые принципиальные изменения. Пока же, на мой взгляд, врач-клиницист должен придерживаться рекомендаций 2001 года (2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia.), лаборатория - Bethesda System для интерпретации мазка.
Journal of the National Cancer Institute, Vol. 97, No. 7, 479-480, April 6, 2005
--------------------------------------------------------------------------------

NEWS

Trial Quickly Changed Management of Cervical Abnormalities
Sarah L. Zielinski
This is part of an occasional series that recalls some of the stories reported 10 years ago in the News section of the Journal.

In less time than it takes some clinical trials to start, the ASCUS/LSIL Triage Study (ALTS) for cervical cancer was completed and had its results incorporated into clinical guidelines and practice.

ALTS was born out of a change in terminology. In 1989, the National Cancer Institute developed standard terminology to describe abnormal cervical results—a lexicon referred to as the Bethesda System—that grouped ambiguous cytological abnormalities under the name "atypical squamous cells of undetermined significance (ASCUS)." About 5% of Pap tests were labeled as ASCUS, but physicians had no way of knowing which of these mild cervical lesions could progress to cancer and which were benign. "There really was no efficient triage test," said Diane Solomon, M.D., senior investigator in the Division of Cancer Prevention at the National Cancer Institute and one of the lead investigators in ALTS.

The NCI designed ALTS in 1995 to figure out the most appropriate follow-up for women who were diagnosed with ASCUS or its neighboring category, low-grade squamous intraepithelial lesions (LSILs), and how the new knowledge of human papillomavirus (HPV) could be used to manage these women. "It became clear that we should be able to use HPV testing to somehow rationalize what we were doing with ASCUS," said Mark Schiffman, M.D., a senior investigator at NCI and another lead investigator in ALTS.
More than 5,000 women diagnosed with ASCUS or LSIL were recruited into the trial at four centers and randomly assigned to one of three management strategies: immediate colposcopy, repeat cytology with colposcopy only if the results showed a high-grade lesion, or HPV testing plus a repeat cytology with referral to colposcopy only if the HPV test was positive or repeat cytology indicated a high-grade lesion. The participants were followed up at 6-month intervals for a total of 2 years, and the trial was complete by the end of 2000.

The investigators determined that for LSIL, HPV testing was not a useful triage method because most cases of LSIL are associated with high-risk types of HPV, so few women would be excluded from colposcopy. However, for ASCUS, HPV testing found nearly as many precancerous lesions and cancers as colposcopy in women ages 29 and older, and only about half of women with ASCUS who were tested for HPV had to undergo colposcopy.

In an unusual move, the ALTS investigators decided to give their data to a consensus conference sponsored by the American Society for Colposcopy and Cervical Pathology in 2001 before their data had been published. "It would have been more timely for us if the ASCCP conference had been held a year later," Schiffman said, but by releasing their data early, "we bypassed several years of process."

The ASCCP guidelines, which were published in 2002, were based mainly on the ALTS data, and clinical management of ASCUS has already changed. Now, "most ASCUS cases are triaged by HPV testing," Solomon said.

ASCCP will hold another consensus conference in September 2006 and will consider data from new studies in addition to late-breaking data from ALTS. The ALTS investigators plan to publish several articles within the next year.

One of the more surprising findings from ALTS was that colposcopy, considered the "gold standard" for cancer detection, is not nearly as good as had been thought. The exam misses about a quarter of precancerous lesions and has its own limitations. It cannot be considered a complete ascertainment of disease, Solomon said.

This has led to the question of what to do with women who are HPV positive but have negative colposcopies, particularly since most of these viral infections disappear on their own and few will ever develop into cancer.

"We've, in a way, solved the problem of ASCUS," Schiffman said. "We know what the different components are." However, researchers are still working to figure out what to do with the categories that have replaced ASCUS in the 2001 update of the Bethesda System and how to handle HPV infections, particularly in young women where they are common. "We're moving to a higher order of confusion," he said.

[dr_medvedev]

Будем ждать более определенных рекомендаций...

[dr_medvedev]

Вот, что пишут об этом российские авторы:
Профилактика папилломавирусной инфекции и рака шейки матки
С.И.Роговская, В.Н.Прилепская

[Ссылки могут видеть только зарегистрированные и активированные пользователи]