Cervical cancer screening: which HPV test should be used—L1 or E6/E7?

Cervical cancer can and should be a historical disease. The reality, however, is that every year more than half a million women are diagnosed with cervical cancer and a quarter of a million die of this disease. The causal factor for cervical cancer is a persistent HPV infection and therefore a vaccine was developed: prophylactic HPV vaccination will reduce cervical cancer by 70%. Screening based on cytology will miss more than 40% of the abnormalities. The introduction of vaccination should lead to the reintroduction of cervical cancer screening based on HPV detection. Primary HPV screening followed by cytology will detect almost all abnormalities. Not all HPV tests, however, are the same! Clinicians are generally not aware that there is a huge difference among HPV tests. If a low grade lesion progresses to a high grade or invasive cancer, their HPV is likely to integrate. During integration L1 expression can be lost, but E6/E7 expression will always remain present. If the viral HPV is completely integrated then a L1 test looking for only L1 expression will miss this (pre)cancer, while the E6/E7 test will not miss it. HPV tests used in cervical cancer screening should be based on the early (E) and the late (L) genes in order not to miss the abnormality.     

Colposcopy and cervical intraepithelial neoplasia

Cervical cancer is both preventable and curable. It has a long natural history with a prolonged pre-cancerous phase that is easily detectable and treatable. Exfoliative cytology has been the mainstay for screening of cervical intra-epithelial neoplasia (CIN). Assessment of women presenting with abnormal cervical cytology and the selection of those requiring treatment relied mainly on colposcopic impressions of the cervical transformation zone and the histological appraisal of directed punch biopsies. The need to maximise clinical resources, achieve quicker and more effective management of patients, limit postoperative complications and preserve reproductive function has led to the popularity of local excisional methods for cervical premalignancy. Although the cure rates for all local ablative and excisional methods are more than 90% after one treatment, the excisional methods provide a more reliable histopathological diagnosis and the patient can be treated at the initial visit. The recognition that persistent infection with oncogenic human papillomavirus (HPV) causes cervical cancer has led to the development of new HPV tests/biomarkers and prophylactic vaccines against HPV. The HPV DNA test that targets the viral DNA has been introduced as a test of cure after CIN treatment and as a triage tool in women presenting with borderline or low-grade findings at cytology. HPV DNA test will be introduced in primary screening in the future. The national HPV immunisation programme was initiated in the NHS in September 2008. The vaccines are safe, well tolerated and highly efficacious in HPV naive women.     

Human papillomavirus testing and screening

Cervical cancer is a largely preventable disease through the detection, treatment and follow-up of its precursors. Traditionally, this has been accomplished through screening women with cervical cytology, and referring women with abnormal cytology for colposcopy, histological sampling and treatment. In organized programmes that achieve wide coverage of the target population at frequent intervals, this approach has resulted in a considerable reduction in cervical cancer. Recently, however, the development of reliable and reproducible tests for the detection of human papillomavirus (HPV) infection of the cervix (which is now accepted to be causally associated with the development of almost all cervical cancers) has led to the evaluation of HPV de-oxyribonucleic acid (DNA) testing as either an alternative or adjunctive test to cytology for the detection of cervical cancer and its precursors. There is now a large body of data supporting the clinical utility of HPV DNA testing for the prevention of cervical cancer, particularly in the settings of primary screening of women older than 30 years, in the triage of women with equivocal cytology and for the follow-up of women post-treatment.     

Cervical cancer prevention: the impact of HPV vaccination

Cervical cancer remains a critical public health problem that is second only to breast cancer in overall disease burden for women throughout the world. In spite of the success of cervical cancer screening, Pap cytology screening is yet to be effectively implemented or has failed to reduce cervical cancer rates to an appreciable extent. Screening appears to benefit only a small fraction of women although a much larger percentage endures the inconvenience of the Pap test in order to avoid cervical cancer. The establishment of Human Papillomavirus (HPV) infection as the necessary cause of cervical precancers and cancers provides a tremendous opportunity for cervical cancer prevention through vaccination. HPV 16 and 18 which cause 70% of cervical cancers worldwide. Thus a prophylactic vaccine to prevent HPV related precancerous lesions and cancers would save lives, reduce the need for costly medical procedures and provide both women and communities throughout the world with substantial benefits. Based on the induction of neutralizing antibodies by non infectious Virus Like Particles (VLP) of L1 capside protein, prophylactic HPV vaccines have consistently induced high titter of neutralizing antibodies with minimal side effects and induce more than 90% protection from persistent HPV 16-18 infection and HPV 16 and 18 associated high-grade Cervical Intraepithelial Neoplasia (CIN) in proof of concept efficacy trials. HPV 16-18 vaccination will prevent HPV16-18 incident infection, and subsequently decrease in 90% the frequency of abnormal Pap attributable to these types and in about 50% overall abnormal Pap. HPV vaccination will reduce the number of women who require colposcopy, biopsy and cervical treatment for precancerous cervical lesions. The level of protection from death due to cervical cancer could exceed 95%. Three large phases prophylactic HPV VLP trials are now in progress and will form the basis for licensing of candidate vaccines in 2006. HPV vaccination targeting young female adolescents, aged 11 to 16 years, with a catch-up of those aged 17-25 years, would be a strategy to be addressed. Cervical cancer screening strategies, that will be cost-effective for the proper surveillance of women protected by HPV vaccination, are under analysis.     

Cribado de cáncer cervical con citología y test del virus del papiloma humano cada 5 años: una realidad

Objective

To analyze screening for cervical cancer with a combination of cytology and HPV testing in women older than 35 years every 5 years and to determine whether the application of this protocol delays diagnosis of cervical cancer.

Material and methods

Cervical cancer screening strategies have been applied in our hospital since 2005. HPV testing was introduced in 2010 for women older than 35 years. We performed a retrospective study of 500 women attended in our hospital. We studied whether we had correctly applied the strategy and the recommended time interval of the next review. We analyzed cervical cancers diagnosed in our hospital since 2005.

Results

The strategy was correctly applied in 100% of the women. Screening was performed with both cytology and HPV testing in 45.6% and with cytology alone in 23.2%; no screening was performed in 31.2%. The recommended interval until the next review was 5 years in 26% of the patients. The implementation of the strategy did not delay the diagnosis of cancer. Cervical cancer was diagnosed in 27 women since 2005. Only one woman with adenocarcinoma had been correctly screened (before the introduction of HPV testing). In the last 2 years, four microinvasive carcinomas were diagnosed with this strategy.

Conclusions

A combination of cytology and HPV testing can be applied in women older than 35 years and screening intervals can be increased to 5 years in routine clinical practice. This protocol does not delay the diagnosis of cervical cancer and optimizes resources by lengthening the interval between screening tests in healthy women.     

Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening

Human papillomavirus (HPV) DNA testing was recently approved by the Food and Drug Administration for use as an adjunct to cytology for cervical cancer screening. To help provide guidance to clinicians and patients when using HPV DNA testing as an adjunct to cervical cytology for screening, a workshop was cosponsored by the National Institutes of Health-National Cancer Institute, American Society of Colposcopy and Cervical Pathology (ASCCP), and American Cancer Society. Consensus was reached based on a literature review, expert opinion, and unpublished results from large ongoing screening studies. The conclusions of the workshop were that HPV DNA testing may be added to cervical cytology for screening in women aged 30 years or more. Women whose results are negative by both HPV DNA testing and cytology should not be rescreened before 3 years. Women whose results are negative by cytology, but are high-risk HPV DNA positive, are at a relatively low risk of having high-grade cervical neoplasia, and colposcopy should not be performed routinely in this setting. Instead, HPV DNA testing along with cervical cytology should be repeated in these women at 6 to 12 months. If test results of either are abnormal, colposcopy should then be performed. This guidance should assist clinicians in utilizing HPV DNA testing in an effective manner, while minimizing unnecessary evaluations and treatments.     

Caring for Women With Abnormal Papanicolaou Tests During Pregnancy

The Papanicolaou (Pap) test is one of the best screening tests available for cancer detection and has achieved widespread acceptance among women. Pregnancy provides a valuable opportunity to educate and screen women for cervical cancer when receiving prenatal care. However, evolving knowledge about the course of human papillomavirus infection (HPV) in women, new technologies, and the advent of vaccines are driving radical changes in practice and new ways to consider cervical cancer screening. Modifications in the 2006 Consensus Guidelines for the Management of Women with Abnormal Cervical Cancer Screening Tests are most evident among adolescents. Because of high rates of HPV regression, pregnant adolescents with minor Pap abnormalities may now be followed rather than referred for immediate colposcopy. Postponing colposcopy in pregnant, reproductive‐age women with minor Pap changes until after delivery is now acceptable. Pregnant immunocompromised women with abnormal Pap tests are followed similarly to pregnant women in the general population. While a strong evidence base is gradually emerging to support guideline revisions, the highest quality evidence may not yet be available for all recommendations. Midwives can keep abreast of the science while using clinical judgment to provide safe and expert cancer screening care to women.     

Acceptability of self-collected human papillomavirus specimens in cervical cancer screening: A review

Cervical cancer morbidity and mortality is an important public health problem around the world. Some of the barriers to cervical cancer screening include the embarrassment, discomfort, lack of privacy and time and cost associated with clinician-collected, clinic-based screening with cytology or human papillomavirus tests. Self-collection of a human papillomavirus (HPV) test has been found to be generally more acceptable, less embarrassing, more comfortable, more private and easy to do and preferred to pelvic examination for cervical cytology by many women worldwide. The most commonly reported limitation to self-collection is a woman’s lack of confidence in her ability to perform it correctly. Self-collected human papillomavirus tests have been shown to be as or more sensitive than cytology or clinician-collected HPV tests. With confidence-building education about self-collection, it is likely a viable method to extend the reach of screening in high and low-resource areas around the world.     

Cervical cancer vaccines: progress and prospects

Cervical cancer remains a leading cause of cancer-related mortality in women, particularly in developing countries. The causal association between genital human papillomavirus (HPV) infection and cervical cancer has been firmly established and the oncogenic potential of certain HPV types has been clearly demonstrated. In recognition of the causal association of cervical cancer with this sexually transmitted viral infection, substantial interest has arisen to develop effective prophylactic and therapeutic vaccines. Prophylactic strategies currently under investigation focus on the induction of effective humoral and cellular immune responses that are potentially protective against subsequent HPV infection. Papillomavirus-like particles have been synthesized to induce neutralizing antibody responses, and impressive immunoprophylactic effects have been demonstrated in both animals and humans. For the treatment of existing HPV infection, techniques to augment cellular immunity by enhancing viral antigen recognition are under investigation. Vaccines targeting the oncogenic proteins E6 and E7 of HPV-16 and -18 are the focus of current clinical trials for cervical cancer patients. It is hoped that the development of successful HPV-specific vaccines will diminish the costs of existing cervical cancer screening programs and reduce the morbidity and mortality associated with the treatment of cervical neoplasias.     

Integrating HPV testing for primary screening?

Cervical cancer, the second most common cancer in young women in France, is still today imperfectly screened even with the advent of primary prevention for this cancer in the form of prophylactic HPV vaccination. Indeed, the cervical Pap smear and its cytologic analysis, both operator and reader dependent, have limited sensitivities requiring repeated samplings and above all, producing a high rate of falsely negative tests. Although most cancers occur in women who are either not or insufficiently screened, the problem with cervical smears is the fact that cancers are also often diagnosed in young women having follow-ups in accordance with professional guidelines. The absence of an organized screening in France results in an inadequate female population coverage. Nowadays, it is unanimously recognized that high-risk papillomaviruses (HR HPV) represent the only independent risk factor for cervical cancer and that there cannot be any disease without this virus. It is therefore this strong association between a viral agent and the cervical cancer which opened the door firstly, to the notion of prophylactic vaccination and secondly, to the integration of HR HPV testing in the screening for precancerous lesions. Molecular biological techniques based on the HR HPV genome detection within the female genital tract have shown a very high sensitivity without any inter and intraobserver variability and an excellent negative predictive value. Their integration in the primary screening for cervical cancer would improve the relevance of the latter and would suit the need for a wider population coverage and even for an organized screening thanks to the possibility for self-sampling. The specificity of these tests is inferior to that of the cervical smear, but the management of the falsely positive HPV tests has proved to be efficient by sorting residual cells obtained from liquid-based cytology. What is urgent in France is the need for an organized screening programme in order to improve population coverage and, this does not go against neither a vaccination promotion nor the integration of new technologies. Moreover, the last three randomized trials published in October 2007 have shown that it was quite safely possible to extend the time interval between two consecutive viral testing and thus improving the cost-effectiveness of cervical cancer screening. The aim of this work was to analyze publications on the subject in order to conclude, according to proof levels obtained by different studies, on its usefulness in the secondary prevention of cervical cancer.     

Prevalence and Clinical Utility of Human Papilloma Virus Genotyping in Patients with Cervical Lesions

Objective

Cervical cancer is the commonest cancer among Indian women. High-risk human papilloma virus (HPV) detection holds the potential to be used as a tool to identify women, at risk of subsequent development of cervical cancer. There is a pressing need to identify prevalence of asymptomatic cervical HPV infection in local population. In our study, we explored the prevalence of HPV genotypes and their distribution in women with cervical lesions.

Methods

Scrape specimens were obtained from 100 women (study group) with cervical abnormalities. HPV was detected with amplicor HPV tests, and the individual genotypes in these specimens were identified by Hybribio Genoarray test kit. Fifty specimens were also collected from females with healthy cervix (control group). The present study also aimed to determine the status of HPV prevalence and its association with different sociodemographic factors.

Results

Out of the total number of 100 samples, 10 (10 %) women tested positive for HPV DNA. Among them, HPV 18 was observed in 6, HPV 16 in 2, HPV 52 and HPV 39 in one each. Fifty specimens collected from patients with healthy cervix were not infected with any of the HPV genotype.

Conclusions

Our study generates data of HPV prevalence in patients with cervical lesions visiting tertiary care institute. The data generated will be useful for laying guidelines for mass screening of HPV detection, treatment, and prophylaxis.     

HPV-based Tests for Cervical Cancer Screening and Management of Cervical Disease

Current cervical cancer screening programs are changing due to the development of tests that detect the presence of human papillomavirus (HPV), the cause of cervical cancer. These tests are more sensitive than cytology-based methods for detecting cervical precancer and a negative test offers long-term assurance that cervical cancer will not develop and therefore longer screening intervals can be achieved. In screening programs, HPV-based tests have been approved to triage women with equivocal cytology results and as a primary testing method in conjunction with cytology. HPV-based tests also have a role in determining risk of recurrence after treatment for cervical precancer as well as in surveillance for vaccine-related changes in HPV genotype prevalence.     

The combined impact of implementing HPV immunisation and primary HPV screening in New Zealand: Transitional and long-term benefits,costs and resource utilisation implications

BackgroundIn response to emergent evidence, many countries are transitioning from cytology-based to HPV screening. We evaluated the impact of an upcoming transition on health outcomes and resource utilisation in New Zealand.MethodsAn extensively validated model of HPV transmission, vaccination, natural history and cervical screening (‘Policy1-Cervix’) was utilised to simulate a transition from three-yearly cytology for women 20–69 years to five-yearly HPV screening with 16/18 genotyping for women 25–69 years, accounting for population growth and the impact of HPV immunisation. Cervical cancer rates, resources use (test volumes), costs, and test positivity rates from 2015 to 2035 were estimated.FindingsBy 2035, the transition to HPV screening will result in declines in cervical cancer incidence and mortality rates by 32% and 25%, respectively, compared to 2018. A potentially detectable 5% increase in cervical cancer incidence due to earlier detection is predicted for the year of transition. Annual numbers of women screened will fluctuate with the five-year screening interval. Cytology volumes will reduce by over 80% but colposcopy volumes will be similar to pre-transition rates, and program costs will be reduced by 16%. A 9% HPV test positivity rate is expected in the first round of HPV screening (2019–2023), with 2.7% of women referred for colposcopy. Transitioning from cytology to primary HPV cervical screening could avert 149 cancer cases and 45 deaths by 2035.ConclusionPrimary HPV screening and vaccination will reduce cervical cancer and resources use. A small transient apparent increase of invasive cancer rates due to earlier detection may be detectable at the population level, reflecting the introduction of a more sensitive screening test. These findings can be used to inform health services planning and public communications surrounding program implementation.     

Colposcopy and cervical intra-epithelial neoplasia

Cervical cancer is both preventable and curable. It has a long natural history with a prolonged pre-cancerous phase that is easily detectable and treatable. Exfoliative cytology remains the mainstay for screening of pre-cancerous lesions. Assessment of women presenting with abnormal cervical cytology and the selection of those requiring treatment relies mainly on colposcopic impressions of the cervical transformation zone and histological appraisal of directed punch biopsies. There is variation in the assessment of cytology, colposcopy and histology findings, and therefore the ‘final’ diagnosis involves of all three disciplines. The need to maximize clinical resources, achieve quicker and more effective management of patients, limit post-operative complications and preserve reproductive function has led to the popularity of local excisional methods for cervical pre-malignancy. Although the cure rates for all local ablative and excisional methods are more than 90% after one treatment, the excisional methods provide a more reliable histopathological diagnosis and the patient may be treated at the initial visit. Cure rates for correlate principally with the extent of the cervical intra-epithelial neoplasia (CIN). The recognition that persistent infection with oncogenic HPV causes cervical cancer has stimulated the search for preventative vaccines. Those vaccines are now available for use and appear to be safe, well tolerated and highly efficacious in HPV naive women. The national HPV immunization programme with the bivalent vaccine was initiated in the NHS in September 2008.     

Advances in cervical cancer screening and human papillomavirus vaccines

Cervical cancer is causally linked to human papillomavirus (HPV) and constitutes a major health problem for women. Nearly 80% of the 510,000 cases reported worldwide each year occur in developing countries which lack organized screening programmes. Cervical screening has effectively reduced the incidence of and mortality from invasive cervical cancer in industrialized countries, but is not completely protective. Cervical screening is now undergoing modernization and has seen several changes in recent years. These aim to enhance the overall efficiency and effectiveness of screening, reduce rates of inadequate sampling, increase sensitivity rates and facilitate ancillary technologies, such as HPV testing. This review discusses these advances and the development of HPV vaccines.     

Role of human papilloma virus testing in cervical cancer prevention

A clear causal relationship has been established between human papilloma virus (HPV) infection and the development of cervical cancer. Genital HPV infection is currently the most common sexually transmitted disease worldwide. The recent 2001 American Society for Colposcopy and Cervical Pathology Consensus Guidelines have included HPV testing for management of women with cervical cytological abnormalities. Clinicians now face the challenge of deciding when to use HPV testing in follow-up of abnormal Pap tests. This article includes updates on HPV, cervical cancer screening, and HPV testing technology. Recommendations for integration of HPV testing into clinical practice are provided.     

Prevalence of genital human papillomavirus among Lebanese women

PURPOSE: The purpose of this study was to determine the prevalence of human papillomavirus (HPV), and more specifically of HPV 16, in a group of Lebanese women. MATERIALS AND METHODS: Type-specific prevalence of cervical HPV and the presence of cytological abnormalities were determined in a cohort of Lebanese women. The population included 1,026 women, 18-76 years, seeking routine gynecological care at a tertiary care center. Demographic and behavioral data were collected. HPV DNA was detected in cervical scrapes by polymerase chain reaction using consensus primers. Cervical cytological abnormalities were identified by Papanicoleau (Pap) smears. RESULTS: The mean age of our population was 40 +/- 11.3 years. General HPV DNA was detected in 50 patients (4.9%). The high-risk HPV type 16 DNA was detected in 31 patients (3%). Patients with HPV 16 were more likely to have an abnormal pap smear than those with negative tests (6.6% vs 1.6%, p < 0.05), and more likely, but not significantly, to be smokers (21.4% vs 18.4%, p = 0.5). The age-specific prevalence of HPV increased with age and peaked at 60-69 years. CONCLUSIONS: The prevalence of HPV in this small group of Lebanese women is similar to its prevalence in the Mediterranean countries. The presence of HPV, its known association with the development of cervical neoplasia, and the lack of a universal screening program for cervical cancer in our country should be used to enforce implementation of proper screening programs.     

Epidemiology and natural history of genital infection by human papillomavirus

Human papillomavirus genital infection is a very common sexual transmitted disease, probably the most common of them. On one hand, this infection is more often than not transient and asymptomatic and induces an effective immunity which allows the infection cure; on the other hand it can be responsible for an intraepithelial lesion which can progress to an invasive cancer. In spite of the decrease of cervical cancer incidence thanks to Pap smear screening, it remains a real preoccupation for clinicians. If HPV is not sufficient for cervical carcinogenesis, it represents however a necessary factor. Near 100% of cervical cancers are indeed positive in HPV DNA. HPV infection is very frequent in young people aged less than 25 years and viral clearance average is 8 months. This clearance is the consequence of host immunity intervention which leads to spontaneous regression of infection and of the overwhelming majority of low grade squamous intraepithelial lesions (more than 80% within a period of two years). The major factor which permits the progression to high grade squamous intraepithelial lesions is the persistent feature of HPV infection. Cervical cancer is clearly the first viral-induced solid tumor discovered in human species. Furthermore it represents a woman death cause that can be avoided.     

Risk factors for cervical cancer in China: a case-control study

OBJECTIVES: To determine the prevalence of human papillomavirus types and investigate the risk factors for cervical cancer in Hubei, China. METHODS: We conducted a case-control study to investigate risk factors. RESULTS: HPV DNA was detected in 94.55% of patients with cervical carcinoma, and 23.64% of control subjects. The most common HPV type in cervical cancer was HPV type 16 (81.82%), followed by HPV 58 (6.36%). HPV infected patients have a higher risk of developing cervical carcinoma, which is 75.79 times more than non-infected people. The other risks were age at first intercourse (p = 0.017) and number of live births (p = 0.032). A history of previous cytologic screening was associated with a substantial reduction in risk (p = 0.001). CONCLUSIONS: The three principal reasons that Hubei has a high rate of women developing cervical carcinoma are HPV infection, age at first sexual intercourse and number of live births. Cervical cytology screening provides efficacious protection.     

Genital Human Papillomavirus Infection in Women

OBJECTIVE: To enhance nurse clinicians' knowledge of genital human papillomavirus infection in women. DATA SOURCES: Several literature searches using the following terms, dating back to 1986: human papillomavirus (HPV), females, human, cervical neoplasia, risk factors, condylomata acuminata, detection, epidemiology, pathology, psychology, Papanicolaou test, immunosuppression, HIV infection, and AIDS. STUDY SELECTIONS: Forty-three formal research studies regarding the association of various types of HPV infection with cervical intraepithelial lesions, the putative precursor lesions for cervical neoplasia; the outcomes of diagnostic techniques for HPV types; the outcomes of diagnostic/screening techniques for abnormal cervical cells; the association of risk factors for acquiring HPV infection; or the outcomes of therapy. Some additional references were chosen for their presentation of epidemiologic or surveillance data, others for their scientific discussions on related topics. DATA EXTRACTION: Data were abstracted according to summary measures of the parameter of interest in the sample studied. In most instances, it was the prevalence of HPV, cervical neoplasia, or frequency of use of screening tests. DATA SYNTHESIS: Immunosuppressed clients are at particular risk for HPV-mediated cervical neoplasia. CONCLUSION: Because Papanicolaou tests are an effective screening tool, cervical cancer is easily detectable. The nurse may facilitate treatment. This is an especially important issue for young women, among whom sexual activity is growing--with attendant increases of HPV and HIV infection.