J. Thomas Cox

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 Consensus was reached based on a literature review, expert opinion, and unpublished results from large ongoing screening studies.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.

Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance

Abstract OBJECTIVE: Our purpose was to determine the clinical value of human papillomavirus deoxyribonucleic acid testing with the hybrid capture test, specifically to examine whether human papillomavirus testing could identify which women with Papanicolaou smears read as atypical squamous cells of undetermined significance were most likely to have histologically confirmed cervical intraepithelial neoplasia. STUDY DESIGN: Hybrid capture testing for 14 human papillomavirus types, repeat Papanicolaou smears, and colposcopically directed biopsies were performed concurrently on 217 women referred to a student health colposcopy clinic with a previous Papanicolaou smear read as atypical squamous cells of undetermined significance. RESULTS: Human papillomavirus deoxyribonucleic acid positivity was associated with an eightfold increased likelihood of histologic confirmation of cervical intraepithelial neoplasia. The sensitivity of hybrid capture for any cervical intraepithelial neoplasia was 86% (4350) and for grade 2 or 3 was 93% (1415), whereas the corresponding values for the repeat Papanicolaou smear were 60% (3050) and 73% (1115), respectively. Moreover, high viral levels of human papillomavirus types known to be associated with cervical cancer were strongly predictive of high-grade cervical intraepithelial neoplasia. CONCLUSIONS: Testing for human papillomavirus deoxyribonucleic acid with hybrid capture appears to offer an effective means by which patients whose cervical Papanicolaou smears have been read as atypical squamous cells of undetermined significance could be triaged for colposcopy. In particular, sensitivity for high-grade cervical intraopithelial neoplasia could be maintained and specificity markedly improved by referring only those patients who had elevated levels of human papillomavirus deoxyribonucleic acid of cancer-associated viral types.

American Cancer Society Guideline for Human Papillomavirus (HPV) Vaccine Use to Prevent Cervical Cancer and Its Precursors

The American Cancer Society (ACS) has developed guidelines for the use of the prophylactic human papillomavirus (HPV) vaccine for the prevention of cervical intraepithelial neoplasia and cervical cancer. These recommendations are based on a formal review of the available evidence. They address the use of prophylactic HPV vaccines, including who should be vaccinated and at what age, as well as a summary of policy and implementation issues. Implications for screening are also discussed.

The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology.

Abstract The terminology for human papillomavirus (HPV)–associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) Project was cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology.

The terminology for human papillomavirus (HPV)-associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) project was co-sponsored by the College of American Pathologists (CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP) and included 5 working groups; three work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted upon at the consensus meeting. The final approved recommendations standardize biologically-relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

Advances in prevention of cervical cancer and other human papillomavirus-related diseases

In theory, recognition that a pandemic infection is responsible for more than half a million cancer cases each year would attract huge media attention, and infection control would become the subject of preventative efforts from all global health agencies. Media attention would likely be particularly acute if the majority of deaths was among women rearing families in the developing world and if the disease were sexually transmitted. A vaccine capable of preventing the disease would be diligently pursued and, once available, promptly distributed for the health and welfare of humankind. Human papillomavirus (HPV) infection fits this scenario; however, HPV has yet to make an impact on either the media or public thinking as outlined in the previous paragraph, even though the link between HPV infection and cervical cancer has been recognized for more than 20 years. It is possible that the delay between acquisition of HPV infection and death, on average 20 years, or the asymptomatic nature of acute infection, greatly diminishes the immediacy of the public impact of this epidemic. Although apparently safe vaccines capable of preventing 90% of HPV infections are in the offing, focus on prevention of HPV associated deaths is being diverted by debates about the morality of vaccination against a sexually transmitted infection and its hypothesized impact on human sexual behavior. A roundtable discussion was held in Vancouver, British Columbia to consider and develop a consensus statement among informed clinicians about HPV infection, the role of HPV in cervical cancer, the role of HPV in other anogenital malignancies, the role of HPV in genital warts and the prospects for control of the global HPV pandemic through vaccination. The consensus statements outlined within have been agreed upon and represent the informed opinions of this expert working group.

Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing, and genotyping for HPV 16/18: results from the ATHENA HPV study.

OBJECTIVE The objective of the study was to compare 9 cervical cancer screening strategies to the current screening standard (cytology with human papillomavirus [HPV] triage of atypical squamous cells of undetermined significance) for the detection of high-grade cervical disease. STUDY DESIGN Women (n = 34,254) aged 30 years or older from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study underwent screening with cytology and HPV testing with simultaneous HPV16/18 genotyping; those with atypical squamous cells of undetermined significance cytology or greater or HPV-positive status were referred for colposcopy. RESULTS In general, screening strategies that offered greater sensitivity also required more referral to colposcopy. HPV testing was more sensitive than cytology for detection of cervical intraepithelial neoplasia grade 2 or greater, but strategies that depended on cytology for triage of HPV-positive women decreased this sensitivity. Various strategies of cotesting with cytology increased sensitivity but did so by increasing testing. Strategies that included integrated HPV16/18 testing provided more efficient referral to colposcopy. CONCLUSION Strategies that maximize detection of women at greatest risk of cervical intraepithelial neoplasia grade 3 or greater by immediate referral to colposcopy, with follow-up testing of women at intermediate risk, maximize the benefits of cervical cancer screening while decreasing the potential harm. Incorporating screening with HPV and triage of HPV-positive women by a combination of genotyping for HPV16/18 and cytology provided a good balance between maximizing sensitivity (benefit) and specificity by limiting the number of colposcopies (potential harm).

The age-specific relationships of abnormal cytology and human papillomavirus DNA results to the risk of cervical precancer and cancer.

BACKGROUND: To estimate the relationship of human papillomavirus (HPV) detection and abnormal cytology with histologic diagnoses of cervical precancer and cancer. METHODS: From 2003 to 2008 we examined the HPV, cytology, and diagnostic results from almost one million cervical cancer screenings done on women aged 30 and older who were members in Kaiser Permanente Northern California, a large health maintenance organization that introduced cotesting in 2003. Women were screened using conventional Pap tests and a DNA test for a pool of 13 high-risk HPV genotypes. Women with HPV-positive atypical squamous cells of undetermined significance and other abnormal cervical cytology, independent of their HPV results, routinely underwent colposcopy. Results were stratified by 5-year age groups from 30 to 64. RESULTS: High-grade squamous intraepithelial lesions (HSIL), atypical squamous cells, cannot exclude HSIL (ASC-H), and atypical glandular cells were more strongly associated with cervical intraepithelial neoplasia grade 3 while low-grade squamous intraepithelial lesions (LSIL) and HPV-positive atypical squamous cells of undetermined significance were more strongly associated with cervical intraepithelial neoplasia grade 2 (CIN2). Cervical cancer was most commonly found in women with HSIL and atypical glandular cells cytology. Human papillomavirus–negative women with ASC-H cytology were at a reduced but significant risk of CIN2 or more severe (CIN2+) (10.6%) compared with HPV-positive women with ASC-H cytology. Human papillomavirus–negative women with LSIL were at a 4.0% risk of CIN2+, and among women 50 and older, at a 0.5% risk of CIN2+ with no cancers were diagnosed. CONCLUSION: Human papillomavirus testing may be useful for triage for colposcopic referral for LSIL cytology in older women but not for ASC-H cytology at any age. LEVEL OF EVIDENCE: II

Management of cervical intraepithelial neoplasia.

Three outpatient therapies--cryotherapy, laser vaporization, and loop electrosurgical excision procedure (LEEP)--are used in the US for the treatment of cervical intraepithelial neoplasia (CIN). There has been considerable controversy, however, about the relative safety, efficacy, and costs of these methods. A rigorous study (Mitchell et al.) in which patients were stratified by key prognostic variables provided irrefutable evidence of the similarity of efficacy of the three methods. This suggests that only cost and concern over the small risk of missing adenocarcinoma-in-situ or microinvasive cancer need influence decisions about CIN treatment. Women with lesions affecting more than two-thirds of the surface of the cervix are more than 19 times more likely to have persistent disease than women with smaller lesions, regardless of therapy type. The amount of tissue removed by laser, cryotherapy, and LEEP is small, so these techniques have no adverse affect on pregnancy. The issue of whether low-grade lesions should be treated, even though most are self-limiting, continues to be debated.

An analysis of high-risk human papillomavirus DNA-negative cervical precancers in the ASCUS-LSIL Triage Study (ALTS)

OBJECTIVE: To describe women diagnosed with cervical intraepithelial neoplasia-grade 3 (CIN-3) diagnosed over the 2-year duration of the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) Triage Study (ALTS) that tested negative for high-risk human papillomavirus (HPV) at enrollment. METHODS: Clinical center pathologists and quality control pathology group reviewed all histology; any CIN-3 diagnosis on biopsy or loop electrosurgical excision procedure (n=621) by at least one pathology review over the duration of ALTS led to inclusion in this analysis. Enrollment cervical specimens were tested for high-risk HPV DNA by two HPV assays; results were combined to minimize simple testing errors. We compared the characteristics of baseline high-risk HPV-negative (n=33) to baseline high-risk HPV-positive (n=588) cumulative diagnosed CIN-3. RESULTS: High-risk HPV-negative CIN-3 cases were less likely to have a second, confirming diagnosis of CIN-3 (24% compared with 56%) by the other pathology group, were more likely to be diagnosed later in follow-up, and more likely to be referred into ALTS because of an ASCUS Pap test rather than an LSIL Pap. Upon review of case histories of the 33 baseline high-risk HPV-negative CIN-3 (5.3% of all cases), there was evidence that these cases were due to incident (new) cases (n=12, 1.9%), non–high-risk HPV (n=5, 0.8%), misclassified histology (n=8, 1.3%), and false-negative high-risk HPV (n=8, 1.3%). CONCLUSION: In any sizeable population, even among women with evidence of cytologic abnormalities, there will be a few cases of cervical precancer that will test high-risk HPV negative for one or more reasons. LEVEL OF EVIDENCE: II