Evaluating HPV-negative CIN2+ in the ATHENA trial.

A post hoc analysis of the ATHENA study was performed to determine whether true HPV-negative cervical lesions occur and whether they have clinical relevance. The ATHENA database was searched for all CIN2 or worse (CIN2+) cases with cobas HPV-negative results and comparison was made with Linear Array (LA) and Amplicor to detect true false-negative HPV results. Immunostaining with p16 was performed on these cases to identify false-positive histology results. H&E slides were re-reviewed by the study pathologists with knowledge of patient age, HPV test results and p16 immunostaining. Those with positive p16 immunostaining and/or a positive histopathology review underwent whole tissue section HPV PCR by the SPF10/LiPA/RHA system. Among 46,887 eligible women, 497 cases of CIN2+ were detected, 55 of which tested negative by the cobas(®) HPV Test (32 CIN2, 23 CIN3/ACIS). By LA and/or Amplicor, 32 CIN2+ (20 CIN2, 12 CIN3/ACIS) were HPV positive and categorized as false-negatives by cobas HPV; nine of 12 false-negative CIN3/ACIS cases were p16+. There were 23 cases (12 CIN2, 11 CIN3/ACIS) negative by all HPV tests; seven of 11 CIN3/ACIS cases were p16+. H&E slides were available for six cases for re-review and all were confirmed as CIN3/ACIS. Tissue PCR was performed on the six confirmed CIN3/ACIS cases (and one without confirmation): four were positive for HPV types not considered oncogenic, two were positive for oncogenic genotypes and one was indeterminate. In summary, subanalysis of a large cervical cancer screening study did not identify any true CIN3/ACIS not attributable to HPV.

Prevalence of high-risk human papilloma virus genotypes and associated risk of cervical precancerous lesions in a large U.S. screening population: data from the ATHENA trial.

OBJECTIVE: We assessed the age-related prevalence of high risk human papillomavirus (HR-HPV) genotypes and the genotype-associated risk for high-grade cervical intraepithelial neoplasia (CIN) in a large U.S. screening population. METHODS: A total of 40,901 women aged ≥25 years were screened with liquid-based cytology and HPV testing in the ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial. Genotyping was performed using the LINEAR ARRAY HPV Genotyping Test. RESULTS: HPV16 was the most prevalent genotype in all age groups, ranging from 3.5% to 0.8% in women aged 25-29 and ≥50 years, respectively. The next most prevalent genotypes were HPV52, HPV31 and HPV18. In the overall population, HPV16 conferred the greatest absolute risk of ≥CIN3 both in women aged 25-29 and ≥30 years (14.2% and 15.1%, respectively) followed by HPV31 (8.0% and 7.9%), HPV52 (6.7% and 4.4%) and HPV18 (2.7% and 9.0%). Similar trends were seen in women with negative cytology. The percent positivity increased markedly with disease progression for HPV16 and HPV18 which were responsible for 45.6% and 8.4% of ≥CIN3, respectively. Of note, HPV 18 was responsible for 50% of adenocarcinoma in situ (AIS) and 50% of invasive cancer cases. CONCLUSIONS: HPV16 played a major role in the development of ≥CIN3 irrespective of age, supporting the identification of HPV16 in primary screening for all women. Identification of HPV18 is also warranted, given its significant contribution to AIS and cancer. Identification of non-16/18 genotypes as a pool should provide sufficient information for screening.

Evolution of terminology for human-papillomavirus-infection-related vulvar squamous intraepithelial lesions.

OBJECTIVE: The aim of this study was to review the nearly 100-year evolution of terminology applicable to oncogenic human papillomavirus (HPV)-related vulvar intraepithelial squamous lesions and present current consensus terminology. METHODS: An extensive literature search of the English language was performed, which included articles that reviewed French and German publications, from 1922 to 2012. The database search was assisted by representatives of the American Society for Colposcopy and the College of American Pathologists as part of a comprehensive study and consensus effort to achieve unified terminology among gynecologists, dermatologists, pathologists, and other related experts to develop for reporting female and male lower genital and anal HPV related squamous lesions. This was done by the committee referred to as the "LAST" Committee. Some of the results and conclusions have been previously presented and published. This presentation is specifically related to vulvar squamous intraepithelial lesion (SIL)/vulvar intraepithelial neoplasia terminology. RESULTS: This work will review past terminology related to HPV-related vulvar SIL, beginning in 1922. The most current terminology will be presented as proposed by the LAST Committee and considered by the World Health Organization this year in accord with the US-Canadian Academy of Pathology. CONCLUSIONS: A consensus of terminology for HPV-related vulvar SIL has been sought for some time, and currently, some consensus has been achieved. The term "squamous intraepithelial lesion" is favored over "intraepithelial neoplasia." A 2-tier classification, of "high grade (HSIL)" or "low grade (LSIL)," is favored over a 3- or 4-tier classification. The application of this terminology will be discussed.

Cervical cancer rates after the transition from annual Pap to 3-year HPV and Pap.

OBJECTIVE: Kaiser Permanente Northern California (KPNC) introduced 3-year Pap and human papillomavirus DNA cotesting for cervical cancer screening in women 30 years or older in 2003 to 2004. Patient and provider willingness to extend screening intervals and the impact on annual cervical cancer incidence after interval extension are evaluated. MATERIALS AND METHODS: Age-adjusted cervical cancer rates and screening intervals were calculated from KPNC Regional Laboratory databases and Northern California Cancer Registry from 2000 to 2009. RESULTS: The median screening interval between negative cotests was 36 months compared to the 16 months after a negative Pap test alone before the implementation of cotesting. The age-adjusted invasive cancer rate was 6.5 per 100,000 women in 2000 and 6.3 in 2009; there was no difference in the rates of cervical cancer in women 30 years or older from 2000 to 2009 (p(trend) = .7). CONCLUSIONS: Patients and providers were compliant with the extension of screening intervals with cotesting. Cervical cancer rates remained constant during the 10-year study period despite extending screening intervals after a negative cotest.

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).

Screening history preceding a diagnosis of cervical cancer in women age 65 and older.

OBJECTIVE: To characterize the antecedent screening of women 65 years of age and older diagnosed with cervical cancer. METHODS: Screening histories of women 65 years of age and older who were diagnosed with cervical cancer between 2003 and 2008 were examined utilizing the organization's databases and the regional Cancer Registry. Stopping screening was recommended at age 65 for members who had either 3 consecutive negative Paps or a single negative Pap plus HPV test ("cotest"). RESULTS: From 2003 through 2008 there were 56 Kaiser Permanente Northern California members 65 years of age and older diagnosed with cervical cancer. During the same time period there were 1,323,100 woman-years of membership in women age 65 and older. The risk of invasive cancer among women age 65 and older was 4.2/100,000/year in 2003-2008. 33 of 56 (59%) had one or more Pap smears prior to diagnosis. Of the 33, 14 women (25%) had 3 consecutive negative Pap smears prior to diagnosis. Three of 46,401 women with 1 or more negative cotests at age 65 and older were subsequently diagnosed with invasive cancer during 132,639 women-years of follow-up (2.3/100,000/year). CONCLUSIONS: Most cervical cancers diagnosed at age 65 and older occur in women who have not met our criteria for stopping screening. A few cancers will continue to occur at age 65 and older despite multiple negative tests, as is true in other age groups. We currently have no evidence that these cancers would be prevented with continued screening at ages 65 and older.

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 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.

Characteristics of 44 cervical cancers diagnosed following Pap-negative, high risk HPV-positive screening in routine clinical practice.

OBJECTIVE: To characterize the cervical cancers diagnosed following a Pap-negative, high risk human papillomavirus (HPV)-positive (Pap-/HPV+) screen in routine clinical practice. METHODS: Using data from Kaiser Permanente Northern California, we investigated the cases of cervical cancer diagnosed between January, 2003 and January, 2009 following Pap-/HPV+ screen. Two cervical specimens were routinely collected for cervical cancer screening, one for conventional cytology and the other for high risk HPV testing using Hybrid Capture 2 (Qiagen). RESULTS: Forty-four women (median age at diagnosis=44years) were diagnosed with primary invasive cervical cancer with a recent history of one or more Pap-/HPV+ screens. Twenty-six women had one Pap-/HPV+ screen preceding the diagnosis of cancer, 15 had two, and three had three. There were 16 squamous cancers, one small cell cancer, 24 adenocarcinomas, 2 adenosquamous carcinomas, and one case with separate invasive squamous and adenocarcinoma. FIGO Stage was IA in 11 women, IB in 31 women and IIA in 2 women. Treatment included a pelvic node dissection in 30, 2 (6.7%) of whom had positive nodes. CONCLUSIONS: HPV testing contributes to early cervical cancer diagnosis detection in women with negative Pap tests. Most women in this cohort have early stage, node negative, treatable and potentially curable disease. Adenocarcinoma predominated as might be expected because cytology misses these cancers and their precursors. The majority of cancers were diagnosed following a single Pap-/HPV+ screen, suggesting that effective triage to colposcopy of women with a Pap-/HPV+ screen would be preferable to retesting in one year as currently recommended.

Risk of cervical precancer and cancer in women aged 30 years and older with an HPV-negative low-grade squamous intraepithelial lesion screening result.

OBJECTIVE: To characterize the 6- and 18-month cumulative risk of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and grade 3 or worse (CIN 3+) in women aged 30 years and older after a low-grade squamous intraepithelial lesion (LSIL) cytology and high-risk human papillomavirus (HPV)-negative screening result in routine clinical practice. MATERIALS AND METHODS: Comprehensive quality assurance databases of screening test and biopsy results from the Regional Laboratory of the Kaiser Permanente Northern California Health Plan were reviewed. All women aged 30 years and older with LSIL cytology were sorted by high-risk HPV status. Associated biopsy results were tabulated, and the corresponding risks of CIN 2+ and CIN 3+ diagnosed within 18 months after LSIL cytology were calculated overall and by decade of age. RESULTS: During the 6-year period, from 2003 to 2008, 4,113 LSIL cases were interpreted in women aged 30 years and older for which corresponding high-risk HPV and biopsy results were available. The proportion of women with LSIL testing positive for HPV declined with age, from 89% in the group aged 30 to 39 years to 76% in women older than 50 years (p < .001). Of 622 women with HPV-negative LSIL cytology, there was no case of cancer detected at colposcopy occurring within 6 months of the screening test. The 18-month risks of CIN 2+ and CIN 3+ were 3.5% and 1.4%, respectively. CONCLUSIONS: The risk of CIN 3+ is sufficiently low in women aged 30 years and older with high-risk HPV-negative LSIL that 1 year follow-up rather than immediate colposcopy should be considered when it occurs in routine clinical practice.

Lessons from practice: risk of CIN 3 or cancer associated with an LSIL or HPV-positive ASC-US screening result in women aged 21 to 24.

OBJECTIVE: To characterize the risks of cervical intraepithelial neoplasia 3 (CIN 3) and cancer in women aged 21 to 24 with human papillomavirus (HPV)-positive atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) screening results in routine clinical practice. MATERIALS AND METHODS: Quality assurance databases containing records of screening test and histologic findings from the Regional Laboratory of the Northern California Kaiser Permanente Medical Care Program were reviewed. Numbers of LSIL and HPV-positive ASC-US results and associated cancers and CIN 3 in women aged 21 to 24 during 2003 to 2007 were tabulated, and the corresponding risks were calculated overall and by year of age. RESULTS: During the 5-year period from 2003 to 2007, 1,620 HPV-positive ASC-US and 2,175 LSIL were diagnosed in women aged 21 to 24, for which corresponding histologic finding is available. No invasive cancers were detected in association with LSIL and HPV-positive ASC-US screening results in this age group during this period. The risk of cancer was therefore 0% (95% CI = 0.00%-0.10%). The risk of CIN 3 associated with an HPV-positive ASC-US was 2.90% (95% CI = 2.14%-3.84%), with LSIL was 2.44% (95% CI = 1.83%-3.18%), and, for the 2 combined, the risk was 2.64% (95% CI = 2.15%-3.20%). CONCLUSIONS: The risk of CIN 3 and cancer is low enough that management of women aged 21 to 24 with ASC-US and LSIL smears without immediate colposcopy should be considered, as is currently recommended for women aged 20 and younger.

Factors influencing histologic confirmation of high-grade squamous intraepithelial lesion cytology.

OBJECTIVE: To examine the predictors of histologic confirmation of high-grade squamous intraepithelial lesion (HSIL) cytology occurring in follow-up of young women originally referred into a trial because of less severe cytology. METHODS: We used enrollment HSIL cytology (N=411) as read by clinical center pathologists for women participating in the ASCUS-LSIL Triage Study (ALTS). The primary outcome was histologic cervical intraepithelial neoplasia (CIN) grade 3 and early cancer (n=195; 191 CIN 3 and four cancers) as diagnosed by the Pathology Quality Control Group during the 2-year duration of ALTS. RESULTS: The 2-year absolute risk of CIN 3 or worse after an HSIL cytology was 47.4% (95% confidence interval 42.5-52.4%). The 2-year absolute risk of CIN 3 or worse was lowest (14.3%) for women who were human papillomavirus (HPV)-16-negative, had colposcopic impression of less than low-grade, and whose HSIL cytology as called by the clinical center was not also called HSIL or equivocal HSIL cytology by the Pathology Quality Control Group. The 2-year absolute risk of CIN 3 or worse was highest (82.4%) for women who were HPV16-positive, had colposcopic impression of low-grade or worse, and whose HSIL cytology also was called HSIL or equivocal HSIL cytology by the Pathology Quality Control Group. CONCLUSION: Histologic confirmation of precancer among young women with HSIL cytology was more likely when other risk factors (eg, HPV16) for cervical precancer were present.

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.

Cervical cytology specimen adequacy: patient management guidelines and optimizing specimen collection.

OBJECTIVE: To provide updated management guidelines according to cervical cytology specimen adequacy and techniques to optimize adequacy based on literature review and expert opinion. MATERIALS AND METHODS: Selected members of the American Society for Colposcopy and Cervical Pathology committee and invited experts conducted a literature review and discussed appropriate management and areas for future research emphasis. RESULTS: The guidelines recommend a repeat Pap test in a short interval of 2 to 4 months for most women when the cytology result is unsatisfactory. The preferred follow-up for women with a negative cytology result lacking an endocervical/transformation zone component or showing other quality indicators is a repeat Pap test in 12 months. Indications for an early repeat Pap test in 6 months are provided, and the influence of human papillomavirus testing results on management is discussed. Techniques for optimizing specimen adequacy are provided in detail. CONCLUSION: The specimen adequacy management guidelines will help promote uniform and optimal follow-up of patients receiving cervical cytology screening. The topics for future research emphasis will be helpful in promoting studies in needed areas.

Human papillomavirus testing in primary cervical screening and abnormal Papanicolaou management.

Human papillomavirus (HPV) infection is a necessary cause of cervical cancer; HPV testing capitalizes on this fact to maximize the clinical benefits of cervical screening and abnormal Papanicolaou (Pap) test management. HPV tests in combination with Pap tests are 96% to 100% sensitive for detection of cervical intraepithelial neoplasia (CIN) 2/3 and cancer. However, because HPV infection is common in young women and most commonly transient, HPV testing is not recommended as part of primary cervical screening for women younger than 30 years of age. HPV testing is recommended for women of any age for the clarification of atypical cells of undetermined significance (ASC-US) and as an option for follow-up of women with HPV-positive ASC-US, atypical squamous cells "cannot rule out high-grade," or low-grade squamous intraepithelial lesions not found to have CIN 2/3. HPV testing is also recommended as an alternative to colposcopy and/or cytology for follow-up of treated cases. Proper use of HPV testing improves the management of women with cytologic abnormalities. In addition, a negative HPV test in combination with a normal Pap test result in women age 30 and older allows the safe extension of the interval between cervical screenings. Thus, when used properly, HPV testing may reduce morbidity and mortality and do so in a cost-effective manner.

The development of cervical cancer and its precursors: what is the role of human papillomavirus infection?

Human papillomavirus (HPV) is a significant health care burden in the United States. The majority of sexually active men and women will be infected with HPV at some point in their lives and are subject to developing human papillomavirus-associated disease. Current estimates suggest that 20 million Americans are currently infected, and more than 5 million new infections occur each year. The prevalence of human papillomavirus is highest in populations in their late teens and early twenties, with nearly half of all new human papillomavirus infections occurring within 3 years of first intercourse. HPV is the necessary cause of genital warts, cervical intraepithelial neoplasia, and invasive cervical cancer. As such, human papillomavirus is responsible for significant medical morbidity and health care costs. Screening with cervical cytology has significantly reduced mortality rates; however, approximately 3900 women will die in 2005 from cervical cancer in the United States. Human papillomavirus DNA testing has shown promise in identifying high-grade abnormalities as an adjunct to traditional cytology, and should be used according to guidelines established by the American Cancer Society and the American College of Obstetricians and Gynecologists. The epidemiology of HPV infection and a brief introduction to the natural history of HPV infection will be presented here.

Effects of age and human papilloma viral load on colposcopy triage: data from the randomized Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS).

BACKGROUND: Testing for oncogenic human papillomavirus (HPV) DNA at a 1.0-pg/mL threshold represents a promising approach for colposcopy triage of atypical squamous cells of undetermined significance (ASCUS), but not for low-grade squamous intraepithelial lesions (LSIL). Considering age or viral load could improve colposcopy triage. METHODS: We determined the sensitivity for detecting Cervical Intraepithelial Neoplasia 3 (CIN3) and cancer and the percentage of referrals for colposcopy using HPV testing and repeat thin-layer cytopathology in 2198 women with ASCUS and in 848 women with LSIL enrolled in ALTS from November 1996 through December 1998. We analyzed results by age and at two thresholds for HPV load and repeat cytopathology. RESULTS: For ASCUS, the overall sensitivity of HPV testing at 1.0 pg/mL was 96.1% (95% confidence interval [CI] = 92.8 to 99.5%) and varied minimally with age (range, 93.9% to 97.8%). HPV testing at this threshold would refer 31.2% (95% CI = 28.0% to 34.3%) of women aged 29 years or older as compared with more than 65% of younger women. Among women aged 29 years or older with ASCUS, referral for repeat cytopathology of ASCUS had a sensitivity of 90.9% (95% CI = 81.1% to 100.0%) and would refer 50.1% (95% CI = 46.7 to 53.5%). Among all ASCUS, HPV testing using a 10.0-pg/mL threshold decreased sensitivity to 91.5% and referrals to 41.7%. More than 63% of LSIL would have been referred using any strategy achieving 90% sensitivity. CONCLUSION: For women with ASCUS, HPV testing was highly sensitive for detecting CIN3 and cancer with dramatically fewer referrals of older women. Neither a single HPV test nor repeat cytopathology provides useful triage for women with LSIL.

Epidemiology and natural history of HPV.

Human papillomavirus (HPV) is a highly prevalent, sexually transmitted infection responsible for significant morbidity and mortality. High-risk HPV types are now known to be necessary in the etiology of cervical cancer and to lead to both high-grade and low-grade cervical lesions. They are also implicated in a substantial portion of anal, penile, and head and neck precancers and cancers. HPV 16 and 18 are the most common HPV types found in cervical cancer and are responsible for approximately 70% of these cancers. In contrast, low-risk HPV types, the most common of which are HPV 6 and 11, cause genital warts, low-grade cervical lesions, and recurrent respiratory papillomatosis, but they do not cause cervical or other HPV-related cancers. Infection is most common in young, sexually active populations, and an estimated three fourths of adults will be infected with HPV during their lifetime. Cervical screening programs exist in the United States and other developed countries to identify and treat precancerous cervical lesions, but they do not reach all women and are costly. Until recently, no highly effective primary prevention strategy to reduce the risk of HPV acquisition existed. However, a quadrivalent HPV vaccine, which protects against the most common high-risk and low-risk HPV infections (HPV 16, 18, 6, and 11), is now available. In addition, a bivalent HPV vaccine that protects against high-risk HPV types 16 and 18 is in the late stages of clinical development. If implemented widely, vaccination against HPV promises to dramatically reduce HPV-associated morbidity and mortality.

The budget impact of cervical cancer screening using HPV primary screening.

OBJECTIVES: This study assessed the clinical and budgetary impacts of human papillomavirus (HPV) primary screening with HPV16/18 genotyping, in contrast to current cervical cancer screening strategies. STUDY DESIGN: A decision-tree framework and Markov model were used to model clinical and cost implications of screening and diagnosis of disease. METHODS: A model was developed to compare the annual clinical and budgetary impact of HPV screening with genotyping versus cytology, and co-testing with and without genotyping. Epidemiology and test performance inputs are from the literature and the Addressing THE Need for Advanced HPV Diagnostics (ATHENA) trial. Costs are from a US payer perspective. Clinical impact was measured as the resulting incidence of cervical cancer, and budget impact is reported as annual cost per screened woman. The model considered the impact of patient noncompliance (loss to follow-up) at both the initial screen and re-test. RESULTS: Cytology was found to be inferior to both co-testing and HPV primary screening. Co-testing was inferior to co-testing with genotyping. Co-testing with genotyping every 3 years (incidence = 5.5 per 100,000 women; annual investment = $61) or 5 years (incidence = 7.4 per 100,000 women; annual investment = $37) was slightly more effective, but more costly than HPV primary screening every 3 years (incidence = 6.2 per 100,000 women; annual investment = $48) or 5 years (incidence = 8.1 per 100,000 women; annual investment = $30). Genotyping strategies were relatively stable to the effects of patient noncompliance. CONCLUSIONS: Primary HPV screening with genotyping represents a sensible combination of clinical effectiveness and costs, while reducing the risks associated with patient noncompliance.

ASCCP patient management guidelines: Pap test specimen adequacy and quality indicators.

Our objective was to provide management guidelines according to Papanicolaou (Pap) test specimen adequacy based on literature review and expert opinion. A task force named by the American Society for Colposcopy and Cervical Pathology (ASCCP) conducted a literature review and discussed appropriate management. The Steering Committee of the ASCCP and other experts reviewed the guidelines. The guidelines recommend a repeated Pap test in 12 months for most women undergoing routine annual/biennial screening if the current Pap test is negative but either lacks an endocervical/ transformation zone component or is partially obscured. Indications for considering an earlier repeat are also provided. The preferred managementfor unsatisfactory Pap tests is a repeated Pap test within a short interval of 2 to 4 months. The management guidelines will help promote optimal and uniform follow-up of women according to Pap test specimen adequacy.