Cells Of Undetermined Significance Cytology Research Articles

Atypical squamous cells of undetermined significance cervical cytology in Bahrain: Reporting rates, high-risk HPV testing, and cytologic and histopathologic follow-up findings.

Atypical squamous cells of undetermined significance cytology (ASC-US) is a challenging and equivocal diagnosis for pathologists in cervical Pap smears. The data on ASC-US cervical cytology in Bahrain are deficient. This study reviewed and identified the reporting rates, high-risk human papillomavirus (HPV) testing results, histopathologic follow-up findings, and the cytologic progression of patients diagnosed with ASC-US in Bahrain. A retrospective chart review was conducted on the medical records of 23,888 women who had Pap smear test results between January 2019 and March 2022 at the main referral tertiary hospital in Bahrain to identify the ASC-US cases. High-risk HPV (hrHPV) genotype was identified, and the histopathological results of the cervical biopsy was recorded. In addition, cytologic follow-up Pap smear tests conducted within 1 year of ASC-US diagnosis were tracked to monitor the progression or regression of ASC-US. In this study, 259 out of 23,888 women reported to have ASC-UC cytology results with a reporting rate of 1.1%. The mean age of the ASC-US cases was 43 ± 11.6. Thirty percent of the ASC-US cases tested positive for hrHPV, and they were predominantly infected with the other hrHPV genotype (75%). When the histopathological changes of the cervix were analyzed, 82.1% had normal histopathologic findings. However, low-grade cervical intraepithelial neoplasia-1 was reported in 2 cases (7.1%), and high-grade cervical lesions (cervical intraepithelial neoplasia-2 and higher) were reported in 3 cases (10.7%). Regarding the cytologic follow-up, most of the ASC-US cases were negative for intraepithelial lesion or malignancy (NILM) (73.8%) or had persistent ASC-US (17.9%). The remaining minority of cases progressed into either low-grade squamous intraepithelial lesions (6%) or high-grade squamous intraepithelial lesions (2.4%). There was a statistically significant and relatively strong association between the cytology follow-up findings and the hrHPV test results (χ2 [2] = 8.869, P < 0.012, Cramer's V = 0.417). This is the first and largest study to characterize the ASC-US cytology cases in Bahrain. The reporting rates of ASC-US fell within the worldwide reported range. Although most of the ASC-US cases regressed into NILM, ASC-US showed progression into more advanced cervical cytologic diagnoses or contributed to the malignant transformation of cervical tissue, especially in the presence of hrHPV infection which was positive in 30% of the ASC-US cases. This emphasizes the role of cotesting (combination of hrHPV genotyping and Pap smear test) and the importance of colposcopic evaluation of those women with cytologic follow-up tests at 1 year of diagnosis. Implementing these recommendations in the cervical cancer screening practice in Bahrain will help in having a better management plan for women diagnosed with ASC-US cervical cytology.

The IMproving Primary Screening And Colposcopy Triage trial: human papillomavirus, cervical cytology, and histopathologic results from the baseline and 1-year follow-up phase

An increase in human papillomavirus test volumes is expected in the near future because human papillomavirus-based screening protocols are expected to become more widely adopted. The IMproving Primary Screening And Colposcopy Triage trial, a prospective, multicenter, US-based cervical cancer screening trial, was conducted to obtain US Food and Drug Administration approvals for the new, high-throughput cobas human papillomavirus (cobas HPV) test for use on the cobas 6800/8800 Systems (cobas HPV) for detecting cervical precancerous and cancerous cells (cervical intraepithelial neoplasia of grade 2 or worse and grade 3 or worse). Here, the baseline demographics, human papillomavirus test results, cervical cytology, and histopathologic results are presented. In addition, the baseline and 1-year risks of cervical intraepithelial neoplasia grade 2 or worse and grade 3 or worse associated with the human papillomavirus results are reported. In total, 35,263 women aged between 25 and 65 years undergoing routine screening were enrolled; liquid-based cytology and 2 polymerase chain reaction-based tests for high-risk human papillomavirus were performed. Women with abnormal Papanicolaou cytology, women positive for high-risk human papillomavirus by either of the 2 human papillomavirus tests, and a random subset of women negative according to the Papanicolaou cytology and the 2 human papillomavirus tests were referred for a colposcopy and cervical biopsy. Women who did not meet the study endpoint were eligible for the 1-year follow-up study phase. Verification bias-adjusted cervical disease prevalence and risks and 95% confidence intervals were computed. The prevalence of atypical squamous cells of undetermined significance and worse than atypical squamous cells of undetermined significance cytology were 6.5% and 3.2%, respectively. Prevalence of high-risk human papillomavirus, human papillomavirus 16, and human papillomavirus 18 based on the new cobas HPV test were 15.1%, 3.1%, and 1.4%, respectively. Both cytologic abnormalities and human papillomavirus positivity declined with increasing age. Among women who had a colposcopy and biopsy, the prevalence of cervical intraepithelial neoplasia grade 2 or worse and grade 3 or worse were 8.8% and 3.6%, respectively. The baseline and 1-year cumulative risks for cervical intraepithelial neoplasia grade 3 or worse were 13.6% and 16.9%, respectively, among women who tested positive for human papillomavirus 16. Women who tested negative for human papillomavirus had the lowest 1-year cumulative risk for cervical intraepithelial neoplasia grade 3 or worse (0.06%). The contemporary, age-specific prevalence of human papillomaviruses (including human papillomavirus 16 and 18), cytologic abnormalities, and cervical intraepithelial neoplasia in a large, US-based cervical cancer screening population provides benchmarks for healthcare policies, screening programs, and for laboratories and clinicians.

High-risk human papillomavirus test in anal smears: can it optimize the screening for anal cancer?

The current method for screening anal cancer is anal cytology, which has low sensitivity. Since high-risk human papillomavirus (HR-HPV) is associated with almost 90% of cases of anal cancer, the objective of this study is to evaluate whether testing for HR-HPV can optimize the screening. Prospective study with patients enrolled in a screening program for anal dysplasia. Considering high-resolution anoscopy (HRA)-guided biopsy as the gold standard for diagnosis of high-grade squamous intraepithelial lesions, the diagnostic performance of anal cytology, HR-HPV testing, and the combination of both was calculated. A single center for anal dysplasia. A total of 364 patients (72% males, 82% HIV-positive). Patients underwent anal cytology, HR-HPV test, and HRA-guided biopsy of the anal canal. Ability of cytology and HR-HPV test (individually and combined) to detect high-grade squamous intraepithelial lesions, and analysis of the cost of each diagnostic algorithm. Cytology alone was the cheapest approach, but had the lowest sensitivity [59%, 95% confidence interval (CI) 46-71%], despite of highest specificity (73%, 95% CI 68-78%). Cotesting had the highest sensitivity (85%, 95% CI 74-93%) and lowest specificity (43%, 95% CI 38-49%), and did not seem to be cost-effective. However, HR-HPV testing can be used to triage patients with normal and atypical squamous cells of undetermined significance cytology for HRA, resulting in an algorithm with high sensitivity (80%, 95% CI 68-89%), and specificity (71%, 95% CI 65-76%), allied to a good cost-effectiveness. HR-HPV testing is helpful to optimize the screening in cases of normal and atypical squamous cells of undetermined significance cytology.

Comparison of immediate colposcopy, repeat conventional cytology and hrHPV testing for the clinical management of ASC-US cytology in routine health services of Medellin, Colombia: The ASCUS-COL Trial.

In the context of opportunistic cervical cancer screening settings of low-and-middle-income countries, little is known about the benefits of high-risk human papillomavirus (hrHPV) testing on high-grade cervical abnormality detection among women with atypical squamous cells of undetermined significance (ASC-US) cytology in routine clinical practice. We compared the effectiveness of immediate colposcopy (IC), conventional cytology at 6 and 12 months (colposcopy if ≥ASC-US) (RC), and hrHPV testing (colposcopy if hrHPV-positive) (HPV) to detect cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) among women aged 20-69 years with ASC-US in routine care. Participants (n=2,661) were evenly randomized into three arms (n=882 IC, n=890 RC, n=889 HPV) to receive services by routine healthcare providers and invited to an exit visit 24 months after recruitment. Histopathology was blindly reviewed by a quality-control external panel (QC). The primary endpoint was the first QC-diagnosed CIN2+ or CIN3+ detected during three periods: enrolment (≤6 months for IC and HPV, ≤12 months for RC), follow-up (between enrolment and exit visit), and exit visit. The trial is completed. Colposcopy was done on 88%, 42%, and 52% of participants in IC, RC, and HPV. Overall, 212 CIN2+ and 52 CIN3+ cases were diagnosed. No differences were observed for CIN2+ detection (p=0.821). However, compared to IC, only HPV significantly reduced CIN3+ cases that providers were unable to detect during the 2-year routine follow-up (relative proportion 0.35, 95% CI 0.09-0.87). In this context, hrHPV testing was the most effective and efficient management strategy for women with ASC-US cytology.

Immediate histologic correlation in women with atypical squamous cells of undetermined significance cytology and positive high-risk HPV: A retrospective review of 6000 cases in a large academic women's hospital.

Previous studies of the histologic correlation in women who have atypical squamous cells of undetermined significance cytology (ASC-US) and are positive for high-risk human papillomavirus (hrHPV+) have predominantly utilized the Hybrid Capture 2 (HC2) test, whereas the use of other US Food and Drug Administration (FDA)-approved methods is relatively limited. Cases of ASC-US/hrHPV+ that were tested using HC2, Cervista, or Aptima were retrieved, and the immediate histologic correlations were analyzed. Overall, 53.9% (n=3238) of women with ASC-US/hrHPV+ had immediate histologic correlation. The detection rates for grade 1 cervical intraepithelial neoplasia (CIN1) were similar among the 3 methods (37.1%-41.8%), while the overall detection rates for grade 2 CIN or higher (CIN2+) were much lower (5.1%-9.0%). CIN2+ detection rates were similar among different age groups for HC2 testing, whereas for Cervista and Aptima testing, detection rates were highest in the youngest group (age <25years) and decreased with age. Statistical analyses revealed that the CIN2+ detection rate was significantly higher in younger women who were tested with Cervista. These hrHPV testing methods revealed low CIN2+ detection rates in women with ASC-US/hrHPV+ but demonstrated different patterns when using age-stratified analyses. The high rate of CIN2+ detection in women aged <25years by the Cervista and Aptima testing platforms, but not the HC2 platform, suggest that continual investigation of FDA-approved clinical hrHPV testing-especially large-scale, long-term, prospective studies-is needed to evaluate the best options for management of ASC-US/hrHPV+ in this age group.

Performance of the cobas HPV Test for the Triage of Atypical Squamous Cells of Undetermined Significance Cytology in Cervical Specimens Collected in SurePath.

Determine performance of the cobas human papillomavirus (HPV) test for triage of atypical squamous cells of undetermined significance (ASC-US) in SurePath. Women presenting for routine screening had cervical specimens collected in SurePath and specimen transport medium (STM); those with ASC-US cytology underwent colposcopy. Performance of cobas HPV in SurePath specimens that had undergone a preanalytic procedure to reverse possible cross-linking of HPV DNA was compared with Hybrid Capture 2 (hc2) specimens in STM. Among 856 women, HPV prevalence was 45.8%; HPV 16 and HPV 18 prevalences were lower than expected in the 21- to 29-year-old group in this highly vaccinated population. cobas HPV performance in SurePath was comparable to hc2 in STM. Sensitivity and specificity for detection of cervical intraepithelial neoplasia grade 3 or worse were 87.5% (95% confidence interval [CI], 71.9%-95.2%) and 55.5% (95% CI, 52.1%-58.9%) for cobas and 85.3% (95% CI, 69.9%-93.6%) and 54.7% (95% CI, 51.4%-57.9%) for hc2. Sensitivity was negatively affected by random biopsies performed at colposcopy; comparable sensitivities were achieved in the nonvaccinated and vaccinated populations with disease determined by directed biopsy only. Performance of cobas HPV for ASC-US triage in pretreated SurePath specimens meets criteria for validation. Preliminary data indicate reliable performance of HPV testing in a highly vaccinated population.

Clinical progress of human papillomavirus genotypes and their persistent infection in subjects with atypical squamous cells of undetermined significance cytology: Statistical and latent Dirichlet allocation analysis.

The present study aimed to investigate differences in prognosis based on human papillomavirus (HPV) infection, persistent infection and genotype variations for patients exhibiting atypical squamous cells of undetermined significance (ASCUS) in their initial Papanicolaou (PAP) test results. A latent Dirichlet allocation (LDA)-based tool was developed that may offer a facilitated means of communication to be employed during patient-doctor consultations. The present study assessed 491 patients (139 HPV-positive and 352 HPV-negative cases) with a PAP test result of ASCUS with a follow-up period ≥2 years. Patients underwent PAP and HPV DNA chip tests between January 2006 and January 2009. The HPV-positive subjects were followed up with at least 2 instances of PAP and HPV DNA chip tests. The most common genotypes observed were HPV-16 (25.9%, 36/139), HPV-52 (14.4%, 20/139), HPV-58 (13.7%, 19/139), HPV-56 (11.5%, 16/139), HPV-51 (9.4%, 13/139) and HPV-18 (8.6%, 12/139). A total of 33.3% (12/36) patients positive for HPV-16 had cervical intraepithelial neoplasia (CIN)2 or a worse result, which was significantly higher than the prevalence of CIN2 of 1.8% (8/455) in patients negative for HPV-16 (P<0.001), while no significant association was identified for other genotypes in terms of genotype and clinical progress. There was a significant association between clearance and good prognosis (P<0.001). Persistent infection was higher in patients aged ≥51 years (38.7%) than in those aged ≤50 years (20.4%; P=0.036). Progression from persistent infection to CIN2 or worse (19/34, 55.9%) was higher than clearance (0/105, 0.0%; P<0.001). In the LDA analysis, using symmetric Dirichlet priors α=0.1 and β=0.01, and clusters (k)=5 or 10 provided the most meaningful groupings. Statistical and LDA analyses produced consistent results regarding the association between persistent infection of HPV-16, old age and long infection period with a clinical progression of CIN2 or worse. Therefore, LDA results may be presented as explanatory evidence during time-constrained patient-doctor consultations in order to deliver information regarding the patient's status.

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

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. 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. 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. 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).

High-Risk HPV DNA Testing and HPV-16/18 Genotyping

There are currently 2 tests approved for clinical use that nonspecifically detect the presence of multiple oncogenic or high-risk human papillomavirus (HPV) types. One HPV genotyping test is also available for use that specifically detects the presence of high-risk HPV types 16 and 18. The purpose of this review was to evaluate the clinical performance of these HPV DNA tests and the utility of the tests within current screening recommendations. The sensitivity and specificity of currently available HPV DNA tests to detect the presence of precancerous high-grade cervical lesions are reviewed. Appropriate test usage is discussed in the context of the natural history of HPV infection. Molecular testing for the presence of high-risk HPV is more sensitive but less specific than cytologic testing for the detection of high-grade cervical lesions. Current patient management guidelines recommend the use of high-risk HPV DNA testing to triage women 21 years or older with equivocal cytology results and in conjunction with cytology for cervical screening in women 30 years or older. The HPV-16/18 genotyping test may be used in women 30 years or older with negative cytology and positive high-risk HPV DNA test results to determine the need for colposcopy. Although infection with high-risk HPV is highly prevalent in adult females, most infections are transient and do not require intervention. Clinical application of appropriate age-adjusted use of HPV DNA testing and its use in conjunction with atypical squamous cells of undetermined significance cytology will avoid unnecessary follow-up procedures.

Analytical performance of Cervista ® HPV 16/18 genotyping test for cervical cytology samples

Background Human papillomavirus (HPV) types 16 and 18 are the 2 most frequent types associated with cervical cancer. Identifying their presence or absence in cervical samples may assist in triaging women for subsequent management. The Cervista ® HPV 16/18 genotyping test specifically detects the presence of HPV 16 and 18 in ThinPrep ® cervical specimens. Objectives The objective was to establish the analytical performance of the CERVISTA HPV 16/18 genotyping test. Study design These studies were performed in support of a regulatory submission to the US Food and Drug Administration. Here we report the analytical sensitivity (limit of detection), accuracy compared to consensus L1 gene PCR/bi-directional sequencing, precision, reproducibility, and cross-reactivity (specificity) of the genotyping test. Results Analytical sensitivity for detection of HPV 16 and 18 ranged between 625 and 1250 copies/reaction for both types. When compared to PCR/sequencing for women with atypical squamous cells of undetermined significance cytology, the positive percent agreement was 94.1% (95% confidence interval [CI], 89.8–96.7) and the negative percent agreement was 85.7% (95% CI, 82.4–88.4). The test demonstrated high within-laboratory and inter-operator precision. Reproducibility within sites and between 3 testing sites resulted in 100% agreement with expected results (150 positive, 90 negative results). The genotyping test did not exhibit cross-reactivity to DNA from common low-risk HPV types and other microorganisms found in the human female reproductive tract. Conclusions These analytical performance data support the use of CERVISTA HPV 16/18 genotyping test for the detection and differentiation of HPV 16 and 18 in ThinPrep cervical cytology specimens.

A Weakly Positive Human Papillomavirus Hybrid Capture II Result Correlates With a Significantly Lower Risk of Cervical Intraepithelial Neoplasia 2,3 After Atypical Squamous Cells of Undetermined Significance Cytology

A Weakly Positive Human Papillomavirus Hybrid Capture II Result Correlates With a Significantly Lower Risk of Cervical Intraepithelial Neoplasia 2,3 After Atypical Squamous Cells of Undetermined Significance Cytology

Detection of Oncogenic Human Papillomavirus Impacts Anal Screening Guidelines in Men Who Have Sex With Men

It has been shown that testing for oncogenic human papillomavirus (HPV+) improves the sensitivity of cytologic diagnosis of atypical cells of undetermined significance in the cervix and anus, reducing the number of patients requiring colposcopy or high-resolution anoscopy. Some recommend that men who have sex with men with any abnormal cytology undergo high-resolution anoscopy. We endeavored to determine whether HPV testing could predict future high-grade dysplasia (high-grade squamous intraepithelial lesions) and modify screening internals. This investigation was conducted via a retrospective chart review of subjects with atypical cells of undetermined significance anal cytology, high-resolution anoscopy, and HPV testing. Records were abstracted for prior and subsequent screenings. Four hundred men who have sex with men (285 HIV-) underwent 2224 screenings. Of 224 subjects monitored for >2 years, the hazard ratio for developing high-grade dysplasia was 77% less for men who have sex with men who never had oncogenic HPV (HPV-) vs those who stayed HPV+ (P < .013). The hazard ratio for high-grade dysplasia in those who were HPV- vs those who became HPV- was not different. Risk of high-grade dysplasia was 28% within 6 months of becoming HPV+. The 3-year high-grade dysplasia risk was 15% and 54% for HPV- vs HPV+ subjects (P = .0006). Frequency of high-grade dysplasia in subjects who remained HPV- with predominantly atypical cells of undetermined significance cytology for 1, 2, or 3 years was 2%, 0% and 0% and was 17%, 0%, and 0% in HIV+ subjects. Kaplan-Meier analysis for HIV- subjects with HPV- predominantly atypical cells of undetermined significance cytology for 1 year showed <5% incidence of high-grade dysplasia at 4 years. Change in HPV status can predict the risk of high-grade dysplasia. Subjects with predominantly HPV- atypical cells of undetermined significance cytology for 2 years have a decreased risk of high-grade dysplasia. HPV testing when screening for anal dysplasia could alter screening parameters.

A Weakly Positive Human Papillomavirus Hybrid Capture II Result Correlates With a Significantly Lower Risk of Cervical Intraepithelial Neoplasia 2,3 After Atypical Squamous Cells of Undetermined Significance Cytology

The Hybrid Capture II assay (hc2; QIAGEN, Inc) for high-risk human papillomavirus (hrHPV) is an in vitro nucleic acid hybridization assay using chemiluminescence for the qualitative detection of hrHPV DNA in cervical samples. Results are reported as a ratio of relative light units (RLUs) to a cutoff value based on a positive control. Specimens with RLU ratios of 1.0 or higher are scored positive for hrHPV. We tested the hypothesis that hrHPV positives with low-positive RLU ratios (1-10) had a lower prevalence of cervical intraepithelial neoplasia 2,3 (CIN 2,3) on histologic follow-up. Relative light unit ratios for 388 consecutive hrHPV-positive cervical cytologic specimens interpreted as atypical squamous cells of undetermined significance (ASCUS) were reviewed. Individual RLU ratios were compared with outcome histologic diagnosis in cases with colposcopic follow-up and tissue sampling (biopsy and/or endocervical curettage; n = 236). Of 236 cases with histologic follow-up, 63 had RLU ratios in the range of 1 to 10; of these, 53 (84.1%) were negative for CIN, 7 (11.1%) had CIN 1, 1 (1.6%) had CIN of uncertain grade, and 2 (3.2%) had CIN 2,3. The difference in CIN 2,3 outcome between RLU ratios of 1 to 10 (3.2%) versus over 10 (17.3%) was significant (p =.0047). The difference in prevalence of CIN 1 was not significant (p =.67). An RLU ratio of 10 or less was associated with a significantly lower prevalence of CIN 2,3 on biopsy outcome after a Pap test result of ASCUS. The much lower prevalence of underlying CIN 2,3 in patients who are weakly HPV-positive may justify modification of the management algorithm for this subset of women with ASCUS.

Detection of Oncogenic Human Papillomavirus and Other Predictors of Anal High-Grade Dysplasia in Men Who Have Sex with Men with Abnormal Cytology

The incidence of anal high-grade dysplasia in men who have sex with men is increasing. Anal cytology that shows atypical squamous cells of undetermined significance is common, nonspecific, and rarely predicts high-grade squamous intraepithelial lesion. We want to know whether Hybrid-Capture II(R) testing for oncogenic human papillomavirus (human papillomavirus+) in men who have sex with men with atypical squamous cells of undetermined significance is beneficial and whether other predictors of high-grade squamous intraepithelial lesion exist. We performed a retrospective chart review of men who have sex with men undergoing anal screening with atypical squamous cells of undetermined significance cytology, Hybrid-Capture(R) II testing, and biopsy. Records were analyzed for all screenings. A total of 597 men who have sex with men enrolled and had 1,015 atypical squamous cells of undetermined significance cytology results: 185 (18.2 percent) had high-grade squamous intraepithelial lesion and 156 (84 percent) were human papillomavirus+. The rates for sensitivity, specificity, positive predictive value, and negative predictive value were 84, 53, 29, and 94 percent, respectively. Of 390 low-grade squamous intraepithelial lesion cytology results, high-grade squamous intraepithelial lesion was found in 141 and 127 (90 percent) were human papillomavirus+. Those with previous high-grade squamous intraepithelial lesions or human immunodeficiency virus had increased risk of high-grade squamous intraepithelial lesion (hazard ratio = 2.2 and hazard ratio = 1.95, respectively). Age was not a factor. Hybrid-Capture II(R) testing is useful in men who have sex with men with atypical squamous cells of undetermined significance. Referring only those with oncogenic human papillomavirus for biopsy reduces the number requiring this by almost half but some high-grade squamous intraepithelial lesions are missed. History of high-grade squamous intraepithelial lesion and human immunodeficiency virus are predictors of high-grade squamous intraepithelial lesion while screening intervals might be lengthened absent oncogenic human papillomavirus or in those free of high-grade squamous intraepithelial lesion for long periods.

Human Papillomavirus Infection and Cervical Disease in Human Immunodeficiency Virus-1–Infected Women

To report on the natural history of high-risk human papillomavirus (HPV) infection and cervical disease in human immunodeficiency virus (HIV)-1-infected women living in Cape Town, South Africa. This was a prospective study of 400 untreated, HIV-1-infected women who underwent high-risk HPV DNA testing, cytology, colposcopy, histology, and CD4 count testing every 6 months for 36 months. Human immunodeficiency virus viral loads and HPV type distribution were determined at entry and after 18 months. Sixty-eight percent of the women were high-risk HPV DNA positive at entry, 35% had a cytologic diagnosis of low-grade squamous intraepithelial lesion (LSIL), and 13% had high-grade squamous intraepithelial lesion (HSIL). There were no cancers. Abnormal cytology and high-risk HPV positivity were strongly correlated with low CD4 counts and high HIV viral loads. The most prevalent types of HPV were HPV-16, -52, -53, -35, and -18. Incident high-risk HPV infection occurred in 22%, and of those infected with high-risk HPV, 94% of infections persisted over an 18-month period, and 6% cleared their infections. Cytologic progression to SIL from normal/atypical squamous cells of undetermined significance cytology occurred in 17% of cases, but only 4% of cases of LSIL progressed to HSIL. There is a high level of high-risk HPV infection in HIV-1 infected women, but progression to HSIL over 36 months occurred in the minority of cases. We recommend an initial colposcopy for an abnormal test, and if no high-grade lesion is identified, triennial screening would be appropriate. Human papillomavirus type 16 was the commonest, and HPV-18 was the fifth commonest, suggesting that vaccination against these two types would have a significant effect. II.

Hybrid Capture II Detection of Oncogenic Human Papillomavirus: A Useful Tool When Evaluating Men Who Have Sex with Men with Atypical Squamous Cells of Undetermined Significance on Anal Cytology

In the cervix and anus, patients with atypical squamous cells of undetermined significance often do not have high-grade squamous intraepithelial lesions. In women with atypical squamous cells of undetermined significance, Hybrid-Capture II testing for oncogenic high-risk human papillomavirus is performed and those without high-risk human papillomavirus often are observed. We endeavored to determine whether Hybrid-Capture II testing would be beneficial in men who have sex with men with atypical squamous cells of undetermined significance. We performed a retrospective chart review of men who have sex with men with atypical squamous cells of undetermined significance who had high-resolution anoscopy and Hybrid-Capture II. A total of 290 men were identified (mean age, 42 years), and 212 (73 percent) were HIV-negative. High-grade squamous intraepithelial lesions were found in 50 (17 percent): 23 (10 percent) who were HIV-negative and 27 (35 percent) who were HIV-positive men. High-risk human papillomavirus was found in 138 (48 percent); 91 (43 percent) of HIV-negative and 47 (60 percent) of HIV-positive men. The sensitivity, specificity, positive predictive value, and negative predictive value of atypical cells of undetermined significance cytology combined with Hybrid-Capture II were 84, 60, 30, and 95 percent, respectively. There was no significant difference between all men vs. those who were HIV-positive or HIV-negative except for the positive predictive value. Hybrid-Capture II testing for high-risk human papillomavirus in men who have sex with men with atypical cells of undetermined significance and referring only those with high-risk human papillomavirus reduces the number who require high-resolution anoscopy by more than half. Five percent with high-grade squamous intraepithelial lesions would be missed.

Risk of Precancer and Follow-up Management Strategies for Women With Human Papillomavirus–Negative Atypical Squamous Cells of Undetermined Significance

To investigate the relative performances of follow-up cytology and carcinogenic human papillomavirus (HPV) DNA testing among carcinogenic HPV-negative women with atypical squamous cells of undetermined significance (ASCUS), for detection of cervical precancer. Twelve-month follow-up management strategies to detect cervical intraepithelial neoplasia grade 3 (CIN3) or worse using cytology or HPV testing or both were compared among women with HPV-negative ASCUS in the Atypical Squamous Cells of Undetermined Significance-Low-Grade Squamous Intraepithelial Lesion (ASCUS-LSIL) Triage Study. Overall only 22 of 1,559 (1.4%) HPV-negative ASCUS women developed CIN grade 3 or worse during follow-up compared with 269 of 1,767 (15.2%) HPV-positive ASCUS women (P<.001). Because of the low risk of disease among HPV-negative ASCUS women, only 7 cases of CIN3 were diagnosed between 12 and 24 months of follow-up, limiting power to distinguish meaningful differences in sensitivity among 12-month testing strategies. The specificity of HPV testing (84%) was significantly higher than cytology using an ASCUS threshold (71%) (P<.001). Cotesting with cytology and HPV testing at 12 months resulted in even lower specificity (61%). Because cases were uncommon, the positive predictive value for subsequent CIN3 or worse was low for cytology (2.6%), Hybrid Capture 2 (3.8%), and cotesting with cytology and HPV testing (2.2%). The negative predictive value for all three management strategies was very high (99.70%, 99.82%, and 100.0% for HPV testing, cytology, or cotesting, respectively.) Women with HPV-negative ASCUS have very low absolute risk of subsequently detected CIN3 or worse in the subsequent 2 years, similar to women with a negative cytology in the absence of HPV testing. The results suggest that women with HPV-negative ASCUS should return to routine screening intervals which may be longer than 1 year depending on age and screening history. However, if increased surveillance is chosen, a single HPV test for carcinogenic types at 12 months has significantly higher specificity and lower referrals than cytology.

A Comparison of 2 Management Strategies for Patients with Atypical Squamous Cells of Undetermined Significance Cytology

A Comparison of 2 Management Strategies for Patients with Atypical Squamous Cells of Undetermined Significance Cytology

Human Papillomavirus Triage for Young Women With Atypical Squamous Cells of Undetermined Significance

Human papillomavirus testing is a cost-effective strategy for the management of atypical squamous cells of undetermined significance. Young women have a high prevalence of transient human papillomavirus infections and low incidence high-grade cervical lesions, which may limit the usefulness of human papillomavirus testing in this cohort. We sought to estimate the usefulness of human papillomavirus testing for young women with atypical squamous cells of undetermined significance. A retrospective study of women with atypical squamous cells of undetermined significance was undertaken. Reflex human papillomavirus results and pathologic follow-up were evaluated. Age-stratified rates of human papillomavirus positivity, rates of high-grade dysplasia, and sensitivity and specificity were estimated. A total of 1,290 women with atypical squamous cells of undetermined significance cytology were identified. The rate of human papillomavirus positivity decreased with age from 55% for those aged 25 years or younger to 12% for women aged older than 50 years (P < .001). The cumulative rate of high-grade lesions increased with age; 12% for patients aged 25 years or younger compared with 24% for women aged older than 50 years (P = .05). A negative human papillomavirus test more effectively excluded high-grade disease in the young women. No high-grade lesions were detected in the human papillomavirus negative women aged 25 years or younger compared with 3.8% of those aged older than 50 years (P = .04). The sensitivity for detection of high-grade disease was higher in women aged younger than 25 years compared with those aged older than 50 years (100% compared with 50%), whereas specificity was lower (14% compared with 44%). Given the high prevalence of human papillomavirus and low occurrence of high-grade lesions in young women with atypical squamous cells of undetermined significance, a human papillomavirus-based triage strategy will result in the referral of a large number of women for colposcopy and may limit its cost-effectiveness. III.

Atypical Squamous Cells of Undetermined Significance in Girls and Women

To estimate the outcome of adolescents with atypical squamous cells of undetermined significance (ASC-US) on cytology. A review of ASC-US cytology in girls and women aged 10-19 years between 1995 and 1999 was performed. The cytologic and histologic follow-up of each patient was evaluated. The outcome was recorded as the most significant (highest grade) subsequent cervical smear or biopsy. Overall, 535 of 7897 (6.8%) cervical cytologic specimens were reported as ASC-US. The study group consisted of 398 patients for whom pathologic follow-up was available. The mean duration of follow-up was 19 months. Follow-up consisted of repeat cytology in 251 (63%) patients and colposcopy with cervical biopsies and/or endocervical curettage in 147 (37%) of the adolescents. Two hundred fifty-three (64%) adolescents had no pathologic abnormalities on follow-up. Persistent ASC-US was identified in 65 (16%), low-grade squamous intraepithelial lesions/cervical intraepithelial neoplasia (CIN) 1 was found in 44 (11%) and high-grade squamous intraepithelial lesions/CIN 2 or 3 occurred in 36 (9%) of the adolescents. No cases of invasive carcinoma were found. Among adolescents with ASC-US, the rate of squamous intraepithelial lesions/CIN is similar to that of adults. Although the optimal management of ASC-US in adolescents is unknown, these patients warrant close follow-up. III