High-risk Human Papillomavirus Results Research Articles

Distribution of 14 High-Risk HPV Types and p16/Ki67 Dual-Stain Status in Post-Colposcopy Histology Results: Negative, Low- and High-Grade Cervical Squamous Intraepithelial Lesions.

Determining the distribution of high-risk human papillomavirus (HR-HPV) types in histologic low-(LSIL) and high-grade (HSIL/CIN2+) squamous intraepithelial lesions through a diagnostic process in a cervical cancer prevention provides one of the key etiological factors behind further progression and persistence. Incorporating novel high-grade cervical lesion biomarkers such as p16/Ki67 dual staining (DS) alongside HPV typing has become important in detecting cervical precancers. Among 28,525 screening tests and 602 histology results, 559 cases with HR-HPV and histology results obtained from colposcopic biopsy were retrospectively analyzed, together with DS status. The χ2 test with Bonferroni correction evaluated the differences in HR-HPV type prevalence and DS positivity across three histologic study groups. A statistically significant difference in the prevalence of HPV 16 was observed between negative and HSIL/CIN2+ (p = 0.00027) groups, as well as between the LSIL/CIN1 and HSIL/CIN2+ groups (p = 0.00041). However, no significant difference was found between the negative and LSIL/CIN1 groups. Similarly, the DS positivity difference was significant between the negative and HSIL/CIN2+ (p < 0.0001) and between the LSIL/CIN1 and HSIL/CIN2+ groups (p < 0.0001), but there was no significant difference between the negative and LSIL/CIN1 groups. The study highlights the heterogeneous nature of HPV-related cervical pathologies, and the distinct risks associated with different cervical lesion grades, emphasizing the importance of HR-HPV type distribution and DS status.

Evaluating the Feasibility of Machine-Learning-Based Predictive Models for Precancerous Cervical Lesions in Patients Referred for Colposcopy.

Background: Colposcopy plays an essential role in cervical cancer control, but its performance remains unsatisfactory. This study evaluates the feasibility of machine learning (ML) models for predicting high-grade squamous intraepithelial lesions or worse (HSIL+) in patients referred for colposcopy by combining colposcopic findings with demographic and screening results. Methods: In total, 7485 patients who underwent colposcopy examination in seven hospitals in mainland China were used to train, internally validate, and externally validate six commonly used ML models, including logistic regression, decision tree, naïve bayes, support vector machine, random forest, and extreme gradient boosting. Nine variables, including age, gravidity, parity, menopause status, cytological results, high-risk human papillomavirus (HR-HPV) infection type, HR-HPV multi-infection, transformation zone (TZ) type, and colposcopic impression, were used for model construction. Results: Colposcopic impression, HR-HPV results, and cytology results were the top three variables that determined model performance among all included variables. In the internal validation set, six ML models that integrated demographics, screening results, and colposcopic impression showed significant improvements in the area under the curve (AUC) (0.067 to 0.099) and sensitivity (11.55% to 14.88%) compared with colposcopists. Greater increases in AUC (0.087 to 0.119) and sensitivity (17.17% to 22.08%) were observed in the six models with the external validation set. Conclusions: By incorporating demographics, screening results, and colposcopic impressions, ML improved the AUC and sensitivity for detecting HSIL+ in patients referred for colposcopy. Such models could transform the subjective experience into objective judgments to help clinicians make decisions at the time of colposcopy examinations.

Anal cytology and high-risk human papilloma virus testing in atypical squamous categories: Value of concurrent testing in management of high-risk population.

Anal squamous cell carcinoma is relatively rare, but its incidence and mortality have been increasing worldwide. While anal cytology is a sensitive cancer screening modality, its specificity is low, and data for concurrent high-risk human papilloma virus (HR-HPV) testing are limited. At our institution, anal cancer screening consists of combined anal cytology and high-risk human papilloma virus (HR-HPV) testing on all specimens. The aims of the study were to correlate results of atypical cytological diagnoses [atypical squamous cells of undetermined significance (ASCUS) and atypical squamous cells cannot exclude high grade squamous intraepithelial lesion (ASC-H)] with HR-HPV testing and determine if co-testing may potentially influence management. A retrospective search over 24-months was performed for anal cytology specimens with diagnoses of ASCUS and ASC-H. Corresponding HR-HPV (HPV 16/18 and Other-31/33/35/39/45/51/52/56/58/59/66/68) results were retrieved, and concordance/discordance was recorded. Cytology results were correlated with anal biopsy diagnoses, when available. A total of 139 patients, including 127 with ASCUS and 12 with ASC-H, were identified. Of the ASCUS cases, 90/127 (70.9%) had HR-HPV, and a squamous intraepithelial lesion (SIL) was evident in 20/39 (51.2%) of biopsies. All 12/12 (100%) ASC-H were associated with HR-HPV and 3/6 (50%) biopsies had a SIL. Our study supports use of concurrent cytology and HR-HPV for anal cancer screening cytology. Co-testing improves specificity of atypical cytology diagnoses and can identify patients requiring further intervention.

Incomplete excision of cervical intraepithelial neoplasia as a predictor of the risk of recurrent disease—a 16-year follow-up study

Women treated for high-grade cervical intraepithelial neoplasia (grade 2 or 3) are at elevated risk for developing cervical cancer. Suggested factors identifying women at highest risk for recurrence post-therapeutically include incomplete lesion excision, lesion location, size and severity, older age, treatment modality, and presence of high-risk human papilloma virus after treatment. This question has been intensively investigated over decades, but there is still substantial debate as to which of these factors or combination of factors most accurately predict treatment failure. In this study, we examine the long-term risk of residual/recurrent high-grade cervical intraepithelial neoplasia among women previously treated for cervical intraepithelial neoplasia 2/3 and how this varies according to margin status (considering also location), as well as comorbidity (conditions assumed to interact with high-risk human papilloma virus acquisition and/or cervical intraepithelial neoplasia progression), posttreatment presence of high-risk human papilloma virus, and other factors. This prospective study included 991 women with histopathologically confirmed cervical intraepithelial neoplasia 2/3 who underwent conization in 2000-2007. Information on the primary histopathologic finding, treatment modality, comorbidity, age, and high-risk human papilloma virus status during follow-up, and residual/recurrent high-grade cervical intraepithelial neoplasia was obtained from the Swedish National Cervical Screening Registry and medical records. Cumulative incidence of residual/recurrent high-grade cervical intraepithelial neoplasia was plotted on Kaplan-Meier curves, with determinants assessed by Cox regression. During a median of 10 years and maximum of 16 years offollow-up, 111 patients were diagnosed with residual/recurrent high-grade cervical intraepithelial neoplasia or worse. Women with positive/uncertain margins had a higher risk of residual/recurrent high-grade cervical intraepithelial neoplasia or worse than women with negative margins, adjusting for potential confounders (hazard ratio, 2.67; 95% confidence interval, 1.81-3.93). The risk of residual/recurrent high-grade cervical intraepithelial neoplasia or worse varied by anatomical localization of the margins (endocervical: hazard ratio, 2.72; 95% confidence interval, 1.67-4.41) and both endo- and ectocervical (hazard ratio, 4.98; 95% confidence interval, 2.85-8.71). The risk did not increase significantly when only ectocervical margins were positive or uncertain. The presence of comorbidity (autoimmune disease, human immunodeficiency viral infection, hepatitis B and/or C, malignancy, diabetes, genetic disorder, and/or organ transplant) was also a significant independent predictor of residual/recurrent high-grade cervical intraepithelial neoplasia or worse. In women with positive high-risk human papilloma virus findings during follow-up, the hazard ratio of positive/uncertain margins for recurrent/residual high-grade cervical intraepithelial neoplasia or worse increased significantly compared to that in women with positive high-risk human papilloma virus findings but negative margins. Patients with incompletely excised cervical intraepithelial neoplasia 2/3 are at increased risk for residual/recurrent high-grade cervical intraepithelial neoplasia or worse. Margin status combined with high-risk human papilloma virus results and consideration of comorbidity may increase the accuracy for predicting treatment failure.

Atypical Squamous Cells in Liquid-Based Cervical Cytology: Microbiology, Inflammatory Infiltrate, and Human Papillomavirus-DNA Testing

Objective: The aim of this study was to assess the correlation between atypical squamous cells (ASC) and inflammatory infiltrate and vaginal microbiota using cervical liquid-based cytological (SurePath®) and high-risk human papillomavirus (HR-HPV) tests. Study Design: A cross-sectional study was conducted using a 6-year database from a laboratory in Fortaleza (Brazil). Files from 1,346 ASC cases were divided into subgroups and results concerning inflammation and vaginal microorganisms diagnosed by cytology were compared with HR-HPV test results. Results: An absence of specific microorganisms (ASM) was the most frequent finding (ASC of undetermined significance, ASC-US = 74%; ASC - cannot exclude high-grade squamous intraepithelial lesion, ASC-H = 68%), followed by bacterial vaginosis (ASC-US = 20%; ASC- H = 25%) and Candida spp. (ASC-US = 6%; ASC-H = 5%). Leukocyte infiltrate was present in 71% of ASC-US and 85% of ASC-H (p = 0.0040), and in these specific cases HR-HPV tests were positive for 65 and 64%, respectively. A positive HR-HPV test was relatively more frequent when a specific microorganism was present, and Candida spp. was associated with HR-HPV-positive results (p = 0.0156), while an ASM was associated with negative HR-HPV results (p = 0.0370). Conclusion: ASC-US is associated with an absence of inflammation or vaginosis, while ASC-H smears are associated with Trichomonas vaginalis and inflammatory infiltrate. A positive HR-HPV is associated with Candida spp. in ASC cytology.

Correlation between High Grade Squamous Intraepithelial Lesion and High Risk Human Papillomavirus Results with Histologic Follow-up: One Institution’s Experience

Correlation between High Grade Squamous Intraepithelial Lesion and High Risk Human Papillomavirus Results with Histologic Follow-up: One Institution’s Experience

Exploration of treatment strategies for normal cytology smears with reactive cellular changes

ObjectiveTo evaluate the use of high-risk humanpapillomavirus (HR-HPV) DNA testing in women who have normal cytology result with reactive cellular changes to identify high risk patients of developing precancerous cervical lesions and cervical cancer. Study designOutpatient patients with normal liquid-based cytology (LCT) results showing reactive cellular changes (case group, n=1085) and normal LCT without reactive cellular changes (control group, n=1085) were recruited from cervical clinics at the International Peace Maternity & Child Health Hospital from January 2012 to December 2013. The HPV status and cervical biopsy pathology results were analyzed. ResultsThe HR-HPV positive rate of the case group (598/1085) was higher than that of the control group (163/1085) (P<0.001). HR-HPV prevalence among CIN1, CIN2, CIN3 and cervical cancer was 73%, 87%, 100%, and 100% respectively (P<0.05). In patients with positive HR-HPV results, more CIN2+ were found significantly in case group (37/598) than those in control group (3/163), P=0.027. The sensitivity of diagnosis of CIN2+ lesions by HR-HPV testing was 92.5%, the specificity was 36%, the positive predicted value was 8.6%, and the negative predictive value was 98.6%. The incidence of CIN2+ lesions was not different among different age groups (P>0.05). ConclusionReactive cellular changes in normal cervical smears should be further investigated. HR-HPV testing could be used as an effective triage in cases of reactive cellular changes. Colposcopy is recommended for those cases showing reactive cellular changes combined with HR-HPV positivity to reduce the risk of failure to diagnose cervical cancer and precancerous lesions.

HPV Co-testing in Patients over 30: Significance of a Positive HPV Result in the Cytology Negative Diagnosis

Introduction: Combined cytology and high-risk human papillomavirus (HR-HPV) screening for women over the age of 30 (HPV 30) became available at our institution in September of 2007. The goal of this study was to investigate patient follow up on cytology negative HR-HPV positive cases over a four year time period in women over the age of 30. Materials and Methods: HR-HPV screening using Hybrid Capture/Digene and routine cytology were performed as part of clinical practice for women over the age of 30 between September 2007 and September 2011. Patients with a negative cytology result and a positive HR-HPV test were retrospectively identified. Tissue and cytology follow-up data were collected. Results: A computer based search identified 32,803 HPV 30 tests that were ordered between September 2007 and September 2011. Of the 30,671 cases that were negative by cytology, 979 had positive HR-HPV results. Of these 979 cases with a negative cytology/positive HR-HPV diagnosis, 476 patients had tissue or cytology follow up. These cases comprise our study population.

Evaluation of HPV-16 and HPV-18 Genotyping for the Triage of Women With High-Risk HPV+ Cytology-Negative Results

The ATHENA (Addressing THE Need for Advanced HPV Diagnostics) HPV study evaluated the clinical usefulness of the cobas HPV Test (Roche Molecular Systems, Pleasanton, CA) for high-risk human papillomavirus (HR-HPV) testing (14 HR types) and individual HPV-16/HPV-18 genotyping in women undergoing routine cervical cytology screening in the United States. For the study, 47,208 women were recruited, including 32,260 women 30 years or older with negative cytology. All women with positive results for HR-HPV (n = 4,219) plus a subset of HR-HPV- women (n = 886) were referred for colposcopy and biopsy. The overall prevalence of HR-HPV was 6.7% and of HPV-16/HPV-18 was 1.5%. Cervical intraepithelial neoplasia grade 2 (CIN 2) or worse was found in 1.2% of women examined. The estimated absolute risk of CIN 2 or worse in HPV-16+ and/or HPV-18+ women was 11.4% (95% confidence interval [CI], 8.4%-14.8%) compared with 6.1% (95% CI, 4.9%-7.2%) in HR-HPV+ and 0.8% (95% CI, 0.3%-1.5%) in HR-HPV- women. These analyses validate the 2006 American Society of Colposcopy and Cervical Pathology guidelines for HPV-16/HPV-18 genotyping, which recommend referral to colposcopy of HPV-16/HPV-18+ women with negative cytology.

Predictors of atypical squamous cell of undetermined significance cervical cytology with high-risk human papilloma virus genotypes

To investigate epidemiological factors that predicts high-risk human papillomavirus (HR-HPV) types among women with atypical squamous cells of undetermined significance (ASCUS). Case-control study of women with ASCUS and 'reflex' HR-HPV DNA test results at the Prentice Ambulatory Care (PAC) outpatient clinic, Northwestern University, Chicago, USA. Univariate analysis and logistic regression were done to generate measures of association between various epidemiological variables and positive HR-HPV. A total of 2,539 women had liquid-based Pap smear and 126 (4.96%) were confirmed ASCUS. Of the 126 with ASCUS, 125 (99.2%) had 'reflex' HR-HPV results. The prevalence of HR-HPV among women with ASCUS was 43.2%. Among the 54 with a positive HR-HPV, 76.0% were women <30 years and 24.0% were ≥ 30 years. The prevalence of HR-HPV was 61.2% among women <30 years versus 22.4% among women ≥ 30 years (P < 0.001). The mean age and standard deviations (SD) was 26.5 (6.2 years) and 34.6 (10.2 years) for women with a positive HR-HPV and negative HR-HPV test, respectively (P < 0.001). Age category <30 years was independently predictive of HR-HPV (adjusted odds ratio 4.6, 95% CI 2.0-10.7; P < 0.001). Age <30 years significantly predicts presence of HR-HPV types among women with diagnosis of ASCUS. A strategy of limiting HPV testing to older women and referral of those <30 years for colposcopic assessment appears more effective.

Women ≥30 years of age with low grade squamous intraepithelial lesion (LSIL) have low positivity rates when cotested for high‐risk human papillomavirus: Should we reconsider HPV triage for LSIL in older women?

High-risk human papillomavirus (HR-HPV) testing for colposcopy triage of low grade squamous intraepithelial lesion (LSIL) is not recommended because of high positive rates in young women. It remains unclear whether HR-HPV testing may be useful for triage of older women. We compiled HR-HPV data for women aged >or=30 years with LSIL for the period March 1, 2006 to February 28, 2008. Follow-up cervical biopsy information was collected for the period March 1, 2006 to August 15, 2008. We used the Hybrid Capture II test performed on residual material from liquid-based Pap tests. Of 735 women, 254 had HR-HPV testing, and of these 144 had positive HR-HPV results. Among women with positive HR-HPV results 79 underwent biopsy (54.9%) and 11 had cervical intraepithelial neoplasia (CIN) 2 or 3 (13.9% of women with biopsy follow-up). A total of 481 women did not undergo HR-HPV testing, of whom 192 underwent biopsy (39.9%) and 11 had CIN 2 or 3 (5.7% of biopsied women [P = 0.04]). Among women who tested negative for HR-HPV and had follow-up biopsies, only one had a high grade lesion found (CIN 2). The overall HR-HPV positive rate in tested women >or=30 years old with LSIL was 56.7% if women who had reflex HR-HPV testing for ASC-US are included. The HR-HPV positive rate in residual material from Pap tests interpreted as LSIL was 63.8%. Among women >or=30 years of age with LSIL, CIN 2-3 is significantly more likely in HR-HPV positive women. Relatively few older women with LSIL test positive for HR-HPV. Colposcopy triage using HR-HPV may be justified in this population.

Using the Rate of Positive High-Risk HPV Test Results for ASC-US Together With the ASC-US/SIL Ratio in Evaluating the Performance of Cytopathologists

We reviewed our experience with 2 indicators of cytopathologist performance: the relative frequency of the interpretations atypical squamous cells of undetermined significance (ASC-US) and squamous intraepithelial lesion (SIL) and the frequency of positive test results for high-risk human papillomavirus (HR-HPV) DNA associated with a cytologic interpretation of ASC-US. Data derived for 9 cytopathologists were reviewed. ASC-US/SIL ranged from 0.99 to 4.02 (mean, 1.77) in 2005 and from 0.82 to 3.68 (mean, 1.81) in 2006. The HR-HPV+ rate for ASC-US ranged from 31.5% to 54.6% for individual cytopathologists (mean, 46.1%) in 2005 and from 29.6% to 61.8% (mean, 45.8%) in 2006. Combined data from both years showed only a slight negative correlation for these 2 variables. Both indicators together provide useful feedback to cytopathologists. We provide a working schema for interpreting perturbations in these indicators to assist in improving the quality of gynecologic cytology interpretations.