Biopsy-proven High-grade Squamous Intraepithelial Lesion Research Articles

A phase I study of intra-anal artesunate (suppositories) to treat anal high-grade squamous intraepithelial lesions

Background Ablation or surgical excision is the typical treatment of anal high-grade squamous intraepithelial lesions (HSIL). Recurrences are common due to the persistence of underlying human papillomavirus (HPV) infection. Additional well-tolerated and effective non-surgical options for HPV-associated anal disease are needed. Methods This 3+3 dose escalation Phase I clinical trial evaluated the safety and tolerability of artesunate suppositories in the treatment of patients with biopsy-proven HSIL. Results The maximal tolerated dose was 400 mg, administered in 3 cycles. All adverse events associated with the use 200- and 400-mg artesunate suppositories were Grade 1. At the 600-mg dose, patients experienced clinically significant nausea. Conclusion Artesunate suppositories are a safe treatment option for anal HSIL.

High Grade Anal Dysplasia in People Living with HIV: A Review of the Anal Cancer/HSIL Outcomes Research (ANCHOR) Trial. Implications for Screening and Treatment Strategies to Minimize Anal Cancer in a Very High-risk Population

The rates of AIDS-defining cancers have plummeted for people living with HIV (PLWH) and who have access to highly active antiretroviral therapies. In contrast, as survival of PLWH has improved and now rivals that of age-matched controls, rates of non-AIDS-defining cancers are increasing. Exposure to oncogenic viruses including human papillomavirus (HPV) as well as to traditional carcinogens, such as tobacco and alcohol are among the reasons for many of these cancers. Worldwide, anal cancer rates are increasing, and this is particularly true for high-grade squamous intraepithelial lesions (HSIL) evolving into invasive anal cancer in PLWH. Herein, I briefly review the oncogenic viruses most important in the pathogenesis of AIDS-defining and non-AIDS-defining malignancies and then focus on the link between HPV and anal cancer and efforts to minimize the risk of anal cancer in PLWH. The Anal Cancer/HSIL Outcomes Research (ANCHOR) study is a randomized phase III clinical trial which enrolled nearly 4500 participants across 25 diverse cities in the United States. PLWH who at time of enrollment were 35 years of age or older and who had biopsy-proven HSIL were eligible to take part in the study. The study is the first to show that screening and treating HSIL in a group at high risk for anal cancer can lead to a reduction in anal cancer incidence. Lessons learned from the ANCHOR study may also provide a blueprint for best practices when reaching out and recruiting marginalized groups with cancer into clinical trials. Much work is needed to plan for screening and treatment programs, including better algorithms for referral for high resolution anoscopy (HRA), and increased training to develop a workforce proficient in HRA screening and treatment of anal cancer. The development of progression biomarkers to identify those with HSIL most in need of treatment is essential. Finally, a more detailed analysis of costs and benefits of screen and treat algorithms for this malignancy is necessary for anal cancer screening to be implemented on a global scale.

Comorbid Vulvar Lichen Sclerosus and High-Grade Squamous Intraepithelial Lesions: A Management Conundrum.

This study aimed to determine if treating lichen sclerosus (LS) with high-potency topical corticosteroids (TCS) increases the risk of high-grade squamous intraepithelial lesion (HSIL) recurrence in patients with comorbid vulvar LS and HSIL. This is a retrospective study of patients with comorbid vulvar LS and HSIL treated with TCS between 2015 and 2020. Patients with clinically diagnosed or biopsy-proven LS and biopsy-proven HSIL of the vulva were included. Clinical data included demographics, tobacco use, immune-modifying conditions, specimen pathology, treatment types, and HSIL recurrence. Bivariate analysis was performed to compare demographic and clinical characteristics between patients with and without HSIL recurrence. Twenty-six patients with comorbid LS and HSIL were identified. The median age was 66.0 years and median time in treatment for LS was 5.5 years. Thirteen (50%) had recurrence of HSIL and 13 (50%) did not have recurrence. Exposure to high-potency TCS was present in 20 (77%) patients, with 17 (65%) having use of more than 1-year duration and 9 (35%) having use at the time of HSIL diagnosis. When comparing the groups with and without HSIL recurrence, there was no significant difference in high-potency TCS exposure, duration of use, or use at time of HSIL diagnosis. High-potency TCS use for the treatment of LS did not seem to increase the risk of HSIL recurrence in patients with comorbid vulvar LS and HSIL. This suggests that high-potency TCS can be appropriately used for the treatment of LS even when HPV-associated disease is present.

Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer

BackgroundThe incidence of anal cancer is substantially higher among persons living with the human immunodeficiency virus (HIV) than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking.MethodsWe conducted a phase 3 trial at 25 U.S. sites. Persons living with HIV who were 35 years of age or older and who had biopsy-proven anal HSIL were randomly assigned, in a 1:1 ratio, to receive either HSIL treatment or active monitoring without treatment. Treatment included office-based ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod. The primary outcome was progression to anal cancer in a time-to-event analysis. Participants in the treatment group were treated until HSIL was completely resolved. All the participants underwent high-resolution anoscopy at least every 6 months; biopsy was also performed for suspected ongoing HSIL in the treatment group, annually in the active-monitoring group, or any time there was concern for cancer.ResultsOf 4459 participants who underwent randomization, 4446 (99.7%) were included in the analysis of the time to progression to cancer. With a median follow-up of 25.8 months, 9 cases were diagnosed in the treatment group (173 per 100,000 person-years; 95% confidence interval [CI], 90 to 332) and 21 cases in the active-monitoring group (402 per 100,000 person-years; 95% CI, 262 to 616). The rate of progression to anal cancer was lower in the treatment group than in the active-monitoring group by 57% (95% CI, 6 to 80; P=0.03 by log-rank test).ConclusionsAmong participants with biopsy-proven anal HSIL, the risk of anal cancer was significantly lower with treatment for anal HSIL than with active monitoring. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02135419.)

Comparison of two sample collection devices for anal cytology in HIV-positive men who have sex with men: Cytology brush and Dacron swab.

HIV-positive men who have sex with men (MSM) are a vulnerable group for anal cancer (AC), a cancer with a well-described precursor lesion, which can be detected early in screening programs using anal liquid-based cytology (aLBC). We aim to compare two aLBC sample collection devices: cytology brush (CB) and Dacron swab (DS). Retrospective analysis of two consecutive study periods, the first using CB and the second DS. Participants underwent an aLBC, a human papillomavirus (HPV) DNA test and a high-resolution anoscopy (HRA), and a biopsy was performed for suspicious lesions. The sensitivity and specificity of aLBC, area under the receiver operating characteristic (ROC) curve (AUC), and concordance between cytology and HRA were assessed using Cohen's kappa coefficient. A total of 239 participants were enrolled (CB group, 120; DS group, 119). aLBC was benign in 46% of samples, and high-grade squamous intraepithelial lesion (HSIL) was detected in 11.7%. Prevalence of biopsy-proven HSIL was 15.3%. No differences in cytological and histological results were observed between the groups. aLBC-HRA concordance was weak for benign results (CB group, k=0.309; DS group, k=0.350) as well as for HSIL (k=0.321 and 0.387, respectively). Sensitivity and specificity were 100% and 51.4%, respectively, in the CB group and 88% and 54.3% in the DS group (AUC=0.711 and 0.759, respectively, P-value=.514). Representation of the transformation zone (TZ) was adequate in 83.3% of samples in the CB group and 50.4% in the DS group (P-value <.001). Our data suggest that both devices had similar accuracy to detect anal HSIL, although samples collected with CB are more likely to have an adequate TZ representation, the presence of which could be an indicator of sample quality.

Screening for Anal Cancer in Women With a History of Vulvar High-Grade Squamous Intraepithelial Lesions.

The primary obkective was to determine the prevalence of (a) a positive anal cancer screen and (b) histological anal high-grade squamous intraepithelial lesion (HSIL) in women undergoing surveillance for previously diagnosed and treated human papillomavirus (HPV)-associated vulvar HSIL. The secondary objective was to determine the patients' acceptability of the screen. This is a single-institution, cross-sectional pilot study. Women, aged 30 to 80 years, with a history of biopsy-proven vulvar HSIL were invited to undergo screening for anal cancer. Positive screen characterized by abnormalities in any of the following: anal high-risk HPV (HR-HPV); anal cytology; and digital anorectal examination. All women with an abnormal screen were referred for high-resolution anoscopy. All women completed a postscreen questionnaire. Fifty-seven patients were recruited. The median (interquartile range) age was 61.5 (51.0-68.0) years. The prevalence of a positive screen was 56.1% (95% CI = 43.3%-68.2%). Of the 32 screen-positive patients, 12 had both abnormal cytology and HR-HPV, 3 had positive HR-HPV alone, and 17 had abnormal cytology alone. Of the 29 patients with a positive screen who went on to anoscopy, the prevalence of anal HSIL was 33.3% (95% CI = 19.2%-51.2%). The prevalence of anal HSIL among all of those who had screening (N = 57) was 18.2% (95% CI = 10.2%-30.3%). The examination was well tolerated with 100% of patients, indicating that they would have the screening again. Women with vulvar HSIL have an increased risk of developing anal HSIL. Larger studies are needed to define optimal screening protocols as well as algorithms for management in high-risk populations.

Value of large loop excision of the transformation zone (LLETZ) without histological proof of high-grade cervical intraepithelial lesion: Results of a two-year continuous retrospective study

ObjectiveLarge loop excision of the transformation zone (LLETZ) conization has been associated with adverse obstetrical outcomes. In an approach to reduce the number of performed LLETZ procedures, we conducted this study to evaluate whether “diagnostic” LLETZ should still be performed, by analyzing their yield in terms of detection (and treatment) of real high-grade squamous intraepithelial lesion (HSIL). MethodsDuring a two-year study period, all patients who underwent a LLETZ procedure in our institution were retrospectively included. Study participants were divided into two groups according to LLETZ indication: a biopsy-proven HSIL group, and a non-biopsy-proven HSIL group. The results of the final histological examination were recorded, as well as excision margin status and specimen dimensions. ResultsDuring the two-year study period, 396 LLETZs were performed, 283 (71%) of which were indicated by biopsy-proven HSIL. In the non-biopsy-proven group, final histology showed 50 cases of HSIL (44%) and 4 cases of carcinoma (3.6%), versus respectively, in the biopsy-proven group, 221 (78%) HSIL and 28 (9.9%) carcinoma (p<0.001). Regarding margin status and specimen dimensions, no intergroup difference was observed between the two groups. ConclusionSo called “diagnostic” LLETZ allowed the detection of severe cervical lesions in almost half of cases, without increasing specimen dimensions in comparison with classical conization indications. Moreover, they also allowed an efficient treatment as showed by similar margins status. Our results therefore strengthen the idea that “diagnostic” LLETZ, when specific indications are respected, should not be overlooked as a major part of our therapeutic arsenal.

Evaluation of nuclear chromatin using grayscale intensity and thresholded percentage area in liquid-based cervical cytology.

Development of computerized image analysis techniques has opened up the possibility for the quantitative analysis of nuclear chromatin in pathology. We hypothesized that the features extracted from digital images could be used to determine specific cytomorphological findings for nuclear chromatin that may be applicable for establishing a medical diagnosis. Three parameters were evaluated from nuclear chromatin images obtained from the liquid-based cervical cytology samples of patients with biopsy-proven high-grade squamous intraepithelial lesion (HGSIL), and compared between non-neoplastic squamous epithelia and dysplastic epithelia groups: (1) standard deviation (SD) of the grayscale intensity; (2) difference between the maximum and minimum grayscale intensity (M-M); and (3) thresholded area percentage. Each parameter was evaluated at the mean, mean-1SD, and mean-2SD thresholding intensity levels. Between the mean and mean-1SD levels, the thresholded nuclear chromatin pattern was most similar to the chromatin granularity of the unthresholded grayscale images. The SD of the gray intensity and the thresholded area percentage differed significantly between the non-neoplastic squamous epithelia and dysplastic epithelia of HGSIL images at all three thresholding intensity levels (mean, mean-1SD, and mean-2SD). However, the M-M significantly differed between the two sample types for only two of the thresholding intensity levels (mean-1SD and mean-2SD). The digital parameters SD and M-M of the grayscale intensity, along with the thresholded area percentage could be useful in automated cytological evaluations. Further studies are needed to identify more valuable parameters for clinical application.

Anal High-Grade Squamous Intraepithelial Lesions in Human Immunodeficiency Virus-Infected Men: A Study of 100 Cases With Emphasis on Cytohistologic Correlation.

Anorectal cytology (ARC) is a widely used screening tool for anal cancer in human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Its diagnostic accuracy needs to be improved, especially for high-grade squamous intraepithelial lesions (HSILs). Using 100 HIV+ MSM with biopsy-proven anal HSILs, we correlated histologic/cytologic findings. Upon review, HSIL cells were present in 58 cytology samples and absent in 42. Positive samples were higher in cellularity and contained transformation zones ( P < .05). Cytology was able to predict HSILs in 36%, 48%, 68%, and 78% of patients with one, two, three, and four or more high-grade lesions. HSIL cells were identified in all cytology samples initially reported as HSILs or atypical squamous cells, cannot exclude HSIL and in 34 samples reported as low-grade squamous intraepithelial lesions or less. Notably, among this last category, 15 (44%) were keratinized-type HSILs. Our findings should improve the ARC detection rate for anal HSILs, helping to implement ARC as the primary screening tool for anal cancer.

Do We Perform Too Many Procedures for Cervical Dysplasia in Young Women?

This study aimed to determine if there are differences in the histological findings of excisional biopsies between younger women (aged ≤25 years) and older women who undergo large loop excision of the transformation zone or cone biopsy for a biopsy-proven high-grade squamous intraepithelial lesion (HSIL). A retrospective cohort analysis of women referred to a tertiary hospital colposcopy clinic with a colposcopically directed biopsy of HSIL (cervical intraepithelial neoplasia 2 [CIN 2] or CIN 3) during the period of 2008 to 2011 was performed.The histological excisional biopsy specimens for younger women (aged ≤25 years) were compared with those of older women (aged >25 years.) Bivariate analysis comparing demographic characteristics and outcomes across the 2 study groups was initially undertaken to identify potential confounders for inclusion in the multivariate analysis. Of 348 women who had a satisfactory colposcopic assessment and reported no previous treatment for cervical intraepithelial neoplasia, 87 were 25 years or younger, and 261 women were older than 25 years. After excisional biopsy of the cervix, the histological specimen for younger women was more likely to be reported as CIN 1 or no dysplasia (16.3% vs 8.2%). When adjusted for confounders (parity, smoking, previous sexual infection, and referring Pap smear), age less than 25 years remained an independent predictor of having a histological excisional biopsy specimen reported as CIN 1 or no dysplasia (adjusted odds ratio = 2.35; 95% confidence interval = 1.0-5.49). Younger women with biopsy-proven HSIL (CIN 2/3), have a higher likelihood that the histological specimen after an excisional biopsy of the cervix will be reported as CIN 1 or no dysplasia.

Progression of anal high‐grade squamous intraepithelial lesions to invasive anal cancer among HIV‐infected men who have sex with men

The incidence of anal cancer is elevated in human immunodeficiency virus (HIV)-infected men-who-have-sex-with-men (MSM) compared to the general population. Anal high-grade squamous intraepithelial lesions (HSIL) are common in HIV-infected MSM and the presumed precursors to anal squamous cell cancer; however, direct progression of HSIL to anal cancer has not been previously demonstrated. The medical records were reviewed of 138 HIV-infected MSM followed up at the University of California, San Francisco, who developed anal canal or perianal squamous cancer between 1997 and 2011. Men were followed up regularly with digital anorectal examination (DARE), high-resolution anoscopy (HRA) and HRA-guided biopsy. Although treatment for HSIL and follow-up were recommended, not all were treated and some were lost to follow-up. Prevalent cancer was found in 66 men. Seventy-two HIV-infected MSM developed anal cancer while under observation. In 27 men, anal cancer developed at a previously biopsied site of HSIL. An additional 45 men were not analyzed in this analysis due to inadequate documentation of HSIL in relation to cancer location. Of the 27 men with documented progression to cancer at the site of biopsy-proven HSIL, 20 men progressed from prevalent HSIL identified when first examined and seven men from incident HSIL. Prevalent HSIL progressed to cancer over an average of 57 months compared to 64 months for incident HSIL. Most men were asymptomatic, and cancers were detected by DARE. Anal HSIL has clear potential to progress to anal cancer in HIV-infected MSM. Early diagnosis is facilitated by careful follow-up. Carefully controlled studies evaluating efficacy of screening for and treatment of HSIL to prevent anal cancer are needed.

Large loop excision of the transformation zone (LLETZ): a pathology evaluation in the Limpopo province, South Africa

AbstractObjective: To evaluate the cytological and histopathological concordance in large loop excision of the transformation zone (LLETZ) specimens, and the outcomes according to the characteristics of the excision margins.Method: A prospective observational study of 413 consecutive cases of LLETZ performed for cytologically diagnosed high-grade squamous intraepithelial lesion (HGSIL)/cervical intraepithelial neoplasia (CIN) 2-3 over a three-year period.Results: The discordance rate between the initial cytological diagnosis and biopsy-proven HGSIL was 24.5%. The overall rate of margins believed to be clear and of severe thermal artefacts was 30.4% and 7.4% respectively. Pathology follow-up was available only in 83 (26.5%) of the 313 biopsy-confirmed HGSIL. The persistence or recurrence rate was 78.0%; 90.5% occurred among the cases where the margins were believed to be involved. In 20.5% the reported marginal status was discordant with follow-up surgical pathology.Conclusion: Reporting marginal status ha...

Atypical Squamous Cells, Cannot Exclude High-Grade Squamous Intraepithelial Lesion

In the current study, we explore the diagnostic parameters and pitfalls in the follow-up of 123 cases of Pap smears diagnosed as high-grade atypical squamous cells (ASC-H) at our institution.A computer database search was performed from the archives of the Ottawa Hospital Cytopathology Service for cases diagnosed with ASC-H between January 2003 and July 2005.Follow-up of the 123 cases of ASC-H showed high grade squamous intraepithelial lesion (HSIL) in 73 patients (59.4%), low grade squamous intraepithelial lesion (LSIL) in 11 (8.9%), immature squamous metaplasia in 23 (18.7%), reactive squamous cell changes in 12 (9.8%), benign glandular lesions (endocervical atypia, degenerated glandular cells) in 2 (1.6%) and atrophy in 2 (1.6%). In our study, 83 patients were younger than 40 years (67.4%), with biopsy-proven HSIL found in 54 patients (65.1%). The remaining 40 patients (32.6%) were older than 40 years of age, and follow-up biopsies showed HSIL in 19 patients (47.5%).In our study, 59.4% of the cases that were diagnosed cytologically as ASC-H were found to have HSIL on subsequent biopsies. This correlation was stronger in patients below the age of 40 years (65.1% vs. 47.5%). The cytopathologic feature most strongly associated with HSIL was the presence of coarse nuclear chromatin (84%).

Detection of cervical high-grade squamous intraepithelial lesions from cytologic samples using a novel immunocytochemical assay (ProEx™ C)

Routine liquid-based cytology (LBC) provides excellent sensitivity for the detection of cervical high-grade squamous intraepithelial lesion (HSIL); however, its specificity is low. Consequently, many women who have atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL) cytology undergo unnecessary colposcopy. The authors hypothesized that a novel immunocytochemical assay (ProEx C) that can be performed on LBC slides had a significantly higher positive predictive value (PPV) for biopsy-proven HSIL compared with routine LBC. The ProEx C immunocytochemical assay utilizes a cocktail of monoclonal antibodies directed against proteins associated with aberrant S-phase cell cycle induction (topoisomerase IIA, minichromosome maintenance protein 2). The ProEx C reagents were validated in the authors' laboratory for staining and scoring reproducibility, open-vial stability, and accuracy before a retrospective analysis using these reagents was performed on 317 residual cytology samples. Sensitivity, specificity, PPV, and negative predictive value (NPV) for the detection of biopsy-proven HSIL were determined. The ProEx C assay was validated successfully in the authors' cytology laboratory. Using biopsy-proven HSIL as an endpoint, the ProEx C assay yielded a sensitivity of 85.3%, specificity of 71.7%, PPV of 44.6%, and NPV of 94.8%. Compared with the routine LBC results in the same cohort, the ProEx C sensitivity for biopsy-proven HSIL was 70.6% greater than HSIL+ cytology (50% vs. 85.3%). ProEx C also showed a 114% increase in PPV relative to ASC-US cytology (21.1% vs. 44.6%). The ProEx C immunocytochemical assay can be integrated into a clinical cytology laboratory and may increase the PPV of LBC for biopsy-proven HSIL.

The Potential for Failure in Gynecologic Regulatory Proficiency Testing With Current Slide Validation Criteria: Results From the College of American Pathologists Interlaboratory Comparison in Gynecologic Cytology Program

Current regulatory proficiency testing scoring results in an automatic failure for identifying high-grade squamous intraepithelial lesion (HSIL) as negative. The College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology data from January 2004 to April 2005 were analyzed to estimate the percentage of failure based on negative responses for HSIL and validation criteria. More than 15,000 participants received field-validated and educational slide sets for conventional, ThinPrep, and SurePath modules. Educational sets fulfilled the validation criteria of the Center for Medicare and Medicaid Services, which required the consensus diagnosis of biopsy-proven HSIL (not field-validated) after review by 3 pathologists. The College of American Pathologists field validation required at least 20 responses to the HSIL+ series, with 70% matched to HSIL+ (standard error < or = 0.05). Minimum regulatory proficiency testing failure estimates were based on incorrect negative responses for the reference category of HSIL. For both cytotechnologists and pathologists, there was a statistically significant higher failure rate for slides that were not field-validated versus those that were field-validated. In conventional modules, 5.3% of the slides that were not field-validated were called negative, versus 1.2% of the field-validated slides. In all liquid-based preparations, 4.0% of the non-field-validated versus 2.2% field-validated slides were called negative. Pathologists would have failed more often than cytotechnologists for the slides that were not field-validated, whereas there was no statistical difference in failure performance with field-validated slides. Failures were significantly greater with the slides that were not field-validated for both conventional and liquid-based preparations (ThinPrep only) and have implications for both regulatory proficiency testing and expert legal review. Poor performance of pathologists relative to that of cytotechnologists may reflect a lack of prescreening of slides or scope of practice issues.

Screening for Cervical Cancer in High-Risk Populations: DNA Pap Test or Hybrid Capture II Test Alone?

This study was designed to evaluate whether Hybrid Capture II (HC2) test alone refer women to colposcopy as appropriately as DNA Papanicolaou (Pap) test, in the context of a high-risk group of women using the recently validated DNACitoliq LBC system. Women with suspected cervical disease were included in this cross-sectional study at a tertiary center in São Paulo, Brazil, for further workup. All women had cervical material collected for LBC and HC2 for high-risk human papillomavirus (hrHPV)-DNA test. Irrespective of cytology and HC2 results, colposcopy, and cervical biopsy when applicable, was systematically performed. All tests were performed blindly. Sensitivity, specificity, positive and negative predictive values, and overall accuracy of both methods were computed in relation to histology. A total of 1,080 women were included: 36.4% (393/1080) had ACUS+, 10.2% (110/1080) were high-grade squamous intraepithelial lesions (HSIL) or cancer. Mean age was 33.5 years. All women underwent colposcopy, and cervical biopsies were performed in 38.4% (415/1080): 33% (137/415) of the biopsies were negative, 14.4% (155/415) were low-grade squamous intraepithelial lesions (LSIL), 10.7% (116/415) were HSIL, and 0.6% (7/415) were cancer. HC2 sensitivity to diagnose biopsy-proven HSIL was 100%. Because all HSIL cases had a positive HC2 test, sensitivity could not be improved by adding LBC. Specificity and positive and negative predictive values of DNA Pap were not significantly different from HC2 test alone when considering LSIL+ histology as "gold standard" and HSIL+ histology. As a screening strategy for women with high-risk for cervical cancer, DNA Pap test does not seem to add substantially to HC2 alone in terms of appropriately referring to colposcopy.

Should women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, receive reflex human papillomavirus-DNA testing?

The 2001 American Society for Colposcopy and Cervical Pathology Consensus Guidelines recommend that women who have Papanicolaou (Pap) smears diagnosed as atypical squamous cells (ASC), cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H) should be referred for immediate colposcopic examination. The objective of this pilot study was to evaluate whether reflex human papillomavirus (HPV)-DNA testing performed on smears diagnosed as ASC-H may obviate the need for immediate colposcopic examination. All ThinPrep Pap smears that were diagnosed as ASC-H or atypical squamous metaplastic cells (ASMT) between 2001-2003 and that had HPV-DNA testing and subsequent histologic and/or cytologic follow-up were evaluated. Those smears that were diagnosed as ASMT were reviewed and reclassified under the 2001 Bethesda System as either ASC of undetermined significance (ASCUS) or ASC-H. Smears that were diagnosed as ASCUS were excluded from the study. The study included of 48 smears that were diagnosed as ASC-H. All patients with biopsy-proven HSIL had positive high-risk (HR)-HPV results (100% negative predictive value). Approximately 80% of patients with ASC-H who had biopsy-proven, low-grade intraepithelial lesion on follow-up had positive HR-HPV results. Among the patients who had ASC-H with negative follow-up, 50% had positive HR-HPV results, and 50% had negative HR-HPV results. Among patients with ASC-H, a negative HR-HPV result was found to be an excellent predictor of the absence of HSIL. The results of this pilot study suggested that HPV-DNA testing may serve as a means to better select which patients with ASC-H on Pap smear should undergo colposcopic examination. This approach potentially may reduce medical costs and eliminate the need for routine colposcopic examination among patients with ASC-H Pap smears.

Managing atypical squamous cells of undetermined significance (ASCUS): Human papillomavirus testing, ASCUS subtyping, or follow-up cytology?

OBJECTIVE: This study related morphologic subtype, human papillomavirus status, and a second cytologic examination to the follow-up biopsy-proven high-grade squamous intraepithelial lesion (HSIL; grade II or III cervical intraepithelial neoplasia) after a cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS). STUDY DESIGN: Seven hundred four liquid-based cervical cytology specimens were classified as normal, “ASCUS, favor reactive” (AFR), “ASCUS, not otherwise specified,” “ASCUS, favor low-grade squamous intraepithelial lesion,” “ASCUS, favor HSIL” (AFHS), low-grade squamous intraepithelial lesion, and HSIL. Human papillomavirus typing used polymerase chain reaction-restriction fragment length polymorphism analysis. A longitudinal review of the cytologic and histologic records of ASCUS cases with ≥1 follow-up test or biopsy ascertained the frequency of a follow-up diagnosis of biopsy-proven HSIL (grade II or III cervicalintraepithelial neoplasia). RESULTS: Three hundred eighty-six cases (208 ASCUS, 68 normal, 86 with low-grade squamous intraepithelial lesions, and 24 with HSIL) were evaluated. High-risk human papillomavirus (HRHPV positive) was lowest with normal cytology (13%), highest with HSIL (71%), and was present in 29.8% of ASCUS cases, ranging from 22.2% (AFR) to 75% (AFHS). Most ASCUS tests (64%) were followed by a negative cytologic or histologic examination. Overall, 3.8% and 11% of ASCUS and HRHPV-positive ASCUS had histologic outcomes of HSIL. AFHS had the highest (25%) and AFR had the lowest (1.1%) proportion of HSIL outcomes. Sensitivity, specificity, and positive predictive values of human papillomavirus testing for biopsy-proven HSIL were 87.5%, 72.5%, and 11.3%, respectively. CONCLUSION: HSIL and AFHS are distinguished by the highest frequency of HRHPV types and higher rates of HSIL outcome. The remaining categories of ASCUS are heterogeneous with respect to human papillomavirus type and HSIL risk, and the value of subclassification of these entities is dependent on the practice. A human papillomavirus detection system based on polymerase chain reaction-restriction fragment length polymorphism identifies a smaller percentage of high-risk human papillomaviruses than mixed probe-based methods, probably because of the more precise exclusion of cross-reacting low-risk human papillomavirus. Negative HRHPV findings by either system show a markedly reduced risk of an HSIL outcome. However, the relative advantage of human papillomavirus testing over follow-up cytology will be influenced by the frequency of negative follow-up cytologic examination and sensitivity of liquid-based preparations in a given practice. (Am J Obstet Gynecol 2002;186:396-403.)

Relative Risk of High Grade Squamous Intraepithelial Lesion Associated With Prior Abnormal Pap Smears

OBJECTIVE: Pap smear frequency remains controversial, especially for women with consecutive negative smears. We undertook the current study to ascertain the association of high grade | squamous intraepithelial lesions (HSIL) and prior abnormal Paps. STUDY DESIGN: Women with biopsy-proven HSIL (cervical intraepithelial neoplasia 2 and 3) diagnosed between September 1996 and December 1997 and age-matched controls with a negative Pap obtained during the same time period were selected. RESULTS: Sixty-three cases (mean age = 32 years) of HSIL and 69 controls (mean age = 33 years) constituted the study population. Any prior abnormal diagnosis conferred a 15-fold increased risk of HSIL on the current Pap (50/63 vs. 14/69, P<.0001). When limited to the 60 women with at least three prior Paps, the odds ratio for HSIL on the current Pap with any prior abnormal was 18 (28/31 vs. 10/29, P<.0001). Three cases had at least three consecutive negative Paps prior to the diagnosis of HSIL. CONCLUSION: Women with one or more prior negative Pap smears had a significantly decreased risk of HSIL on the current Pap. Consecutive negative Paps did not appear to further decrease the risk; 10% of HSIL patients had had three or more consecutive prior negative Paps. To detect HSIL at its earliest stage, women should be advised to continue annual Pap screening in spite of consecutive negative results.

Automated screening for quality control using PAPNET: a study of 638 negative Pap smears.

To determine if the PAPNET screening system can be used for quality control to lower false-negative rates for Pap smears 638 manually screened, "negative" Pap smears were subjected retrospectively to the PAPNET screening system. Twenty-nine of the smears came from 18 patients who subsequently had biopsyproven high-grade squamous intraepithelial lesions (SIL). The remaining 609 negative smears were arbitrarily selected as controls. One hundred twenty-eight (128) of the retrospectively reviewed smears (20%) were selected by PAPNET for microscopic referral because of potential abnormalities. Abnormalities were confirmed on 14 of these smears upon microscopic evaluation. Five of these 14 smears were from smears obtained from four of the 18 women with high-grade SIL. The incidence of manually screened false-negatives detected by PAPNET rescreening was 14/638 or 2.2% for the entire patient population in this study and 5/29 or 17.24% for the targeted patients known to have subsequently developed highgrade lesions. The 2.2% decrease in the false-negative rate in this experiment may be partly artificial as this study group was seeded with false-negative cases at high risk for containing missed abnormalities. The implementation of the PAPNET system for quality control may lower false-negative rates for Pap smears.