Digital holographic microscopy as screening tool for cervical cancer preliminary study.

Reports for atypical squamous cells of undetermined significance (ASC-US) and histologic findings are rare in China. To analyze the correlation findings of ASC-US cytology with high-risk human papillomavirus (hrHPV) test and histopathologic follow-ups. ASC-US cases with hrHPV test and histologic follow-ups between 2011 and 2015 were analyzed at a College of American Pathologists-certified laboratory. A total of 2 206 588 Papanicolaou (Pap) tests were performed, including 1 513 265 liquid-based cytology preparations (68.58%), and 693 323 conventional Pap tests (31.42%). The overall ASC-US reporting rate was 3.77% (83 199 of 2 206 588), with the highest in women aged 40 to 49 years. Of 18 574 women with ASC-US Pap and HPV testing, the hrHPV positivity rate was 34.98% (6498 of 18 574) with the highest in women younger than 30 years. A total of 6012 women with ASC-US Pap test findings had histologic follow-ups within 6 months; the overall cervical intraepithelial neoplasia 2 and above (CIN2+) detection rate was 7.87% (473 of 6012). One thousand nine hundred nine women with ASC-US Pap and HPV testing had histologic results. CIN2+ lesion was found in 13.98% (124 of 887) of women with ASC-US Pap/HPV-positive test results, significantly higher than 2.84% (29 of 1022) for women with ASC-US Pap/HPV-negative test results. Cervical squamous cell carcinoma was found in 3.95% (35 of 887) of women with ASC-US/HPV-positive test results. This is one of the largest studies to investigate HPV and histologic follow-up findings in women with ASC-US in China. The ASC-US reporting rate, HPV positivity rate, and CIN2+ detection rate were all within the currently recognized benchmark ranges. These findings may contribute to establishing a baseline for better understanding of the status of cervical screening in China.

Multiple human papillomavirus infection and high grade cervical intraepithelial neoplasia among women with cytological diagnosis of atypical squamous cells of undetermined significance or low grade squamous intraepithelial lesions

Cervicography combined with repeat Papanicolaou test as triage for low-grade cytologic abnormalities

To investigate using detection of human papillomavirus (HPV) L1 capsid protein to predict the course of mild or moderate cervical intraepithelial neoplasia (CIN).Immunocytochemical analysis using antibody against HPV L1 capsid protein was carried out on 274 Pap tests from women positive for high-risk HPV detected by hybrid capture, with cytologic diagnoses of atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cell cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H), HSIL and squamous cell carcinoma (SCC). Histologic diagnosis was available for patients after initial cytologic diagnosis.L1 capsid protein was positive in 69.79% of cervicitis, 83.53 % of CIN 1, 41.81% of CIN2, 3.13% of CIN3 and 0% of SCC. Cytologic diagnosis revealed a higher expression rate in LSIL than in ASCUS and HSIL + SCC. In 71 ASCUS/LSIL without treatment, no L1-positive cases progressed in cytology; 18.75% of L1-negative cases progressed to ASC-H/HSIL.The decreased expression of HPV L1 may correlate with progressed cytopathology. The expressions of HPV L1 in liquid-based cell specimens implied the histopathology diag- nosis of cervix. Expression of HPV L1 may have significance in treating ASCUS and LSIL.

BackgroundA protocol for cervical cancer screening among sexually active women 25 to 65 years of age was introduced in 2006 in Catalonia, Spain to increase coverage and to recommend a 3-year-interval between screening cytology. In addition, Human Papillomavirus (HPV) was offered as a triage test for women with a diagnosis of atypical squamous cells of undetermined significance (ASC-US). HPV testing was recommended within 3 months of ASC-US diagnosis. According to protocol, HPV negative women were referred to regular screening including a cytological exam every 3 years while HPV positive women were referred to colposcopy and closer follow-up. We evaluated the implementation of the protocol and the prediction of HPV testing as a triage tool for cervical intraepithelial lesions grade two or worse (CIN2+) in women with a cytological diagnosis of ASC-US.MethodsDuring 2007-08 a total of 611 women from five reference laboratories in Catalonia with a novel diagnosis of ASC-US were referred for high risk HPV (hrHPV) triage using high risk Hybrid Capture version 2. Using routine record linkage data, women were followed for 3 years to evaluate hrHPV testing efficacy for predicting CIN2+ cases. Logistic regression analysis was used to estimate the odds ratio for CIN2 +.ResultsAmong the 611 women diagnosed with ASC-US, 493 (80.7%) had at least one follow-up visit during the study period. hrHPV was detected in 48.3% of the women at study entry (mean age 35.2 years). hrHPV positivity decreased with increasing age from 72.6% among women younger than 25 years to 31.6% in women older than 54 years (p < 0.01).At the end of the 3 years follow-up period, 37 women with a diagnosis of CIN2+ (18 CIN2, 16 CIN3, 2 cancers, and 1 with high squamous intraepithelial lesions -HSIL) were identified and all but one had a hrHPV positive test at study entry. Sensitivity to detect CIN2+ of hrHPV was 97.2% (95%confidence interval (CI) = 85.5-99.9) and specificity was 68.3% (95%CI = 63.1-73.2). The odds ratio for CIN2+ was 45.3 (95% CI: 6.2-333.0), when among ASC-US hrHPV positive women were compared to ASC-US hrHPV negative women.ConclusionsTriage of ASC-US with hrHPV testing showed a high sensitivity for the detection of CIN2+ and a high negative predictive value after 3 years of follow-up. The results of this study are in line with the current guidelines for triage of women with ASC-US in the target age range of 25-65. Non adherence to guidelines will lead to unnecessary medical interventions. Further investigation is needed to improve specificity of ASC-US triage.

There is an increasing number of articles regarding the long term follow-up of Papanicolaou (Pap) smears with the diagnosis of atypical squamous cells of undetermined significance (ASCUS). Much controversy exists regarding the management of patients with this diagnosis. In a prior study in 1992, the authors performed automated rescreening of 101 ASCUS cases and 91 negative (control) cases. They found that through PAPNET-directed rescreening, 35 of 101 ASCUS cases (35%) could be reclassified as a squamous intraepithelial lesion (SIL). These 192 women were followed since 1992 through manual look backs of subsequent Pap smears and surgical biopsies over a 4-year period. The population studied was comprised of predominantly black women between the ages of 14 and 85 years. The majority were considered a high risk population because many had a history of several sexual partners and multiple pregnancies. Eighteen of 74 patients (24.3%) with an original diagnosis of ASCUS were found on subsequent Pap smears to have an SIL. Only 4 of 64 patients (6%) who originally had a negative Pap smear subsequently were found to have a low grade squamous intraepithelial lesion (LGSIL) within 4 years. Through ordinal logistic regression analysis, it was found that patients with an ASCUS diagnosis had a risk of developing SIL that was 2.6 times greater than the risk for patients with a negative smear diagnosis. Comparing the surgical biopsies in the control and ASCUS groups, there was no statistically significant difference in the risk of developing SIL. This may be because the number of follow-up biopsies were small. A statistically significant difference of the risk of developing SIL exists between patients with a negative smear versus those with an ASCUS smear. Long term follow-up is essential in the management of the patients with an ASCUS smear because there is clearly an increased risk of developing SIL.

To estimate the accuracy of vaginal cytology in postoperative surveillance for detecting recurrent endometrial cancer and to estimate the optimal management of squamous abnormalities detected in this setting. This review included women who underwent hysterectomy for endometrial cancer between January 1, 2006, and December 31, 2010, and had at least one postoperative Pap test. Clinical and demographic data were collected and outcomes including abnormal vaginal cytology, results of colposcopic examination, and endometrial cancer recurrence were assessed. A Cox regression model to estimate the risk of abnormal cytology was created. Sensitivity, specificity, and negative and positive predictive values of detecting vaginal recurrences were calculated. Four hundred thirty-three women contributed 2,378 Pap tests. At least one abnormal cytology result was found during follow-up of 55 (13%) women, representing 3% of all Pap tests. No recurrent endometrial cancers were diagnosed on the basis of isolated abnormal cytology. No cases of recurrent cancer were diagnosed in women with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion (LSIL) Pap test results. In multivariable analysis, abnormal cytology was highly associated with prior postoperative radiation therapy (P<.001). The sensitivity, specificity, and positive and negative predictive values of an abnormal Pap test result in detecting a local recurrence are 40%, 87.9%, 7.3%, and 98.4%, respectively. Colposcopy is not needed after a Pap test result read as atypical squamous cells of undetermined significance or LSIL. III.

Follow-up of women with cervical cytological abnormalities showing atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion: a nationwide cohort study

Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance

The Papanicolaou (PAP) test is widely used to screen for cervical cancer. All high-grade lesions such as atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H), and high-grade squamous intraepithelial lesion, identified on a PAP test should be followed-up by a confirmatory cervical biopsy. In this review, we discuss the challenges in interpreting cervical tissue specimens and the various ancillary techniques used in the evaluation of cervical dysplasia. Ancillary studies include deeper levels, p16 immunohistochemistry (IHC), human papillomavirus (HPV) testing, and, importantly, cyto-histologic correlation. Of these, p16 IHC is consistently sensitive and specific for detecting HSIL. HPV RNA in situ hybridization (ISH) is a newer technique with excellent sensitivity and specificity for detecting virally infected cells and it may be more broadly applicable to both low- and high-grade squamous intraepithelial lesions.

The 2014 Bethesda System for Reporting Cervical Cytology classifies squamous intraepithelial lesions (SILs) of cervix into two main categories: low-grade SIL (LSIL) and high-grade SIL (HSIL). In some clinical practices, the LSIL cannot rule out high-grade lesion (LROH) interpretive category is used in cases with LSIL and findings that may raise the possibility of HSIL. Our purpose is to assess follow-up histopathology and high-risk human papillomavirus (hrHPV) results in patients with LROH, in comparison with LSIL, atypical squamous cells, cannot rule out HSIL (ASC-H), and HSIL in our institution. Cervical Papanicolaou tests with LROH, LSIL, ASC-H and HSIL interpretation, surgical follow-up, and hrHPV status were retrieved from the computer database from May 2014 to December 2016. Of 109963 total Papanicolaou tests, LROH comprised 0.3%, LSIL 3.1%, ASC-H 0.2% and HSIL 0.4%. Only 3272 cases with surgical diagnoses were included in the study. The most common histological outcome for ASC-H was cervical intraepithelial neoplasia (CIN)2/3 (32.6%); LSIL was CIN 1 (45.7%); LROH was CIN 1 (46.7%) and HSIL was CIN 2/3 (64.4%). For LROH and LSIL, 31.1% and 7.5% respectively, had CIN 2/3. Approximately 79% of cases were hrHPV positive. Of LROH cases with surgical follow-up, 86.9% tested hrHPV positive, accounting for the second most common positive group after HSIL (92.6%). In our study cohort, LROH interpretation is associated with a higher number of CIN 2 or higher lesions on follow-up compared to patients with LSIL (P<0.0001), and is associated with a significant percentage of positive other hrHPV, supporting LROH as a useful diagnostic category that triggers appropriate follow-up in affected women.

Cervical screening in the United States increasingly involves newer US Food and Drug Administration-approved cytologic methods and adjunctive high-risk human papillomavirus (hrHPV) DNA testing. To document cervical screening test performance preceding histopathologic cervical intraepithelial neoplasia (CIN) 2/3 diagnoses. Preceding screening test results with computer-imaged, liquid-based cytology (LBC) and hrHPV results were analyzed for 2827 patients with histopathologic CIN 2/3 diagnoses. Of 2827 patients with CIN 2/3 diagnoses, 2074 (73.4%) had system LBC findings within 4 months of CIN 2/3 diagnoses: high-grade squamous intraepithelial lesion (n = 862; 41.6%), low-grade squamous intraepithelial lesion (n = 464; 22.4%), atypical squamous cells of undetermined significance (n = 445; 21.5%), atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (n = 288; 13.9%), and atypical glandular cells/adenocarcinoma in situ (n = 15; 0.7%). Of the 2827 patients, 1488 (52.6%) also had earlier system LBC results at more than 4 months to 3 years before CIN 2/3 diagnoses: one or more abnormal LBC results (n = 978; 65.7%), one or more negative LBC results (n = 911; 61.2%), both abnormal and negative LBC (n = 401; 26.9%). Of 807 patients with hrHPV cotest results within 4 months of CIN 2/3 diagnoses, 786 (97.4%) had hrHPV(+) results. Of 454 patients who also had earlier hrHPV results at more than 4 months to 3 years before CIN 2/3 diagnoses: 377 (83.0%) had one or more hrHPV(+) result, 110 (24.2%) had one or more hrHPV(-) result, and 33 (7.3%) had both positive and negative HPV results. Patients with histopathologic CIN 2/3 had recent abnormal LBC results, most often, high-grade squamous intraepithelial lesions. Among cotested patients, 97.4% (786 of 807) tested hrHPV(+). However, a significant number of patients tested during an extended period of several years had earlier negative Papanicolaou or negative HPV test results, suggesting the recent development of some CIN 2/3 lesions and supporting the value of cotesting for enhanced detection of other developing, small, inaccessible, or nondiagnostic precursor lesions.

The authors noticed a significant increase in the rate of atypical squamous cells of undetermined significance (ASCUS) diagnoses in postmenopausal women receiving hormone replacement therapy with ThinPrep (monolayer) Papanicolaou (Pap) tests (8.3%) as compared with conventional Pap tests (2.3%; P = 0.025). The purpose of this study was to correlate these morphologic changes with human papillomavirus (HPV) DNA detection by in situ hybridization and clinical outcome. Twenty-five monolayer Pap tests diagnosed as ASCUS in postmenopausal women receiving hormone replacement, as well as 2 cases of low-grade squamous intraepithelial lesion (SIL) from the same group, were destained in acid alcohol. In situ HPV hybridization was performed with a consensus probe that can detect greater than 90% of the HPV types that occur in cervical SIL. In addition, 11 of the ASCUS tests were analyzed with the periodic acid-Schiff (PAS) stain. All 25 ASCUS tests were negative for HPV DNA as compared with a detection rate of 15 of 17(88%) for low-grade SIL. Glycogen that was PAS positive was present in the atypical squamous cells of the postmenopausal women for whom HPV was not detected. Clinical follow-up demonstrated that only 2 of the 25 women with ASCUS had a subsequent biopsy proven SIL. The ThinPrep preparation can produce artifactual HPV-like changes in postmenopausal women receiving hormone replacement therapy that may be caused by glycogenization and, because of the high incidence of HPV negativity and negative clinical outcome, are best considered as benign cellular changes.

Cervical cancer screening in China is largely limited to occasional opportunistic screening in urban centers. The current study reports histopathologic follow-up and human papillomavirus (HPV) results in women with high-grade squamous intraepithelial lesion (HSIL) Papanicolaou (Pap) tests reported at the largest academic women's hospital in China and compares these findings with those of published Western studies among frequently screened women. A retrospective cohort study documented HSIL Pap tests, patient age, HPV results, and histopathologic follow-up from 2011 through 2015 in the Obstetrics and Gynecology Hospital of Fudan University (OGHFU) in Shanghai, China. Of 886,122 Pap test results, 4269 (0.48%) reported HSIL. Histopathologic follow-up was available for 2351 cases and HPV results were available for 2092 cases. HSIL reporting rates increased with patient age from 0.16% at age <30 years to 0.58% at ages 30 to 49 years and 0.75% at age ≥50 years. HSIL rates were found to be significantly higher for women tested using liquid-based cytology (0.52%-0.55%) compared with conventional Pap tests (0.19%). Among 2351 cases with histopathologic follow-up, cervical intraepithelial neoplasia of type 2/3 was diagnosed in 74.1% of cases and squamous cell carcinoma in 14.2% of cases. Squamous cell carcinoma was diagnosed in 22.8% of patients aged ≥50 years who underwent biopsy. HPV-positive HSIL rates using 3 different HPV tests ranged from 88.1% to 93.9%. At OGHFU, the finding of an increase in HSIL cytology rates with increasing patient age contrasted with a finding of decreasing HSIL rates with increasing age previously reported in regularly screened cotested patients in the United States. The increasing HSIL rates with older age and high rates of cervical cancer diagnoses noted at OGHFU appear to be best explained by the absence of consistent intraepithelial lesion ablation achievable with frequent screening and treatment. Cancer Cytopathol 2017;125:947-53. © 2017 American Cancer Society.

High-risk human papillomavirus (hrHPV) DNA detection is generally accepted for the triage of women with a cytologic diagnosis of atypical squamous cells of undetermined significance (ASC-US). However, no consensus has been reached on the optimal management of low-grade squamous intraepithelial lesions (LSIL). In this meta-analysis, the diagnostic accuracy of nucleic acid sequence-based amplification (NASBA) detection of messenger ribonucleic acid (mRNA) of 5 hrHPV types (the PreTect HPV-Proofer and NucliSENS EasyQ tests) for detecting grade 2 cervical intraepithelial neoplasia or worse (CIN2+) and CIN3+ was assessed in women who had a diagnosis of ASC-US and LSIL. The results were compared with the Hybrid Capture-2 (HC2) assay, which detects the DNA of 13 hrHPV types. A bivariate random-effect model that incorporated the intrinsic correlation between the true-positive and false-positive rates was used for a pooled meta-analysis. Considering underlying CIN2+, the pooled absolute sensitivity of the 10 included studies was 75.4% (95% confidence interval [CI], 68.1%-82.7%) and 76.2% (95% CI, 68.3%-76.9%) for the triage of ASC-US and LSIL, respectively. The pooled absolute specificity to exclude CIN2+ was 77.9% (95% CI, 70.1%-85.7%) and 74.2% (95% CI, 69.5%-78.8%) in women with ASC-US and LSIL, respectively. Five studies allowed direct comparison of the mRNA assays with HC2. Considering CIN2+ in women with ASC-US and LSIL, mRNA testing was substantially more specific than the HC2 assay (ratio: 1.98 and 3.36, respectively; P < .001) but was less sensitive (ratio: 0.80 and 0.74, respectively; P < .001). HPV assays for detecting the mRNA of 5 hrHPV types may reduce the over-diagnosis of women who have minor cytologic abnormalities. However, given the lower sensitivity, women with negative mRNA test results cannot be considered free of CIN2+ and require further surveillance.