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Objectives Anal squamous cell carcinoma (ASCC) has a higher incidence described in certain groups, namely, in women with vulvar high-grade squamous intraepithelial lesions (vHSILs) and/or human papillomavirus squamous cell carcinoma (VSCC). This review describes terminology, vHSIL, and VSCC in their association with ASCC and the published recommendations for early detection of this cancer in these women. Materials and methods A narrative review was conducted by the authors on vHSIL and VSCC as risk factors for ASCC. Results The ASCC and VSCC incidence are increasing. Women with vHSIL and/or VSCC can present with ASCC at diagnosis, being one of the highest-risk groups. Suspicious symptoms include rectal bleeding, pain, and a sensation of an anal mass. Digital anorectal examination can help detect early ASCC. Sensitivity of anal cytology in women with vHSIL and VSCC seems low, with the exception of immunosuppressed women with genital neoplasia (cervix, vagina, and vulva). There are still insufficient data on high-resolution anoscopy in women with vHSIL and/or VSCC as a screening method. Conclusions Clinicians need be aware that women with vHSIL and VSCC comprise one of the highest-risk groups for ASCC. Inquiring suggestive symptoms of ASCC and a digital anorectal examination can help in the early detection of this type of cancer.

Human papillomavirus (HPV) causes anal warts and anal squamous cell carcinoma (SCC). A higher incidence of anal cancer has been found among individuals previously diagnosed with anogenital warts. We aimed to investigate the association between anal warts and the presumed anal SCC precursor high-grade squamous intraepithelial lesion (HSIL), among participants in the Study of the Prevention of Anal Cancer (SPANC). SPANC was a longitudinal study of anal HPV infections and related lesions among gay and bisexual men (GBM) age 35 years and older, in Sydney, Australia. Anal cytology and high-resolution anoscopy were performed. Logistic regression was used to investigate the association between clinically diagnosed anal warts and intra-anal composite-HSIL (cytology and/or histology) at the baseline visit. The prevalence of HSIL within biopsies from intra-anal warts was calculated. Laser capture microdissection (LCM) and HPV-genotyping was performed on HSIL lesions. Among 616 participants at study entry, 165 (26.8%) and 51 (8.3%) had intra-anal and perianal warts, respectively. Warts were associated with composite-HSIL, even after adjustment for HIV status, age, lifetime receptive anal intercourse partner number, and smoking (perianal: aOR 2.13, 95% CI 1.17-3.87

Two etiopathogenic types of vulvar squamous cell carcinoma (VSCC) have been described: human papillomavirus (HPV)-associated and HPV-independent. Precursor lesions, frequently identified in the adjacent skin, are also distinct in the 2 types of VSCC: high-grade squamous intraepithelial lesions (HSILs) in HPV-associated VSCC and differentiated vulvar intraepithelial neoplasia (dVIN) or vulvar acanthosis with altered differentiation in HPV-independent VSCC. Although HPV-independent precursors mimicking HSIL have been described in the vulva, their frequency and morphologic spectrum have not been completely characterized. We explored, in a large series of HPV-independent VSSC, the frequency and the histologic features of precursors mimicking HSIL. We included 779 DNA HPV-negative/p16-negative VSCC with at least 1\xE2\x80\x89cm of adjacent skin. We evaluated the histologic and immunohistochemical (p16 and p53) characteristics of the intraepithelial lesions, focusing on precursors mimicking HPV-associated vulvar HSIL. A total of 254 tumors (33%) had adjacent premalignant lesions. Of them, 186 (73%) had dVIN, 22 (9%) had vulvar acanthosis with altered differentiation, and 46 (18%) had lesions that mimicked HSIL. The mean age of the patients with these HSIL-like lesions was 72\xC2\xB115 years. Twenty-six of these HSIL-like lesions had basaloid morphology, 13 warty, and 7 mixed basaloid/warty features. All the HSIL-like precursors were DNA HPV-negative/p16-negative; 74% of them showed p53 abnormal staining and 35% of them had areas of conventional dVIN. In conclusion, about one fifth of the HPV-independent precursors mimic HSIL, showing either basaloid or warty features. Older age and the presence of areas of typical HPV-independent intraepithelial lesions, together with p16 negativity, should raise suspicion of an HPV-independent etiology.

An early screening of HPV and the Thinprep Cytology Test (TCT) can effectively prevent cervical cancer. However, patients with high-grade cervical intraepithelial neoplasia usually escape current screening methods and commonly develop cervical cancer. Hence, to identify effective and specific screening methods for high-grade cervical intraepithelial neoplasia is of vital necessity. In this study, 541 patients collected in Sun Yat-Sen hospital from January 2007 to December 2016 were selected. HPV genotype detection and SCC-ag detection were done in these patients. It was found that when serum SCC-ag level exceeded over 0.39 ng/ml in HPV-16 positive patients, the sensitivity and specificity of this novel approach to predict high-grade cervical intraepithelial neoplasia could reach to 83.1% and 62.1%, respectively. The result suggested that the combination of serum SCC-ag level and HPV-16 infection could be used as a novel approach for high-grade cervical intraepithelial neoplasia screening.Impact statementWhat is already known on this subject? Patients with a high-grade cervical intraepithelial neoplasia usually escape current screening methods.What do the results of this study add? When serum SCC-ag level exceeded over 0.39 ng/ml in HPV-16 positive patients, the sensitivity and specificity to predict high-grade cervical intraepithelial neoplasia could reach to 83.1 and 62.1%, respectively.What are the implications of these findings for clinical practice and/or further research? Combination of serum SCC-ag level and HPV-16 infection could be used to screen high-grade cervical intraepithelial neoplasia.

Every year cervical cancer affects more than 300,000 people, and on average one woman is diagnosed with cervical cancer every minute. Early diagnosis and classification of cervical lesions greatly boosts up the chance of successful treatments of patients, and automated diagnosis and classification of cervical lesions from Papanicolaou (Pap) smear images have become highly demanded. To the authors’ best knowledge, this is the first study of fully automated cervical lesions analysis on whole slide images (WSIs) of conventional Pap smear samples. The presented deep learning-based cervical lesions diagnosis system is demonstrated to be able to detect high grade squamous intraepithelial lesions (HSILs) or higher (squamous cell carcinoma; SQCC), which usually immediately indicate patients must be referred to colposcopy, but also to rapidly process WSIs in seconds for practical clinical usage. We evaluate this framework at scale on a dataset of 143 whole slide images, and the proposed method achieves a high precision 0.93, recall 0.90, F-measure 0.88, and Jaccard index 0.84, showing that the proposed system is capable of segmenting HSILs or higher (SQCC) with high precision and reaches sensitivity comparable to the referenced standard produced by pathologists. Based on Fisher’s Least Significant Difference (LSD) test (P < 0.0001), the proposed method performs significantly better than the two state-of-the-art benchmark methods (U-Net and SegNet) in precision, F-Measure, Jaccard index. For the run time analysis, the proposed method takes only 210 seconds to process a WSI and is 20 times faster than U-Net and 19 times faster than SegNet, respectively. In summary, the proposed method is demonstrated to be able to both detect HSILs or higher (SQCC), which indicate patients for further treatments, including colposcopy and surgery to remove the lesion, and rapidly processing WSIs in seconds for practical clinical usages.

PurposeHigh rate of false-positive tests is a major obstacle to use human papillomavirus (HPV) detection as a diagnostic tool for high-grade squamous intraepithelial lesions or cervical cancer (HSIL+). We investigated whether type-specific viral load or physical state of HPV 16, 18, and 58 are useful biomarkers for HSIL+.Materials and MethodsType-specific viral loads of E6 and E2 genes in cervical cells from 240, 83, and 79 HPV 16–, 18–, and 58–infected women, respectively, were determined using real-time polymerase chain reaction. Viral loads were normalized to cellular DNA (copy/cell). Total and integrated viral loads and physical state were compared between HSIL+ and controls, and diagnostic value was determined using receiver operating characteristic analysis.ResultsViral loads of HPV 16, 18, and 58 were significantly different in lesions in the same pathologic grade. High type-specific total viral loads were significantly associated with HSIL+ (odds ratio [OR], 14.065, 39.472, and 7.103 for HPV 16, 18, and 58, respectively). High integrated viral load was related to HSIL+ in women with HPV 16 (OR, 8.242), and integrated state was associated with HSIL+ in women with HPV 18 (OR, 9.443). Type-specific total viral load was significantly associated with HSIL+ (area under curve, 0.914, 0.937, and 0.971 for HPV 16, 18, and 58, respectively), indicating an excellent performance in detecting HSIL+.ConclusionType-specific total viral load may be a powerful diagnostic marker for HSIL+ in HPV 16–, 18–, and 58–infected HSIL+ lesions. If demonstrated in all other high-risk HPV types, this method can lead to a paradigm shift in the strategy of equivocal cytologic abnormalities.

Cervical cancer is a major public health problem that continues to be one of the leading female genital cancers worldwide. In the kingdom of Saudi Arabia (KSA), cervical cancer ranks the fifteenth most frequent cancer among females. This study is the first published research study addressing the screening of cervical cancer in Madinah region of KSA. Aim: To evaluate the abnormal cytological entities detected by cervical Pap smear in Madinah region of KSA and to compare the results with other national and international studies. Methods: This retrospective case-control study was conducted in the Departments of Obstetrics and Gynecology, and Histopathology at the Maternity and Children Hospital (MCH), Madinah, KSA from January 2013 to December 2015. Results: Of the 1594 cases reviewed, only 38 cases (2.4%) had epithelial cell abnormalities. High grade squamous intraepithelial lesions (HSIL) and low grade squamous intraepithelial lesions (LSIL) were the most common diagnosis categories, and cervical cancer accounted for 36.8% of the total cases for each, followed by atypical squamous cells of uncertain significance (ASCUS) found in (15.9%). Squamous cell carcinoma (SCC ) was found in (5.3%) of the cases. Patients with abnormal epithelial changes had higher parity (P=0.021) and presented more with a complaint of postcoital bleeding (P

Objective: To determine the factors associated with the increased risk of developing high-grade squamous intraepithelial lesions (HSIL) of the uterine cervix in women younger than 30 years compared with those aged ≥ 30 years who also had HSIL. Methods: Patients with HSIL who underwent loop electrosurgical excision procedure (LEEP) between January 2006 and July 2017 at Chiang Mai University Hospital were retrospectively reviewed. We analyzed the factors associated with the development of HSIL by comparing two age groups between women aged < 30 years and those aged ≥ 30 years. The factors analyzed included the well-recognized risk factors for cervical cancer, i.e. age at sexual debut, number of sexual partners, use of oral contraceptive (OC) pills, smoking history, sexually transmitted diseases and HIV status. Univariate and multivariate logistic regressions were used to assess factors associated with the increased risk of developing HSIL in women younger than 30 years compared with those aged ≥ 30 years. Results: During the study period, there were 345 patients with HSIL, 30 were < 30 years (case group) and 315 aged ≥ 30 years (control group). By multivariate analyses , early sexual debut(OR, 2.86; 95% CI, 1.01-8.13; P=0.047), multiple sexual partners (OR, 2.94; 95% CI, 1.23-7.02; P=0.015), history of genital warts (OR, 20.46; 95% CI, 2.27-183.72; P=0.007) and history of smoking (OR, 2.95; 95% CI, 1.10-7.93; P=0.032) were significantly associated with the development of HSIL in women younger than 30 years when compared with those aged ≥ 30 years. The OC use, HIV status and underlying diseases were not significantly different in both groups. Conclusion: Early age at sexual debut, multiple sexual partners, history of genital warts and smoking are significant risk factors for developing HSIL in women younger than 30 years. Cervical cancer screening should be considered in young women with such factors.

Background Hyperchromatic crowded groups (HCGs) are often classified as atypical squamous cells, cannot exclude a high grade squamous intraepithelial lesion (ASC-H) on ThinPrep Pap tests. This study reports on the association of HCG's with high grade squamous intraepithelial lesions (HSIL) involving endocervical glands. Methods Over a 3-year period (January 1, 2018-December 31, 2020), 115 (0.2%) of 63,817 Pap tests were diagnosed as ASC-H. Histologic follow-up was available in 76 (66%) cases; 42 (55%) cervical biopsies; and 34 (45%) cervical cones/LEEPs. Results Based on the histologic results, 49 ASC-H cases showed HSIL/CIN 3 and form the basis of this study. ThinPrep Pap tests showed two cell patterns; atypical immature squamous metaplastic cells and HCGs, each of which was difficult to distinguish from HSIL. On histologic correlation all 10 ASC-H Pap Tests with individual atypical immature squamous metaplastic cells showed HSIL/CIN 3 without endocervical gland involvement and 37 (95%) of the 39 Pap Tests with HCGs showed HSIL/CIN 3 with endocervical gland involvement. Conclusion The results of this study support the premise that a subset of HCGs represent endocervical gland involvement by HSIL as opposed to a glandular lesion; in particular endocervical adenocarcinoma in-situ.

Background Primary human papillomavirus (HPV) screening (PHS) utilizes oncogenic human papillomavirus (oncHPV) testing as the initial cervical cancer screening method and typically, if positive, additional reflex-triage (eg, HPV16/18-genotyping, Pap testing). While US guidelines support PHS usage in the general population, PHS has been little studied in women living with HIV (WLWH). Methods We enrolled n = 865 WLWH (323 from the Women’s Interagency HIV Study [WIHS] and 542 from WIHS-affiliated colposcopy clinics). All participants underwent Pap and oncHPV testing, including HPV16/18-genotyping. WIHS WLWH who tested oncHPV[+] or had cytologic atypical squamous cells of undetermined significance or worse (ASC-US+) underwent colposcopy, as did a random 21% of WLWH who were oncHPV[−]/Pap[−] (controls). Most participants additionally underwent p16/Ki-67 immunocytochemistry. Results Mean age was 46 years, median CD4 was 592 cells/µL, 95% used antiretroviral therapy. Seventy WLWH had histologically-determined cervical intraepithelial neoplasia grade 2 or greater (CIN-2+), of which 33 were defined as precancer (ie, [i] CIN-3+ or [ii] CIN-2 if concurrent with cytologic high grade squamous intraepithelial lesions [HSILs]). PHS had 87% sensitivity (Se) for precancer, 9% positive predictive value (PPV), and a 35% colposcopy referral rate (Colpo). “PHS with reflex HPV16/18-genotyping and Pap testing” had 84% Se, 16% PPV, 30% Colpo. PHS with only HPV16/18-genotyping had 24% Colpo. “Concurrent oncHPV and Pap Testing” (Co-Testing) had 91% Se, 12% PPV, 40% Colpo. p16/Ki-67 immunochemistry had the highest PPV, 20%, but 13% specimen inadequacy. Conclusions PHS with reflex HPV16/18-genotyping had fewer unnecessary colposcopies and (if confirmed) could be a potential alternative to Co-Testing in WLWH.

Background There is currently a lack of information on full anogenital evaluation of women with a previous history of anogenital neoplasia. Methods Retrospective analysis of the Homerton Anogenital Neoplasia Service records from January 2012 to March 2017, to identify all new referrals of women with previous anogenital neoplasia, who had had at least one complete examination of all anogenital sites. Multizonal anogenital disease (MZD) was defined as the presence of high-grade squamous intraepithelial lesions (HSIL)/carcinoma concurrently at two or more of the following sites/zones: perianus, anal canal, vulva, vagina or cervix. Results 253 women were included, mean age was 47 (SD=15) years and median duration of follow-up was 12 (IQR=21) months. Fifty-six women (22%) were diagnosed with MZD at first assessment and/or during follow-up. Current smokers (RR=1.84, 95% CI 1.21–2.79, p=0.004) and women on immunodulators/immunosuppressive drugs (RR=2.57, 95% CI 1.72-3.86, pp=0.006). Conclusions Multizonal assessment was important to diagnose occult areas of disease and should be especially considered in current smokers, pharmacologically immunocompromised and those with a previous history of anogenital HSIL/cancer.

Author(s): Chiao, Elizabeth Y; Lensing, Shelly Y; Wiley, Dorothy J; Deshmukh, Ashish A; Lee, Jeannette; Darragh, Teresa M; Einstein, Mark H; Jay, Naomi; Berry-Lawhorn, John Michael; Palefsky, Joel M; Wilkin, Timothy; Barroso, Luis F; Cranston, Ross D; Levine, Rebecca; Guiot, Humberto M; French, Audrey L; Citron, Deborah; Rezaei, Masoumeh Katayoon; Goldstone, Stephen E; Stier, Elizabeth A | Abstract: ObjectiveHIV-infected women (WLHIV) have more than 10-fold higher risk for squamous cell cancer of the anus. Experts suggest cytology-based strategies developed for cervical cancer screening may prevent anal cancer by detecting anal cytologic or histological high-grade squamous intraepithelial lesion (hHSIL) for treatment. Currently, there is no consensus on anal-hHSIL screening strategies for WLHIV.DesignBetween 2014 and 2016, 276 WLHIV were recruited at 12 US AIDS Malignancy Consortium clinical trials sites to evaluate hHSIL prevalence and (test) screening strategies.MethodsParticipants completed detailed questionnaire, underwent anal assessments including high-risk human papillomavirus (hrHPV) testing using hrHPV-Hybrid Capture 2 (HC2) and hrHPV-APTIMA, anal cytology, and concurrent high-resolution anoscopy. Screening test characteristics for predicting hHSIL validated by central review of histologic diagnosis were estimated sensitivity, specificity, positive predictive value, and false-omission rate. Paired analyses compared sensitivity and specificity for hrHPV single tests to anal cytology alone.Results83% (229/276) of enrolled WLHIV had complete anal assessment data and were included in this analysis. Mean age was 50, 62% black and 60 (26%) had hHSIL. Anal cyotology (gatypical squamous cells of undetermined significance), hrHPV-HC2, and hrHPV-APTIMA sensitivity estimates were similarly high (83, 77, and 75%, respectively, P values g 0.2). Specificity was higher for both hrHPV-APTIMA and hrHPV-HC2 compared with anal cytology (67 vs. 50%, P l 0.001) and (61 vs. 50%, P = 0.020), respectively.ConclusionAnal hrHPV testing demonstrated similar sensitivity for anal cytology (gatypical squamous cells of undetermined significance) to predict anal hHSIL. Among tests with similar sensitivity, the specificity was significantly higher for hrHPV-APTIMA and hrHPV-HC2. Thus, anal hrHPV testing may be an important alternative strategy to anal cytology for anal hHSIL screening among WLHIV.

Background Women living with HIV (WLWH) experience high rates of anal cancer. Screening using anal cytology, high-resolution anoscopy (HRA) with biopsies, can histologically diagnose anal cancer precursors called high-grade squamous intraepithelial lesions (HSIL). The low specificity of screening using anal cytology results in HRA referral for many WLWH without HSIL. Screening using high-risk human papillomavirus (HR-HPV) may improve specificity. Methods Two hundred seven WLWH (63% non-Hispanic black) were screened for anal histologic HSIL (hHSIL) using cytology, HRA-guided biopsies, and Xpert HPV. Xpert performance for predicting anal hHSIL was compared with that of cytology. Usng Xpert 5 HPV genotypic results and accompanying cycle thresholds, receiver operator characteristic curve and recursive partitioning analyses were used to create predictive models for hHSIL. Results The performance of Xpert to predict hHSIL was not different from that of cytology with a sensitivity (Sn) of 89% and specificity (Sp) of 49%. Interpretation of Xpert was modified using genotypic results and receiver operator characteristic curve analysis, which produced a screen with an Sn and Sp of 75% and 84% for hHSIL, respectively. Another reinterpretation of Xpert was created using recursive partitioning and cycle thresholds, which predicted hHSIL with an Sn and Sp of 75% and 86%, respectively. The detection of HPV-16 was highly predictive of hHSIL in all analyses. These modified screening tests would reduce HRA referral in this population by almost half compared with anal cytology. Conclusions Xpert HPV is an alternative to anal cytology to screen for anal HSIL and can be optimized to reduce the number of unnecessary HRAs performed in WLWH.

Background/aim To investigate the clinicopathological characteristics of high-grade squamous intraepithelial lesions (HSILs) and squamous cell carcinomas (SCCs) involving endocervical polyps (ECPs). Patients and methods We collected the endocervical polypectomy cases and performed pathological examination and cytohistological correlation. Results During a period of 12 years, 21 (1.1%) HSILs and two (0.1%) SCCs involving ECPs were identified in 1,905 cases. Twelve (63.1%) of the 19 cases were cytohistologically concordant. In five HSILs and one SCC with polypectomy margin involvement, residual HSIL was identified in conization or hysterectomy specimens. Furthermore, in two HSIL patients and one SCC patient with negative polypectomy margins, residual HSILs were found in the conization specimens. Conclusion The prevalence of HSIL and SCC involving ECP in our cohort was similar to the rates found in previous studies. The presence of residual HSIL in nonpolypoid cervical tissue regardless of the polypectomy margin involvement suggests that conization or hysterectomy is needed for diagnostic or treatment purposes.

Inflammation has been reported as a facilitator in cervical oncogenesis, but the correlation between inflammation and cytological abnormality remains uncertain. The aim of this study was to investigate the correlation between inflammation and cytological abnormality. ThinPrep cytological test (TCT) was used to detect cervical cytological abnormalities and inflammation degrees of 46,255 women in this prospective cross-sectional study. Histopathological examination was used to define the cervical intraepithelial neoplasia (CIN) in patients with cervical cytological abnormalities. The study revealed that 8.87% (4102/46,255) of TCT results had cytological abnormalities. The 4102 included cases were classified as the case group, including atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). Women with negative intraepithelial lesion or malignancy (NILM) were classified as the control group. About 88.83% (3644/4102) of women with cytological abnormalities showed inflammations. The rate of severe inflammation was significantly higher in the case group than the control group (23.86% vs. 2.0%, P = 0.000). Our results also showed that patients with severe inflammation had a significantly increasing incidence of cytological abnormality by 12.598 times and elevated the risk of HSIL by 756.47 times, compared to the inflammation negative group. Severe inflammation was positively related to HSIL. Patients with severe cervical inflammation should be given more follow-ups and regular examinations and treated more carefully than those with mild or no inflammation.

Women living with HIV (WLHIV) are at increased risk for human papillomavirus (HPV)-associated anal cancer. Given the “field effect” of HPV pathogenesis, some recommend that anal cancer screening should be limited to WLHIV with prior genital disease. This study aimed to characterize the relationship between anal and genital disease in WLHIV in order to better inform anal cancer screening guidelines. We retrospectively studied 153 WLHIV with biopsy-proven anal high-grade squamous intraepithelial lesions (AHSIL) and long-term evaluable cervical/vaginal/vulvar histopathology. Based on the absence or presence of genital HSIL, subjects were categorized as having isolated AHSIL or multicentric HSIL. Demographics, HIV parameters and cervical/anal HPV status were recorded. Chi-square test was used for bivariate analyses. Of 153 WLHIV with AHSIL, 110 (72%) had isolated AHSIL, while 43 (28%) had multicentric HSIL (28 cervical, 16 vulvar, and 8 vaginal HSIL). The median genital surveillance was 8 years (range 1–27). Cervical HPV16/18 infection was associated with multicentric disease (P = 0.001). Overall, 53% of multicentric cases presented genital HSIL preceding AHSIL with median interval 13 years (range 2–23). Paired anal and cervical high-risk HPV results were available for 60 women within 12 months of AHSIL diagnosis: 30 (50%) had anal infection alone, while 30 (50%) had anal/cervical coinfection by 16/18 (15%), non-16/18 (13%), or different types (22%). In conclusion, WLHIV frequently develop AHSILs without pre-existing genital disease or after long latency following a genital HSIL diagnosis. Our findings support anal cancer screening for WLHIV irrespective of prior genital disease.

Objective: To investigate pathologic discrepancies between colposcopy-directed biopsy (CDB) of the cervix and loop electrosurgical excision procedure (LEEP) in women with cytologic high-grade squamous intraepithelial lesions (HSILs). Methods: We retrospectively identified 297 patients who underwent both CDB and LEEP for HSILs in cervical cytology between 2015 and 2018, and compared their pathologic results. Considering the LEEP to be the gold standard, we evaluated the diagnostic performance of CDB for identifying cervical intraepithelial neoplasia (CIN) grades 2 and 3, adenocarcinoma in situ, and cancer (HSIL+). We also performed age subgroup analyses. Results: Among the study population, 90.9% (270/297) had pathologic HSIL+ using the LEEP. The diagnostic performance of CDB for identifying HSIL+ was as follows: sensitivity, 87.8%; specificity, 59.3%; balanced accuracy, 73.6%; positive predictive value, 95.6%; and negative predictive value, 32.7%. Thirty-three false negative cases of CDB included CIN2,3 (n=29) and cervical cancer (n=4). The pathologic HSIL+ rate in patients with HSIL- by CDB was 67.3% (33/49). CDB exhibited a significant difference in the diagnosis of HSIL+ compared to LEEP in all patients (p

Human papillomavirus (HPV) infection is associated with the vast majority of cervical cancer cases as well as with other anogenital cancers. PepCan is an investigational HPV therapeutic vaccine for treating cervical high-grade squamous intraepithelial lesions. The present study was performed to test whether the cervical microbiome influences vaccine responses and to explore host factors as determinants of the cervical microbiome composition in women with biopsy-proven high-grade squamous intraepithelial lesions. In a recently completed Phase I clinical trial of PepCan, histological response rate of 45% (14 of 31 patients), a significant increase in circulating T-helper type 1 cells, and a significant decrease in HPV 16 viral load were reported. DNA, extracted from liquid cytology specimens collected before and after vaccinations, were amplified and then hybridized to a G4 PhyloChip assay to characterize the microbiome. We describe trends that certain bacterial taxa in the cervix may be enriched in non-responders in comparison to responders ( Padj = .052 for phylum Caldithrix and Padj = .059 for phylum Nitrospirae). There was no difference in bacterial diversity between the 2 groups. A permutational analysis of variance performed for various demographic and immune parameters showed significant clustering with microbiome beta diversity for race, HPV 16 status, peripheral T-helper type 1 cells, and HLA-B40 ( P = .001, .014, .037, and .024, respectively). Further analyses showed significant differences at the empirical Operational Taxonomic Unit level for race and HPV 16 status. As these results are from a small Phase I study, further studies are needed to examine the role of cervical microbiome in response to HPV therapeutic vaccines.

Background Our objective was to identify virological and serological predictors of anal high-grade squamous intraepithelial lesions (HSIL) in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). Methods HIV-positive MSM were recruited from a longitudinal study during which anal self-swabs and serum were collected at up to 5 bi-annual visits. Swabs were human papillomavirus (HPV) genotyped, and the type-specific HPV viral load in the anal swabs was determined. Serum antibodies to the E6, E7, E1, E2, and L1 proteins of 7 high-risk HPV (hrHPV) types and HPV6 and 11 were analyzed. The participants who had a high-resolution anoscopy after the last study visit were included in the current analysis. Anal HSIL was diagnosed by histopathological examinations of anal biopsies. The causative HPV type of anal HSIL was determined in whole tissue sections (WTS) and by laser capture micro-dissection if more than one HPV-type was found in WTS. Multivariable logistic regression was used to study whether persistent anal HPV infections, HPV viral loads, and seropositivity for HPV were predictors of anal HSIL, either in general or caused by the concordant HPV type. Results Of 193 HIV-positive MSM, 50 (26%) were diagnosed with anal HSIL. HrHPV persistence in anal swabs was common, varying by hrHPV type between 3-21%. Anal HPV persistence was the only determinant independently associated with anal HSIL, both in general and by concordant, causative HPV type. Conclusions Persistent HPV infections were strongly associated with anal HSIL, in general as well as for the concordant HPV type.

Objectives This study investigated anal high-risk HPV (HR-HPV) prevalence in HIV-infected women using the Cepheid Xpert HPV assay and compares its performance with that of Hybrid Capture-2 (hc2). Methods A total of 199 HIV-infected women were recruited from Helen Joseph Hospital, Johannesburg. Stored ThinPrep anal swabs that had previously been tested using hc2 were tested for HPV using Xpert. Results The HR-HPV prevalence by Xpert was 40.8% and similar to hc2 (41.8%) with overall agreement of 86.7%; Cohen's kappa 0.73 (95% CI 0.63-0.82). High grade squamous intraepithelial lesions (HSIL) was associated with increasing number of multiple HPV infection (P < .001). Xpert and hc2 were similarly sensitive (77.4% and 77.4%, respectively) and specific (66.1% and 64.8% respectively) for HSIL detection. HPV16 (OR: 14.0, 95% CI: 3.9-48.0, P < .0001), HPV39/68/56/66 (OR: 4.1, 95% CI: 1.4-12, P = .01) and HPV51/59 (OR: 2.8, 95% CI: 1.1-7.6, P = .04) were independently associated with anal HSIL. Conclusions Xpert HPV typing is a promising anal screening test in HIV-infected women that performs similarly to hc2.

Objective: HIV-positive MSM are at increased risk for developing anal squamous cell carcinoma. Detection of precursor lesions of anal cancer [anal high-grade squamous intraepithelial lesions (HSIL)] is cumbersome and expensive. Our objective was to identify potential risk factors for anal HSIL in HIV-positive MSM to develop more stringent screening criteria. Design: We studied a cohort of MSM screened by high-resolution anoscopy at three HIV clinics in Amsterdam, the Netherlands. Methods: For every first high-resolution anoscopy performed in a patient, we analyzed five demographic and seven HIV-related potential risk factors for four different outcome measures: histologically proven anal HSIL vs. no squamous intraepithelial lesions (SIL), HSIL-anal intraepithelial neoplasia 2 vs. no SIL, HSIL-anal intraepithelial neoplasia 3 vs. no SIL, and HSIL vs. no HSIL. We used univariable and multilevel, multivariable logistic regression. Results: From 2008 through 2015, 497 out of 1678 (30%) screened HIV-positive MSM had anal HSIL. The mean age was 49 years (SD 9.6), 96% used combination antiretroviral therapy, and median duration of combination antiretroviral therapy use was 7.8 years (interquartile range 4.0–12.4). Increasing age [adjusted odds ratio (aOR) 0.82, 95% confidence interval (CI) 0.70–0.94, P = 0.006] and years living with suppressed viral load [1–5 years suppressed aOR 0.52 (95% CI 0.34–0.80), 5.01–10 years aOR 0.47 (95% CI 0.29–0.74), >10 years aOR 0.54 [0.34–0.87], all compared to less than 1 year suppressed, P = 0.009] were found to be protective for HSIL vs. no SIL. Conclusion: Young HIV-positive MSM without viral suppression are statistically at highest risk for anal HSIL, but given the high prevalence among all virally suppressed men, we advise that all HIV-positive MSM should be screened for HSIL.

Background: Anal intraepithelial neoplasia grade 2 (AIN2) and AIN grade 3 (AIN3) are commonly grouped together as high grade squamous intraepithelial lesions (HSIL). We assessed risk factors for HSIL-AIN2 and HSIL-AIN3 in a cohort of homosexual men. Methods: At the baseline visit in the Study for the Prevention of Anal Cancer (SPANC), all men completed a questionnaire and underwent anal swabbing for cytology and HPV genotyping, followed by high resolution anoscopy. Results: Composite-HSIL prevalence was 47% and 32% among 220 HIV-positive and 396 HIV-negative men, respectively. HSIL-AIN3 (37.7% versus 24.7%; p

Topical imiquimod is a potential treatment for intra-anal condyloma and squamous intraepithelial lesions caused by human papillomavirus (HPV). We aimed to assess the effectiveness and tolerability of imiquimod suppositories for the treatment of anal high-grade intraepithelial lesions (HSIL) and condylomas in HIV-infected patients. We conducted a retrospective analysis in a prospectively followed cohort. High-resolution anoscopy was used for diagnosis and assessment following treatment. Patients’ tolerability was assessed with a self-administered survey. Ninety-five patients (94.7% men) were analyzed. All were on combination antiretroviral therapy. Median CD4 T-cell count was 690 cells/µL, 89% had undetectable plasma viral load. Response to imiquimod was seen in 46.3% (complete: 12.5%, partial: 33.8%) in the intent-to-treat analysis, and in 55.2% (complete: 14.9%, partial: 40.3%) in the on-treatment analysis. Higher response rates were observed for anal condyloma compared with HSIL. A significantly poorer response rate was observed in smokers and in individuals with lower nadir CD4 T-cell counts. Imiquimod tolerability was “good” in 57.1% (n = 36), “acceptable” in 33.3% (n = 21), and “poor” in 9.5% (n = 6). Systemic side effects were reported in 20.7% (n = 13). There was no association between treatment effect and tolerability. In conclusion, imiquimod stands as a well-tolerated option for the treatment of HPV-associated intra-anal pathology in HIV-infected individuals.

Objectives To investigate factors associated with larger burden of intra-anal high-grade squamous intraepithelial lesions (HSIL) in a natural history study of HSIL. Methods 617 gay and bisexual men (GBM) attended a baseline visit. High-resolution anoscopy-directed biopsy was performed of suspected HSIL. GBM with biopsy-confirmed HSIL (bHSIL) affecting a single-octant were compared with those who had bHSIL affecting a larger area. Results Of 196 men with bHSIL at baseline, 73 (37.2 %) had larger bHSIL burden. Larger burden was independently associated with anal HPV16 detection (aOR 2.06, 95 % CI 1.09–3.89, p = 0.026) and infection with a greater number of high-risk HPV types (aOR per type increase 1.25, 95 % CI 1.05–1.49, p-trend = 0.010). Conclusion The observation that men with a larger burden of HSIL also had more risk factors for anal cancer suggests this group may warrant closer observation to ensure earlier detection, and thus improved prognosis, of individuals whose HSIL may progress to anal cancer.

In rare cases, equivocal histomorphology ('deceiving dysplasia') does not allow immediate diagnosis of cervical high-grade squamous intraepithelial lesion (HSIL). We studied whether these cases are correlated with specific high-risk human papillomavirus (hr HPV) types. During 2011-2017, 39 cases of p16-positive cervical tissue biopsies with unusual ('deceiving') dysplastic histomorphology were identified and matched with the same number of controls (typical HSIL samples). Histomorphological characteristics were reviewed blindly and HPV testing was performed using the clinically validated RealTime test (Abbott) and Anyplex HPV 28 (Seegene). HPV 16 and HPV 31 were the two most frequent HPV types in both groups, although minimum, proportional, hierarchical and any etiological attribution estimates for HPV 16 were significantly lower in the deceiving group (13.2%, 21.3%, 23.7% and 23.7%) than in the control group (32.4%, 48.1%, 48.6% and 48.6%). In addition, the distribution of other hr HPV types differed between the two study groups, with five HPV types (HPV 56, 58, 59, 73 and 82) detected only in the deceiving group. Histomorphologic review of both groups (regardless of HPV type) confirmed significant differences in nuclear atypia, maximum lesion thickness and cellularity, although these were diminished when cross-comparisons between HPV16/18 and non-HPV16/18 cases pooled from both study groups were evaluated. Different attribution estimates for HPV 16, HPV 16/18 and non-16/18 hr HPV types in deceiving and control groups were observed, in particular for HPV 16. However, an unusual (deceiving) histomorphology may also depend on unknown HPV-related molecular changes.

Objective To evaluate the efficacy of modified Swede Colposcopic Index (MSCI) to predict high-grade lesion and cancer of cervix (CIN2+, cervical intraepithelial neoplasia grade 2 or worse) in women with abnormal cervical cytology who underwent a colposcopy. Methods We conducted a retrospective study and MSCI using 5 features of cervical lesions evidenced from colposcopy: acetouptake, margin and surface, vessels, lesion size, and location of lesion. Each feature was scored from cervicograhpic findings which transformation zone was completely seen. Odds ratio of each feature was obtained by logistic regression analysis. Receiver operating characteristic curve was used to assess the efficacy of summation score to predict CIN2+. An appropriate cut-off point score was assigned. Results Two hundred and twenty women were included in the study. The assigned score for each factor in level 1 to 3 was 1, 2 and 3 points with a total score of 15 points. The most appropriate cut-off points score for MSCI to predict CIN2+ was 11 points. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy using MSCI were 82.2%, 96.2%, 96.0%, 85.0%, and 90.0% respectively. Conclusion MSCI showed a high efficacy for predicting CIN2+ in satisfactory colposcopy.

To construct a scoring system for pap smears to objectify cytological appraisal and to enhance the accuracy and comparability of pap smear interpretation in pregnancy. For development of a scoring system for cell appraisal of pap smears the style of the Modified Masood’s Scoring Index for appraisal of cells from fine needle aspirations of breast lesions was used. Cohort analysis of n = 54 dysplastic pap smears for polymorphology of cells, anisonucleosis, structure of the nucleus, signs of tissue destruction, nucleus/plasma relation and signs of tumordiathesis. Each criteria was classified into three stages: The first with little evidence for dysplasia (one point), second stage with sporadic evidence (two points) or third stage with frequent evidence (three points). To further evaluate if pregnancy associated cells changes interfere with this scoring system we compared the results of pregnant and non-pregnant women. Histological result was used as an indicator of correctness of the score. Statistical analysis showed a good correlation of the scoring system with histological results. Especially in pregnancy statistical analysis shows promising results (sensitivity 86.67 %, Specificity 100 %, receiver operating characteristic analysis p ≤ 0.05). The Luebeck Score seems to be a useful approach for appraisal of pap smears in pregnancy. Further studies containing high numbers of cases are needed for further evaluation of potential benefits of the scoring system compared to conventional evaluation of pap smears.

OBJECTIVES: Cervical cancer screening by visual inspection with acetic acid (VIA) is a widely used alternative to cytology in developing countries. This study aimed to evaluate risk factors associated with a positive VIA test and with cervical high-grade lesions on cytology.METHODS: We conducted a large cross-sectional study among 3339 women from urban and rural Tanzania. Study participants were interviewed about socio-demographic, reproductive and lifestyle factors. Blood samples were tested for HIV, and a gynaecological examination was performed. Human papillomavirus (HPV) status was determined by Hybrid Capture 2, and HPV genotyping was done using the LiPA Extra test. We used multivariable logistic regression to estimate adjusted odds ratios (ORs) and confidence intervals (CIs).RESULTS: The strongest risk factors for VIA positivity were positivity to HIV (OR = 3.48; 95% CI: 2.34-5.17) or to high-risk HPV (HrHPV) (OR = 1.97; 95% CI: 1.37-2.85). HrHPV was by far the strongest predictor of high-grade cytology (OR = 110.1; 95% CI: 50.4-240.4), while there was no significant association with HIV in the multivariable analysis (OR = 1.27; 95% CI: 0.78-2.08). After adjustment for HrHPV, HIV and age, the risk of high-grade cytology also increased with increasing age, number of births and low body mass index (BMI), while high BMI decreased the risk of VIA positivity.CONCLUSIONS: Infection with HrHPV is a major risk factor for high-grade cytology, while VIA positivity is associated with HIV and to a lesser extent with HrHPV.

This study explores understanding of primary and secondary prevention of anal cancer among human immunodeficiency virus (HIV)-infected foreign-born Latino gay and bisexual men (GBM). Between August 2015 and December 2016, researchers conducted 33 in-depth, semi-structured interviews with HIV-infected foreign-born Latino GBM. Interview questions sought to determine participants’ knowledge and perceived barriers and facilitators to primary and secondary prevention of anal cancer. Researchers analyzed interview transcripts using a qualitative content analysis approach. For primary prevention, men reported a lack of knowledge about the human papillomavirus (HPV) vaccine. However, for secondary prevention, roughly 60% of participants had previously screened for anal dysplasia via anal Papanicolaou (Pap) smear. However, participants reported willingness to screen, and provider recommendation was the most common screening facilitator. Men reported stigma related to their HIV status, sexual orientation, and anal Pap smear procedures as anal cancer screening barriers. Participants reported willingness to use a self-screening anal Pap smear test if it was commercially available. Health providers continue to be the leading source of health information. Therefore, provider recommendation for HPV vaccination and anal cancer screening among age-eligible foreign-born Latino HIV-infected GBM is critical. More work is needed to destigmatize HIV and sexual orientation to influence positive health behaviors among this population. Future intervention research could test the effects of provider-led interventions and also media campaigns aimed at influencing HPV vaccine uptake and anal cancer screening among this population.

This study explores HIV-positive gay and bisexual men's (GBM) understanding of human papillomavirus (HPV) and the HPV vaccine.Researchers conducted 15 in-depth interviews with HIV-positive GBM between the ages of 18-30 years old.Two participants had received a single dose of the HPV vaccine. Otherwise, the majority of participants had either never heard of the HPV vaccine or they perceived it as a resource for women only. Other commonly cited barriers to getting the vaccine included lack of provider recommendation to complete the vaccine series and vaccine costs.Future provider-driven interventions should focus on increasing HPV vaccine among age-eligible HIV-positive GBM.

OBJECTIVES Follow-up of women with biopsy-confirmed CIN2+ who were either treated immediately with LLETZ or managed conservatively to determine the rates of patients back on routine screening programme after a median of three years in two groups. METHODS In this retrospective study, 310 patients were involved who had undergone biopsy with result of CIN2+ between January 2011 and December 2014. Depending on the management, i.e. based on whether cytology and colposcopy follow-up or immediate treatment were performed, they were divided in two groups. Then the number of patients back on routine screening up to 15/2/2016 as well as the results of last cytology were compared within both groups. RESULTS A total of 310 women at average age of 30 years met the inclusion criteria. Of them, 230 (74 %) had immediate treatment whereas 80 (26 %) were managed conservatively. There were no statistically significant demographic differences between the two groups. The mean time of follow up was 1.091 days (2.98 years). The patients managed conservatively required more follow-up visits at colposcopy clinic (p

We performed a hospital-based, unmatched case-control study to investigate the association between progressive stages of cervical neoplasia and digital analysis of cell proliferation by silver stained nucleolus organizer region associated proteins (AgNORs). We measured cell proliferation levels in the cervical epithelial cells of 10 women with low grade squamous intraepithelial lesions (LG-SIL), eight with high grade squamous intraepithelial lesions (HG-SIL), 11 with cervical cancer (CC) and eight with no cervical lesions (controls) using the AgNORs technique. Cell proliferation was measured by digital image analysis (DIA). DIA revealed increased total areas of AgNORs in HG-SIL and CC compared to LG-SIL and control patients. AgNORs with a kidney or cluster shape exhibited greater areas than those with a spherical or long shape. We propose a cut-off of 118 pixels to differentiate benign (control and LG-SIL) from malignant (HG-SIL and CC) lesions. DIA of AgNORs is a simple and inexpensive method for studying proliferation. The increased total area of AgNORs in malignant lesions provides information regarding cell behavior and may be related to cervical carcinogenesis; however, further validation studies are required to establish its usefulness in cytological analysis.

The natural history of high-grade cervical intraepithelial neoplasia (CIN) is largely unpredictable and current histopathological examination is unable to differentiate between lesions that will regress and those that will not. Therefore, most high-grade lesions are currently treated by surgical excision, leading to overtreatment and unnecessary complications. Prognostic biomarkers may differentiate between lesions that will regress and those that will not, making individualized treatment of high-grade CIN possible. This review identifies several promising prognostic biomarkers. These biomarkers include viral genotype and viral DNA methylation (viral factors), human leukocyte antigen-subtypes, markers of lymphoproliferative response, telomerase amplification and human papillomavirus-induced epigenetic effects (host factors) and Ki-67, p53 and pRb (cellular factors). All identified biomarkers were evaluated according to their role in the natural history of high-grade CIN and according to established criteria for evaluation of biomarkers (prospective-specimen-collection, retrospective-blinded-evaluation [PROBE] criteria). None of the biomarkers meets the PROBE criteria for clinical applicability and more research on prognostic biomarkers in high-grade CIN is necessary.

High-risk (carcinogenic) genotype human papillomavirus (HPV) infections can be associated with significant morbidity in the immunocompromised solid organ transplant (SOT) recipient. Immunosuppression-associated persistent infection can predispose to the development of rapidly progressive high-grade squamous intraepithelial lesions (HSIL) in this population. We present a case report of an adolescent bilateral lung transplant recipient who developed HSIL of the esophagus, cervix, and skin secondary to HPV. This review highlights the unique developmental needs of the sexually active adolescent SOT recipient and reviews guidelines for HPV-related screening and education of this population.

p16 immunohistochemistry is recommended by the CAP-ASCCP Lower Anogenital Squamous Terminology (LAST) Standardization Project for human papillomavirus associated Lesions as an adjunct to morphologic assessment in the diagnosis of high-grade squamous intraepithelial lesion. This study evaluates the performance of different p16 clones as compared with E6H4 (CINtec) in detecting high-grade squamous intraepithelial lesion. The 54 high-quality articles addressing the performance of p16 identified by work group 4 of the LAST Project were evaluated for: specific p16 clone, scoring method, number of cases, anatomic site, and histologic diagnoses. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each clone. Two-proportion z tests (pooled) were used to evaluate significance. In total, 32 of the 54 studies met the inclusion criteria. The most commonly used clone was E6H4 (17 studies, 3507 cases) with smaller numbers (1-4) of studies evaluating the following: 16P04, JC8, 16P07, G175-405, K5334, K5336, and 7962. p16 clones 16P04 and JC8 performed better than E6H4 with 16P04 exhibiting statistically significant higher sensitivity (94% vs. 87% for E6H4), specificity (94% vs. 81%), and positive predictive value (96% vs. 69%) while JC8 exhibited higher specificity (91% vs. 81%) and positive predictive value (88% vs. 69%). 16P07 performed similarly to E6H4 and the other 4 clones did not perform as well as E6H4. p16 clones 16P04, JC8, and 16P07 clones perform as well or better than the widely used p16 clone E6H4 (CINtec). However, further studies are indicated to determine the reproducibility of these findings and the impact of interlaboratory variation on test performance.

Objectives We questioned whether the use of p16(INK4a) immunohistochemistry in endocervical curettage (ECC) specimens would improve the detection of high-grade squamous intraepithelial lesions (HSIL) in a high-risk patient population. Methods Papanicolaou test results were retrieved in 58 consecutive ECC specimens that were previously diagnosed as no histopathologic abnormality in patients with antecedent HSIL or atypical squamous cells, cannot exclude HSIL. An H&E recut and immunohistochemistry for p16(INK4a) were performed on all cases. Results HSIL were found in 18 (31%) ECC specimens originally interpreted as negative. Of these 18 cases, three had moderate-sized fragments of ectocervical epithelium with HSIL seen on the recut H&E with concurrent positivity for p16(INK4a). Fourteen cases had rare to occasional clusters of atypical cells with strong immunoreactivity for p16(INK4a). A single case showed a medium-sized fragment of HSIL on the p16(INK4a)-stained section. Conclusions The use of recuts and adjunct p16(INK4a) should be considered when evaluating ECC specimens in high-risk patient populations.

The WHO defines thin high-grade squamous intraepithelial lesions (HSIL) as a high-grade intraepithelial lesion of the cervix that is usually ≤9 cells thick. These lesions usually develop in early metaplastic squamous epithelium without anteceding low-grade squamous intraepithelial lesions (LSIL). The prevalence of thin HSIL is not well documented. We evaluated different characteristics of thin HSIL at time of treatment. We studied 25 formalin-fixed and paraffin-embedded conization specimens processed as step-serial sections. HSIL≤9 cells thick were classified as thin HSIL. HSIL≥10 cells thick were classified as classic HSIL. Immunohistochemical p16 staining was used to confirm lesions of thin HSIL. Overall, 19 (76%) specimens contained both thin HSIL and classic HSIL, 4 (16%) contained thin HSIL only, 1 (4%) contained classic-type HSIL only, and 1 (4%) contained thin HSIL and LSIL. Thin HSILs developed in both the columnar surface epithelium and deep cervical glandular epithelium. Most thin HSILs were 5 cells thick. All HSILs (thin and classic) were located inside the transformation zone and had a median horizontal extension of 8 mm (range, 0.3 to 21 mm). Our findings suggest that thin HSILs are frequent findings, that they coexist with classic HSIL, and preferably arise in the exposed parts of the transformation zone including the glandular crypts.

Objectives: To assess the diagnostic value of cervical cytology and HPV HR DNA testing for the diagnosis of low grade and high-grade squamous intraepithelial lesions across different age groups. Material and methods: The study included 1103 patients, age 25–70 years. All patients underwent in-depth diagnostic tests following either an abnormal Pap test result or a clinically suspicious cervical lesion. In all women the following examinations were performed: a molecular test detecting 14 high-risk types of HPV, a colposcopy examination, as well as directed-biopsy of the cervix. The studied population was subdivided into four age groups. Results: It was observed that the percentage of high grade squamous intraepithelial lesions (HSIL) and cancers increased with women’s age. Sensitivity of both methods for detecting high-grade squamous intraepithelial lesions was highest for women aged 40–49 years. Sensitivity values of HPV testing was higher than that of cervical cytology among women under age 50. Conclusions: Specificity of HPV testing increased significantly with age of women and was several fold higher across all age groups than the specificity of cervical cytology.

Objective: A vast majority of cervicovaginal intraepithelial lesions are caused by high-risk human papillomaviruses (HPVs). The Pap test has been the sole method used for the screening of cervicovaginal squamous intraepithelial lesions (SIL). Recently, the FDA approved an HPV-DNA assay as a method of primary screening. We report on a series of FDA-approved HPV-DNA test-negative SIL with HPV genotyping, using an alternative method on the corresponding surgical biopsy specimens. Study Design: A retrospective review identified cytology-positive HPV-negative cases over a 15-month period at a tertiary care gynecologic oncology institution. Corresponding biopsies were reviewed and genotyped for high-risk HPVs. Results: Of the 18,200 total cases, 17 patients meeting the study criteria were selected with 27 surgical specimens corresponding to their cytologic diagnoses. Four patients with high-grade lesions were identified, 3 of whom (75%) were positive for HPV. One of these 4 patients (25%) showed high-grade SIL on biopsies from 4 separate sites in the cervix and vagina. Multiviral HPV infections were frequent. Conclusions: We discuss the relevance of cotesting for screening cervical SILs and emphasize that false-negative results are possible with the FDA-approved HPV screening assay, also in patients with high-grade SIL. These cases may be detectable by cytologic examination and this suggests that the Pap test remains an important diagnostic tool.

Objective DNA methylation has been shown to be a potential biomarker for early cancer detection. The aim of this study was to evaluate DNA methylation profiles according to liquid-based Pap (LBP) test results and to assess their diagnostic value in a Korean population. Methods A total of 205 patients with various Papanicolaou test results were enrolled to this study (negative, 26; atypical squamous cells of undetermined significance, 39; low grade squamous intraepithelial lesion, 44; high grade squamous intraepithelial lesion (HSIL), 48; and cancer, 48). DNA methylation analysis of four genes, ADCYAP1, PAX1, MAL, and CADM1, was performed on residual cervical cells from LBP samples using a quantitative bisulfite pyrosequencing method. To evaluate the diagnostic performance of the four methylated genes for cancer detection, receiver operating characteristic (ROC) curves were drawn. Sensitivities and specificities were also tested at cutoffs determined from the ROC curves. Results Cervical cancer cells showed dramatically increased methylation levels for the four genes analyzed. ADCYAP1 and PAX1 also trended toward elevated methylation levels in HSIL samples, although the levels were much lower than those in cancer cells. The sensitivities of methylated ADCYAP1, PAX1, MAL, and CADM1 for the detection of cancer were 79.2%, 75.0%, 70.8%, and 52.1%, and the specificities were 92.0%, 94.0%, 94.7%, and 94.0%, respectively. Methylated ADCYAP1 and PAX1 demonstrated relatively better discriminatory ability than did methylated MAL and CADM1 (area under the curves 0.911 and 0.916 vs. 0.854 and 0.756, respectively). Conclusion DNA methylation status, especially in the ADCYAP1 and PAX1 genes, showed relatively good specificity, ranging from 90% to 94%. The possible additive and complementary roles of DNA methylation testing with respect to conventional cervical cancer screening programs will need to be validated in prospective population-based studies.

Objective: It has been reported that the low level of consistency of diagnosis of atypical squamous cells cannot exclude high-grade squamous intraepithelial lesions (ASC-H) in uterine cervical cancer screening using the Bethesda System, indicating the necessity of a large-scale survey. We presented cases cytologically judged as ASC-H on our website and invited our members to give their opinions regarding the diagnosis by voting online. The Web voting results were analyzed and ASC-H was cytologically investigated. Study Design: Virtual slides of atypical cells in cytology preparations of 53 cases were prepared and presented on a website. ASC-H cases were divided into 42 cases sampled by brush scraping and 11 cases sampled by cotton swab scraping. Fifty-three cases cytologically judged as ASC-H were classified into benign and CIN2/3, and their patterns of arrangement of atypical cells and 8 cytological parameters were morphologically investigated. Results: The frequency of ASC-H diagnosis in the Web votes was low: 29.2% for brush-scraped and 26.2% for cotton swab-scraped cases. Three-dimensionality, coarse chromatin and irregular nuclei were significantly different between high-grade squamous intraepithelial lesions and benign cases. Conclusion: Web-based surveys showed the difference of cytological findings between high-grade squamous intraepithelial lesions and benign cases. To increase interobserver consistency, it may be useful to share information online, which avoids geographical and temporal limitations.

Objective In the present study the potential therapeutic effects of zinc-citrate compound (CIZAR®) in women infected with high-risk human papillomavirus (HR-HPV) was investigated. Methods A total of 194 women diagnosed with HR-HPV infection using the Hybrid capture (HC) II assay with no evidence of high grade squamous intraepithelial lesions (HSIL) or worse by Pap smear and colposcopy were enrolled. Among them, 76 women were treated by twice weekly self administered intra-vaginal infusion of 0.5mM zinc citrate solution containing CIZAR® for 12weeks and were evaluated for clearance of the HR-HPV infection compared to 118 women without treatment (Control group). Results The 12weeks zinc citrate solution treatment resulted in the elimination of HR-HPV in 49/76 (64.47%) patients compared to the spontaneous clearance of 15.25% (18/118) in the control group ( p =0.000). By logistic regression analysis, the 12week zinc citrate solution treatment reduced the risk of persistent HR-HPV infection significantly (OR 0.079; 95% CI 0.039-0.165; p =0.000). Conclusion The results of this study showed for the first time that treatment with intra-vaginal infusion of a zinc-citrate compound (CIZAR®) can result in elimination of HR-HPV infection from the uterine cervix.

Academic research has made a significant advancement in understanding the viral causes of cervical cancer and generating the technology for prevention, both at the primary and secondary levels. Human papillomaviruses (HPVs) have been recognized as the first necessary cause of cervical cancer, the second most common cancer in women worldwide.This paper reviews the epidemiological evidence of the causality of HPV in relation to cervical cancer, other genital tract cancers and some cancers of the oral cavity and oropharynx. The review also covers HPV DNA testing as a screening tool. DNA probes of high-risk HPV types in different formats have been fully validated as primary screening tests, as secondary triage tests and as a prognostic marker following treatment of high grade squamous intraepithelial lesions (HSIL). They consistently showed significant superiority over the conventional Pap smears. Biomarkers of the activation of oncogenes (HPV mRNA, p16 and other) are being tested as screening options to improve in sensitivity and specificity, with promising results. HPV vaccines against the two most common HPV types in cancer have completed their Phase III trials with excellent results in efficacy and safety. Combined strategies of HPV vaccination and HPV-based screening tests could theoretically control cervical cancer in any population in which a large coverage with both preventive options is ensured. Accessibility of developing countries to vaccination and low-cost HPV screening options are the barriers to overcome at present.This paper provides a synthesis of the evidence available supporting the novel paradigm for cervical cancer prevention that has reached a large consensus within the mainstream HPV and cervical cancer prevention research communities. The available technology for prevention and its developments allows real opportunities for cervical cancer elimination in defined populations to be foreseen.

Objective: High-grade squamous intraepithelial lesions (HSIL) are the precursors of invasive cervical carcinomas and are generally associated with the integration of mucosotropic human papillomavirus (HPV) DNA into the host cell genome. Detection of HPV is easy to perform nowadays, even in laboratories with limited technological capacity, and follow-up procedures for patients with HSIL are well established. Study Design: HPV detection was performed in a large group of patients with HSIL, and results were correlated with cytological, histological, and colposcopic findings. Discrepancies were examined and discussed. Results: Conventional Papanicolaou (Pap) screening detected 446 HSIL (0.20%) in 218,906 cervical smears. HPV detection by PCR was positive in 339/358 (94.7%) patients. The strains involved were: HPV 16 in 180 patients (53.1%), HPV 18 in 35 (10.3%), HPV 31/33 in 27 (8%), HPV 6/11 in 10 (2.96%), and an unidentified type in 73 (30%). For the last 97 patients (2006–2007), HPV typing was expanded with the following results: HPV 52 was detected in 9 patients (9.2%), HPV 58 in 6 (6.1%), HPV 51 in 4 (4.1%), HPV 68 in 2 (2.0%), and HPV 39 in 1 (1.0%). The number of nonidentified patients dropped to 9 (9.4%); in addition, 14/97 (14.4%) patients were infected with 2 or more viral types. Finally, 19 (5.3%) patients were HPV negative. Colposcopy revealed minor changes in 59 patients (17.3%), major changes in 264 (77.6%), and normal findings in 17 (5.1%). A biopsy was taken in 331/446 patients, and the diagnosis of HSIL or overt malignancy was histologically confirmed in 281 (84.9%) patients: CIN II in 46, CIN III in 224, and histologically upgraded in 11 (6 microinvasive squamous carcinomas, 1 squamous carcinoma, 2 in situ endocervical adenocarcinomas, and 2 microinvasive endocervical adenocarcinomas). Thirty-five patients (10.6%) were downgraded to CIN I and 15 (4.5%) patients had a negative biopsy. Follow-up in the negative-biopsy patients confirmed the existence of SIL in 11 patients [1 HSIL and 10 low-grade squamous intraepithelial lesions (LSIL)] while 4 were considered false positives (atrophic changes, 2; reactive changes, 2). After treatment, 31/331 (9.36%) patients displayed recurrence (HSIL in 29 and LSIL in 2). The viral strains involved in patients with recurrence were HPV 16 in 16 patients (51.6%); HPV 18 in 4 (12.9%); HPV 16 and 18 in 1 (3.2%); HPV 31 in 1 (3.2%); HPV 52 in 1 (3.2%); HPV 18, 31, and 58 in 1 (3.2%); HPV 68 in 1 (3.2%); HPV 51 and 73 in 1 (3.2%), and an unidentified type in 5 (16.1%). Follow-up in 14/19 HSIL and HPV-negative patients confirmed the existence of cervical pathology. Conclusions: HPV detection improves diagnostic sensitivity and provides an ideal tool for monitoring the response to treatment in HSIL patients. The pathogenic relevance of HPV strain 18 may be greater than previously assumed.

Objective: To evaluate the diagnostic value and compare morphological features of cell block sections of high-grade squamous intraepithelial lesions (HSIL) and squamous cell carcinomas (SCC). Study Design: A total of 135 cell blocks were prepared from residual Liqui-PREP samples. Of these, 43 biopsy-confirmed cases (24 HSIL and 19 SCC) were reviewed. Morphological features determined included cell clusters, epithelial-stromal interface, stromal invasion and tumor necrosis. Results: Ninety-three percent (40/43) of cell block diagnoses were consistent with histological diagnoses, which was better than the cytological diagnoses (81.4%; 35/43). The mean cell block size was 0.54 cm (range, 0.3–1.0 cm) for HSIL and 0.84 cm (range, 0.4–1.4 cm) for SCC (p < 0.0001). Cell clusters were present in 70.8% (17/24) of HSIL and 100% (19/19) of SCC (p < 0.0001). No epithelial-stromal interface, stromal invasion or tumor necrosis was observed on HSIL cell block sections, which is in contrast to the 84.2% (16/19), 68.4% (13/19) and 42.1% (8/19) on SCC cell blocks, respectively (p < 0.05). Conclusion: Cell blocks may increase the diagnostic accuracy of liquid-based cytology. The presence of stromal invasion, epithelial-stromal interface and tumor necrosis on cell block sections may be useful for accurate SCC diagnosis.

Colposcopic grading provides an objective and meaningful guide to histologic severity and neoplastic progression of squamous intraepithelial lesions of the cervix. The objective of this study was to develop a more efficient and convenient method to overcome procedural complexities involved with the traditional Reid index in prediction of high-grade squamous intraepithelial lesion (HSIL). The Reid index uses four colposcopic signs (margin, color, vessel, and iodine staining). The proposed modified Reid index system specifically incorporates the location of the lesion within the transformation zone in place of iodine staining. Three hundred women with suspected or abnormal cytologies or abnormal cervicographic findings were evaluated by colposcopy, directed biopsy, and HPV testing by the Hybrid Capture II method, which detects high-risk HPV DNA types. The sensitivity of high-risk HPV testing for detecting HSIL was 94.4%, the specificity was 65.0%, the positive predictive value was 75.5%, and the negative predictive value was 91.0%. The results of the colposcopic impression using the modified Reid index were superior to HPV testing. The sensitivity, specificity, positive predictive value, and negative predictive value of the colposcopic impression for detecting HSIL were 91.3, 92.9, 93.6, and 90.3% respectively. These results strongly indicate that the modified Reid index can accurately predict the histologic grade of squamous intraepithelial lesions of the cervix and can be applied easily and objectively in clinical practice without affecting the diagnostic accuracy of the traditional Reid index.