High-grade Squamous Intraepithelial Neoplasia Research Articles

Do HPV 16 positive/ASC-H cervical cancer screening results predict CIN 2+ better than other high-risk HPV subtypes?

To determine whether patients with atypical squamous cells, cannot exclude high grade squamous intraepithelial neoplasia (ASC-H) cytology have a correlation between high-risk human papillomavirus (HPV) type and CIN 2+1 lesion in final pathology. The study was conducted retrospectively, using data from three tertiary gynecologic oncology centers located in various regions of Turkey. Data from 5,271 patients who had colposcopy between January 2003 and January 2021 were analyzed. A total of 163 patients who had ASC-H cervical cytology test results, based on the Bethesda 2014 classification were eligible, and of these 83 (50.9%) who tested positive for HPV were included in the study. There was no correlation between the occurrence of CIN 2+ lesions and age (p=0.053). If there was any HPV 16 positivity (only HPV 16, HPV 16 and 18, HPV 16 and others) the presence of CIN 2+ lesions in the final pathology increased significantly. In HPV 16 positive ASC-H patients, the probability of CIN 2+ lesions in the final pathology were 72.5% while this rate was 48.1% in HPV 16 negative group (p=0.033). The guidelines do not provide a comprehensive definition of the role of the HPV test in managing ASC-H. Positive high-risk HPV types, especially HPV 16, together with an ASC-H smear result should bring to mind the possibility of high-grade dysplasia.

Risk of cervical high-grade squamous intraepithelial neoplasia in cytologic negative and persistently high-risk human papillomavirus positive patients according to genotypes: a retrospective single center analysis

In January 2020, a different cervical cancer screening program started in Germany. Women above the age of 35 are recommended to have a combined HPV and cytology swab every three years. Showing persistent high-risk human papillomavirus (hrHPV), cytologic negative cervical samples at baseline and after 12 months, patients are referred to colposcopy. Entailing considerable additional workload due to the required colposcopies, we analyzed the risk of high-grade cervical intraepithelial neoplasia (CIN 3) in cytologic negative and persistent hrHPV women according to their hrHPV genotypes.Methods In this single center retrospective study, patients with persistent hrHPV, cytology negative cervical samples from our certified Colposcopy Unit in 2020 and 2021 were analyzed. Patient demographics, hrHPV types, biopsy rates and histological reports were collected.Results During the study, 69 patients were enrolled. Most frequent hrHPV genotypes were: hrHPV other 72.5%; HPV 16, 20.3% and HPV 18, 7.2%. Colposcopy showed no or minor changes in 92.7% and major changes in 7.2%. CIN 3 was found in 7 patients (10.1%). Prevalence of CIN 3 by hrHPV genotypes was 27.3% for HPV16, 20.0% for HPV18 and 7.1% for HPVO. A statistically significant dependency between hrHPV and cervical intraepithelial neoplasia was demonstrated (p = 0.048).Conclusion Within this single center study of persistent hrHPV, cytologic negative samples, patients with HPV 16 were more likely to have high-grade disease compared to other hrHPV subtypes. Larger prospective randomized trials are needed to substantiate our results and obtain adjusted cervical cancer screening time intervals according to the hrHPV genotypes.

Paraganglioma with high-grade intraepithelial neoplasia in the oesophagus treated by endoscopic submucosal dissection.

A 37-year-old woman was hospitalised with a 4-month history of retrosternal pain. Gastroscopy revealed a protrusion lesion of approximately 0.6 cm in diameter in the left wall of the oesophagus, approximately 27 cm from the incisor (Fig. 1). Consequently, one biopsy specimen was taken from the oesophagus. Based on the pathology and immunohistochemistry findings, the patient was initially diagnosed with paraganglioma with high-grade squamous intraepithelial neoplasia. The patient underwent endoscopic submucosal dissection 12 days after the biopsy. The protrusion lesion was again observed under gastroscopy, with visible scarring on the surface (Fig. 2A). A hypoechoic and heterogeneous mass of about 7.1 mm × 2.0 mm in the muscularis mucosae layer was detected on endoscopic ultrasonography (Fig. 2B). The mass was excised after submucosal injection of adrenaline, melphalan, and glycerol fructose injection (Fig. 2C). The postoperative gross specimen was a mucosal tissue measuring 2 cm × 1.8 cm × 0.2 cm, with a bulging mass underneath (Fig. 2D). The results of immunohistochemical analysis were positive for CD56, Syn, CK8/18, LCK, and S-100 and negative for SSTR2 (Fig. 3D, E). Expression of wild-type P53, focal positivity of CgA, and weak positivity of NSE were noted. The Ki-67 labelling index was 1–2%. The diagnosis of paraganglioma with high-grade squamous intraepithelial neoplasia was confirmed based on the histopathology findings (Fig. 3A, B, C). The patient recovered well during the follow-up. Fig. 2(A) The protrusion lesion was found again under gastroscopy, with visible scarring on the surface. (B) Endoscopic ultrasonography detected a hypoechoic and heterogeneous mass of about 7.1 mm × 2.0 mm in the muscularis mucosae layer. (C) Adrenaline, melphalan and glycerol fructose injection was injected in the submucosa after the lesion was marked with a dual knife. (D) Gross specimen after endoscopic submucosal dissection. View Large Image Figure Viewer Download Hi-res image Fig. 3Microscopic examination. (A) Significant cytological atypia in squamous epithelium with continuous basement membrane, and arrangement of the cells in nests (“Zellballen”) in muscularis mucosae. (HE stain × 4) (B) The tumour was composed of chief cells and sustentacular cells. (HE stain × 10) (C) The chief cell is polygonal with a fine granular cytoplasm of acidophilia as well as basophilia. The nucleus is round to elliptical. The sustentacular cells of spindle-shape are distributed around the tumour cell nests or interdigitated amongst the sustentacular cells. (HE stain × 40) (D) positivity of S-100 protein (× 10). (E) positivity of Syn. (× 10). View Large Image Figure Viewer Download Hi-res image

The crossroads: divergent roles of virus-specific CD4+ T lymphocytes in determining the outcome for human papillomavirus infection.

Despite the widespread availability of effective prophylactic vaccines to prevent human papillomavirus (HPV) infection, HPV remains a major health burden. For health care systems in countries with the capacity for vaccine roll out, incomplete strategies result in citizens with naturally occurring infection, who are at an a posteriori risk of HPV-driven disease. Genital HPV infection is the most common sexually transmitted virus globally. Those classified as high-risk HPV strains are more likely to generate persistent disease. Within this group, HPV16 and 18 are the most prevalent and likely to induce persistent high-grade squamous intraepithelial neoplasia; neoplasia is a large step toward cancerous growth known as a squamous cell carcinoma which contribute to all cervical, 70% of oropharyngeal, 78% of vaginal and 88% of anal cancers. This review will illuminate the relevance of CD4+ T lymphocytes in determining the outcome of papillomavirus infection from the perspective of oropharyngeal and anogenital HPV-driven disease in the immune competent and immunocompromised. The focus is on recent investigations for this "silent" pandemic among current global health crises that should not be forgotten. Informing effective strategies that control viral infection through naturally acquired or induced immunity will identify aspects of scientific and clinical practice that may improve outcome.

Prediction of cervical cancer precursor lesions by quantitative methylation specific PCR: A retrospective study.

This study was undertaken to evaluate the performance of FAM19A4 and hsa-mir-124-2 hypermethylation as a triage tool for women who are at risk of developing cervical cancer or high-grade cervical cancer precursor lesions by taking into consideration the cytology report, histology diagnosis, and human papillomavirus (HPV) status. A total of 330 cervical ThinPrep samples were retrospectively collected and used for DNA isolation. HPV DNA was detected by real-time polymerase chain reaction (PCR), and HPV genotypes were identified by Sanger-based sequencing. DNA extracts were bisulphite-treated, and hypermethylation of FAM19A4 and hsa-mir-124-2 genes was detected by a quantitative methylation-specific PCR (qMSP) test using the QIAsure Methylation assay. Hypermethylated genes were detected in 27 (9.6%) cervical samples, mostly found in women diagnosed with high-grade squamous intraepithelial legions (77.8%) or cervical intraepithelial neoplasia grade 3 (CIN3) (72.7%). The sensitivity and the specificity of the qMSP test for predicting CIN3 lesions among women with high-risk HPV was 75% and 91%, respectively. There was a significant correlation between high-grade cervical cancer precursor lesions and detection of hypermethylated genes in samples positive for high-risk HPV. Our results suggest that the QIAsure Methylation test can be used as a triage tool to identify women at risk for cervical cancer progression.

Association of P16, Ki-67, and CD44 expression in high-grade squamous intraepithelial neoplasia and squamous cell carcinoma of the cervix.

Stem cells exist in niches in the cervical tissue at squamocolumnar junction, which when infected with HR-Human Papilloma Virus undergo malignant transformation to cancer stem cells and have a role in carcinogenesis and metastasis. The expression of CD44, P16, and Ki67 in high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma (SCC) is assessed in this study. Twenty-six cases each of normal cervix, HSIL, and SCC of cervix cases were subjected to immunohistochemistry markers; p16, Ki-67, and CD44. The association of expression of these markers between normal, HSIL, SCC cervix, and clinic-pathological parameters was statistically analyzed. P < 0.05 was considered significant. Of 26 cases of HSIL, 61.5%, 7.7%, and 30.8% cases were positive, ambiguous, and negative respectively for p16 expression. About 11.5%, 53.8%, and 34.6% of cases were strongly positive, positive, and weakly positive, respectively, for Ki-67 expression. About 42.3%, 42.3%, and 15.4% cases were strongly positive, positive, and weakly positive, respectively, for CD44 expression. Among 26 cases of SCC of the cervix 92.3% and 7.7% were positive and ambiguous respectively. About 73.1% and 26.9% of cases were strongly positive and positive, respectively, for Ki-67 expression. 65.4%, 30.8%, and 3.8% of cases were strongly positive, positive, and weakly positive, respectively, for CD44 expression. p16, Ki-67, and CD44 expression between the three groups were statistically significant. p16 expression versus FIGO stage including lymph node involvement and CD44 expression versus lymph node involvement in carcinoma cervix was statistically significant. Expression of p16, Ki-67, and CD44 increases as the lesion progress from normal to HSIL to carcinoma cervix. p16 and CD44 expression increase with lymph node involvement. P16 expression was maximum in Stage II than Stage III.

101. Effect of Human Papillomavirus Vaccine to Interrupt Recurrence of Vulvar and Anal Neoplasia (VIVA): A Randomized, Placebo-Controlled Trial

Abstract Background Anal and vulvar high-grade intraepithelial lesions (HSIL) often recur after primary treatment, with 30%-50% recurrence in the 5-years following treatment. Treatment for recurrent lesions can be uncomfortable, debilitating, and costly. The VIVA trial evaluated the effects of the nonavalent human papillomavirus (HPV) vaccine (9vHPV) on recurrent anal or vulvar HSIL. Methods We conducted a randomized, double-blinded, placebo-controlled trial of the 9vHPV in vaccine-naïve persons aged 27-69 years who were previously treated for anal or vulvar HSIL and HSIL-free at enrollment. Participants had high-resolution anoscopy or vulvoscopy at screening, month 18 and 36 visits. Eligible participants were randomly assigned (1:1) to receive 9vHPV or placebo on day 1, month 2 and 6. We hypothesized that 9vHPV leads to a 50% reduction of HSIL recurrence. The primary endpoint was anal or vulvar HSIL recurrence, which was assessed in the intent-to-treat (ITT) population. Results Between July 2017 and December 2021, 187participants (99 cis-men, 86 cis-women, 2 transgender persons) with a history of anal (104, 56%) or vulvar (83, 44%) HSIL enrolled in the trial. 181 (97%) participants were included in the ITT analysis. Median age was 55 years (IQR 48-63); 71 out of 181 participants (39%) had well-controlled HIV infection. The DSMB recommended stopping the study early because it met specified futility boundaries at interim analysis. Predictive power to show a significant difference in the primary endpoint was 6.4% should the study continue to accrue. With 46% of planned information accrued, the vaccine was not significantly more efficacious than the placebo in preventing recurrent HSIL, with 15 cases in the 9vHPV arm versus 18 cases in placebo (incidence 9.1 versus 10.0/100 person-years; p= 0.83 by log-rank test). We found no differences in HSIL recurrences among vaccine versus placebo recipients by anatomical site or HIV status. The 9vHPV was safe and well-tolerated. Kaplan-Meier Curve for overall high-grade squamous intra-epithelial neoplasia (HSIL) recurrences for nonavalent-HPV vaccine vs placebo recipients Conclusion We found no benefit of the 9vHPV vaccine for prevention of recurrent anal or vulvar HSIL. Our study underlines the importance of HPV prevention with prophylactic HPV vaccines and the need for novel therapeutic vaccines and antivirals to manage prevalent HSIL that have a high potential to recur. Disclosures Denise Galloway, PhD, Merck: Grant/Research Support Anna Wald, MD, MPH, Aicuris: Advisor/Consultant|Auritec: Advisor/Consultant|Crozet: Advisor/Consultant|DXNow: Advisor/Consultant|GSK: Grant/Research Support|Merck: Advisor/Consultant|sanofi: Grant/Research Support|VIR: Advisor/Consultant|X-Vax: Advisor/Consultant.

Pagetoid Squamous Intraepithelial Neoplasia of the Vulva as a Mimicker of Vulvar Extramammary Paget Disease: Two Cases with Basal Layer Sparing.

Human papillomavirus-associated vulvar intraepithelial neoplasia (high-grade squamous intraepithelial neoplasia [HSIL] or VIN of usual type) is a lesion characterized by atypia extending from the basal layer to the upper epidermis. There are only rare reports of vulvar intraepithelial morphology exhibiting a pagetoid pattern of intraepithelial dissemination. We herein report two cases of vulvar HSIL in which a pagetoid pattern of spread and a largely uninvolved basal layer represented a diagnostic pitfall for extramammary Paget disease. Nuclear atypia reminiscent of HSIL in addition to expression of p16, KRT5/6, and p40 were however in favor of pagetoid HSIL. Although there is morphological and immunohistochemical overlap between these two entities, an accurate diagnosis is important, since an erroneous diagnosis of vulvar extramammary Paget disease may lead to an extensive workup comprising radiological imaging, colonoscopy, and cystoscopy.

Vulvar High-Grade Squamous Intraepithelial Lesions Treated with Imiquimod: Can Persistence of Human Papillomavirus Predict Recurrence?

Simple SummaryVulvar high-grade intraepithelial lesion (vulvar HSIL) is a premalignant vulvar condition that requires intervention, usually surgery. It recurs frequently, and its treatment involves repeated disfiguring surgeries. Vulvar HSIL is associated with human papillomavirus. Imiquimod is a medical treatment option currently attracting attention because vulvar high-grade intraepithelial neoplasia is frequent in young women with multiple vulvar lesions. Few studies have evaluated the long-term effects of the response to imiquimod and the association of human papillomavirus with response and recurrence. We describe a retrospective (with cases already treated) study designed to determine the long-term response to imiquimod in patients with vulvar HSIL, and also to analyze the role of human papillomavirus (HPV), and different HPV types, in the persistence or recurrence of vulvar HSIL after imiquimod treatment.Objectives: Vulvar high-grade squamous intraepithelial lesion (vulvar HSIL) or vulvar intraepithelial neoplasia (VIN) is a premalignant condition that can progress to carcinoma. Imiquimod is a topical drug with high effectiveness and low morbidity. We aimed (1) to assess the long-term response to imiquimod in a cohort of patients with vulvar HSIL and (2) and to analyze the role of HPV determined in pre- and post-imiquimod treatment biopsies in the persistence or recurrence of vulvar HSIL. Design: Retrospective study between 2011 and 2022. Setting: Referrals from the primary care area of Baix Llobregat treated in the gynecology department of a university hospital in Barcelona, Spain. Population: 20 women with vulvar HSIL treated with imiquimod. Methods: The inclusion criteria were vulvar HSIL, vulvar HPV determination by pre- and post-treatment biopsy, acceptance of medical treatment, at least one follow-up and 4 weeks of treatment. Main outcome measures: Histological diagnosis of vulvar HSIL with pre- and post-imiquimod HPV determination. Response to treatment (complete, partial, no response, recurrence). Results: After imiquimod, 10 (50%) and 6 (30%) cases had complete and partial responses, respectively. Another 4 cases (20%) did not respond. Before treatment, 19 (95%) cases were positive for vulvar HPV (16 cases had HPV type 16). After treatment, 10 cases (50%) were positive for HPV (8 cases with HPV type 16): 2 cases (20%) with a complete response, 5 cases (83.3%) with a partial response and 3 cases (75%) with no response. Eight of the 10 HPV-negative cases (80%) post-treatment showed a complete response. HPV type 16 was present in 16 cases (84.2%) pre-treatment and in 8 cases (80%) post-treatment. Ten patients underwent additional treatments following a partial response, no response or recurrence. The 2 HIV and 3 immunosuppressed patients treated with imiquimod showed a partial response and required additional treatment. All these patients were HPV-positive pre- and post-treatment (100%). Response to imiquimod was associated with post-treatment vulvar HPV positivity (p = 0.03). The median time to a complete response in HPV-negative cases was 4.7 months versus 11.5 months in HPV-positive cases post-imiquimod treatment. Recurrence of vulvar HSIL was observed in 7 patients (35%), with a median time to recurrence of 19.7 months (range 3.2–32.7). Recurrence was experienced in 10% of cases with a complete response, in 4/6 (66.6%) cases with a partial response, and in 2/4 (50%) women with no response. Four of the 7 recurrent cases (57%) were infected with HIV or immunosuppressed. Six (85%) of the recurrent cases were HPV-positive post-treatment (all were HPV type 16). Four (30.7%) of the non-recurrent cases were HPV-positive post-treatment with imiquimod (p = 0.05), two of which were HPV type 16 (50%). Conclusions: Imiquimod effectively treats vulvar HSIL. Cases with a complete response showed less HPV positivity post-treatment than partial or non-response cases. Recurrences were more frequent in those with a partial or no response to imiquimod, and in immunosuppressed patients. In recurrent cases, 85% were HPV-positive post-treatment, while 30.7% of non-recurrent cases were HPV-positive. HPV positivity in the post-treatment biopsy suggests the need for stricter follow-up of patients.

Complete resection of an esophageal tubular duplication with high grade squamous intraepithelial neoplasia by endoscopic submucosal dissection.

Complete resection of an esophageal tubular duplication with high grade squamous intraepithelial neoplasia by endoscopic submucosal dissection.

Prognostic value of HPV 16/18 genotyping and geminin mRNA quantification in low-grade cervical squamous intraepithelial lesion

ABSTRACT Low-grade cervical squamous intraepithelial lesion is a precancerous neoplasia that has appreciable probability to evolve into malignancy. To explore the prognostic value of HPV 16/18 genotyping and geminin mRNA quantification in predicting the progressiveness of LSIL. We recruited 212 participants who were negative for intraepithelial lesion or malignancy (NILM 76), low-grade squamous intraepithelial lesion (LSIL 85), high-grade squamous intraepithelial lesion (HSIL 36) and cervical intraepithelial neoplasia grade cervical cancer grade 3, (CIN3 15) patients. Tissues were obtained during excisional treatment. HPV 16/18 genotyping and geminin mRNA qRT-PCR were performed. HPV 16/18 positivity rate and geminin mRNA level were integrated with the clinical parameters into a multivariate logistic model. Area under curve was yielded based on receiver operation curve derived from this multivariate logistic model. Follow-up visits were performed to LSIL patients with progression. HSIL patients have higher HPV 16/18 positivity rate and geminin mRNA levels than LSIL. Among HSIL, CIN3 have higher HPV 16/18 positivity rate and geminin mRNA levels. Multivariate logistic analysis showed that HPV 16/18 positivity and geminin mRNA expression status are independent factors for differentiating HSIL and LSIL. The baseline HPV 16/18 positivity rate and geminin mRNA levels of 18 LSIL patients who developed HSIL are significantly higher than non-progressive LSIL patients. The values examined at follow-up timepoints were also higher than baseline. These results suggest that geminin is implicated in the progression of LSIL and combining HPV 16/18 genotyping and geminin mRNA qRT-PCR could potentially differentiating the progressive LSIL and improve the efficacy of clinical intervention.

Lower accuracy of cytological screening for high-grade squamous intraepithelial neoplasia in women over 50\xa0years of age in Japan

BackgroundAs the population ages in developed countries, the number of Pap smears for cervical cancer screening of older women is increasing. There is concern that cervical atrophy may cause misinterpretation of results for this segment of the population. The present study evaluated the accuracy of screening for high-grade intraepithelial lesions (HSILs) in women younger or older than 50 years, to determine whether aging affects cytological interpretation.MethodsPatients with HSIL cytology (N = 1565) were dichotomized into those aged 20–49 years or aged ≥ 50 years. Association between histology results and age was examined. Pearson’s chi-squared test and Cochran-Armitage trend test were used for statistical analysis.ResultsThe positive predictive value (PPV) for cervical intraepithelial neoplasia (CIN)2 and worse was 65.2% (62/95) in older women but 87.3% (482/552) in younger women (p < 0.001). Older patients had a significantly lower PPV (p = 1.69 × 10–8). Separately analyzing chronic cervicitis, CIN1 and overt cancer grouped together, compared with another group composed of CIN2 and CIN3, we found that the PPV for CIN2 and CIN3 was lower in older than in younger women [44.2% (42/95)-vs-82.4% (455/552), p < 0.001], respectively.ConclusionsHSILs are associated with a wide range of disease categories as age increases, and the accuracy of HSIL interpretation is lower in older women.

Risk factors associated with the persistence of human papillomavirus after cervical excision in patients with high-grade squamous intra-epithelial neoplasia

ObjectiveTo evaluate risk factors associated with the persistence of human papillomavirus (HPV) after cervical excision in patients with high-grade squamous intra-epithelial neoplasia (HSIL). MethodsA retrospective cohort study enrolled 550 patients who underwent cervical excision for HSIL between January 2015 and January 2018. The effects of various factors were assessed using univariate and multi-variate analyses. ResultsThe mean age of patients was 42.6 [standard deviation (SD) 8.7, range 22–64] years, and the mean duration of follow-up was 29.0 (SD 4.8, range 24–36) months. Persistent HPV infection after cone excision was detected in 78 (14.2%) patients. Univariate logistic regression analysis revealed that advanced age (>35 years), menopausal status, HPV type (HPV16/18), abnormal vaginal micro-ecological morphology, type of excision (loop electrosurgical excision procedure) and positive margin were closely associated with the persistence of HPV. Multi-variate analysis indicated that menopausal status [odds ratio (OR) 4.708, 95% confidence interval (CI) 2.770–8.001; p < 0.001], abnormal vaginal micro-ecological morphology (OR 2.320, 95% CI 1.372–3.922; p = 0.002) and positive margin (OR 3.346, 95% CI 1.261–8.876; p = 0.015) were significant risk factors for the persistence of HPV after treatment. Furthermore, infection with HPV16/18 increased the risk of persistent infection, and a higher rate of HPV persistence was found in patients who were infected with HPV18 (OR 1.020, 95% CI 0.415–2.505) or co-infected with HPV16/18 (OR 2.064, 95% CI 0.272–2.041) compared with HPV16. ConclusionPersistent HPV infection after surgical treatment for HSIL is considered to be strictly related to the recurrence and progression of disease. Patients who are at increased risk of HPV persistence should receive intensive follow-up after surgery, especially in the first year.

Exploiting the Microbiota for the Diagnosis of Anal Precancerous Lesions in Men Who Have Sex With Men.

While the microbiota has been associated with human papillomavirus malignant transformation, it is unclear whether anal bacteria could improve the low specificity of anal cytology for the screening of high-grade intraepithelial squamous neoplasia (HSIL). We recruited men who have sex with men undergoing anal cytology and high-resolution anoscopy. We assessed the microbiota composition from fecal samples and cytobrush anal samples using 16S ribosomal DNA sequencing in participants with or without biopsy-proven HSIL (bHSIL). We selected bacterial biomarkers based on their linear discriminant analysis. We assessed their predictive performance using logistic regression and bootstrap resampling. We included 128 individuals, 47 (36.7%) with bHSIL and 99 (77.3%) with human immunodeficiency virus. We detected 40 potential predictors of bHSIL. Ruminococcaceae NK4A214 group, Alloprevotella genus, Prevotella melanonigenica, and Ruminococcaceae UCG-014 were the most predictive of bHSIL. From 35 false-positive cytologic results, the combination of these 4 biomarkers with the anal cytology reclassified to true-negative 33 individuals (94%) and showed good diagnostic performance (area under the receiver operating characteristic curve, 0.805; 95% confidence interval, .728-.882). We found anal-associated bacteria indicative of a higher risk of precancerous anal lesions, which combination was highly specific. The microbiota could be developed as a complementary diagnostic tool to overcome the limitations of the current screening strategy for anal cancer.

Immunohistochemical expression of p16INK4A in the lesions of uterine cervix

Background: Cervical cancer is the major cause of cancer deaths among women. Globally, around 5,70,000 new cases of cervical cancer and 3,11,000 deaths occurred in the year 2018. In India, Cervical cancer is a leading cause of cancer related mortality among women and the number of deaths is 60,000 per year among 97,000 diagnosed patients, especially those from lower socioeconomic group. Human Papilloma Virus (HPV) plays a crucial role in causing cervical dysplasia. This is done by upregulating p16INK4A, a cyclin dependent kinase inhibitor through interaction with cellular regulatory proteins. Hence p16INK4A can be used as a biomarker, since it is directly related variable for the presence of HPV. This study was conducted to evaluate the expression of p16INK4A in benign, premalignant and malignant cervical lesions and to assess its utility in diagnosing and grading cervical lesions.&#x0D; Methods: A total of 80 cervical specimens categorized histopathologically into nonspecific cervicitis, low grade squamous intraepithelial neoplasia (LSIL), high grade squamous intraepithelial neoplasia (HSIL) and squamous cell carcinoma cervix were included in this prospective study of one-year duration. Immunohistochemical study of p16INK4A were interpreted qualitatively and semi-quantitatively by Allred scoring system (0 to 8 points) which measures the proportion of stained cells and intensity of staining of cells. The collected data were statistically analyzed by ANOVA and chi square test.&#x0D; Result: Qualitative method showed absence of p16INK4A expression in all nonspecific cervicitis. 16.7% (2/12) LSIL, 100% (12/12) HSIL and 100% (28/28) squamous cell carcinoma cases showed p16INK4A positivity. Allred scoring of p16INK4A showed 66% (8/12) HSIL and 85.7% (24/28) squamous cell carcinoma cases with score 3 positivity. Hence high-grade lesions showed higher expression of this marker.&#x0D; Conclusion: IHC expression of p16INK4A showed increasing degree of expression from benign to premalignant and malignant lesions suggesting its diagnostic and prognostic value in the cervical cancer management

A Unique Case of Arterial Thrombosis and Recurrent CVA in ICU: Unfathomable Presentation of an Occult Malignancy

IntroductionCritically ill patients may present with prothrombotic manifestations. Carcinoma cervix with prothrombotic manifestations are not common. Arterial thrombosis in such cases is very rare. We present a case of carcinoma cervix which posed a diagnostic dilemma and difficulty in localizing primary. This patient also had recurrent strokes and cardiac metastasis with metastatic arterial thrombosis.Case DescriptionA 34-year-old lady presented with a history of acute lower limb ischemia and recurrent strokes. Transthoracic echocardiography showed valvular vegetations. Prothrombotic and infective endocarditis workup were negative. Histopathological examination (HPE) of clot showed metastatic squamous cells. Contrast CT of chest and abdomen only showed mediastinal lymphadenopathy. Endobronchial ultrasound (EBUS) with mediastinal lymph node biopsy showed metastatic squamous cells. As the patient gave a history of hysterectomy, Pap smear from the vault was sent, which was suggestive of high grade squamous intraepithelial neoplasia. Palliative chemotherapy was started. The patient made a good recovery and was discharged home in a stable condition.ConclusionArterial thrombosis is an uncommon manifestation of occult malignancy. Carcinoma cervix usually does not metastasize to heart, brain, and arteries, which was the case in our patient. A high index of suspicion and systematic evaluation can clinch the diagnosis even when rare complications of malignancy are presented by critically ill patients.Clinical significanceAny unprovoked thrombotic episodes should be extensively worked up for occult malignancies. We present a case demonstrating challenges faced by critical care physicians and benefits of methodical evaluation when confronted with unusual presentation of a malignancy.How to cite this articleRangappa R, Shetty RM, Denzil M, Haranahalli PE, Susmita S, Chaurasia S. A Unique Case of Arterial Thrombosis and Recurrent CVA in ICU: Unfathomable Presentation of an Occult Malignancy. Indian J Crit Care Med 2020;24(7):585–588.

SOX1 Promoter Hypermethylation as a Potential Biomarker for High-Grade Squamous Intraepithelial Neoplasia Lesion and Cervical Carcinoma: A Meta-Analysis With Trial Sequential Analysis.

Background: DNA methylation has been widely assessed as a potential biomarker for the early detection of cervical cancer (CC). Herein, we assessed the associations of SOX1 promoter hypermethylation with squamous intraepithelial lesion and CC.Methods: Published studies and genome-wide methylation datasets were searched from electronic databases (up to April 2019). The associations of SOX1 hypermethylation with high-grade squamous intraepithelial lesion (HSIL) and CC risks were evaluated by odds ratios (ORs) and 95% confidence intervals (CIs). The summary receiver operator characteristic test was used to assess the diagnostic value of the SOX1 promoter hypermethylation of CC and intraepithelial neoplasia type III or worse (CIN3+). Trial sequential analysis (TSA) was performed to evaluate the stability of results and estimate the required information size (RIS).Results: In this meta-analysis of 17 published studies, the SOX1 methylation rates increased among low-grade SIL (LSIL, 27.27%), HSIL (40.75%), and CC (84.56%) specimens. Compared with control specimens, SOX1 promoter hypermethylation progressively increased the risk of HSIL by 4.20-fold (p < 0.001) and CC by 41.26-fold (p < 0.001). The pooled sensitivity of SOX1 methylation was estimated to be 0.85 (95% CI: 0.81–0.88) in differentiating patients with CC, corresponding to a specificity of 0.72 (95% CI: 0.69–0.75) and an area under the curve (AUC) of 0.93. Furthermore, the pooled sensitivity of SOX1 methylation was estimated to be 0.75 (95% CI: 0.72–0.78) in differentiating patients with CIN3+, corresponding to a specificity of 0.71 (95% CI: 0.69–0.73) and an AUC of 0.84. The pooled results of TCGA and GEO datasets showed that all CpG sites in SOX1 were associated with CC and 16 of 19 CpG sites were associated with HSIL. The results of TSA illustrated that the size was sufficient and significant associations were observed.Conclusion: This meta-analysis indicated that SOX1 promoter hypermethylation might have a potential value in the clinical diagnosis of CC and CIN3+.

Management of Vulvar Cancer Precursors: A Survey of the International Society for the Study of Vulvovaginal Disease.

The aim of the study was to determine how experts treat vulvar high-grade squamous intraepithelial neoplasia (VHSIL) and differentiated vulvar intraepithelial neoplasia (dVIN). A 26-question survey was designed through a literature review, reviewed by the Survey Committee of the International Society for the Study of Vulvovaginal Disease (ISSVD), and distributed to all ISSVD members via e-mail in January 2019. Overall, 90 of 441 physician members consented to participate and 78 of 90 were eligible to complete the survey. Most respondents were gynecologists (77%), followed by dermatologists (12%). Forty-five percent responded that their pathology was being reported using the 2015 ISSVD terminology of vulvar squamous intraepithelial lesions. The most common first-line treatments were as follows: unifocal VHSIL-excision (65%), multifocal VHSIL-imiquimod 5% (45%), VHSIL in a hair-bearing area-excision (69%), and clitoral disease-imiquimod 5% (47%). In the recurrent VHSIL, excision was favored (28%), followed by imiquimod 5% (26%) and laser (19%). Differentiated vulvar intraepithelial neoplasia was most often first treated with excision (82%), and more patients were referred to gynecologic oncology. Most patients were seen in follow-up at 3 months (range: 1 week-6 months). Sixty-seven respondents provided 26 different ways to follow treated patients, which were most commonly every 6 months for 2 years and then yearly (25%), followed by every 6 months indefinitely (18%). Treatment of VHSIL and dVIN varies among vulvar experts with excision being the most common treatment, except in multifocal VHSIL where imiquimod is commonly used. There is wide variation in how patients are followed after treatment.

Prevalence of human papillomavirus genotypes and precancerous cervical lesions in a screening population in Beijing, China: analysis of results from China\u2019s top 3 hospital, 2009\u20132019

BackgroundCervical cancer is the fourth most common cancer in women. Early detection and diagnosis play an important role in secondary prevention of cervical cancer. This study aims to provide more information to develop an effective strategy for the prevention and control of cervical cancer in northern China.MethodsA retrospective single-centre descriptive cross-sectional study was conducted in Chinese PLA General Hospital located in Beijing, covering the period from January 2009 to June 2019. The patients who underwent a polymerase chain reaction (PCR)-based HPV genotyping test and cervical pathological diagnosis were included. Furthermore, we limited the interval between the two examination within 180 days for the purpose of making sure their correlation to analyse their relationship. Moreover, the relationship between different cervical lesions and age as well as single/multiple HPV infection was assessed.ResultsA total of 3134 patients were eligible in this study after HPV genotyping test and pathological diagnosis. Most of the patients (95%) were from northern China. Among the patients, 1745(55.68%) had high-grade squamous intraepithelial neoplasia (HSIL), 1354 (43.20%) had low-grade squamous intraepithelial neoplasia (LSIL) and 35 (1.12%) were Normal. The mean age was 42.06 ± 10.82(range, 17–79 years). The women aged 35–49 years accounted for the highest incidence rate. The top five most commonly identified HPV genotypes in each lesion class were as follows: HPV16, 58, 52, 31 and 51 in the class of HSIL; HPV16, 52, 58, 56 and 51 in the class of LSIL; HPV16, 31, 6,11, 52 and 58 in the class of normal. The frequencies of HPV single genotype infection and multiple genotypes infection were 55.26 and 34.18%, respectively. There was no difference in the attributable proportions of multiple genotypes infection amongst HSIL, LSIL and Normal.ConclusionsIn Northern China, HPV16 was the most dominant genotype in the patients with pathological examination. The peak age of the onset of HSIL was between 35 and 49 years of age. Infection with multiple HPV genotypes did not increase the risk of HSIL. Type-specific HPV prevalence and attribution proportion to cervical precancerous lesions should be taken into consideration in the development of vaccines and strategy for screening in this population.

Efficacy of the AS04-Adjuvanted HPV16/18 Vaccine: Pooled Analysis of the Costa Rica Vaccine and PATRICIA Randomized Controlled Trials.

The AS04-adjuvanted HPV16/18 (AS04-HPV16/18) vaccine provides excellent protection against targeted human papillomavirus (HPV) types and a variable degree of cross-protection against others, including types 6/11/31/33/45. High efficacy against any cervical intraepithelial neoplasia grade 3 or greater (CIN3+; >90%) suggests that lower levels of protection may exist for a wide range of oncogenic HPV types, which is difficult to quantify in individual trials. Pooling individual-level data from two randomized controlled trials, we aimed to evaluate AS04-HPV16/18 vaccine efficacy against incident HPV infections and cervical abnormalities . Data were available from the Costa Rica Vaccine Trial (NCT00128661) and Papilloma Trial Against Cancer in Young Adults trial (NCT00122681), two large-scale, double-blind randomized controlled trials of the AS04-HPV16/18 vaccine. Primary analyses focused on disease-free women with no detectable cervicovaginal HPV at baseline. A total of 12 550 women were included in our primary analyses (HPV arm = 6271, control arm = 6279). Incidence of 6-month persistent oncogenic and nononcogenic infections, excluding known and accepted protected types 6/11/16/18/31/33/45 (focusing on 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74), was statistically significantly lower in the HPV arm than in the control arm (efficacy = 9.9%, 95% confidence interval [CI] = 1.7% to 17.4%). Statistically significant efficacy (P < .05) was observed for individual oncogenic types 16/18/31/33/45/52 and nononcogenic types 6/11/53/74. Efficacy against cervical abnormalities (all types) increased with severity, ranging from 27.7% (95% CI = 21.7% to 33.3%) to 58.7% (95% CI = 34.1% to 74.7%) for cytologic outcomes (low-grade squamous intraepithelial neoplasia lesion or greater, and high-grade squamous intraepithelial neoplasia lesion or greater, respectively) and 66.0% (95% CI = 54.4% to 74.9%) to 87.8% (95% CI = 71.1% to 95.7%) for histologic outcomes (CIN2+ and CIN3+, respectively). Comparing Costa Rica Vaccine Trial and Papilloma Trial Against Cancer in Young Adults results, there was no evidence of heterogeneity, except for type 51 (efficacy = -28.6% and 20.7%, respectively; two-sided P = .03). The AS04-HPV16/18 vaccine provides some additional cross-protection beyond established protected types, which partially explains the high efficacy against CIN3+.