Intraepithelial Neoplasia Grade Research Articles

Improving indicator-condition guided testing for HIV in the hospital setting (PROTEST 2·0): A multicenter, interrupted time-series analysis.

SummaryBackgroundIndicator-condition (IC) guided HIV testing is a feasible and cost-effective strategy to identify undiagnosed people living with HIV (PLHIV), but remains insufficiently implemented. We aimed to promote IC-guided HIV testing in seven ICs.MethodsRelevant departments in five hospitals of the Amsterdam region participated. HIV testing among adult patients without known HIV infection but with an IC was assessed using electronic health records during pre-intervention (January 2015–June 2020) and intervention (July 2020–June 2021) periods. The multifaceted intervention included audit and feedback. The primary endpoint was HIV testing ≤3 months before or after IC diagnosis and the effect of the intervention was evaluated using segmented Poisson regression.FindingsData from 7986 patients were included, of whom 6730 (84·3%) were diagnosed with an IC in the pre-intervention period and 1256 (15·7%) in the intervention period. The proportion HIV tested ≤3 months before or after IC diagnosis increased from 36.8% to 47.0% (adjusted risk ratio [RR]= 1.16, 95% CI=1.03–1.30, p=0.02). For individual ICs, we observed significant increases in HIV testing among patients with cervical cancer or intraepithelial neoplasia grade 3 (adjusted RR=3.62, 95% CI=1.93–6.79) and peripheral neuropathy (adjusted RR=2.27 95% CI=1.48–3.49), but not the other ICs. Eighteen of 3068 tested patients were HIV positive (0.6%).InterpretationOverall IC-guided testing improved after the intervention, but not for all ICs. Variations in effect by IC may have been due to variations in implemented developments, but the effect of separate elements could not be assessed.FundingHIV Transmission Elimination Amsterdam (H-TEAM) initiative, Aidsfonds (grant number: P-42702).

Abstract 2208: Unexpected pattern in estimated prevalence of precancerous cervical lesions at a safety net hospital in Virginia: A case for epidemiologic surveillance

Abstract Objectives: High-grade squamous lesions of the cervix, (Cervical Intraepithelial Neoplasia (CIN) grade 2 and 3), are concerning, common, and costly precancerous findings, particularly for safety net hospitals who provide healthcare regardless of finances or insurance status. Epidemiologic surveillance of these lesions is uncommon but might be useful to guide preventive interventions. We sought to estimate the prevalence of CIN 2/3 and its racial and ethnic distribution, accounting for patient’s clinical and sociodemographic characteristics. Methods: We used data from hospital and physician billing claims for any CIN diagnosis occurring at the Virginia Commonwealth University Health System (VCUHS) from 01/01/2016 through 12/31/2020, along with respective clinical and sociodemographic characteristics at the time of diagnosis. We estimated average adjusted prevalence of CIN 2/3 lesions by race and ethnicity, from average marginal effects, after selecting most relevant patient factors from a logistic regression (LR) using backward selection (removing terms with p ≥ 0.2 and adding those with p < 0.1). Results: There were 1,538 women diagnosed with CIN 1, 2, 3, and unspecified dysplasia of the cervix uteri with respective prevalence of 45%, 14%, 12%, and 30%. CIN2/3 prevalence (26%) varied by race and ethnicity: Asians (39%) > Latinas (32%) > Whites (28%) >Blacks (23%) > Other (20%). Of the variables included in the LR model (age, marital status, religion, preferred language, insurance status, Body Mass Index, HIV, HPV, presence of bacterial vaginosis, hypertension, cholesterol, diabetes, pulmonary conditions, arthritis, heart conditions, pregnancy status, parity, smoking, alcohol, and previous cancer diagnoses), only age, diabetes, pulmonary conditions, smoking, and heart disease remained in the final LR model. The estimated average adjusted prevalence of a CIN 2/3 diagnosis remained highest for Asian women (35%, 95%CI: 17-52%), followed by Latinx (28%, 95%CI: 19-37%), Whites (25%, 95%CI 22-29%), Blacks (23%, 95%CI: 20-27%), and other (18%, 95%CI: 9-26%). Conclusions: The higher CIN 2/3 prevalence estimates among Asian women relative to other races and ethnicities is unexpected, as it does not align with current distribution of cervical cancer diagnoses at VCUHS (only 3% Asian), nor with the patterns of cervical cancer incidence and mortality rates in Virginia and in the United States, where Asian women have the lowest incidence and mortality. However, it potentially suggests a higher rate of regression, a finding supported by at least one surveillance study with similar findings. Citation Format: Shreya R. Raman, Stephanie A. Sullivan, Katherine Y. Tossas. Unexpected pattern in estimated prevalence of precancerous cervical lesions at a safety net hospital in Virginia: A case for epidemiologic surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2208.

Digital analysis of colposcopic images with acetowhite epithelium in "real-time" mode

Digital analysis is a method of assessing qualitative data by converting them into quantitative data using a personal computer’s graphics processing unit (GPU). Visual changes on the cervical surface in human papillomavirus (HPV)-associated pathology can be evaluated by extended colposcopy with a 3–5% acetic acid test and Schiller’s test. Acetowhite epithelium (appears after a test with acetic acid) in the form of flat condyloma is one of the main clinical manifestations of HPV infection (excluding manifestations on the metaplastic epithelium). The intensity of acetowhite epithelium (AWE) is a subjective parameter during gynecological examination, and to exclude the malignant process, a histology or liquid-based cytology should be performed. Objective assessment of the AWE intensity is introduced by digital image analysis using specialized software. The aim. To improve the assessment of visual changes of acetowhite epithelium on the cervical surface using a digital approach as an additional tool when performing extended colposcopy. Materials and methods. Colposcopy images of 359 patients were estimated by digital approach. Colposcopy images were made with a screenshot function after performing extended colposcopy. Screenshots of the cervix were converted to 8-bit type. This allowed us to estimate the intensity of AWE by software ImageJ. Index grey value (IndGV) was calculated to estimate the intensity of AWE. The IndGV data were assessed by MS office 365 (Excel v16.46) and RStudio v1.2.5042 statistical packages. Results and conclusion. The quantification approach detects the severity of AWE on the cervical surface. IndGV correlates with the grades of cervical intraepithelial neoplasia (CIN) and clinical manifestations of HPV. The clinical manifestations of HPV infection in CIN have a direct dependence on digital measurement as grey value (GV). These indicators give the opportunity to evaluate clinical manifestations in digital analysis in real-time mode, which does not require a significant financial investment. IndGV can be used as a prognostic factor of the severity of HPV infection and its clinical forms (CIN I–III and cervical cancer). Key words: digital medicine, quantitative approach, acetowhite epithelium, HPV infection

Significance of the viral load of high-risk HPV in the diagnosis and prediction of cervical lesions: a retrospective study

BackgroundThe significance of HPV viral load in the detection of cervical lesions is still controversial. This study analyzed the correlation between the high-risk HPV viral load and different cervical lesion degrees.MethodsThis retrospective study included women positive for high-risk HPV DNA and screened for cervical lesions between 01/2015 and 06/2018. The high-risk HPV DNA load was measured by the second-generation Hybrid Capture technology and classified as low, moderate, and high. Colposcopy and biopsy were performed in all patients. The patients were grouped as normal, cervical intraepithelial neoplasia (CIN) grade 1, CIN grade 2, CIN grade 3, and cervical cancer. Multivariable logistic regression was performed to explore the association between high-risk HPV DNA load and cervical lesions. The odds ratios (ORs) represent the odds for increasing from low to high viral load.ResultsFinally, 265 patients were grouped as normal (n = 125), CIN 1 (n = 51), CIN 2 (n = 23), CIN 3 (n = 46), and cervical cancer (n = 20). Among them, 139 (52.5%) had a low viral load, 90 (34.0) had a moderate viral load, and 36 (13.4%) had a high viral load. Taking the normal control group as a reference, a high viral load was an independent factor for CIN 1 (OR = 3.568, 95% CI: 1.164–10.941, P = 0.026), CIN 2 (OR = 6.939, 95% CI: 1.793–26.852, P = 0.005), CIN 3 (OR = 7.052, 95% CI: 2.304–21.586, P = 0.001), and cervical cancer (OR = 8.266, 95% CI: 2.120–32.233, P = 0.002).ConclusionsAmong women who underwent cervical biopsy, higher high-risk HPV viral load in cervical lesions was associated with a higher risk of high-grade cervical lesions.

ALDH1 & CD133 in invasive cervical carcinoma & their association with the outcome of chemoradiation therapy.

Background & objectives:Chemoradiation is the standard therapy for locally advanced invasive cervical cancer and response to treatment determines the outcome. Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT) play a role in response to treatment and hence the aim of this study was to evaluate if their levels in pre-treatment biopsies by immunohistochemistry (IHC) could predict response to treatment and outcome.Methods:The study comprised 60 patients with FIGO Stage IIB/III invasive cervical carcinoma treated by chemoradiation. They were divided into two groups based on their clinical outcome: group 1, 30 patients who had no evidence of disease at 48 month follow up and group 2, 30 patients who had disease relapse within 6-12 months of treatment completion. IHC was performed for CSC markers (ALDH1, CD133, Nanog and Oct-4), EMT markers (E-cadherin and vimentin) and squamocolumnar junction (KRT7) markers and H-scores determined. Intergroup comparison was performed. The expression of these markers was also evaluated in histological sections of cervical pre-cancer (CIN1 and CIN3) in comparison to normal cervix.Results:Cervical Intraepithelial Neoplasia grade 3 (CIN3) showed high expression of ALDH1 and KRT7 as compared to normal cervical epithelium. Aldehyde dehydrogenase 1 (ALDH1) and CD133 were overexpressed in 70 and 24 per cent cervical carcinoma cases whereas E-cadherin showed reduced expression in invasive carcinoma as compared to normal controls. ALDH1 overexpression was significantly associated with disease relapse in invasive cervical carcinoma treated by chemoradiation (P<0.01).Interpretation & conclusions:Determination of ALDH1 levels in pre-treatment cervical biopsies of invasive cervical carcinoma may be useful for prediction of response to chemoradiation, with high levels predicting for a poor response.

Necessity for subsequent surgery in women of child-bearing age with positive margins after conization

Background20–25% of women with high-grade cervical intraepithelial neoplasias (HSIL) have residual lesions after conization. The state of the margin is generally considered to be a risk factor for recurrence or persistent lesions. Predictors of positive margins and residual lesions need to be identified. A design for postoperative management and avoidance of overtreatment needs to be provided, especially for women of child-bearing age.MethodsThis study was a retrospective analysis of 1309 women of child-bearing age with HSIL, who underwent cold knife conization (CKC). Age, gravidity, parity, human papillomavirus (HPV) species, cytology, transformation zone type, results of endocervical curettage (ECC), quadrant involvement, glandular involvement, and Cervical Intraepithelial Neoplasia (CIN) grade were analyzed. Among those with positive margins, 245 patients underwent secondary surgery within three months, including CKC, a loop electrosurgical excision procedure, and total hysterectomy. Risk factors for positive margins and residual lesions were assessed.ResultsThere was no significant difference in age, gravidity, parity, glandular involvement, and CIN grade between the two groups (P > 0.3). There was a significant difference in HPV species, cytology, ECC results, and quadrant involvement (P < 0.002). Multivariate analysis showed a major cytology abnormality, high-risk HPV infection, type III transformation zone, positive ECC result, and multiple quadrant involvement were independent risk factors for positive margins and residual lesions (P < 0.02). Age > 35 years was also a risk factor for residual lesions (P < 0.03).ConclusionHigh-risk women should be treated appropriately considering fertility. Patients with positive margins should be managed uniquely. Surgery for women without fertility may be appropriate. Close follow-up is necessary for women who have fertility requirements or are unwilling to undergo subsequent surgery if they have no risk factors, especially women < 35 years.

Multicentre Evaluation of Hepika Test Clinical Accuracy in Diagnosing HPV-Induced Cancer and Precancerous Lesions of the Uterine Cervix.

Objective: To evaluate the clinical accuracy of Hepika test to identify cancer/precancerous lesions of the uterine cervix. Materials and Methods: A multicentre retrospective study was carried out in 2018 and included 330 liquid-based cytology samples from three Italian centres of women aged 25–64 who had been tested for the human papillomavirus (HPV) and whose histology or follow-up outcome was known. Hepika is an enzyme-linked immunosorbent assay (ELISA) targeting the protein complexes E6#p53 and E7#pRb. After excluding samples without sufficient residual material, the clinical accuracy of Hepika test was evaluated in 274 samples: adenocarcinoma (ADC) (4), squamous cell carcinoma (SCC) (7), adenocarcinoma in situ (AIS) (1), cervical intraepithelial neoplasia (CIN) grade 3 (60), CIN2 (51), CIN1 (34), and negative histology (117). Association, sensitivity, and specificity for carcinoma, CIN3+ and CIN2+ are reported. Results: Positive Hepika test was associated with a high probability of carcinoma (odds ratio (DOR) = 33.68, 95% confidence interval (CI) 7.0–163.1); sensitivity was 81.8%, specificity, 88.2%. A positive Hepika test showed a weaker association with CIN3+ lesions (DOR = 3.5; 95% CI 1.75–6.99) and lower sensitivity (27.8%). Conclusion: The Hepika test was found to be an accurate biomarker for HPV-induced cervical carcinoma. Population-based prospective studies are needed to confirm the clinical usefulness of the Hepika test in the differential diagnosis of HPV-induced invasive lesions.

Rate of detecting CIN3+ among patients with ASC-US using digital colposcopy and dynamic spectral imaging.

The present study compared two methods for the detection of severe cervical dysplasia in women with atypical squamous cells of underdetermined significance (ASC-US) cytology; digital colposcopy with adjunctive dynamic spectral imaging (DSI) and conventional colposcopy. IMPROVE-COLPO was a two-arm cross-sectional study of US community-based colposcopy. The active (prospective) arm of this study recruited patients examined by digital colposcopy and adjunctive DSI. Preceding consecutive patients that had been examined with conventional methods were used as historical controls in the retrospective arm of the study after being matched in number to those in the prospective arm by a colposcopist. In the present study, the primary measure was the number of women detected with cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) following punch biopsy. The study included 1,353 retrospective and 1,226 prospective patients eligible for this analysis who were examined by 146 colposcopists in 42 community-based clinics. The patient baseline characteristics were comparable between the two arms. The average number of biopsies taken per patient was higher among the prospective arm patients (including standard and DSI-assisted biopsies) compared with the retrospective arm control patients (1.21 vs. 0.97 respectively). Biopsy detected 31 patients with CIN3+ [2.29%; 95% confidence interval (CI), 1.56-3.24] in the retrospective arm, and 48 patients with CIN3+ (3.92%; 95% CI, 2.90-5.16) in the prospective arm. The difference in the number of patients detected with CIN3+ in the two arms of the study was 1.62% (95% CI, 0.30-3.04; P=0.022), which corresponds to a 70.9% relative increase in the prospective compared with the retrospective arm. Biopsy appeared less efficient in detecting patients with CIN3+ in the retrospective arm compared with the prospective arm. However, there was no statistically significant difference between the retrospective arm and the prospective arm in terms of: i) Biopsies taken (over the entire population) per patient detected with CIN3+ (42.2 in the retrospective arm vs. 30.8 in the prospective arm; P=0.164) and ii) positive predictive value of using biopsies to identify patients with CIN3+ (2.83 vs. 3.92; P=0.118). Adoption of digital colposcopy with DSI increased the number of biopsies collected from ASC-US patients compared with retrospective controls of standard colposcopy and detected a significantly higher number of patients who were CIN3+. The number of additional biopsies taken in the prospective arm compared with the retrospective arm was too small to explain the increased detection of patients with CIN3+ observed in the prospective arm, suggesting that biopsies in the prospective arm were better at identifying CIN3+.

Differential expression of human papillomavirus 16-, 18-, 52-, and 58-derived transcripts in cervical intraepithelial neoplasia

BackgroundHuman papillomavirus (HPV) infection is a primary cause of cervical cancer. Although epidemiologic study revealed that carcinogenic risk differs according to HPV genotypes, the expression patterns of HPV-derived transcripts and their dependence on HPV genotypes have not yet been fully elucidated.MethodsIn this study, 382 patients with abnormal cervical cytology were enrolled to assess the associations between HPV-derived transcripts and cervical intraepithelial neoplasia (CIN) grades and/or HPV genotypes. Specifically, four HPV-derived transcripts, namely, oncogenes E6 and E6*, E1^E4, and viral capsid protein L1 in four major HPV genotypes—HPV 16, 18, 52, and 58—were investigated.ResultsThe detection rate of E6/E6* increased with CIN progression, whereas there was no significant change in the detection rate of E1^E4 or L1 among CIN grades. In addition, we found that L1 gene expression was HPV type-dependent. Almost all HPV 52-positive specimens, approximately 50% of HPV 58-positive specimens, around 33% of HPV 16-positive specimens, and only one HPV18-positive specimen expressed L1.ConclusionsWe demonstrated that HPV-derived transcripts are HPV genotype-dependent. Especially, expression patterns of L1 gene expression might reflect HPV genotype-dependent patterns of carcinogenesis.

A Comparative Study between Conventional Pap Smear and Liquid-Based Cytology: A Clinco-Cytological Study of Iraqi Women with Some Health Problems of Cervix

A cervical screening by Pap test is necessary in recognizing precancerous and cancerous cases to reduce mortality due to cervical cancer among women. Regular screening and follow up can make it easier to early diagnose and eventually, to treat and control cervical cancer.&#x0D; This study aimed to detect atypical pathological changes of the vagina and uterine cervix of a sample of Iraqi women by macro- and micro-examination, and to determine the link with the demographic features. Also the study aimed to evaluate the two Pap smear techniques; the conventional and the base liquid methods.&#x0D; The study included 50 women with genital health problems (18-50 years old) who were referred to the National Cancer Research Center (NCRC), the University of Baghdad, during the period from 1st April to 30st of September 2018. Both visual inspection of the uterine cervix and Papanicolaou smear were performed for all of the participants.&#x0D; The results showed that most patient women (96%) were married and sexually active, with 51% being married under 20 years of age .Visual inspection of the cervix showed that 30% of the women had translucent, opaque or erosion lesions. Upon cytology examination, 92% of the women showed nonspecific inflammation, 70% revealed reactive squamous metaplasia, 10% had Koilocytotic atypia, and 8% suffered from cervical intraepithelial neoplasia (CIN1) or low grade squamous intraepithelial lesion (LGSIL). Contraception was used by 82% of the patients, while 36% used pills. The causes of the referral to the centre were abnormal vaginal discharge (44%) and post-coital bleeding "and\or" dyspareunia (20% each). Lastly, 74% of the participants did not make this test previously. Liquid-based cytology technique outperformed conventional pap smears because of improved fixation, decreased impurities factors, and standardization of cell transfer.&#x0D; We conclude that routine screening and Pap smear testing for uterine cervix and vagina might be useful to prevent the occurrence of precancerous lesions in the genital system of sexually active women. We recommend to apply this test before and after treatment and to activate the cellular examination in the basal fluid method

Clinical significance of human papillomavirus 16/18 E6 protein detection in shunting and prognosis of patients with atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions

Objective To evaluate the value of human papillomavirus (HPV) 16/18 E6 protein detection in shunting and prognosis in patients with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL). Methods A total of 98 patients with ASCUS or LSIL from the Affiliated Cancer Hospital of Shanxi Medical University between May 2014 and May 2015 were selected as the subjects. All of them received the thin-cytologic test (TCT), HPV DNA, HPV16/18 E6 protein tests and colposcopy examination. After 3-year follow-up of patients with cervical intraepithelial neoplasia (CIN) grade Ⅰor bellow lesions diagnosed by biopsy and 30 negative controls, the above tests were performed again. The efficacies of all the tests were analyzed. The value of CIN grade Ⅱ or above was predicted. Results The sensitivity, specificity, positive predictive value and negative predictive value in predicting CIN grade Ⅱ or above lesions of HPV16/18 E6 protein, HPV DNA and HPV16/18 DNA was 30.8%, 95.3%, 50.0%, 90.0%, respectively; 84.6%, 37.6%, 17.2%, 94.1%, respectively and 61.5%, 67.1%, 22.2%, 91.9%, respectively in shunting study. The relative risk (RR) of CIN grade Ⅱor above lesions in patients with positive HPV16/18 E6 protein, persistent positive HPV16/18 DNA and positive HPV16/18 DNA was 13.429, 10.231 and 8.343, respectively in the follow-up study. Odds ratio (OR) of HPV16/18 E6 positive protein presenting persistent positive HPV16/18 DNA was 34.833 (95% CI 5.020-241.711). Conclusions In patients with ASCUS and LSIL, the specificity and positive predictive value of HPV16/18 E6 protein in predicting CIN grade Ⅱ or above lesions are higher than those of HPV DNA and HPV16/18 DNA. Moreover, these patients with HPV16/18 E6 protein positive have a higher risk of developing CIN grade Ⅱ or above lesions and persistent positive HPV16/18 DNA. Key words: Atypical squamous cells of undetermined significance; Low-grade squamous intraepithelial lesions; Human papillomavirus 16; Human papillomavirus 18; E6 protein

Profile of the BD HPV OnclarityTM assay

ABSTRACTIntroduction: Validated molecular assays for the detection of high risk (hr) Human Papillomavirus (HPV) DNA underpin the screening protocols against cervical cancer. New molecular assays based on real-time PCR also display the genotype of hrHPV.Areas covered: Recently, the BD Onclarity™ HPV assay (Onclarity), extended HPV genotyping test, for use on the BD Viper™ LT Instrument, has been developed. Onclaritys application for the detection and genotyping of hrHPV has been validated for the identification of women at high risk for cervical intraepithelial neoplasia of grade 2 or more in accordance with European Guidelines and FDA specifications.Expert opinion: Onclarity displays good sensitivity and specificity performance for HR-HPV detection and offers the possibility for genotype-specific reporting: the latter could provide risk-stratification for high-grade cervical disease during screening and facilitate surveillance for persistent genotypes in women at follow-up visits.

Clinical Evaluation of Human Papillomavirus Screening With p16/Ki-67 Dual Stain Triage in a Large Organized Cervical Cancer Screening Program

As cervical cancer screening transitions from Papanicolaou cytologic screening to primary human papillomavirus (HPV) testing worldwide, effective triage tests are needed to decide who among the HPV-positive women should receive further diagnostic evaluation to avoid unnecessary colposcopies and biopsies. To evaluate the performance of the p16/Ki-67 dual stain (DS) and HPV16/18 genotyping for the triage of HPV-positive women. A prospective observational study was conducted within the cervical cancer screening program at Kaiser Permanente Northern California of 3225 HPV-positive women undergoing HPV and Papanicolaou cytologic testing with a valid DS result from September 16 to October 31, 2015, with follow-up through December 31, 2018. Human papillomavirus screening with partial genotyping and cytologic triage compared with DS triage. Cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) and grade 2 or more severe (CIN2+), diagnosed within 3 years after sample collection. A total of 3225 women (mean [SD] age, 37.9 [11.3] years) participated in the study. For triage of HPV-positive women with partial genotyping, DS showed better risk stratification for CIN3+ than did Papanicolaou cytologic testing, with women with positive DS results having a higher risk than women with positive Papanicolaou test results for CIN3+ (218 of 1818 [12.0%; 95% CI, 10.5%-13.5%] vs 219 of 2128 [10.3%; 95% CI, 9.0%-11.6%]; P = .005). Similarly, DS showed better risk stratification for CIN3+ compared with Papanicolaou cytologic testing in HPV-positive women, irrespective of genotyping. The greatest reassurance against CIN3+ was observed in HPV16/18-negative women with negative DS results, with a risk low enough to extend retesting intervals. Dual stain triage strategies required substantially fewer colposcopies per detection of CIN3+ compared with Papanicolaou cytologic testing, with a 32.1% (859 of 2677) reduction of colposcopies compared with the currently recommended triage strategy of HPV screening with Papanicolaou cytologic testing. Results for CIN2+ were very similar. Triage of HPV-positive women with DS was superior to Papanicolaou cytologic testing in this study, demonstrating equal immediate detection of precancerous lesions and substantially reduced referral to colposcopy. These findings suggest that DS can safely replace Papanicolaou cytologic testing as a triage strategy for primary HPV screening, and that retesting intervals in HPV16/18-negative women with negative DS results can be safely extended to 3 years.

A man with repeated cholangitis

A 67-year-old man, with a past medical history of remarkable left intrahepatic biliary stones and recurrent episodes of acute cholangitis, presented to our hospital with low-grade fever and epigastric dull aching followed by tea-colored urine for 1 week. Initial laboratory data were as follows: Hb 11.5 g/dL, WBC (white blood count) 17 700/mm3, CRP (C-Reactive Protein) 25.13 mg/dL, AST/ALT (aspartate transaminase/alanine transaminase) 39/45 IU/L, bilirubin (T/D) 7.5/4.6 mg/dL, alkaline phosphatase 596 IU/L, CEA (carcinoembryonic antigen) 1.92 ng/mL, AFP (Alpha-FetoProtein) 4.10 ng/mL, PSA (prostate specific antigen) 5.57 ng/mL, and CA 19-9 (Carbohydrate Antigen 19-9) 92.56 U/mL. Abdominal computed tomography demonstrated a new-onset mass lesion (10 cm in diameter) occupying the left lobe of liver. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the liver demonstrated a 10 cm liver mass with dilatation of adjacent IHDs (intrahepatic duct) in the left lobe (mainly in segment 4), indicating a malignant neoplasm (Figure 1). The preoperative diagnosis was ICC according to his clinical presentation and radiological images. He received an extended left hepatectomy after a thorough preoperative evaluation, including the ICG (Indocyanine green) test. The histopathological examination demonstrated intraductal papillary neoplasm of bile duct (IPNB) with low-grade dysplasia and marked chronic inflammation (Figure 2). His postoperative course was uneventful, and he was discharged 10 days after the operation. IPNB, formerly named biliary papillomatosis, is a rare biliary epithelial tumor with an exophytic nature exhibiting a papillary mass within the bile duct lumen and with a prominent intraductal growth pattern. It has been considered as a precursor lesion of invasive cholangiocarcinoma. The grade of intraepithelial neoplasia is defined as either low-intermediate, high, or invasive carcinoma according the World Health Organization's 2010 classification system.1 The clinical picture of IPNB consists of recurrent colicky abdominal pain and repeated episodes of acute cholangitis with fever and jaundice due to partial or intermittent biliary obstruction.2 Common radiological findings for IPNB are bile duct dilatation or intraductal masses, and liver solid tumors are rarely seen. It is difficult to distinguish IPNB from other inflammatory and neoplastic lesions based on radiological appearance alone, including DCE-MRI of liver.3 Patients with IPNB should be considered for treatment because of the high risk of recurrent cholangitis and malignant transformation. Resection is the treatment of choice when IPNB is localized according to preoperative imaging workup. The overall prognosis is better in patients with IPNB than ICC, and long-term survival is anticipated after curative resection.4 The author declares no conflict of interest.

Over Expressed TKTL1, CIP-2A, and B-MYB Proteins in Uterine Cervix Epithelium Scrapings as Potential Risk Predictive Biomarkers in HR-HPV-Infected LSIL/ASCUS Patients.

High oncogenic risk human papillomaviruses (HR-HPVs) promote cervical carcinoma development, the fourth most common feminine cancer. A slow oncodevelopmental phase—defined histopathologically as Cervical Intraepithelial Neoplasia (CIN) grades 1–3, or cytologically as Low- or High-grade Squamous Intraepithelial Lesions (LSIL or HSIL)—precedes the malignancy. Cervical carcinoma screenings through HR-HPV genotyping and Pap smears are regularly performed in Western countries. Faulty cytology screening or genotyping or patients' non-compliance with follow-ups can let slip an oncoprogression diagnosis. Novel biomarker tests flanking HR-HPV genotyping and cytology could objectively predict the risk of disease progression thus helping triage LSIL/ASCUS patients. Here, anonymized leftovers of fresh cervical epithelium scrapings from twice (LSIL/ASCUS and HR-HPV DNA)-positive and twice (Pap smear- and HR-HPV DNA)-negative (control) patients in a proteome-preserving solution served to assess the biomarker worth of three cervical carcinoma-related proteins, i.e., B-MYB (or MYBL2), Cancerous Inhibitor of PP2A (CIP-2a), and transketolase-like1 (TKTL1). Leftovers anonymity was strictly kept and storage at −80°C, protein extraction, immunoblotting, and band densitometry were blindly performed. Only after tests completion, the anonymous yet code-corresponding HR-HPV-genotyping and cytology data allowed to assign each sample to the twice-positive or twice-negative group. Descriptive statistics showed that the three proteins levels significantly increased in the twice-positive vs. twice-negative scrapings. Diagnostic ROC curve analysis identified each protein's Optimal Decision Threshold (OTD) showing that TKTL1 and CIP-2a are stronger risk predictive biomarkers (Sensitivity, 0.91–0.93; Specificity, 0.77–0.83) than B-MYB. Logistic Regression coupled with Likelihood-Ratio Tests confirmed that a highly significant relation links increasing TKTL1/CIP-2a/B-MYB protein levels in twice-positive cervical scrapings to the risk of HR-HPV-driven oncoprogression. Finally, a 3 year clinical follow-up showed that 13 patients (50% of total) of the twice-positive group with biomarker values over OTDs compliantly underwent scheduled colposcopy and biopsy. Of these, 11 (i.e., 84.7%) received a positive histological diagnosis, i.e., CIN1 (n = 5; 38.5%) or CIN2/CIN2+ (n = 6; 46,2%). Therefore, TKTL1/CIP-2a/B-MYB protein levels could objectively predict oncoprogression risk in twice (HR-HPV- and Pap smear)-positive women. Further studies will assess the translatability of these findings into clinical settings.

Prevalence of human papillomavirus and subtype distribution in male partners of women with cervical intraepithelial neoplasia (CIN): a systematic review

BackgroundHuman Papillomavirus (HPV) infection is estimated to be the most common sexually transmitted infection. The present systematic review summarizes data regarding the prevalence of HPV and the distribution of subtypes in heterosexual male partners of women, who were diagnosed with any grade of cervical intraepithelial neoplasia (CIN).MethodsWe conducted a systematic review of the literature by Medline and Google Scholar databases using the terms “Human Papillomavirus” or “HPV” plus “men” or “male partners” or “women with CIN”. We included original published English-language articles published from 1/1/2000 until 1/1/2018 that had screened male partners of women with CIN using HPV DNA testing. We excluded studies that they overlapped with other included studies or were unrelated to the study subject.ResultsWe included a total of 12 publications, which reported the prevalence of HPV in free-clinical signs male partners of women with CIN. The largest proportion of the studies were from South America (seven studies), and the rest from Europe. The mean age of participants was 35.18 + − 3.47 years. HPV prevalence ranged from 12.9 to 86%; the total HPV prevalence among the studies was 49.1%, while ten out twelve studies (83.3%) demonstrated prevalence > 20%. Between the studies, the distribution of HPV subtypes varied on the basis of the method used, on the population and on the geographic region. A great variety of subtypes were detected, including 6, 11, 16, 18, 31, 33, 40, 42, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 62, 66, 68, 81 and 83. In six studies the HPV 16 was the most frequent, while in two others the HPV 6 and HPV 83.ConclusionsUntil now, there are not precise screening or surveillance guidelines for the management of partners of women with CIN. This population is frequently colonized by various HPV subtypes and therefore need to be screened in an effort to reduce the infection in both sexes. The screening test could include detection/identification of HPV subtypes by a molecular assay, followed by peniscopy only in the positive cases.

MiRNA detection in cervical exfoliated cells for missed high-grade lesions in women with LSIL/CIN1 diagnosis after colposcopy-guided biopsy

BackgroundLow-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 (LSIL/CIN1) preceded by colposcopy guided biopsy is recommended conservative follow-up, although some of these lesions are actually high-grade lesions, which are missed on an initial colposcopy. Therefore, in this work, we evaluate the potential role of miRNA detection in cervical exfoliated cells in a clinic-based population for predicting missed high-grade lesions in women diagnosed with LSIL/CIN1 after colposcopy-guided biopsy.MethodsA total number of 177 women with a diagnosis of LSIL/CIN1 obtained by colposcopy-guided biopsy were grouped into two categories according to the histology of the conization specimens: consistent LSIL/CIN1 group (surgical pathology consistent with colposcopic diagnosis) and missed high-grade lesion group (surgical pathology found high-grade lesion). The expression of eight miRNAs, such as miRNA195, miRNA424, miRNA375, miRNA218, miRNA34a, miRNA29a, miRNA16–2, and miRNA20a was detected by real time-quantitative polymerase chain reaction (RT-qPCR) in cervical exfoliated cells of the 177 patients. Pearson Chi-Square was used to compare the performance efficiency of patients’ characteristics. Nonparametric Man-Whitney U test was used to assess differences in miRNA expression. The receiver operating characteristic (ROC) curve was used to assess the performance of miRNA evaluation in detecting missed high-grade lesions.ResultsAmong the 177 women with biopsy-confirmed CIN1, 15.3% (27/177) had CIN2+ in the conization specimen (missed high-grade lesion group) and 84.7% (150/177) had CIN1-(consistent LSIL/CIN1 group). The relative expression of miRNA-195 and miRNA-29a in the missed high-grade lesion group was significantly lower than that in the consistent LSIL/CIN1 group. The relative expression of miRNA16–2 and miRNA20a in the missed high-grade lesion group was significantly higher than that in the consistent LSIL/CIN1 group. No significant difference was observed between these two groups regarding the other four miRNAs. Of these significant miRNAs, miRNA29a detection achieved the highest Youden index (0.733), sensitivity (92.6%), positive predictive value (46.2%), negative predictive value (98.3%) and higher specificity (80.7%) when identifying missed high-grade lesions.ConclusionsDetection of miRNA might provide a new triage for identifying a group at higher risk of missed high-grade lesions in women with colposcopy diagnosis of LSIL/CIN1.

MRNA Biomarker in Anal Cytology: A Feasible Approach for Anal Cancer Screening in Men Who Have Sex with Men Living with HIV

Background: There is a growing interest in developing screening strategies for anal cancer to target high-risk populations. However, cytological and molecular evaluation of anal samples is challenging. We aimed to determine the feasibility of detecting, in anal liquid-based cytology samples, the mRNA of three biomarkers involved in the cell cycle disturbance elicited by human papillomavirus (HPV) infection. The accuracy of this approach in the identification of high-grade squamous intraepithelial lesions/anal intraepithelial neoplasia grade 2-3 (HSIL/AIN2-3) was also evaluated. Methods: Two-hundred and fifteen anal cytologies from men having sex with men living with human immunodeficiency virus were evaluated. Patients showing concordant cytological and anoscopy-directed biopsy diagnosis were selected: 70 with a negative cytology and HPV test, 70 with cytology and biopsy showing low-grade SIL (LSIL/AIN1) and 75 with cytology and biopsy of HSIL/AIN2-3. CDKN2A/p16, MKI67 and TOP2A mRNA expression was analyzed by reverse transcription qPCR. HPV detection was performed using the Xpert HPV Assay (Cepheid, Sunnyvale, CA). Adequate material for mRNA analysis was obtained from 199/215 (92.6%) samples. Results: mRNA expression for the three biomarkers was significantly higher in HSIL/AIN2-3 compared with LSIL/AIN1 or negative samples. The estimated specificity for the identification of HSIL/AIN2-3 for a sensitivity established at 70% was 44.7% (95% confidence interval [95%CI] 36.5-53.2) for TOP2A and MKI67 and 54.5% (95%CI 46.0-62.8%) for CDKN2A/p16. Conclusions: mRNA detection of cell biomarkers in anal liquid-based cytology is feasible. Further studies are warranted to confirm the possible role of strategies based on mRNA detection in the secondary prevention of anal cancer. Funding Statement: This work was supported by the Instituto de Salud Carlos III (ICSIII)-Fondo de Investigacion Sanitaria and ERDF ‘One Way to Europe’ (grants PI15/00546 and PI17/00772). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The study was approved by the institutional ethical review board.

Value of HPV 16/18 Genotyping and p16/Ki-67 Dual Staining to Predict Progression to HSIL/CIN2+ in Negative Cytologies From a Colposcopy Referral Population.

To assess the prognostic value of human papillomavirus (HPV) 16/18 genotyping and p16/Ki-67 dual staining cytology in high-risk HPV (hrHPV)-positive women with no lesion or minor abnormalities. We evaluated progression to high-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grades 2 to 3 or cervical cancer (HSIL/CIN2+), persistence/regression of hrHPV infection in women referred to colposcopy showing hrHPV infection, histology diagnosis different from HSIL/CIN2+, and negative cytology. HPV 16/18 genotyping and dual staining were performed in liquid-based cytologic specimens obtained on the first visit. Progression was observed in 16 (8.0%) of 200 women. Those with HPV 16/18 infection had an increased risk of progression compared with women infected by other hrHPV types, and they also showed more persistence. However, no association was observed between progression or persistence and the result of the dual staining. HPV 16/18-positive women with no lesions or minor abnormalities are at high risk of progression to HSIL/CIN2+ and hrHPV persistence.

Pancreatic intra-epithelial neoplasia and histological grade of pancreatic cancer predict poor survival after pancreaticoduodenectomy

Pancreatic intra-epithelial neoplasia and histological grade of pancreatic cancer predict poor survival after pancreaticoduodenectomy