HPV16 genotype, p16/Ki-67 dual staining and koilocytic morphology as potential predictors of the clinical outcome for cervical low-grade squamous intraepithelial lesions

Abstract Background To improve the efficiency of early diagnosis systems for cervical cancer, the use of cellular and viral markers for identifying precancerous lesions with a greater probability to progress to cancer has been proposed. Several cellular proteins and markers of oxidative DNA damage have been suggested as possible biomarkers of cervical carcinogenesis; however, they have not been evaluated together. In this study, we analyzed the expression of the cellular markers p16INK4a, Ki-67, CyclinE1, TOP2A/MCM2, and telomerase, as well as the DNA oxidative damage markers ROS and 8-OHdG. The analyses were performed in liquid-based cervical cytology samples or biopsies with premalignant lesions or cervical cancer diagnosis, with the purpose of selecting a panel of biomarkers that allow the identification of precursor lesions with greater risk of progression to cervical cancer. Methods We analyzed 1485 liquid-based cytology samples, including 239 non-squamous intraepithelial lesions (NSIL), 901 low-grade squamous intraepithelial lesions (LSIL), 54 high-grade squamous intraepithelial lesions (HSIL), and 291 cervical cancers (CC). The biomarkers were analyzed by immunocytochemistry and Human Papilloma Virus (HPV) genotyping with the INNO-LiPA genotyping Extra kit. Results We found that all tested cellular biomarkers were overexpressed in samples with high risk-HPV infection, and the expression levels increased with the severity of the lesion. TOP2A/MCM2 was the best biomarker for discriminating between LSIL and HSIL, followed by p16INK4a and cyclinE1. Statistical analysis showed that TOP2A/MCM2 provided the largest explanation of HSIL and CC cases (93.8%), followed by p16INK4a (91%), cyclin E1 (91%), Ki-67 (89.3%), and telomerase (88.9%). Conclusions We propose that the detection of TOP2A/MCM2, p16INK4a and cyclin E1 expression levels is useful as a panel of biomarkers that allow identification of cervical lesions with a higher risk for progression to CC with high sensitivity and precision; this can be done inexpensively, in a single and non-invasive liquid-based cytology sample.

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Comparative Evaluation of P16, Ki-67, and Shape-correlated Genes as Biomarkers for Cervical High-grade Squamous Intraepithelial Lesions

10.21203/rs.3.rs-33881/v1 ◽

2020 ◽

Author(s):

hengzi Sun ◽

Shuhong Li ◽

Dongyan Cao ◽

Jiaxin Yang ◽

Peng Peng ◽

...

Keyword(s):

Sensitivity And Specificity ◽

Comparative Evaluation ◽

Referral Rate ◽

The Other ◽

High Grade ◽

Squamous Intraepithelial Lesions ◽

Ki 67 ◽

Intraepithelial Lesions ◽

Dual Staining

Abstract Background:Colposcopy was referred in cases with severe abnormalities in co-testing. However, approximately 60%-80% patients did not receive proper benefits. Although p16/Ki67 dual staining reduced the referral rate, its sensitivity and specificity need to be enhanced. Methods:The expression of p16, Ki-67, SMAD3, YAP1, RELA were evaluated inthe colposcopy referral population. Results:The sensitivity and specificity of p16+ combined with Ki-67+ for predicting CIN2+ were 62.1% and 89.5%, respectively. p16+ combined with YAP1+ and/or RELA+ provided a sensitivity and specificity of 70.9% and 89.5%, respectively, while 72.8% and 86.4% were achieved by p16+ combined with YAP1+ and/or SMAD3+ and/or RELA+. In HPV16/18+ and LSIL subgroups, the sensitivity and specificity of p16+ combined with Ki-67+ for predicting CIN2+ were 67.7% and 87.6%, respectively, for the former group and 58.6%, 88.8%, respectively, for the latter group, whereas those of RELA alone were 76.9% and 90.5%, respectively, and 82.8% and 92.1%, respectively. p16+, YAP1+/RELA+ showed a better performance for predicting CIN2+ with a better sensitivity (86.7% vs. 52.2%, p=0.028) and considerable specificity (86.7% vs. 90.0%, p=0.486) in the other HPV+ combined with ASCUS groupthan were achieved by p16+ combined with Ki-67+. RELA+ and the combination of p16 and RELA/YAP1 also provided the Max AUC area. Conclusions:Our study shows that RELA and the combination of p16 and RELA/YAP1 achieved better sensitivity and specificity for detecting morphologically CIN2+ lesions.

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Predictive Value of the Combined p16INK4aand Ki-67 Immunocytochemistry in Low-Grade Squamous Intraepithelial Lesions

Acta Cytologica ◽

10.1159/000367838 ◽

2014 ◽

Vol 58 (5) ◽

pp. 489-494 ◽

Cited By ~ 5

Author(s):

Peter Ziemke ◽

Katrin Marquardt ◽

Henrik Griesser

Keyword(s):

Predictive Value ◽

Low Grade ◽

Squamous Intraepithelial Lesions ◽

Ki 67 ◽

Intraepithelial Lesions

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The Role of Cytology in the 21st Century: The Integration of Cells and Molecules

Acta Cytologica ◽

10.1159/000449402 ◽

2016 ◽

Vol 60 (6) ◽

pp. 540-542 ◽

Cited By ~ 3

Author(s):

Christine Bergeron ◽

Magnus von Knebel Doeberitz

Keyword(s):

Cervical Cancer ◽

Invasive Cervical Cancer ◽

Routine Practice ◽

Specific Marker ◽

Low Grade ◽

Hpv Testing ◽

Care Providers ◽

Squamous Intraepithelial Lesions ◽

Ki 67 ◽

Intraepithelial Lesions

Objectives: Cervical cancer screening test performance has been hampered by either a lack of sensitivity in Pap cytology or a lack of specificity of human papillomavirus (HPV) testing. This is disturbing for patients and a cause of high costs for health care providers. Study Design: The identification of p16INK4a as a specific marker for the neoplastic transformation of cervical squamous epithelial cells by HPVs allows the identification of HPV-transformed cells in cytopathology specimens. Results: When compared to molecular HPV tests for triaging minor cytologic atypia, such as atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions, the immunochemical detection of dual p16INK4a/Ki-67-stained cells demonstrates a significantly improved specificity with good relative sensitivity. Conclusions: HPV testing has shown earlier detection of persistent high-grade squamous intraepithelial lesions (HSIL) compared to cytology and is more effective in preventing invasive cervical cancer. The next challenge for the HPV primary screening program is to find the best method(s) for selecting, among HPV-positive women, those patients in need of immediate colposcopy because they are at a higher risk of developing a precancerous lesion. An HSIL cytology result and/or dual p16/Ki-67 staining could be the best candidates, but further randomized studies are required before these approaches can be used in routine practice.

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Colposcopic characteristics and Lugol׳s staining differentiate anal high-grade and low-grade squamous intraepithelial lesions during high resolution anoscopy

Papillomavirus Research ◽

10.1016/j.pvr.2015.06.004 ◽

2015 ◽

Vol 1 ◽

pp. 101-108 ◽

Cited By ~ 17

Author(s):

Naomi Jay ◽

J. Michael Berry ◽

Christine Miaskowski ◽

Misha Cohen ◽

Elizabeth Holly ◽

...

Keyword(s):

High Resolution ◽

Low Grade ◽

High Grade ◽

Squamous Intraepithelial Lesions ◽

Intraepithelial Lesions

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Oral contraceptive pills are associated with artifacts in ThinPrep Pap smears that mimic low-grade squamous intraepithelial lesions

Cancer ◽

10.1002/cncr.11056 ◽

2002 ◽

Vol 99 (2) ◽

pp. 75-82 ◽

Cited By ~ 6

Author(s):

Carl Morrison ◽

Patricia Prokorym ◽

Clara Piquero ◽

Paul E. Wakely ◽

Gerard J. Nuovo

Keyword(s):

Oral Contraceptive ◽

Pap Smears ◽

Low Grade ◽

Squamous Intraepithelial Lesions ◽

Oral Contraceptive Pills ◽

Contraceptive Pills ◽

Intraepithelial Lesions

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Colposcopy, cervical cytology and human papillomavirus detection as screening tools for cervical cancer

Eastern Mediterranean Health Journal ◽

10.26719/2001.7.1-2.100 ◽

2001 ◽

Vol 7 (1-2) ◽

pp. 100-105

Author(s):

Al Alwan Al Alwan

Keyword(s):

Human Papillomavirus ◽

High Risk ◽

Pap Test ◽

Screening Tools ◽

Low Grade ◽

Squamous Intraepithelial Lesions ◽

Sampling Device ◽

Squamous Cells ◽

The Bethesda System ◽

Intraepithelial Lesions

A cohort of 77 women referred for routine screening or investigation of Pap test abnormality underwent colposcopic examination. Pap-stained liquid-based preparations were diagnosed and categorized according to the Bethesda system. Residual material on the sampling device was used to detect high-risk oncogenic human papillomavirus DNA. Although the colposcopic failure rate was higher than that of cytology, no lesion was missed when both methods were used together. High-risk types were recorded in 24% of patients with atypical squamous cells of undetermined significance, 45% with low-grade squamous intraepithelial lesions and 79% with high-grade squamous intraepithelial lesions-indicating that the efficacy of cytological screening can be improved by papillomavirus detection.

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The effectiveness of acetic acid wash protocol and the interpretation patterns of blood contaminated cervical cytology ThinPrep® specimens

CytoJournal ◽

10.4103/1742-6413.168060 ◽

2015 ◽

Vol 12 ◽

pp. 23 ◽

Cited By ~ 2

Author(s):

Nora K. Frisch ◽

Yasin Ahmed ◽

Seema Sethi ◽

Daniel Neill ◽

Tatyana Kalinicheva ◽

...

Keyword(s):

Acetic Acid ◽

Statistical Significance ◽

Cervical Cytology ◽

Low Grade ◽

Squamous Intraepithelial Lesions ◽

Chi Square ◽

Chi Square Test ◽

Acid Wash ◽

The Difference ◽

Intraepithelial Lesions

Background: ThinPrep® (TP) cervical cytology, as a liquid-based method, has many benefits but also a relatively high unsatisfactory rate due to debris/lubricant contamination and the presence of blood. These contaminants clog the TP filter and prevent the deposition of adequate diagnostic cells on the slide. An acetic acid wash (AAW) protocol is often used to lyse red blood cells, before preparing the TP slides. Design: From 23,291 TP cervical cytology specimens over a 4-month period, 2739 underwent AAW protocol due to initial unsatisfactory smear (UNS) with scant cellularity due to blood or being grossly bloody. Randomly selected 2739 cervical cytology specimens which did not undergo AAW from the same time period formed the control (non-AAW) group. Cytopathologic interpretations of AAW and non-AAW groups were compared using the Chi-square test. Results: About 94.2% of the 2739 cases which underwent AAW were subsequently satisfactory for evaluation with interpretations of atypical squamous cells of undetermined significance (ASCUS) 4.9% (135), low-grade squamous intraepithelial lesions (LSIL) 3.7% (102), and high-grade squamous intraepithelial lesions (HSIL) 1% (28). From the 2739 control cases, 96.3% were satisfactory with ASCUS 5.5% (151), LSIL 5.1% (139), and HSIL 0.7% (19). The prevalence of ASCUS interpretations was similar (P = 0.33). Although there were 32% more HSIL interpretations in the AAW group (28 in AAW vs. 19 in non-AAW), the difference was statistically insignificant (P = 0.18). AAW category; however, had significantly fewer LSIL interpretations (P = 0.02). The percentage of UNS cases remained higher in the AAW group with statistical significance (P < 0.01). Conclusions: While AAW had a significantly higher percent of UNS interpretations, the protocol was effective in rescuing 94.2% of specimens which otherwise may have been reported unsatisfactory. This improved patient care by avoiding a repeat test. The prevalence of ASCUS and HSIL interpretations between AAW and non-AAW groups were comparable. Though not statistically significant, HSIL interpretations were relatively higher in the AAW group. LSIL interpretations showed lower prevalence in AAW group.

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Prevalence of antibodies against a cyclic peptide mimicking the FG loop of the human papillomavirus type 16 capsid among Tunisian women

10.21203/rs.3.rs-23621/v4 ◽

2020 ◽

Author(s):

Elham Hassen ◽

Devendra Bansal ◽

Randa Ghdira ◽

Anouar Chaieb ◽

Hedi Khairi ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Human Papillomavirus ◽

Sex Workers ◽

Synthetic Peptide ◽

Cyclic Peptides ◽

Cyclic Peptide ◽

Low Grade ◽

Squamous Intraepithelial Lesions ◽

Intraepithelial Lesions ◽

Peptide Antibodies

Abstract Background In the past decade, cervical cancer has gone from being the second to the fourth most common cancer in women worldwide, but remains the second most common in developing countries. This cancer is most commonly caused by high-risk types of human papillomavirus (HPV), mainly type 16 (HPV16), which are sexually transmitted. This study aimed to investigate the usefulness of a cyclic synthetic peptide designed from the major L1 capsid protein of HPV16 for detecting anti-HPV16 antibodies. Methods We designed and synthetized a peptide that corresponds to the full sequence of the surface-exposed FG loop. We tested the antigenicity of the linear and the cyclic peptides against HPV16 L1 monoclonal antibodies. We used ELISA to detect anti-peptide antibodies in sera and cervical secretions of 179 Tunisian women, and we applied polymerase chain reaction and direct sequencing methods to detect and genotype HPV DNA. Results Both the linear and the cyclic peptides were recognized by the same neutralizing monoclonal antibodies, but the cyclic peptide was more reactive with human sera. The prevalence of the anti-peptide antibodies in sera was higher in women with low-grade squamous intraepithelial lesions (LGSIL) than in women with high-grade squamous intraepithelial lesions (HGSIL) (44% and 15%, respectively). This contrasts with HPV16 DNA prevalence. Compared to women from the general population, systemic IgG prevalence was significantly higher among sex workers (25%; P=0.002) and women with LGSIL (44%; P=0.001). In addition, systemic IgA and cervical IgG prevalence was higher among sex workers only (p=0.002 and P=0.001 respectively). We did not observe anti-peptide IgG antibodies in women with a current HPV16 infection.Conclusion Anti-peptide IgG in sera or in cervical secretions could be markers of an effective natural immunization against HPV16. This may open novel perspectives for monitoring vaccinated women and for the design of synthetic peptide-based vaccines.

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