ArticleThe American journal of surgical pathology2015
Investigating Diagnostic Problems of CIN1 and CIN2 Associated With High-risk HPV by Combining the Novel Molecular Biomarker PanHPVE4 With P16INK4a.
Article in The American journal of surgical pathology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05049252 (Performance of HPV E4 and p16INK4a Biomarkers in Predicting Risk of Regression Among Women Diagnosed With Cervical Intraepithelial Neoplasia Grade 2), which is not on this map. Cited by 21 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Performance of HPV E4 and p16INK4a Biomarkers in Predicting Risk of Regression Among Women Diagnosed With Cervical Intraepithelial Neoplasia Grade 2 (CIN2): a Historical Cohort Study
Who cites it
21 citing papers in PubMed, 40 citations in OpenAlex.
- p16International journal of cancer · 2025Article
- Human papillomavirus (HPV) genotyping and prognostic value of HPV E4 protein and transcription factors NANOG and SOX11 in atypical p16 patchy squamous epithelium of cervix.Radiology and oncology · 2025Article
- FAM19A4/miR124-2 Methylation Testing and Human Papillomavirus (HPV) 16/18 Genotyping in HPV-Positive Women Under the Age of 30 Years.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2023Article
- Expression of E4 Protein and HPV Major Capsid Protein (L1) as A Novel Combination in Squamous Intraepithelial Lesions.Biomedicines · 2023Article
- Assessing Inter-Annotator Agreement for Medical Image Segmentation.IEEE access : practical innovations, open solutions · 2023Article
- Performance of HPV E4 and p16BMJ open · 2022Article
- Review
- Characterisation of anal intraepithelial neoplasia and anal cancer in HIV-positive men by immunohistochemical markers p16, Ki-67, HPV-E4 and DNA methylation markers.International journal of cancer · 2021Article
- Classification of high-grade cervical intraepithelial neoplasia by p16International journal of cancer · 2021Article
- Characterization of cervical biopsies of women with HIV and HPV co-infection using p16Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2020Article
- Relationships of p16 Immunohistochemistry and Other Biomarkers With Diagnoses of Cervical Abnormalities: Implications for LAST Terminology.Archives of pathology & laboratory medicine · 2020Article
- Expression of p16 and HPV E4 on biopsy samples and methylation of FAM19A4 and miR124-2 on cervical cytology samples in the classification of cervical squamous intraepithelial lesions.Cancer medicine · 2020Article
- Grading immunohistochemical markers p16The British journal of dermatology · 2020Article
- Assessment of p16 and Ki67 Immunohistochemistry Expression in Squamous Intraepithelial Lesion with Cytohistomorphological Correlation.Iranian journal of pathology · 2020Article
- Whole tissue cervical mapping of HPV infection: Molecular evidence for focal latent HPV infection in humans.Papillomavirus research (Amsterdam, Netherlands) · 2019Article
- [Squamous cell precancerous lesions of the cervix uteri].Der Pathologe · 2019Review
- HPV E4 expression and DNA hypermethylation of CADM1, MAL, and miR124-2 genes in cervical cancer and precursor lesions.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2018Article
- Risk stratification of cervical disease using detection of human papillomavirus (HPV) E4 protein and cellular MCM protein in clinical liquid based cytology samples.Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology · 2018Article
- Three-tiered score for Ki-67 and p16Journal of clinical pathology · 2018Article
- [Modern biomarkers for precancerous lesions of the uterine cervix : Histological-cytological correlation and use].Der Pathologe · 2016Review
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 4 countries.
Funding
Abstract
Grading cervical intraepithelial neoplasia (CIN) determines clinical management of women after abnormal cytology with potential for overdiagnosis and overtreatment. We studied a novel biomarker of human papillomavirus (HPV) life-cycle completion (panHPVE4), in combination with the minichromosome maintenance (MCM) protein cell-cycle marker and the p16INK4a transformation marker, to improve CIN diagnosis and categorization. Scoring these biomarkers alongside CIN grading by 3 pathologists was performed on 114 cervical specimens with high-risk (HR) HPV. Interobserver agreement for histopathology was moderate (κ=0.43 for CIN1/negative, 0.54 for CIN2/≤CIN1, and 0.36 for CIN3). Agreement was good or excellent for biomarker scoring (E4: κ=0.896; 95% confidence interval [CI]: 0.763-0.969; p16INK4a : κ=0.798; 95% CI: 0.712-0.884; MCM: κ=0.894; 95% CI: NC (this quantity cannot be calculated). Biomarker expression was studied by immunofluorescence and immunohistochemistry and was correlated with 104 final CIN diagnoses after histologic review. All 25 histologically negative specimens were p16INK4a and panHPVE4 negative, although 9 were MCM-positive. There were variable extents of p16INK4a positivity in 11/11 CIN1 and extensive panHPVE4 staining in 9/11. Ten CIN2 lesions expressed panHPVE4 and p16INK4a, and 13 CIN2 expressed only p16INK4a. CIN3 showed extensive p16INK4a positivity with no/minimal panHPVE4 staining. PanHPVE4, unlike MCM, distinguished CIN1 from negative. PanHPVE4 with p16INK4a separated CIN2/3 showing only expression of p16INK4a, indicating transforming HR-HPV E7 expression, from CIN1/2 showing completion of HR-HPV life cycle by E4 expression and variable p16INK4a expression. PanHPVE4 and p16INK4a staining are complementary markers that could provide simple, reliable support for diagnosing CIN. Their value in distinguishing CIN1/2 that supports HR-HPV life-cycle completion (and which might ultimately regress) from purely transforming CIN2/3 needing treatment warrants further research.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.