KaplanMeier curves for overall survival for the three antibody clones and at the three different cutoffs. The accuracy of ambiguous p16 immunoreactivity in predicting oncogenic HPV and HSIL outcome is significantly lower than that of the block-positive pattern but greater than negative staining. Essential features Expression can be detected by immunohistochemistry Negative IHC in tumors with loss of p16 protein function / expression Immunohistochemical positivity commonly considered a surrogate marker for oncogenic HPV infection The electronic search retrieved 207 studies of which 171 were excluded: 101 after review of the title, 5 after review of the abstract, and 65 were duplicated. Most NB69 cells were negative for p16, . p16 immunohistochemistry was also subsequently reviewed by two additional pathologists (NC and BP) in order to assess interobserver variability (Table 6). Six did not describe the population from which ASIL samples were obtained [7, 16,17,18,19, 22]. p16INK4a immunohistochemistry (IHC) is widely used to facilitate the diagnosis of human papillomavirus (HPV)-associated cervical precancerous lesions. Are Histomorphological Features Predictive of p16 Immunopositivity Different for Oral and Oropharyngeal Squamous Cell Carcinoma? p16 is a tumor-suppressor protein that acts like a cyclin-dependent kinase inhibitor in the transition from the G1 to the S phase of the cell cycle. government site. The Diagnostic Utility of p16 Immunostaining in Differentiating Cancer and HSIL from LSIL and Benign in Cervical Cells. There was a total of 790 samples in which p16 was performed and the results reported, and therefore could be considered for the analysis. Eighth edn. p16 immunohistochemistry in oropharyngeal squamous cell carcinoma: a comparison of antibody clones using patient outcomes and high-risk human papillomavirus RNA status. doi: 10.1097/MD.0000000000032273. Ozaki S, Zen Y, Inoue M. Biomarker expression in cervical intraepithelial neoplasia: potential progression predictive factors for low-grade lesions. official website and that any information you provide is encrypted Approximately 28% of the CP-diagnosed CIN2 tested p16 IHC negative in this study; other studies have reported the percentage of p16 IHC-negative CIN2 ranging from approximately 20% 16 to less than 10%. 2007;203(6):445-9. doi: 10.1016/j.prp.2007.03.010. (A, C, and E: H&E, original magnification 200; B, D, and F: corresponding p16 IHC, original magnification 200). Slider with three articles shown per slide. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). KaplanMeier curves for disease-specific survival for the three antibody clones and at the three different cutoffs. p16 immunohistochemistry has become the recommended standalone prognostic test for patients with oropharyngeal squamous cell carcinoma as it is more cost-effective and less technically cumbersome than HPV-specific testing (ie, in situ hybridization and reverse-transcriptase PCR), is widely available and has high interobserver agreement in its assessment,10 and has been consistently shown to have independent prognostic significance.8 Under the new 8th edition American Joint Commission on Cancer (AJCC) staging guidelines, p16 immunohistochemistry as a standalone test is now required in order to stage oropharyngeal squamous cell carcinoma and cervical metastatic squamous cell carcinoma of unknown primary patients,11 as p16-positive ones (as a surrogate marker for high-risk HPV status) have their own separate staging systems. Google Scholar. Epub 2007 May 31. Article Prigenzi KCK, Heinke T, Salim RC, Focchi GRA. Risk stratification by p16 immunostaining of CIN1 biopsies: a retrospective study of patients from the quadrivalent HPV vaccine trials. Although, there is a controversy about its reliability. 2022 Apr 27;6(2):92-99. doi: 10.23922/jarc.2021-077. Staining would be positive for all three antibodies using the 'any staining' cutoff, but would only be positive for the E6H4 clone using the 50 and 75% cutoffs (all images 20 magnification). J Clin Oncol 2015;33:83645. . Google Scholar, Darragh TM, Colgan TJ, Cox JT, et al. Am J Surg Pathol. The PP16 or HPV16 immunostain negative also means that it is more likely a distinct subgroup that lacks any HPV-related genotype. During 12-month surveillance, HSILs were detected in 35% of the p16 block-positive group, 1.5% of negative group, and 16% of the ambiguous group. 2a-g. a Meta-analysis of the normal samples stained positive for p16. This website is intended for pathologists and laboratory personnel but not for patients. Three other authors that were contacted due to insufficient/incomplete data for analysis [12, 13] and a lack of clear definition of a positive result [14] did not respond, and the studies were not included. P16 Immunostain Staining ISSN 1530-0285 (online) Forty-six women between the age of 17 and 58 yr, with a median of 35 yr, were all HPV-negative. Fakhry C, Zhang Q, Nguyen-Tan PF et al, Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. Adv Anat Pathol. Studies that evaluated p16 immunostaining in histological samples of anal and/or perianal squamous intraepithelial lesions and defined a p16-positive result as diffuse block staining with nuclear or nuclear plus cytoplasmic staining were included. This is because most (between 50 and 80%) of the patients with these partial p16 results have high-risk HPV-related tumors. ProEx C is a useful ancillary study for grading anal intraepithelial neoplasia alone and in combination with other biomarkers. HSIL can begin in the anal canal, vagina, vulva, or cervix. Unable to load your collection due to an error, Unable to load your delegates due to an error, Morphologic CIN 2 lesions display distinctly positive and negative p16 results. D, Tangentially sectioned epithelium with substantial expansion of the basal and parabasal layers (H&E, original magnification 200). An unresolved question is whether loss of expression of p16 INK4a (the protein product of the CDKN2A gene which functions as a negative regulator of cyclin-dependent kinase activityhereafter p16) by immunohistochemistry can identify likely CDKN2A-inactivated meningiomas to be selectively confirmed by follow-up molecular testing. CAS In this study, we compared three different antibody clones in a large, well-characterized oropharyngeal squamous cell carcinoma patient cohort. Differentiating the results from the condylomas and AIN1/LSIL (without condylomas) categories poses some challenges. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA, Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada, Department of Pathology, University of Chicago Medicine, Chicago, IL, USA, Department of Biostatistics and Preventive Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA, Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN, USA, You can also search for this author in Although correlation with HPV mRNA status is one way to specifically evaluate the performance of different p16 antibodies and test platforms (many call HPV mRNA detection the 'gold standard' test10), our opinion is that patient outcomes are the ultimate standard by which these methods should be judged.2, 3, 15, 17 The best test or tests are the ones that most widely differentiate favorable and unfavorable survival rates. For low-grade lesions, three categories were described: condyloma acuminate only (as defined by the original study), AIN1/LSIL (anal condylomas excluded or there were no anal condylomas described), and all LSIL (LSIL, condyloma, AIN1, AIN1 and condyloma described together and condyloma with AIN1/LSIL). However, in our study, H-scores showed no benefit over percentage-based cutoffs (Table 3) with almost identical performance to all three cutoffs. p16 Immunohistochemistry is useful in confirming high-grade - PubMed We would like to thank Donna M Posey for her wonderful assistance with clerical support for the various aspects of this study. Hum Pathol. Am J Surg Pathol 2010;34:108896. In biochemistry, immunostaining is an antibody-based method used to detect a particular protein in a sample. 2013;2115:31929. p16ink4 and cytokeratin 7 immunostaining in predicting HSIL outcome for low-grade squamous intraepithelial lesions: a case series, literature review and commentary. Disclaimer. Our outcome was the proportion of p16 positivity according to the histological grade of ASIL/AIN. Albuquerque et al. The proportion of p16 expression increased with the severity of histological grade. Many of the conclusions for HPV-related lower anogenital tract neoplasia management, including p16 immunostaining are considered applicable across all anogenital sites, mostly based on generalizations from the cervix [3]. In low-grade cervical lesions, false-positive results are common and the lower positive predictive value may limit the role of p16 as a prognostic marker [37]. 31 Citations 9 Altmetric Metrics Abstract High-risk human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas have a more favorable prognosis than HPV-negative ones. and transmitted securely. CAS HPV testing through p16 immunocytochemistry in neckmass FNA and its Albuquerque et al. So why did we find that an any staining cutoff was equivalent to, or better than, 75%? Immunohistochemistry for mismatch repair proteins has shown utility in the identification of Lynch syndrome, but majority of tumours with loss MLH1 expression are due to sporadic hypermethylation of the MLH1 promoter. Protein P16 - an overview | ScienceDirect Topics Federal government websites often end in .gov or .mil. Two authors provided further information concerning sample size and expression for different histological grades [6] and for the definition of a positive result consistent with a diffuse block with nuclear plus cytoplasmic staining [7] and were included. For anal high-grade squamous intraepithelial lesions (HSILs), in studies using a two-tiered nomenclature, p16 positivity was 84% (95% CI: 6696%) and for all HSIL (AIN2, AIN3, HSIL combined) it was 82% (95% CI: 7291%). Although results were similar for all antibodies at all cutoffs, the differential between the fraction of patients with disease recurrence in the p16-positive vs -negative cohorts was widest (ie, best stratification) for the E6H4 clone. Subsequent biopsy reveals LSIL. In both reading rounds, ISPs were provided . Google Scholar. Lewis JS Jr., Ukpo OC, Ma XJ et al, Transcriptionally-active high-risk human papillomavirus is rare in oral cavity and laryngeal/hypopharyngeal squamous cell carcinomasa tissue microarray study utilizing E6/E7 mRNA in situ hybridization. p16 immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. g Meta-analysis of all of the combined HSIL (AIN2, AIN3, and HSIL) samples stained positive for p16. Erratum in: J Low Genit Tract Dis. Efficiency of immunohistochemical p16 expression and HPV typing in cervical squamous intraepithelial lesion grading and review of the p16 literature. The Bond Polymer Refine detection system was used for visualization. As was previously suggested by Jordan et al, in their work, a cutoff of 60 was used to dichotomize patients into positive and negative results.10. That is why we do believe, that the p16 immunohistochemical staining, however useful on everyday basis . Three patterns revealed comparably low HPV detection rates (28%, 27%, and 35%). Schlecht NF, Brandwein-Gensler M, Nuovo GJ et al, A comparison of clinically utilized human papillomavirus detection methods in head and neck cancer. Such infected cells can also serve as a source of producing extra p16 immunostain. In 2012, the lower anogenital squamous terminology (LAST) was published and recommended a two-tiered nomenclature for noninvasive HPV-associated lesions of the lower anogenital tract, including the terms low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs) to replace the previous three-tiered system (intraepithelial neoplasia: IN1, IN2, IN3). Although there may be concern for lack of representativeness of the overall tumor by these small samples, they were taken at random from each donor tumor block, the results on this microarray have shown very high prognostic value for p16 and HPV mRNA status in this and other studies,15 and, most compelling of all, is that small biopsies have been clearly proven as totally functional for p16 testing via the large number of literature studies on patients treated with primary chemoradiation after initial diagnosis on such specimens.1, 6, 20, 23, 24 In addition, Ma et al.25 specifically showed that small biopsy specimens reliably indicate p16 status in comparison with surgical resection specimens. In the disease-specific survival analyses, patients who died without disease were censored at their time of death. The proportion of p16 expression increased with the severity of histological grade. Eur J Cancer 2014;50:26362648. In several areas of the human body, pathologists also look out for additional p16 inside groups of cells when they are unsure whether the observed microscopic changes they see are caused by the human papillomavirus or not. Ma C, Lewis J Jr. . One needs to be aware, although, particularly with the G175-405 antibody, that partial nuclear and cytoplasmic, as well as nonspecific nuclear or cytoplasmic only staining, are not uncommon. Decreasing the cutoff to 50% increased correlation with HPV in situ hybridization and improved the survival differential for the JC8 and G175-405 clones without worsening of performance for the E6H4 clone. Role of the biomarker p16 in downgrading -IN2 diagnoses and predicting higher-grade lesions. 2014;21:34158. We did not attempt to modify the staining conditions to alter performance with the various antibodies in this work. Article 2015;32:40918. Anal intraepithelial neoplasia: correlation of grade with p16INK4a immunohistochemistry and HPV in situ hybridization. and JavaScript. Br J Cancer 2013;108:13329. Anal Intraepithelial Neoplasia: Precursor of Anal Squamous Cell Carcinoma. In summary, this evaluation of three commercially available p16 antibodies for performance in prognostication and correlation with high-risk HPV mRNA status in oropharyngeal squamous cell carcinoma shows that all three perform well as prognostic markers and surrogate markers of HPV status. The lesions were categorized based upon the above-mentioned four parameters. MeSH Andreia Albuquerque. Unauthorized use of these marks is strictly prohibited. Walts AE, Lechago J, Hu B, et al. This actually is a low threshold for p16 positivity and is not agreed upon, used, or recommended by most pathologists and organizations for testing. FOIA p16 protein, . Internet Explorer). Appl Immunohistochem Mol Morphol. At the 75% cutoff, there were 161 positive (81%) and 38 negative (19%) cases with the E6H4 clone, 148 positive (74%) and 51 negative (26%) with JC8 and 135 positive (68%) and 64 negative (32%) with G175-405. There was 100% agreement across all pathologists and specimens. By simple disease recurrence (Table 4), performance of the different clones was very similar for each of the three antibody clones at each of the cutoffs. Kreuter A, Wieland U, Gambichler T, et al. Int J Cancer 2013;132:882890. Tissue Fixation Conditions for p16 Immunohistochemistry and Human Papillomavirus RNA In Situ Hybridization in Oropharyngeal Squamous Cell Carcinoma, United States & Canadian Academy of Pathology Annual Meeting Abstracts, Cancel Patients subsequent LEEP reveals HSIL. Practical issues in the application of p16 immunohistochemistry in diagnostic pathology. PubMed Patients may be classified incorrectly and thus, may be treated in a manner that is not appropriate for their cancers biology, or may suffer from either progressive disease or treatment-related morbidity when these could have been avoided. Required fields are marked *. High prevalence of p16 staining in malignant tumors | PLOS ONE Is immunohistochemical evaluation of p16 in oropharyngeal cancer enough Correlation with high-risk HPV RNA in situ hybridization results showed significant false-negative rates (low negative predictive values or NPV) for both the JC8 (NPV=69%) and G175-405 (NPV=56%) clones at the 75% cutoff. It is believed that almost all squamous cell carcinomas of the cervix are associated with HR-HPV infection. In situ hybridization for high-risk HPV E6/E7 mRNA had been performed and interpreted as previously described16 by hand using the RNAscope HPV kit (Advanced Cell Diagnostics, Inc, Hayward, CA, USA) according to the manufacturers instructions. With the any staining cutoff, there was perfect agreement among all pathologists. To obtain HPV-16, a known oncogenic virus in other body sites, tends to be the most commonly identified HPV type, with other high-risk types (18, 31, 33 and rarely others) causative in only 510% of patients.1, 5 Tumors almost always originate from the base of tongue and palatine tonsils, most patients have nodal metastasis at presentation,1, 6, 7, 8 and most have a distinctive, non-keratinizing morphology. Hum Pathol. Role of p16 testing in cervical cancer screening among HIV-infected women. Before That is, p16 IHC . At this cutoff, there were 165 concordant (83%) and 34 discrepant (17%) cases. Progression of cervical low-grade squamous intraepithelial lesions: in search of prognostic biomarkers. Google Scholar. Gao G, Chernock RD, Gay HA et al, A novel RT-PCR method for quantification of human papillomavirus transcripts in archived tissues and its application in oropharyngeal cancer prognosis. Federal government websites often end in .gov or .mil. p16 (INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. PubMed Further, any small fraction of false-negative or -positive results is significant. p16 Immunohistochemistry As a Standalone Test for Risk - Springer Copyright 2017 Elsevier Inc. All rights reserved. Castle PE, Adcock R, Cuzick J, Wentzensen N, Torrez-Martinez NE, Torres SM, Stoler MH, Ronnett BM, Joste NE, Darragh TM, Gravitt PE, Schiffman M, Hunt WC, Kinney WK, Wheeler CM; New Mexico HPV Pap Registry Steering Committee; p16 IHC Study Panel. PubMed p16 immunohistochemistry can be used to detect human - PubMed Copyright 2013, All Rights Reserved. Results showed that the E6H4 clone provided the most consistent and intense staining with the lowest rates of partial staining and lowest nonspecific background reactivity (Figure 1). The findings indicate that p16 immunohistochemistry is a reliable surrogate marker of CDKN2A homozygous deletion in gliomas, with recommended p16 cutoff scores of 5% for confirming and > 20% for excluding biallelic CDKN2A loss. The hazard ratios for death and for death from disease varied little between the E6H4 and JC8 clones, but were slightly lower (better) for the E6H4 clone.
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