It is well known that the discordance rate between tissue p16 expression and HPV infection by PCR could be up to 24-32% [42,44]. Some studies in cervical disease have evaluated the possible role of p16 in determining LSIL progression. The LAST consensus [3] reported that the expected positive rates to be 8090% in IN2 and approximately 99% in IN3 cases in lower anogenital tract squamous lesions. For those patients with 5075% nuclear and cytoplasmic staining, however, regardless of intensity or confluence, one should reflex to an HPV-specific test (ideally mRNA based, such as RNA in situ hybridization, or at least to DNA in situ hybridization or PCR, as the arbitrating result. Approximately 76% of women with negative HPV and diagnosis of HSIL (CIN2 and CIN3) on initial biopsy had confirmed HSIL (CIN2 and CIN3) in subsequent LEEP follow-up. Patients were treated without regard to their p16 status.17, Immunohistochemistry was performed for p16 on formalin-fixed, paraffin-embedded tissue sections. Different patterns of p16INK4a immunohistochemical expression and their biological implications in laryngeal squamous cell carcinoma. Lewis JS Jr., Thorstad WL, Chernock RD et al, p16 positive oropharyngeal squamous cell carcinoma:an entity with a favorable prognosis regardless of tumor HPV status. J Clin Oncol 2015;33:83645. However, we cannot answer medical or research questions or give advice. Knowledge of HPV status can influence pathologists' decision in rendering the diagnosis of cervical squamous intraepithelial lesions (SIL). However, condylomas in different anogenital sites, like the cervix vs. anus, have a different prevalence (rare in the cervix) and, the relative frequency of IN1 vs. condyloma in a given site can have a major impact on the p16 expression rate of low-grade lesions in that site. The importance of this biomarker is not only related to the grading of these lesions, but also for clinical decisions that rely on p16 results, as in the cases of IN2 lesions. Is immunohistochemical evaluation of p16 in oropharyngeal cancer enough The value of Ki67 for the diagnosis of LSIL and the problems of p16 in the diagnosis of HSIL. Acta Cytol. This is minimized by the restricted recommendation of using p16 in IN1 (biopsy specimens interpreted as IN1 that are at high risk for missed high-grade disease) [3]. A frequent type of cancer is squamous cell carcinoma caused by the HPV virus. In the meantime, to ensure continued support, we are displaying the site without styles The principle of this technique is to detect an antigen in the tissues or cells by use of antibodies. showed that 34% of AIN2 are p16 negative, while Maniar et al. There was a marked association between p16 immunohistochemistry status for all antibodies and survival regardless of the cutoff level. The numbers dropped substantially, from 1.0 to as low as 0.42, despite only few disagreements, because the results already are binary (only two class outcomes) and a large degree of agreement is already expected. 2014;134:171524. The .gov means its official. p16 immunohistochemistry has been recommended as a prognostic test in clinical practice. 2017;3:1117. 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. p16 immunostaining in histological grading of anal squamous intraepithelial lesions: a systematic review and meta-analysis. 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 JavaScript. Int J Gynecol Pathol. PubMed The results show that E6H4 provided equivalent or better performance than the other two antibodies, with equivalent or better hazard ratios for overall and disease-specific survival (Table 5 and Figures 2 and 3). A meta-analysis was performed using a random effects model. H-scores were calculated for the E6H4 clone only. p16ink4 and cytokeratin 7 immunostaining in predicting HSIL outcome for low-grade squamous intraepithelial lesions: a case series, literature review and commentary. With KaplanMeier survival plots at the 75% cutoff, the E6H4 clone showed the largest differential in disease specific and overall survival between p16-positive and -negative results. 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. Masterson L, Moualed D, Liu ZW et al, De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials. Some have suggested H-scores as better for interpreting p16 immunohistochemical results.10 We calculated these for the E6H4 clone and used the cutoff of 60 that Jordan et al10 proposed based on ROC curve analysis in their work. Heterogeneity between studies evaluating normal anal samples was I2=0% (95% CI: 013%), in AIN1/LSIL (excluding condyloma) I2=71% (95% CI: 3986%), in all LSIL (including condyloma) I2=59% (95% CI: 2378%), AIN2 I2=77% (95% CI: 5588%), AIN3 I2=15% (95% CI: 079%), HSIL in a two-tiered nomenclature I2=85% (95% CI: 7192%), and for all combined results from HSIL I2=84% (95% CI: 7690%) (Table2). If the JC8 and G175-405 antibodies are used, they appear to function best at a lower cutoff, such as 50% cutoff. 2016;51:6474. Am J Surg Pathol. and transmitted securely. HSIL can begin in the anal canal, vagina, vulva, or cervix. [26] study further demonstrated that the AIN2 p16-negative samples showed lower rates of progression in the follow-up with high-resolution anoscopy. Wu MZ, Wang S, Zheng M, Tian LX, Wu X, Guo KJ, Zhang YI, Wu GP. Yildiz IZ, Usubtn A, Firat P, Ayhan A, Kkali T. Pathol Res Pract. High grade squamous intraepithelial lesion or an HSIL is a precancerous disease. In the disease-specific survival analyses, patients who died without disease were censored at their time of death. 2013;23:16639. Most NB69 cells were negative for p16, . These were categorized as negative, block-positive, and ambiguous patterns. This actually is a low threshold for p16 positivity and is not agreed upon, used, or recommended by most pathologists and organizations for testing. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Immunohistochemical expression of p16 and Ki-67 correlates with degree of anal intraepithelial neoplasia. In human papillomavirus (HPV)-related tumors, E7 oncoprotein functionally inactivates retinoblastoma protein [1, 2]. All show diffuse nuclear and cytoplasmic staining, but the intensity of staining is best with the E6H4 clone. 25 The results seemed to be due to the high sensitivity of JC8 immunohistochemistry on individual cells beyond the limit of detection by molecular techniques. In low-grade anal lesions, false positives are uncommon in most of the studies, so this may not be the same case for prognostic value in ASIL. 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%). So why did we find that an any staining cutoff was equivalent to, or better than, 75%? The studies also needed to have a clear description of the number of cases per histological grade, the number of p16 positive/negative per grade, and a report of anal samples separately (when other anogenital lesions were also present). p16 positivity in ASIL appears to be lower for anal low-grade lesions compared with that commonly described in cervical low-grade lesions. p16 overexpression is strictly defined as continuous, strong, cytoplasmic and nuclear staining in the abnormal cells, which results in a "block" pattern of positivity. Kreuter A, Siorokos C, Oellig F, et al. Appl Immunohistochem Mol Morphol. There is a marked heterogeneity for what is considered a positive result, especially in older cervical studies, thus affecting the accuracy of the expression rates. Although a 7075% cutoff has been widely utilized for p16 immunohistochemistry in the studies defining it as a prognostic marker,1 our results in a high HPV incidence US patient population suggest that results with the E6H4 antibody may be even better with either a 50% or even an any staining cutoff. 2016 Sep;55:51-6. doi: 10.1016/j.humpath.2016.04.010. Given the clinical significance of HPV in oral squamous carcinoma, p16 IHC should be performed in all cases 8600 Rockville Pike p16. 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. We would like to thank Donna M Posey for her wonderful assistance with clerical support for the various aspects of this study. 2016;175:73543. It was worst for the 75% cutoff, but still was what could be considered good (or at least modest) agreement, and was still best for the E6H4 antibody. Nasman A, Attner P, Hammarstedt L et al, Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Our outcome was the proportion of p16 positivity according to the histological grade of ASIL/AIN. Bhatia A, Burtness B . You are using a browser version with limited support for CSS. Yang EJ, Quick MC, Hanamornroongruang S, et al. 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. 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. The proportion of p16 expression increased with the severity of histological grade. . Article Data on p16 immunostaining in lower anogenital tract squamous lesions are mostly based on cervical studies and are largely generalized to other anogenital sites, like the anus. BMC Womens Health. This analysis was exclusively on cervical samples [4] and was conducted before the publication of the LAST classification [3]. Positive staining was identified as brown, punctate dots present in the nucleus and/or cytoplasm. . This disease is caused; by human papillomavirus that makes p16. To assess whether p16 immunostaining is useful in diagnosing HSIL in women with negative HPV testing, we studied the utility of p16 immunohistochemistry in 46 women of HSIL and HPV-negative status. 2006;30:795801. Similarly do Carmo Alves Martins et al. Ma C, Pai RK. 2022 Apr 27;22(1):138. doi: 10.1186/s12905-022-01714-0. 2017 Oct 12;12(10):e0185597. Huang EC, Tomic MM, Hanamornroongruang S, Meserve EE, Herfs M, Crum CP. Semin Diagn Pathol. Maniar KP, Nayar R. HPV-related squamous neoplasia of the lower anogenital tract: an update and review of recent guidelines. Br J Cancer. Unauthorized use of these marks is strictly prohibited. p16 3+ staining correlates with HPV PCR positivity. These findings are not surprising given the higher rates of partial and low intensity staining that were observed with these antibodies. Hum Pathol. 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. p16 immunohistochemistry was also subsequently reviewed by two additional pathologists (NC and BP) in order to assess interobserver variability (Table 6). Different patterns of p16 immunoreactivity in cervical biopsies: correlation to lesion grade and HPV detection, with a review of the literature. p16 protein, . 2014;21:34158. Correlation of p16 immunohistochemistry with clinical and epidemiological features in oropharyngeal squamous-cell carcinoma Chrystiano de C. Ferreira , Rozany Dufloth , Ana C. de Carvalho , Rui M. Reis , Iara Santana , Raiany S. Carvalho , Ricardo R. Gama 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). Quint KD, de Koning MN, Quint WG, et al. Patil DT, Yang B. Although, the inclusion of condylomas has an impact on the positivity in anal low-grade lesions, this does not seem to explain the difference in the rates between low-grade lesions of the anus and the cervix. Medicine (Baltimore). Google Scholar. P16 or INK4A immunostain is a strong indicator. p16 results were classified as block positive (n=40, 18%), negative (n=130, 59%), or ambiguous (n=50, 23%), a category we further grouped into 3 patterns: strong/basal (n=18), strong/focal (n=15), and weak/diffuse (n=17). where a strong correlation was found between p16 negative tumors and homozygous loss of CDKN2A ; as well as in . 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. PubMed 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. Accessibility There are sometimes pre-cancerous diseases that prepare an extra p16 as well. P16 immunostaining can be both positive and negative. The main differences resulted from three cases with negative tissue IHC p16 expression but positive HPV genotypingthey were all in the p16-positive CTC group. ISSN 0893-3952 (print), p16 immunohistochemistry in oropharyngeal squamous cell carcinoma: a comparison of antibody clones using patient outcomes and high-risk human papillomavirus RNA status, https://doi.org/10.1038/modpathol.2017.31, Evaluation of p16INK4a expression as a single marker to select patients with HPV-driven oropharyngeal cancers for treatment de-escalation, Recommendations for determining HPV status in patients with oropharyngeal cancers under TNM8 guidelines: a two-tier approach, HPV RNA CISH score identifies two prognostic groups in a p16 positive oropharyngeal squamous cell carcinoma population, Integrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance, Intratumor heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma, Oncogenic driver mutations predict outcome in a cohort of head and neck squamous cell carcinoma (HNSCC) patients within a clinical trial, Comparison of three PD-L1 immunohistochemical assays in head and neck squamous cell carcinoma (HNSCC), Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma, High Expression of EpCAM and Sox2 is a Positive Prognosticator of Clinical Outcome for Head and Neck Carcinoma, Computer-assisted tumor grading, validation of PD-L1 scoring, and quantification of CD8-positive immune cell density in urothelial carcinoma, a visual guide for pathologists using QuPath, Human Papillomavirus DNA Detection by Droplet Digital PCR in Formalin-Fixed Paraffin-Embedded Tumor Tissue from Oropharyngeal Squamous Cell Carcinoma Patients, Human papillomavirus as a driver of head and neck cancers. Schlecht NF, Brandwein-Gensler M, Nuovo GJ et al, A comparison of clinically utilized human papillomavirus detection methods in head and neck cancer. K07 CA180782/CA/NCI NIH HHS/United States, International Agency for Research on Cancer - Screening Group. Cotter MB, Kelly ME, OConnell PR, et al. Efficiency of immunohistochemical p16 expression and HPV typing in cervical squamous intraepithelial lesion grading and review of the p16 literature. The E6H4 clone provided the cleanest and most intense staining, had equivalent or best correlation with high-risk HPV mRNA status and patient outcomes, and highest interobserver agreement. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. It binds to cyclin-dependent kinases 4 and 6 and maintains the retinoblastoma gene product in its hypophosphorylated state [1], which in turn binds to E2F transcription factor and prevents cell cycle progression. doi: 10.1097/MD.0000000000032273. Concerning publication bias, funnel plots were derived (supplemental digital content Supplementary Figures1A-1G). Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Mod Pathol. 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. Am J Surg Pathol. Mod Pathol 31, 10261035 (2018). and transmitted securely. contracts here. 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). Overdiagnosis of HSIL on cervical biopsy: errors in p16 immunohistochemistry implementation. p16 immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Loss of p16 expression is a sensitive marker of - Springer Three studies [6, 18, 21] in this meta-analysis performed p16 immunostaining in anal squamous cell carcinoma, with a combined total of 28 samples. Discrepancy of p16 immunohistochemical expression and HPV RNA in penile In: Amin MB, Edge S, Greene F et al, (eds). 2009;13:14553. Nonspecific staining, defined as cases with any type of cytoplasmic only or nuclear only staining (in the absence of cells with nuclear and cytoplasmic staining), was present in 12% of all cases evaluated with the G175-405 clone and only 1% of all cases evaluated with both the E6H4 and JC8 clones. 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. All retrospective or prospective studies that evaluated p16 immunostaining in anal and/or perianal squamous intraepithelial lesions/anal intraepithelial neoplasia (AIN) histological samples and clearly described a positive result when there was a diffuse block staining with nuclear or nuclear plus cytoplasmic staining were included. 2011;42:100712. Hissong E, Cimic A, Leeman A, et al. Six did not describe the population from which ASIL samples were obtained [7, 16,17,18,19, 22]. Supplementary Information accompanies the paper on Modern Pathology website, Shelton, J., Purgina, B., Cipriani, N. et al. p16 immunohistochemistry in oropharyngeal squamous cell carcinoma: a The lack of improvement of results using the H-score is also not surprising as it is functionally like a low percentage cutoff. 2022 Apr 27;6(2):92-99. doi: 10.23922/jarc.2021-077. Squamous intraepithelial lesions of the anal squamocolumnar junction: histopathological classification and HPV genotyping. This expression is still lower than what is generally described in the cervix and, in the previous cervical meta-analysis (38%). p16 immunohistochemistry results were correlated with patient survival for all three clones at the various cutoffs. Ideally the staining should be in the basal cell layer with extension upward involving at least one-third of the epithelial thickness, but this is not a strict criterion for a positive result. McGrath CJ, Garcia R, Trinh TT, Richardson BA, John-Stewart GC, Nyongesa-Malava E, Mugo NR, Glynn EH, Sakr SR, De Vuyst H, Chung MH. c Meta-analysis of the LSIL samples (AIN1/LSIL/condyloma) stained positive for p16. This has previously been at least partially evaluated. Nonspecific staining was a significant issue for the G175-405 clone only. 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 . Please always ask your doctor for personalized diagnosis, evaluation, assessment, treatment and care management plan. 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%. Mahajan A. 2016;115:114755. HPV Genotyping by Molecular Mapping of Tissue Samples in Vaginal Squamous Intraepithelial Neoplasia (VaIN) and Vaginal Squamous Cell Carcinoma (VaSCC). Provided by the Springer Nature SharedIt content-sharing initiative, Surgical and Experimental Pathology (2022), Indian Journal of Surgical Oncology (2020), Modern Pathology (Mod Pathol) Studies published only in an abstract form, case reports, evaluation of p16 expression only in anal squamous cell carcinoma (without an evaluation in ASIL) were also not included in this analysis. Relationships of p16 Immunohistochemistry and Other Biomarkers With Currently, there are no studies assessing p16 as a prognostic marker in anal LSIL. Further, a College of American Pathologists evidence-based guidelines committee on this subject now recommends p16 IHC in all patients with newly diagnosed oropharyngeal squamous cell carcinoma in routine clinical practice.
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