Andoniadou, C L

Robinson, M

Santambrogio, A

Sathasivam, H P

Thavaraj, S

English

King's Research Portal

                       King’s Research Portal  DOI:10.1093/annonc/mdy313Document VersionPeer reviewed versionLink to publication record in King's Research PortalCitation for published version (APA):Sathasivam, H. P., Santambrogio, A., Andoniadou, C. L., Robinson, M., & Thavaraj, S. (2018). Prognostic utilityof HPV specific testing in addition to p16 immunohistochemistry in oropharyngeal squamous cell carcinoma.Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 29(10), 2144-2145.https://doi.org/10.1093/annonc/mdy313Citing this paperPlease note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this maydiffer from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination,volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you areagain advised to check the publisher's website for any subsequent corrections.General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyrightowners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain•You may freely distribute the URL identifying the publication in the Research PortalTake down policyIf you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access tothe work immediately and investigate your claim.Download date: 06. Oct. 2023Prognostic utility of HPV specific testing in addition to p16 immunohistochemistry in oropharyngeal squamous cell carcinoma  H. P. Sathasivam1, A. Santambrogio2, C. L. Andoniadou2, M. Robinson1 and S. Thavaraj3*.  1 Centre for Oral Health Research, Newcastle University, Newcastle-upon-Tyne, UK 2 Centre for Craniofacial and Regenerative Biology, King’s College London, UK 3 Mucosal & Salivary Biology, King’s College London, UK.   *Corresponding author: Dr Selvam Thavaraj (Email: selvam.thavaraj@kcl.ac.uk)    Word count: 547 words (excluding title, figure legend and references) Conflict of interest: None Funding: None to declare  © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com  Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy313/5068067by King's College London useron 10 August 2018We read with interest the paper by Nauta et al [1] since it relates to our own experience. The authors described a sub-cohort of oropharyngeal squamous cell carcinomas (OpSCCs) that were p16 positive (+) but HPV DNA negative (-) demonstrating poorer overall survival (OS) compared to p16+/HPVDNA+ individuals. We too have identified p16+/HPVDNA- cases within a UK population, a country with a higher prevalence of p16+ OpSCC than the Netherlands.    In our study, 238 OpSCC specimens from a single centre were assessed using p16 immunohistochemistry (CINtec®, Ventana Medical Systems). 153 cases (64.3%) were p16+ and were subsequently tested for high-risk (HR) HPV DNA using in-situ hybridisation (ISH, Ventana Medical Systems). Of the p16+ cases, 127 (83.0%) were HRHPV DNAISH+ whilst 26 (17.0%) were HRHPV DNAISH-. The p16+/HPVDNA- rate in our cohort was higher than that reported by Nauta et al (17.0% vs 12.4%) which may be explained by differences in sensitivity and specificity between DNAISH and PCR [2].   Similar to Nauta et al, our p16+/HPVDNA- cases demonstrated improved OS compared to p16- individuals but showed poorer survival than p16+/HPVDNA+ patients (p<0.001; Figure 1A). Our p16+/HPVDNA- patients demonstrated better OS compared to the Dutch cohort and this too may be explained by the suboptimal sensitivity of DNAISH [2].  Since p16+/HPVDNAISH- cases could be due to either false positive p16 or false negative DNAISH, we used mRNAISH (RNAScope, ACDBio) as a third-tier test to resolve HPV status in p16+/HPVDNA- cases. This enabled us to further classify 15 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy313/5068067by King's College London useron 10 August 2018(57.7%) and 11 (42.3%) cases as positive and negative for HRHPV, respectively. Interestingly, the OS of p16+/HPVDNAISH-/HPVRNAISH+ was similar to that of p16+/HPVDNAISH+ (Figure 1B), likely reflecting the greater sensitivity of mRNAISH [3]. Conversely, there was no significant difference in OS between p16+/HPVDNAISH-/HPVRNAISH- and p16- OpSCCs (p=0.626, Figure 1C). Our data therefore support the findings of Nauta et al in demonstrating poorer survival outcomes of p16+/HPVDNA- compared to p16+/HPVDNA+ OpSCC. We agree that it is important ‘to perform additional HPV DNA testing for predicting prognosis and when considering treatment de-intensification’ [1].   Several authors have recently detailed the performance and utility of various laboratory HPV testing options in OpSCC [3, 4]. In this context it is important to note that inaccurate assessment of HPV status presents a hazard to patients enrolled in de-intensification trials by inappropriately assigning individuals to dose-reduction arms. In addition to exposing patients to sub-therapeutic regimes, the lack of specificity of p16 indicates that results of such de-intensification trials need to be interpreted with caution. To avoid such complications, we recommend a tiered algorithm utilising p16 immunohistochemistry, HR-HPV DNAISH and HR-HPV mRNAISH where the last provides an alternative to PCR in p16+/DNAISH- cases.   It may be tempting to recommend mRNAISH as a single assay for HPV classification in OpSCCs, but a tiered algorithm with two or more strata almost always demonstrates greater utility in avoiding inaccurate results. Furthermore, the cost implications and lack of widespread availability restricts the routine use of mRNAISH the as the second-tier test in p16+ OpSCCs [5]. We therefore suggest that Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy313/5068067by King's College London useron 10 August 2018mRNAISH be reserved as a third-tier test for OpSCCs that are p16+/DNAISH-. Patients with p16+ tumours that show negativity with both DNAISH and mRNAISH could represent a separate sub-group with a different prognosis altogether, and as such should be considered for exclusion from de-intensification trials.    References 1. Nauta IH, Rietbergen MM, van Bokhoven A et al. Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing. Ann Oncol 2018; 29: 1273-1279. 2. Schache AG, Liloglou T, Risk JM et al. Evaluation of human papilloma virus diagnostic testing in oropharyngeal squamous cell carcinoma: sensitivity, specificity, and prognostic discrimination. Clin Cancer Res 2011; 17: 6262-6271. 3. Schache AG, Liloglou T, Risk JM et al. Validation of a novel diagnostic standard in HPV-positive oropharyngeal squamous cell carcinoma. Br J Cancer 2013; 108: 1332-1339. 4. Mirghani H, Casiraghi O, Amen F et al. Diagnosis of HPV-driven head and neck cancer with a single test in routine clinical practice. Mod Pathol 2015; 28: 1518-1527. 5. Mirghani H, Amen F, Moreau F et al. Human papilloma virus testing in oropharyngeal squamous cell carcinoma: what the clinician should know. Oral Oncol 2014; 50: 1-9.   Figure legend  Figure 1. A. Kaplan-Meier curve for overall survival according to p16+/DNAISH+ (blue line), p16+/DNAISH- (green line), p16- (red line) status (Log rank test; χ2 = 48.83; df = 2; p < 0.001). Significant difference in five-year overall survival was seen Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy313/5068067by King's College London useron 10 August 2018between p16+/DNA ISH- (green line) and p16- (red line) cases (p = 0.023), as well as between p16+/DNA ISH- (green line) and p16+/DNA ISH+ (blue line) cases (p = 0.022).  B. Kaplan-Meier curve for overall survival according to p16+/DNAISH+ (blue line) and p16+/DNAISH-/RNAISH+ (magenta line) status. (Log rank test; χ2 = 0.12; df = 1; p = 0.727). C. Kaplan-Meier curve for overall survival according to p16+/DNAISH-/RNAISH- (grey line) and p16- (red line) status. (Log rank test; χ2 = 0.29; df = 1; p = 0.626).  Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy313/5068067by King's College London useron 10 August 2018    Figure 1. A. Kaplan-Meier curve for overall survival according to p16+/DNAISH+ (blue line), p16+/DNAISH- (green line), p16- (red line) status (Log rank test; Χ2 = 48.83; df = 2; p < 0.001). Significant difference in five-year overall survival was seen between p16+/DNA ISH- (green line) and p16- (red line) cases (p = 0.023), as well as between p16+/DNA ISH- (green line) and p16+/DNA ISH+ (blue line) cases (p = 0.022).  B. Kaplan-Meier curve for overall survival according to p16+/DNAISH+ (blue line) and p16+/DNAISH-/RNAISH+ (magenta line) status. (Log rank test; Χ2 = 0.12; df = 1; p = 0.727). C. Kaplan-Meier curve for overall survival according to p16+/DNAISH-/RNAISH- (grey line) and p16- (red line) status. (Log rank test; Χ2 = 0.29; df = 1; p = 0.626).   49x14mm (300 x 300 DPI)    Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy313/5068067by King's College London useron 10 August 2018

Prognostic utility of HPV specific testing in addition to p16 immunohistochemistry in oropharyngeal squamous cell carcinoma

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Prognostic utility of HPV specific testing in addition to p16 immunohistochemistry in oropharyngeal squamous cell carcinoma

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