Abstract
Human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCC) tend to have good outcomes, however a subset does not share this favourable prognosis. The aim of this paper is to investigate the utility of tumour cell anaplasia and multinucleation as prognostic markers in oropharyngeal squamous cell carcinoma. Retrospective review of 104 patients with OPSCC or squamous cell carcinoma of unknown primary site (SCCUP) who underwent primary resection and/or lymph node dissection. Slides of both primary and nodal metastatic disease were assessed for the presence of anaplasia and multinucleation. 53 patients were HPV-positive. Anaplasia was more frequent in males (p = 0.005), smokers (p = 0.003), and HPV-negative disease (p = 0.04). HPV status and > 10 pack-year smoking history were independent predictors of recurrence-free survival (RFS) and disease-specific survival (DSS). Neither anaplasia, nor multinucleation, at the primary site or in cervical metastases, had any significant impact on RFS or DSS. We did not find either anaplasia or multinucleation to have any significant prognostic impact in OPSCC. However, given the small number of adverse events in the HPV-positive cohort, we may have lacked sufficient power to detect significance in what was the subgroup of primary interest. Our study highlights the challenge of identifying markers of poor prognosis in HPV-positive OPSCC.
Similar content being viewed by others
References
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.
Dayyani F, Etzel CJ, Liu M, et al. Meta-analysis of the impact of human papillomavirus (HPV) on cancer risk and overall survival in head and neck squamous cell carcinomas (HNSCC). Head Neck Oncol. 2010;2:15.
Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261–9.
Fischer CA, Zlobec I, Green E, et al. Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality? Int J Cancer. 2010;126:1256–62.
Hoffman M, Gorogh T, Gottschlich S, et al. Human papillomavirus in head and neck cancer: 8 year-survival-analysis of 73 patients. Cancer Lett. 2005;218:199–206.
Hong AM, Dobbins TA, Lee CS, et al. Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy. Br J Cancer. 2010;103:1510–7.
Posner MR, Lorch JH, Goloubeva O, et al. Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Ann Oncol. 2011;22:1071–7.
Ragin CC, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer. 2007;121:1813–20.
Rich JT, Milov S, Lewis JS Jr, et al. Transoral laser microsurgery (TLM) +⁄- adjuvant therapy for advanced stage oropharyngeal cancer: outcomes and prognostic factors. Laryngoscope. 2009;119:1709–19.
Rischin D, Young RJ, Fisher R, et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 2010;28:4142–8.
O’Sullivan B, Huang SH, Siu LL, et al. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol. 2013;31:543–50.
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. Eur J Cancer. 2014;50:2636–48.
Hafkamp HC, Manni JJ, Haesevoets A, et al. Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas. Int J Cancer. 2008;122:2656–64.
Lindquist D, Romanitan M, Hammarstedt L, et al. Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7. Mol Oncol. 2007;1:350–5.
Iyer NG, Dogan S, Palmer F, et al. Detailed analysis of clinicopathologic factors demonstrate distinct difference in outcome and prognostic factors between surgically treated HPV-positive and negative oropharyngeal cancer. Ann Surg Oncol. 2015;22:4411–21.
Kharytaniuk N, Molony P, Boyle S, et al. Association of extracapsular spread with survival according to human papillomavirus status in oropharynx squamous cell carcinoma and carcinoma of unknown primary site. JAMA Otolaryngol Head Neck Surg. 2016;142:683–90.
Lewis JS Jr, Carpenter DH, Thorstad WL, et al. Extracapsular extension is a poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma. Mod Pathol. 2011;24:1413–20.
Maxwell JH, Ferris RL, Gooding W, et al. Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. Cancer. 2013;119:3302–8.
Chan JKC, Slootweg P. Introduction. In: El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ, editors. WHO Classification of Head and Neck Tumours. Geneva: WHO Press; 2017. p. 64–5.
Lewis JS Jr, Scantlebury JB, Luo J, et al. Tumour cell anaplasia and multinucleation are predictors of disease recurrence in oropharyngeal squamous cell carcinoma, including among just the human papillomavirus-related cancers. Am J Surg Pathol. 2012;36:1036–46.
El-Mofty SK, Lu DW. Prevalence of human papillomavirus type 16 DNA in squamous cell carcinoma of the palatine tonsil, and not the oral cavity, in young patients: a distinct clinicopathologic and molecular disease entity. Am J Surg Pathol. 2003;27:1463–70.
El-Mofty SK, Patil S. Human papillomavirus (HPV)-related oropharyngeal nonkeratinizing squamous cell carcinoma: characterization of a distinct phenotype. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101:339–45.
Carlson DL, Barnes L, Chan J, et al. Protocol for the examination of specimens from patients with carcinomas of the pharynx. http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/ 2012/Pharynx_12protocol.pdf.
Chen AM, Felix C, Wang PC, et al. Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study. Lancet Oncol. 2017;18:803–11.
Haughey BH, Sinha P. Prognostic factors and survival unique to surgically treated p16 + oropharyngeal cancer. Laryngoscope. 2012;122(Suppl 2):S13–33.
Kaczmar JM, Tan KS, Heitjan DF, et al. HPV-related oropharyngeal cancer: risk factors for treatment failure in patients managed with primary transoral robotic surgery. Head Neck. 2016;38:59–65.
Molony P, Kharytaniuk N, Boyle S, et al. Impact of positive margins on outcomes of oropharyngeal squamous cell carcinoma according to p16 status. Head Neck. 2017;39:1680–8.
O’Sullivan B, Lydiatt WM, Haughey BH, Brandwein-Gensler MS, Glastonbury CM, Shah JP. HPV mediated (p16 +) oropharyngeal cancer. In: Amin MB, editor. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.
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. Am J Surg Pathol. 2010;34:1088–96.
Nordfors C, Grun N, Tertipis N, et al. CD8 + and CD4 + tumour infiltrating lymphocytes in relation to human papillomavirus status and clinical outcome in tonsillar and base of tongue squamous cell carcinoma. Eur J Cancer. 2013;49:2522–30.
Ward MJ, Thirdborough SM, Mellows T, et al. Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br J Cancer. 2014;110:489–500.
Jing J, Varier I, Dong J, et al. Prognostic significance of histologic features in HPV-associated tonsillar squamous cell carcinoma. Mod Pathol. 2016;29(Suppl 2):323A–4A.
Thompson LD, Herrera H, Iganej S, et al. Histologically significant features in 390 oropharyngeal squamous cell carcinomas. Mod Pathol. 2018;31(Suppl 2):488A.
Lewis JS Jr, Beadle B, Bishop JA, et al. Human papillomavirus testing in head and neck carcinomas: guideline from the College of American Pathologists. Arch Pathol Lab Med. 2018;142:559–97.
Satgunaseelan L, Chia N, Suh H, et al. p16 expression in cutaneous squamous cell carcinoma of the head and neck is not associated with integration of high risk HPV DNA or prognosis. Pathology. 2017;49:494–8.
Smeets SJ, Hessselink AT, Speel EJ, et al. A novel algorithm for reliable detection of human papilloma virus in paraffin embedded head and neck cancer specimens. Int J Cancer. 2007;121:2465–72.
Funding
Funding for the p16 staining was provided by the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital. The funding source had no input into the study design, collection or analysis of data, interpretation, writing of the manuscript, or decision to submit the article for publication.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
No conflict of interest to disclose
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Molony, P., Werner, R., Martin, C. et al. Tumour Cell Anaplasia and Multinucleation as Prognosticators in Oropharyngeal Squamous Cell Carcinoma. Head and Neck Pathol 14, 606–615 (2020). https://doi.org/10.1007/s12105-019-01081-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12105-019-01081-7