HPV-positive squamous cell carcinoma of the larynx, oral cavity, and hypopharynx: Clinicopathologic characterization with recognition of a novel warty variant

Lisa M. Rooper, Melina J. Windon, Tahyna Hernandez, Brett Miles, Patrick K. Ha, William R. Ryan, Annemieke Van Zante, David W. Eisele, Gypsyamber D'Souza, Carole Fakhry, William H. Westra

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Human papillomavirus (HPV) is a principal driver for most oropharyngeal squamous cell carcinomas (OPSCCs), where it is strongly associated with improved survival. HPV is much less frequently detected in squamous cell carcinomas arising in nonoropharyngeal sites (non-OPSCCs), and its pathogenic role and prognostic value in these tumors is unclear. We evaluated the clinicopathologic features of 52 non-OPSCCs considered HPV-positive based upon p16 immunohistochemistry and direct HPV detection using RNA in situ hybridization (ISH), DNA ISH, or real-time DNA polymerase chain reaction. The HPV-positive non-OPSCCs were from the larynx (n=27), oral cavity (n=21), and hypopharynx (n=4). While most cases (n=34, 65%) showed classic histologic features of HPV-positive OPSCC, including endophytic growth, minimal keratinization, and hyperchromatic nuclei without koilocytic changes, a subset (n=13, 25%) were characterized by exophytic growth, exuberant surface hyperkeratosis and parakeratosis, marked nuclear pleomorphism, and prominent koilocytic atypia. These antithetical features were highly reminiscent of the warty variant of HPV-positive squamous cell carcinoma described in anogenital sites. Compared with tumors without warty features, the warty tumors presented at lower stage and were not associated with lymph node metastasis, local recurrence, or distant spread (4 y disease-free survival of 100% vs. 66%, P=0.069). The presence of transcriptionally active HPV as detected by RNA ISH suggests a pathogenic role for HPV in these nonoropharyngeal sites. While most HPV-positive non-OPSCCs are morphologically similar to their tonsillar counterparts, this study highlights a previously unrecognized warty variant that may be associated with a highly favorable clinical outcome.

Original languageEnglish
Pages (from-to)691-702
Number of pages12
JournalAmerican Journal of Surgical Pathology
Issue number5
StatePublished - May 1 2020

Bibliographical note

Funding Information:
Conflicts of Interest and Source of Funding: Funding was provided by the National Institute of Dental and Craniofacial Research (grant P50 DE019032). W.R.R. is on the scientific advisory boards of Olympus and reports consulting fees from Ziteo and Medtronic outside the submitted work. P.K.H. reports consultant fees from Bristol-Myers Squibb Loxo Oncology, Stryker, and Ethicon outside the submitted work. W.H.W. reports consultation fees from Merck and from Cancer Panels outside the submitted work. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.


  • head and neck squamous cell carcinoma
  • human papillomavirus
  • laryngeal squamous cell carcinoma
  • oral cavity squamous cell carcinoma
  • oropharyngeal squamous cell carcinoma
  • p16

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine


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