Human Papillomavirus-Associated Oral Cavity Squamous Cell Carcinoma: An Entity with Distinct Morphologic and Clinical Features

James S. Lewis, Molly H. Smith, Xiaowei Wang, Fangjia Tong, Mitra Mehrad, Krystle A. Lang-Kuhs

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Background: HPV-associated oral cavity squamous cell carcinoma (SCC) is not well-characterized in the literature, and also has a clinical significance that is poorly understood. Methods: We gathered a cohort of oral cavity (OC) SCC with nonkeratinizing morphology, either in the invasive or in situ carcinoma (or both), tested for p16 by immunohistochemistry and high risk HPV E6/E7 mRNA by RTPCR (reference standard for transcriptionally-active high risk HPV) and gathered detailed morphologic and clinicopathologic data. Results: Thirteen patients from two institutions were proven to be HPV-associated by combined p16 and high risk HPV mRNA positivity. All 13 patients (100%) were males, all were heavy smokers (average 57 pack/year), and most were active drinkers (9/11 or 81.8%). All 13 (100%) involved the tongue and/or floor of mouth. All had nonkeratinizing features, but maturing squamous differentiation varied widely (0–90%; mean 37.3%). Nonkeratinizing areas had high N:C ratios and larger nests, frequently with pushing borders, and minimal (or no) stromal desmoplasia. The carcinoma in situ, when present, was Bowenoid/nonkeratinizing with cells with high N:C ratios, full thickness loss of maturation, and abundant apoptosis and mitosis. HPV was type 16 in 11 patients (84.6%) and type 33 in two (15.4%). Nine patients had treatment data available. These underwent primary surgical resection with tumors ranging from 1.6 to 5.2 cm. Most had bone invasion (6/9–66.7% were T4a tumors), and most (6/9–66.7%) had extensive SCC in situ with all 6 of these patients having final margins positive for in situ carcinoma. Conclusions: HPV-associated OCSCC is an uncommon entity that shows certain distinct clinical and pathologic features. Recognition of these features may help pathologic diagnosis and could potentially help guide clinical management.

Original languageEnglish
Pages (from-to)1073-1081
Number of pages9
JournalHead and Neck Pathology
Issue number4
StatePublished - Dec 2022

Bibliographical note

Funding Information:
Research was performed using discretionary funds from the Department of Pathology, Microbiology, and Immunology. The work also utilized the Translational Pathology Shared Resource (TPSR) at Vanderbilt University Medical Center which is supported by NCI/NIH Cancer Center Support Grant 5P30 CA68485-19 and the Shared Instrumentation Grant S10 OD023475. This work was supported by funds from the NIH Grant R01DE026471 (Wang). This work was also supported by the National Cancer Institute (NCI) K07CA218247 (PI: Krystle Kuhs); Vanderbilt Clinical Oncology Research Career Development Program (K12 CA090625); and the Vanderbilt Institute for Clinical and Translational Research (UL1 TR000445 from NCATS/NIH). This work was supported by funds from the NIH Grant U24 DK059637-16.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.


  • Carcinoma in situ
  • Human papillomavirus
  • Morphology
  • Nonkeratinizing
  • Oral cavity
  • Squamous cell carcinoma
  • mRNA
  • p16 immunohistochemistry

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Otorhinolaryngology
  • Oncology


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