Human Papillomavirus and Squamous Cell Carcinoma of Unknown Primary in the Head and Neck Region: A Comprehensive Review on Clinical Implications

Viruses. 2021 Jul 2;13(7):1297. doi: 10.3390/v13071297.


Squamous cell carcinoma of unknown primary (SCCUP) is a challenging diagnostic subgroup of oropharyngeal squamous cell carcinoma (OPSCC). The incidence of SCCUP is increasing in parallel with the well-documented increase in OPSCC and is likewise driven by the increase in human papillomavirus (HPV). The SCCUP patient often presents with a cystic lymph node metastasis and undergoes an aggressive diagnostic and treatment program. Detection of HPV in cytologic specimens indicates an oropharyngeal primary tumor origin and can guide the further diagnostic strategy. Advances in diagnostic modalities, e.g., transoral robotic surgery and transoral laser microsurgery, have increased the successful identification of the primary tumor site in HPV-induced SCCUP, and this harbors a potential for de-escalation treatment and increased survival. This review provides an overview of HPV-induced SCCUP, diagnostic modalities, and treatment options.

Keywords: cervical lymph node metastasis; head and neck cancer; human papillomavirus; unknown primary.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alphapapillomavirus / pathogenicity*
  • Carcinoma, Squamous Cell / virology*
  • Head and Neck Neoplasms / virology*
  • Humans
  • Lymph Nodes / virology
  • Lymphatic Metastasis
  • Oropharyngeal Neoplasms / pathology
  • Oropharyngeal Neoplasms / virology*
  • Papillomavirus Infections / complications*
  • Papillomavirus Infections / pathology*
  • Squamous Cell Carcinoma of Head and Neck / virology