Original Article

Virchows Archiv

, Volume 461, Issue 3, pp 283-290

First online:

Cancer of unknown primary originating from oropharyngeal carcinomas are strongly correlated to HPV positivity

  • Pamela ZengelAffiliated withDepartment of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig Maximilian University Email author 
  • , Gerald AssmannAffiliated withInstitute of Pathology, Ludwig Maximilian University
  • , Martin MollenhauerAffiliated withInstitute of Pathology, Ludwig Maximilian UniversityInstitute of Pathology, Technical University of Munich
  • , Andreas JungAffiliated withInstitute of Pathology, Ludwig Maximilian University
  • , Karl SotlarAffiliated withInstitute of Pathology, Ludwig Maximilian University
  • , Thomas KirchnerAffiliated withInstitute of Pathology, Ludwig Maximilian University
  • , Stephan IhrlerAffiliated withInstitute of Pathology, Ludwig Maximilian UniversityLaboratory for Dermatohistology and Oral pathology

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Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OSCC) has been identified as a distinct entity within squamous cell carcinoma of the head and neck. It is associated with special characteristics and is preponderantly restricted to palatial tonsils and base of tongue. These primary locations have for long been associated with the clinical situation of cancer of unknown primary (CUP). In order to investigate the putative relationship between CUP and HPV, we investigated 26 patients who initially presented as CUP and were finally diagnosed with carcinomas of these two locations. Twenty-one cases proved to be positive for high-risk HPV. Primary carcinomas were small and frequently presented in a submucosal location. HPV-positive carcinomas, presented more often in women, showed atypical basaloid differentiation and correlated to cystic lymph node metastases. This study demonstrates an over-representation of HPV-associated OSCC in patients who were initially diagnosed with CUP. This finding indicates a strong relationship between HPV-association and CUP in OSCC. The frequent manifestation as CUP is presumably caused by the unusual predisposition for small size and submucosal location combined with early lymphatic metastization. In order not to miss clinically occult carcinomas, consequent interdisciplinary cooperation in combination with meticulous histological workup is mandatory.


HPV CUP Oropharyngeal carcinoma Lymphoepithelial carcinoma p16