Objective:  To recognize specific clinicopathological characteristics of non‐smoking and non‐drinking (NSND) head and neck squamous cell carcinoma (HNSCC) patients. This can increase our knowledge regarding a potentially different carcinogenesis in these patients. Study design/methods:  Retrospective analysis of data for 195 NSND patients with HNSCC and comparison with data for patients with HNSCC obtained from the Netherlands Cancer Registry. Results:  Compared with all HNSCC patients in the Netherlands, our NSND patients with HNSCC were typically female (n = 142; 73%vs 26%), old at disease presentation (mean 73 years vs 64 years), and had tumors mainly of the oral cavity (n = 130; 66%vs 25%). Most tumors were stage I (n = 67; 34%) and stage IVA (n = 59; 30%). The incidence of second primary tumors (SPTs) was high (n = 32; 16%), mainly occurring in the oral cavity (n = 26; 13%). Discussion/conclusion:  Our study confirms that NSND HNSCC patients have different clinicopathological characteristics from those of the overall HNSCC population; however, the frequency of SPTs is as high in NSND patients as in patients who smoke and drink alcohol. More research, and particularly molecular data are needed to obtain a better understanding of head and neck cancer in NSND patients.

Although tobacco and alcohol use are the main risk factors for development of HNSCC, disease outcome was comparable in patients who did or did not use these substances. Tobacco and alcohol use affected overall survival, which emphasizes the importance of substance use cessation.

Differentially expressed genes in non-smoking and non-drinking patients possibly indicate the presence of a different cellular response to carcinogenic events in these patients. Further studies are warranted to validate this gene set and explore possible therapeutic implications to improve prognosis for these patients.

Non-smoking and non-drinking patients with squamous cell carcinoma have the same risk for developing multiple tumors as their smoking and drinking counterparts. As this occurs without an increased expression of p53 or Ki-67, the significance of these proteins as biomarkers indicating pre-malignant mucosal alterations is doubtful. Further research is needed to clarify this predisposition for developing multiple head and neck cancer.

ObjectiveDetermine the presence and prognostic value of human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCPyV), and cell cycle proteins in head and neck squamous cell carcinoma (HNSCC) of non-smokers and non-drinkers (NSND).MethodsClinical characteristics and tumors of 119 NSND with HNSCC were retrospectively collected and analyzed on tissue microarrays. RNAscope in situ hybridization (ISH) was used to screen for the presence of HPV and MCPyV mRNA. Immunohistochemistry was performed for expression of p16 as surrogate marker for HPV, Large T-antigen for MCPyV, and cell cycle proteins p53 and pRb. Positive virus results were confirmed with polymerase chain reaction. For EBV, EBV encoded RNA ISH was performed. Differences in 5-year survival between virus positive and negative tumors were determined by log rank analysis.ResultsAll oropharyngeal tumors (OPSCC) (n = 10) were HPV-positive, in addition to one oral (OSCC) and one nasopharyngeal tumor (NPSCC). The other three NPSCC were EBV-positive. MCPyV was not detected. Patients with HPV or EBV positive tumors did not have a significantly better 5-year disease free or overall survival. Over 70% of virus negative OSCC showed mutant-type p53 expression.ConclusionIn this cohort, all OPSCC and NPSCC showed HPV or EBV presence. Besides one OSCC, all other oral (n = 94), hypopharyngeal (n = 1), and laryngeal (n = 9) tumors were HPV, EBV, and MCPyV negative. This argues against a central role of these viruses in the ethiopathogenesis of tumors outside the oro- and nasopharynx in NSND. So, for the majority of NSND with virus negative OSCC, more research is needed to understand the carcinogenic mechanisms in order to consider targeted therapeutic options.