Non-smoking and Non-drinking patients with Head and Neck Squamous Cell Carcinoma, A Distinct Population

Abstract

195 patients with head and neck squamous cell carcinoma (HNSCC) who had no history of smoking tobacco or drinking alcohol are described. The data is retrieved from the database at the University Medical Center Utrecht which contains information on patient characteristics, risk factors, and tumor classification, including data on development of recurrences, second primary tumors and follow up. During the period 1980-2003, 4404 patients with squamous cell carcinoma of the lip, oral cavity, oropharynx, hypopharynx and larynx were registered. The clinicopathological characteristics of 195 (4.4%) non-smoking and non-drinking patients were analyzed and compared with data for all Dutch patients with HNSCC obtained from the Netherlands Cancer Registry. Non-smoking and non-drinking patients with HNSCC had distinct characteristics. They were typically female, had advanced age at disease presentation and had tumors mainly of the oral cavity. The incidence of second primary tumors (SPTs) was high, mainly occurring in the oral cavity. The prognostic relevance of tobacco and alcohol for patients with HNSCC was addressed. To this end, univariate and multivariate survival analysis were performed for 2012 patients, including 183 non-smoking and non-drinking patients and 1829 patients who consumed both tobacco and alcohol. HNSCC-specific survival was not significantly different for patients who smoked and drank and those who did not. Overall survival was significantly affected by tobacco and alcohol. The expression of tumor suppressor gene p53 and proliferation marker Ki-67 in non-tumorous (tumor-adjacent) mucosal epithelial cells were analyzed to study whether biomarker expression is associated with a history of smoking and drinking and with single and multiple HNSCC. Non-smoking and non-drinking patients with multiple and single tumors, smoking and drinking patients with multiple and single tumors were selected. p53 expression was significantly higher in users of tobacco and alcohol than in non-users. Ki-67 expression was not affected by tobacco and alcohol use. Both Ki-67 and p53 were similarly expressed in the groups with single and multiple tumors and thus not significantly related to the number of tumors. Hence, the significance of these proteins as biomarkers indicating premalignant mucosal alterations in HNSCC was considered as doubtful. A case-case analysis was performed to compare presence of Human papilloma virus (HPV) in tumor cells of 16 non-smoking and non-drinking with 16 matched smoking and drinking patients with oropharyngeal localized tumors. Non-smoking and non-drinking patients had more HPV-positive tumors than smoking and drinking patients. Overall survival and disease-specific survival were better for HPV-positive compared to HPV-negative cases. DNA microarray detected 49 differentially expressed genes for non-smoking and non-drinking patients compared to smoking and drinking patients. Amongst others, 7 genes related to Interferon-γ (IFN-γ) were downregulated. These genes play an important role in controlling the immune response upon pathogenic challenge. Moreover, 2 genes linked to NFKB pathway, which is a key regulator in TRD/TRAIL-mediated apoptosis were upregulated. Our findings suggest that the non-smoking and non-drinking patients with HNSCC have a different immune response to their tumor when compared to their smoking and drinking counterparts which may reflect a different underlying carcinogenetic mechanism.