Abstract
Simple SummaryHead and neck cancer belongs to the six most common cancers worldwide, with the majority of cases being associated with chronic alcohol and/or tobacco consumption. Over the past years, a rising proportion of those cancer cases are rather caused by a mucosal infection with high-risk human papillomavirus (HPV). In general, those patients are younger and respond better to different treatment options, which results in an overall better prognosis. Despite this high importance of HPV status in head and neck cancer, there is no established standard biomarker for the detection of HPV-related tumor biology. In our study, we tested six different detection methods that are currently used and compared their diagnostic and prognostic validity in a collective of 153 head and neck cancer patients. Thereby, immunohistochemical staining of p16—a protein biomarker that is overexpressed in HPV-related cancers—showed the best performance as prognostic biomarker and should be combined with a direct detection of HPV-DNA in case of therapeutic consequences. The incidence of human papillomavirus (HPV)-related head and neck cancer (HNSCC) is rising globally, presenting challenges for optimized clinical management. To date, it remains unclear which biomarker best reflects HPV-driven carcinogenesis, a process that is associated with better therapeutic response and outcome compared to tobacco/alcohol-induced cancers. Six potential HPV surrogate biomarkers were analyzed using FFPE tissue samples from 153 HNSCC patients (n = 78 oropharyngeal cancer (OPSCC), n = 35 laryngeal cancer, n = 23 hypopharyngeal cancer, n = 17 oral cavity cancer): p16, CyclinD1, pRb, dual immunohistochemical staining of p16 and Ki67, HPV-DNA-PCR, and HPV-DNA-in situ hybridization (ISH). Biomarkers were analyzed for correlation with one another, tumor subsite, and patient survival. P16-IHC alone showed the best performance for discriminating between good (high expression) vs poor outcome (low expression; p = 0.0030) in OPSCC patients. Additionally, HPV-DNA-ISH (p = 0.0039), HPV-DNA-PCR (p = 0.0113), and p16-Ki67 dual stain (p = 0.0047) were significantly associated with prognosis in uni- and multivariable analysis for oropharyngeal cancer. In the non-OPSCC group, however, none of the aforementioned surrogate markers was prognostic. Taken together, P16-IHC as a single biomarker displays the best diagnostic accuracy for prognosis stratification in OPSCC patients with a direct detection of HPV-DNA by PCR or ISH as well as p16-Ki67 dual stain as potential alternatives.
Highlights
Head and neck squamous cell carcinomas (HNSCCs) belong to the six most common cancers worldwide and account for approximately 890,000 new cases and 450,000 deaths each year [1,2]
The human papillomavirus (HPV) DNA in situ hybridization is superior, since the DNA is detected directly in the tumor cells. The disadvantage of this method is its low sensitivity [21]. These literature data are in line with our results: We found a markedly higher percentage of HPV-DNA-PCR+ compared to HPV-DNA-ISH+ HNSCC cases, with most ISH+ cases being PCR+, which indicates a favorable sensitivity for the PCR method and a favorable specificity for the ISH method
Taken together, our study showed that p16-IHC as a single biomarker displays the best diagnostic accuracy for prognosis stratification in oropharyngeal cancer patients, with high expression levels indicating a survival benefit
Summary
Head and neck squamous cell carcinomas (HNSCCs) belong to the six most common cancers worldwide and account for approximately 890,000 new cases and 450,000 deaths each year [1,2]. Patients with HPV-related disease are younger, often not alcohol and tobacco consumers, frequently have clinically evident lymph node metastases at presentation, and respond better to radiotherapy and chemoradiation Together, these factors have resulted in significantly improved overall survival among patients with HPV-associated oropharyngeal HNSCC, compared to HPV-negative tumors [8,9,10]. HPVstatus–especially in OPSCC patients–is an important prognostic and predictive biomarker, potentially enabling better prognostication and choice of therapeutic options This clinically important differentiation between HPV-associated and HPV-independent OPSCC is mirrored in the 8th edition of UICC/AJCC staging system for head and neck cancers, which includes p16 immunostaining as a surrogate for HPV status in oropharyngeal cancer cases [12]. The Saarland Medical Association ethics review committee approved the scientific use of the patients’ tissue and clinical data
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