M OLECULAR INSIGHTS INFLUENCING THE MANAGEMENT OF HEAD AND NECK CANCERS

Head and neck cancers represent a clinically diverse group of tumours with distinctive molecular features. Understanding the importance of characteristic molecular changes has permitted the definition of a new clinicopathological entity the Human Papillomavirus (HPV) related subset of oropharyngeal squamous cell carcinomas that are generally associated with a good prognosis. We briefly discuss the key clinical and pathological differences between HPV-related and HPV-unrelated oropharyngeal disease and the underlying molecular differences, and we also consider how these features can inform clinical management. For rarer head and neck tumours or those that lack effective systemic treatment options, such as salivary gland tumours, sinonasal carcinomas and NUT midline tumours, we discuss how an understanding of underlying molecular features can facilitate the exploration of novel treatment options. Thus we demonstrate in this brief review, that despite the rarity of most head and neck cancers, evolving insights into the key molecular drivers are impacting on clinical practice. Though commonly grouped together on the basis of anatomical proximity, the generic terminology of ‘head and neck cancer’ (HNC) refers to a miscellany of clinically and molecularly diverse tumours that arise from more than 15 anatomical subsites and comprise several different histotypes. From a clinical perspective the term HNC is often used to refer to mucosal squamous cell carcinomas, but evidence of differences in patient outcomes according to anatomical subsite and aetiology, have highlighted the need for research in more uniform cohorts. Despite the rarity, HNCs are generally successfully managed with combinations of surgery, radiotherapy and chemotherapy delivered by a multidisciplinary team. The complexities of the sensitive anatomical location, the toxicity of treatment, and the functional consequences of both the tumour and treatment mandates management of these tumours by an expert team, and there is evidence of better outcomes in larger more experienced centres.1 The identification of the molecular changes that characterise subsets in HNC has been useful to improve disease stratification and has impacted upon patient management.2-8 We will highlight selected key molecular insights in HNC. Head and neck squamous cell carcinomas and the role of the Human Papillomavirus The discovery of the causal role of the Human Papillomavirus (HPV) in the majority of oropharyngeal squamous cell carcinomas (OPSCCs) in many countries, including Australia, exemplifies how translational research has improved the clinical management of HNC. The role of HPV has been clearly defined only in the oropharyngeal subsite, where overexpression of p16 is an established robust surrogate marker of the HPVinduced subset of OPSCC.3,9 Importantly, HPV-related OPSCC represents a distinct clinicopathological and molecular entity associated with a favourable prognosis regardless of treatment modality.3,10-14 A summary of clinicopathological differences between HPV-related and HPV-unrelated disease is provided in table 1. From an epigenetic level to protein level, the clinical variances between HPV-related and HPV-unrelated disease are also reflected from a molecular perspective.15-21 Characteristic molecular differences include the lack of association with TP53 mutations or major chromosomal abnormalities in HPV-related disease,17,18,22 while the majority of non-HPV related head and neck squamous cell carcinomas (HNSCC) harbour TP53 mutations,19,20,23 and are known to demonstrate field cancerisation effect.19-21,23 A recent publication using the data from the Cancer Genome Atlas HNSCC Working Group identified the poor prognostic effect of 3p deletions in both HPVrelated and HPV-unrelated disease.22 However, for HPVunrelated disease with simultaneous TP53 mutation and 3p deletion, the additional presence of mir-548k miRNA and MUC5B gene mutations identified further subgroups with even worse survival.