Head and neck squamous cell carcinoma

Head and neck squamous cell carcinomas (HNSCCs) develop from the mucosal epithelium in the oral cavity, pharynx and larynx and are the most common malignancies that arise in the head and neck ( Fig. 1 ). The burden of HNSCC varies across countries/regions and has generally been correlated with exposure to tobacco-derived carcinogens, excessive alcohol consumption, or both. Increasingly, tumours that arise in the oropharynx are linked to prior infection with oncogenic strains of human papillomavirus (HPV), primarily HPV-16, and, to a lesser extent, HPV-18 and other strains 1 – 3 . As the most common oncogenic HPVs, HPV-16 and HPV-18, are covered by FDA-approved HPV vaccines, it is feasible that HPV-positive HNSCC could be prevented by successful vaccination campaigns worldwide. HNSCCs of the oral cavity and larynx are still primarily associated with smoking and are now collectively referred to as HPV-negative HNSCC. No screening strategy has proved to be effective, and careful physical examination remains the primary approach for early detection. Although a proportion of oral premalignant lesions, which present as leukoplakia (white patches) or erythroplakia (red patches), progress to invasive cancer, the majority of patients present with advanced-stage HNSCC without a clinical history of a premalignancy. HNSCC of the oral cavity is generally treated with surgical resection, followed by adjuvant radiation or chemotherapy plus radiation (known as chemoradiation or CRT) depending on the disease stage. CRT has been the primary approach to treat cancers that arise in the pharynx or larynx. HPV-positive HNSCC generally has a more favourable prognosis than HPV-negative HNSCC, and ongoing studies are testing the efficacy of therapeutic dose reduction (of both radiation and chemotherapy) in HPV-positive disease treatment. With the exception of early-stage oral cavity cancers (which are treated with surgery alone) or larynx cancers (which are amenable to surgery or radiation alone), treatment of the majority of HNSCC cases requires multimodality approaches and thus multidisciplinary care. The epidermal growth factor receptor (EGFR; also known as HER1) monoclonal antibody cetuximab is approved by the FDA as a radiation sensitizer, alone or in combination with chemotherapy, for recurrent or metastatic disease 4 . Although inferior to cisplatin as a radiosensitizer in HPV-associated disease, 5 , 6 cetuximab is often used in cisplatin-ineligible patients. The immune checkpoint inhibitors pembrolizumab and nivolumab are approved by the FDA for treatment of cisplatin-refractory recurrent or metastatic HNSCC and pembrolizumab is approved as first-line therapy for patients who present with unresectable or metastatic disease 7 – 9 . Detailed molecular characterization as well as immune profiling of HNSCC suggests that incorporation of prognostic and predictive biomarkers into clinical management may overcome obstacles to targeted therapies and enable prolonged survival. In this Primer, we provide an overview of the types of HNSCC and their epidemiology, as well as the pathogenesis of each type and how this influences the management approach.

Epidemiological studies have revealed a diverse range of risk factors for HNSCC, as classified by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) 21 . These risk factors include tobacco consumption, alcohol consumption, exposure to environmental pollutants and infection with viral agents, namely, HPV and EBV. Interestingly, several risk factors display geographical or cultural and/or habitual prevalence. Tobacco and alcohol consumption are the high-risk factors that occur most widely geographically. Of note, heavy users of both substances have >35-fold higher risk of developing HNSCC 22 . Among some Asia-Pacific populations, oral cavity cancer is associated with chewing of areca nut products including ‘betel quid’, a term that applies to a variety of customized mixtures comprising areca nut ( Areca catechu ; the carcinogen source), betel leaf (the leaf of Piper betle ), slaked lime and/or tobacco, as well as spices per local custom (IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Betel-quid and Areca-nut Chewing and Some Areca-nut-derived Nitrosamines. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 85. Lyon (FR): International Agency for Research on Cancer. https://publications.iarc.fr/103 (2004)) 21 . The use of areca nut or betel quid products is linked to particularly high rates of oral cavity cancer in India (first and fourth most common cancer in Indian men and women, respectively), Taiwan and some provinces in mainland China 23 . In general, the high male:female ratios for HPV-negative HNSCC incidence reflect the sex-specific patterns of modifiable risk behaviours, including the use of the aforementioned tobacco, smokeless tobacco, areca nut, betel quid and alcohol 21 , 24 . The effect of electronic cigarettes on HNSCC risk remains unknown and will only be evident in the coming decades. Exposure to carcinogenic air pollutants, including organic and inorganic chemicals, as well as particulate matter, is a risk factor for HNSCC, especially in developing countries/regions with worsening air pollution, such as India and China 25 , 26 . Other risk factors include ageing, poor oral hygiene and diets lacking in vegetables 27 , 28 . In terms of infectious agents, persistent infection with HPV and EBV are known aetiological risk factors for HNSCC arising from the oropharynx and nasopharynx, respectively 29 , 30 . The male:female ratio for HPV-positive HNSCC incidence ranges from 3 to 6 (ref. 31 ), which is explained by higher rates of persistent oropharyngeal HPV infection among males despite similar prevalence of anogenital HPV infection 32 – 34 . HPV infection that leads to HNSCC is mainly transmitted by oral sex, and the incidence of HPV-positive HNSCC continues to rise, especially in populations that are not vaccinated against HPV prior to HPV exposure 35 , 36 . In addition, genetic factors also contribute to HNSCC risk. Individuals with Fanconi anaemia (FA), a rare, inherited genetic disease characterized by impaired DNA repair (owing to mutations in any of the 22 FANC genes), have a 500–700-fold increased risk of developing HNSCC, primarily cancers of the oral cavity 37 . Although the mechanisms responsible for the unique proclivity of patients with FA to develop HNSCC remain unknown, alterations in FA pathway genes likely have a role. Meta-analyses showed that polymorphisms in genes involved in carcinogen metabolism and in immunity are associated with increased risk, including polymorphisms in cytotoxic T lymphocyte antigen 4 ( CTLA4 ; rs231775 and rs4553808), IL10 (1082A > G), cytochrome P450 1A1 ( CYP1A1 ; Ile462Val and glutathione S-transferase μ1 ( GSTM1 ; null polymorphism) 38 – 41 . Thus, a reduced ability to metabolize carcinogens and weakened immunity may contribute to HNSCC. Decreased use of tobacco products, improved oral health and widespread HPV vaccination should help reduce the global incidence of HNSCC 42 .

HPV-negative HNSCC. Tobacco consumption is the primary risk factor for development of HPV-negative HNSCC. Tobacco consists of over 5,000 different chemicals, of which dozens have been shown to have carcinogenic activity. The chemicals thought to be most responsible for the cancer-causing effects of tobacco are polycyclic aromatic hydrocarbons (PAHs), including benzo(a)pyrene, and nitrosamines, including 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN) 53 , 54 . In smokeless tobacco, nitrosamines are the dominant carcinogen, whereas the carcinogens in areca nut and betel quid are poorly defined 55 . Tobacco-derived carcinogens, including PAHs and nitrosamines, undergo metabolic activation, with detoxication enzymes and pathways promoting excretion ( Fig. 4 ). However, many of the reactive metabolites of these carcinogens can also form covalent DNA adducts, which, if not properly repaired, lead to mutations and other genetic abnormalities. The propensity for tobacco carcinogens to promote genetic changes and neoplastic transformation likely depends on the balance between metabolic activation versus detoxification and DNA repair ( Fig. 4 ). The use of tobacco products is also associated with inflammation in the exposed tissues. Coincident with inflammation is the local production of cytokines, chemokines and growth factors that can have an important role in promoting proliferation, angiogenesis and, ultimately, carcinogenesis. Excessive alcohol consumption is another key risk factor for HPV-negative HNSCC and is known to synergize with tobacco use to promote carcinogenesis 56 . Alcohol might serve as a solvent for carcinogens, enhancing the exposure of epithelial cells to these substances 57 . In addition, alcohol is metabolized to acetaldehyde, which is known to form DNA adducts 58 .

There is a tremendous need to identify molecular biomarkers that can be used to predict progression of premalignant HNSCC lesions, prognosticate survival, reveal new targets for intervention and predict response to therapeutic agents. The search for biomarkers has focused on defining the molecular abnormalities that characterize HNSCC. In this section, we highlight findings regarding genetic and epigenetic alterations, as well as dysregulation of cellular signalling pathways, which occur during HNSCC development. HNSCC is characterized by genetic instability, with frequent loss or gain of chromosomal regions 59 . The availability of a model of ordered histological progression of HNSCC has enabled assignment of some chromosomal abnormalities to specific stages of progression 57 , 68 ( Fig. 3 ). Loss of 9p21 occurs during progression of normal head and neck epithelial mucosa to hyperplasia. The 9p21 region includes the tumour suppressor genes (TSGs) CDKN2A (encoding the CDK4 and CDK6 inhibitor p16 INK4A ) and ARF (encoding p14, a stabilizer of p53). Progression from hyperplasia to dysplasia is marked by loss of 3p21 and 17p13, the site of TP53 . The transition from dysplasia to carcinoma in situ involves loss of 11q13, 13q21 and 14q32, whereas loss of 6p, 8, 4q27, and 10q23 is observed in the progression to invasive carcinoma. Collectively, these studies of chromosomal abnormalities reveal that multiple genetic alterations may be required for full transformation to invasive HNSCC 68 . Furthermore, whether progression of HNSCC is strictly dependent on the temporal sequence of these alterations or, instead, on their collective accumulation, remains unresolved. The Cancer Genome Atlas (TCGA) contains a wealth of data on copy number alterations (CNAs), mutational profiles, mRNA expression and microRNA (miRNA) expression from over 520 human HNSCC tumours 59 . A detailed analysis of 279 of these tumours, consisting of 243 HPV-negative and 36 HPV-positive tumours, revealed a high degree of genomic instability; tumours had an average of 141 CNAs and 62 chromosomal structural abnormalities (for example, fusions) 59 . HNSCC tumours exhibited frequent mutation of CDKN2A (22% of tumours) and TP53 (72% of tumours). Coupled with the aforementioned highly frequent chromosomal loss of CDKN2A and TP53 in HNSCC tumours, these TSGs are regarded as the most frequently altered genes in HNSCC. However, these alterations are largely restricted to HPV-negative tumours, owing to the action of HPV E6 and E7 proteins in eliminating p53 and RB1 (p16 INK4A inhibits phosphorylation of RB1). Mutational profiling revealed that HNSCC-associated mutations are statistically enriched in 11 genes 59 . Interestingly, this list of frequently mutated genes is dominated by known and potential tumour suppressors, including TP53 , CDKN2A , FAT1 , NOTCH1 , KMT2D , NSD1 and TGFBR2 . PIK3CA , encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), is the only oncogene that is found to be frequently mutated (~14%) in HNSCC 59 , 69 – 72 . Mutations in RAS genes are infrequent, with HRAS mutations being the most common (~4% of tumours). Thus, in contrast to many other solid tumour malignancies that are frequently driven by mutations in RAS or other oncogenes, HNSCC might be more frequently driven by loss of tumour suppressors. Comparison of HPV-positive and HPV-negative tumours failed to detect previously reported differences in overall mutation rates 71 . However, HPV-positive tumours are uniquely enriched for frequent loss of TRAF3 and amplification of E2F1 , whereas HPV-negative tumours are enriched for CDKN2A and TP53 alterations, frequent focal deletions in other TSGs (such as NSD1 , FAT1 , NOTCH1 and SMAD4 ) and frequent focal amplification of the genes encoding the receptor tyrosine kinases EGFR, HER2 (also known as ERBB2) and FGFR1 59 . Mutations in the genes encoding NRF2 ( NFE2L2 ) and KEAP1 ( KEAP1 ), key regulators of oxidative stress, are also common and occur exclusively in HPV-negative HNSCC 59 . Two additional members of the TP53 gene family, TP63 and TP73 , are frequently altered in HNSCC. TP63 encodes two major isoforms, ΔNp63 and TAp63 (containing a truncated or complete transactivation (TA) domain, respectively), and is overexpressed in a majority of HNSCC tumours 73 . ΔNp63 promotes HNSCC tumour growth by multiple mechanisms, including suppression of apoptosis and p16 INK4A expression and induction of mitogenic signalling 73 – 76 . By contrast, TAp73, a major isoform encoded by TP73 , exhibits tumour suppressor activity and the function of TAp73 is commonly abrogated in HNSCC. For example, stimulation of HNSCC cells with TNF results in the induction of c-REL oncoprotein that binds to ΔNp63, displacing TAp73 from ΔNp63–TAp73 complexes and inactivating TAp73 77 , 78 . Phosphorylation of Tap73 by casein kinase 2 or Polo-like kinase 2 also leads to TAp73 inactivation and results in induction of NANOG, SOX2 and OCT4, promoting th

HNSCC tumours are also characterized by hypoxia, with roughly similar levels of hypoxia in HPV-positive and HPV-negative tumours of the same stage 119 . High levels of hypoxia in tumours portend poor prognosis and resistance to radiation therapy 120 – 124 . Hypoxia induces the expression of HIF1α, a subunit of the transcription factor HIF1, which drives expression of a range of genes encoding proteins that promote angiogenesis (VEGF) and degradation of ECM (MMPs). HIF1 also upregulates tumour cell expression of glucose transporters (for example, GLUT1) and enzymes that contribute to metabolic reprogramming of the tumour from oxidative phosphorylation to glycolysis (known as the Warburg effect) 73 . In tumour-infiltrating immune cells, hypoxia and HIF1 induce expression of pro-inflammatory and immune-modulatory cytokines and chemokines (such as IL-1β and TNF) 73 .

Multiple pathways and processes contribute to the invasion and metastasis of HNSCC tumour cells. MMPs produced by both tumour and stromal cells in the TME have an integral role in degrading and remodelling the ECM, thereby promoting tumour cell invasion. High levels of MMP2, MMP9 and MMP13 in HNSCC tumours are associated with invasion, metastasis and poor prognosis 128 – 130 . Interestingly, the HNSCC CSC marker CD44 serves as a cell surface receptor that binds to and promotes the activity of MMP9 44 , 131 . CD44 and MMP9 co-localize to the invasive front of HNSCC tumours and their expression levels correlate with metastasis 132 . The epithelial–mesenchymal transition (EMT; the conversion of tumour cells from an epithelial to a mesenchymal phenotype) has a key role in HNSCC metastasis. Cells that undergo EMT exhibit downregulation of E-cadherin, upregulation of vimentin, reduction of cell adhesion and enhanced migration and invasiveness. EMT-associated changes in E-cadherin and vimentin levels are associated with increased metastasis of HNSCC tumours 100 , 133 . The transcription factors TWIST, SNAIL and SLUG mediate downregulation of E-cadherin during EMT, with co-expression of TWIST, SNAIL and HIF1α correlating with high rates of HNSCC metastasis 134 , 135 . Hypoxic conditions in the TME can drive EMT in tumour cells, as HIF1α induces the expression of vimentin, TWIST and SNAIL 100 ; this mechanism may explain the association of elevated levels of hypoxia with HNSCC metastasis 120 , 121 , 134 . The process of EMT is also closely linked with the acquisition of stem cell properties, including expression of HNSCC CSC markers 135 . Tumour cell expression of CD44, CD133 or ALDH1 is closely associated with metastasis in HNSCC 45 . Similarly, OCT3, OCT4 and NANOG promote invasiveness of HNSCC cells and may serve as a predictor of metastasis 45 . Of note, EMT is not a fixed and irreversible process 136 but instead can be context-dependent, occurring in distinct cellular populations at particular sites within the tumour 136 , 137 . Reversal of EMT may be necessary for the establishment of macrometastatic tumour sites, underscoring the plasticity of the process 136 . Furthermore, tumour cells may exhibit only partial EMT (p-EMT), a partial acquisition of EMT markers or properties. Single-cell transcriptomic analyses of primary and metastatic HNSCC tumours revealed that cells with p-EMT are localized to the leading edge of tumours and that p-EMT can serve as an independent predictor of metastasis, tumour grade and detrimental pathologic features 137 . The capacity of HNSCC tumour cells to metastasize also requires an ability to detach from the basement membrane and associated ECM components. Typically, when normal epithelial cells detach they lose access to key survival factors and undergo a form of programmed cell death termed anoikis 138 . Metastasis is dependent on suppression of, or acquired resistance to, anoikis. Growth factors and cytokines in the TME, particularly IL-6, EGF and HGF, activate tumour cell signalling pathways, including the RAS–MAPK, PI3K–AKT–mTOR and STAT3 pathways, which suppresse anoikis 100 , 139 , 140 . Of note, anoikis-suppressive factors in the TME are derived from CAFs, endothelial cells, infiltrating immune cells and the tumour cells themselves 100 , underscoring the complex cross-talk between cell types that contributes to metastasis in HNSCC.

Primary tumours of the oropharynx, including the base of the tongue, the palatine tonsils, the soft palate and the hypopharynx, typically become symptomatic at a later stage, owing to their hidden anatomical location. When present, symptoms such as dysphagia (difficulty eating), odynophagia (pain when swallowing) or otalgia (ear pain) often herald a more advanced tumour. A personal history of combustible tobacco and alcohol use should raise the index of suspicion when such non-specific pharyngeal symptoms are present.

Patients with HPV-related cancers of the oropharynx most commonly present with a new, painless level II (lymph nodes at the upper jugular level) neck mass and an asymptomatic primary tumour. Because the risk factors for HPV-negative HNSCC are often absent, keen awareness of the 21 st century epidemic of HPV-related HNSCC in North America and Western Europe is crucial for appropriate suspicion and early diagnosis. The dominant risk factors for HPV-related HNSCC include male sex and lifetime number of sexual partners 34 . However, the average latency period of 10–30 years from initial oral infection to ultimate diagnosis of p16 INK4A -positive oropharyngeal cancer means that risk factors might be remote 143 . Thus, in all adults, a new neck mass is considered malignant until demonstrated otherwise. In a systematic review of minimally invasive transoral surgery to diagnostically assess an occult primary HNSCC tumour presenting as a cervical neck mass, the majority of tumours were p16 INK4A -positive 144 . Diagnostic transoral robotic surgery, including palatine and lingual tonsillectomies, identified ~70% of primary HNSCC tumours, which were most commonly localized in the base of tongue 145 .

Histopathology. The diagnosis of HNSCC must be established by biopsy of the primary tumour and/or neck mass 147 . The biopsy method depends upon the location of the lesion. Primary tumours are typically approached with cup forceps, incisional biopsy or excisional biopsy, whereas the suspicious cervical neck mass should undergo fine needle aspiration (FNA). Excisional biopsy of a neck mass is not recommended unless the FNA biopsy sample has been persistently non-diagnostic, a primary site has not been identified on cross-sectional imaging or panendoscopy and/or lymphoma is suspected due to concurrent non-cervical lymphadenopathy. As HNSCC is derived from the stratified epithelium of the upper aerodigestive mucosa, the histopathological spectrum is characterized by the extent of cellular atypia and squamous differentiation ( Fig. 6 ). A well-differentiated tumour closely resembles the stratified epithelium, with mature-appearing cells organizing into layers with irregular keratinization, most classically manifesting as a ‘keratin pearl’ ( Fig. 6a ). A poorly differentiated tumour is characterized by immature cells with nuclear pleomorphism and atypical mitoses, with minimal to no organized stratification or keratinization ( Fig. 6b ). Of note, the observed extent of squamous differentiation is closely associated with aetiology: HPV-negative HNSCCs are more often moderately or well differentiated, with preservation of stratification and keratinization, whereas HPV-positive HNSCCs are poorly differentiated or even display basaloid morphology on histopathological analysis 57 . The diagnosis of HNSCC can usually be made on the basis of routine histopathology with haemotoxylin and eosin staining. However, in the case of poorly differentiated or basaloid tumours, immunohistochemistry may be necessary to confirm an epithelial origin. HNSCC tumours routinely stain with pancytokeratin antibodies and markers of squamous differentiation, including antibodies against cytokeratin 5, cytokeratin 6 and p63 (ref. 148 ). HPV testing is mandatory for all oropharyngeal or unknown primary tumours, as it is a major determinant of modern staging and prognosis. Multiple techniques are available for determination of HPV status, including detection of E6 and E7 mRNA (by reverse transcription PCR), HPV DNA (by PCR or in situ hybridization) or the cell cycle protein p16 INK4A (by immunohistochemistry) 143 . Consensus recommendations from the College of American Pathologists include testing all newly diagnosed oropharyngeal cancers for HPV by immunohistochemistry for p16 INK4A , with a diagnostic threshold of diffuse nuclear and cytoplasmic staining in >70% of tumour cells 149 ( Fig. 6c , d ). Of note, the level of p16 INK4A is not a direct measurement of HPV infection; p16 INK4A is upregulated on the degradation of RB, and as such, is a functional surrogate for levels of the oncoprotein E7.

‘Primary prevention’ involves interventions to reduce the incidence of disease in the first place, by decreasing exposures, altering modifiable behaviours or increasing resistance in healthy people who are at risk. When considered as a target for primary prevention, most cases of HNSCC would indeed be preventable with successful global elimination of tobacco use and implementation of HPV vaccination. Tobacco and areca nut use. Worldwide, the majority of HNSCC cases are caused by individual use of tobacco, a known carcinogen. Tobacco use, whether smokeless (chew, snuff) or combustible (cigarettes, cigars or pipes), and chewing of areca nut products including betel quid, are modifiable risk factors. Evidence-based interventions for tobacco cessation at the individual level include programmes of behavioural and psychological support that identify tobacco users, provide personalized advice to quit, assess readiness to quit, provide assistance with a quit attempt and arrange follow up. Quit attempts are more likely to be successful with the use of at least one of seven US FDA-approved first-line pharmacotherapies, including 5 methods of nicotine replacement therapy (NRT; the nicotine patch, gum, lozenge, nasal spray or oral inhaler) and 2 non-nicotine oral medications, bupropion and varenicline 160 . Evidence-based interventions at the national policy level have been ranked according to cost-effectiveness by the WHO, which classifies the following four strategies as ‘best buys’: increased excise taxes on tobacco products; large graphic warnings on cigarette packages; comprehensive bans on tobacco advertising; and enforcement of a national, comprehensive, ban on smoking in public spaces 161 . Unlike tobacco use, for which the WHO has published evidence-based policies for cessation, no global policy exists for the control of areca nut or betel quid use 162 . As with tobacco, the areca nut is addictive, although the biological basis for addiction is less well understood. Research into both the mechanisms and social determinants of dependence is required in order to advance prevention and cessation programmes.

Secondary prevention refers to the early detection of latent, asymptomatic disease and subsequent interventions to halt disease progression to a harmful state. In cancer, secondary prevention typically involves screening, such as mammography to find and treat early stage breast cancers or Papanicolaou smears to identify and ablate precancerous HPV lesions of the cervix. Although recognized oral premalignant lesions (OPLs), including leukoplakia, erythroplakia and dysplastic leukoplakia, are associated with increased risk for HPV-negative HNSCC, most OPLs themselves do not transform into invasive cancer 168 , 169 . Rather, HPV-negative HNSCC arises from the grossly normal upper aerodigestive mucosa subject to ‘epithelial field cancerization’, where chronic exposure to carcinogens has resulted in molecular changes preconditioning towards malignant progression 50 . As such, patients with a first HPV-negative HNSCC are at high risk for a SPT of the upper aerodigestive tract, including in the head and neck, oesophagus or lung 159 . Due to the alarming rate of SPT formation, HNSCC has been a fertile field for the evaluation and eventual failure of multiple chemoprevention agents. For example, in the 1980s, high-dose isotretinoin, a synthetic vitamin A analogue, was found to reverse OPLs and prevent formation of SPTs in two landmark randomized trials; however, ultimately high-dose isotretinoin was too toxic for chronic daily use and has been abandoned 170 , 171 . More recently, the EPOC trial investigated erlotinib, a small-molecule inhibitor of EGFR, in patients with OPLs who had loss of heterozygosity (LOH) at 9p and 3p. Although erlotinib was found to be ineffective, LOH was prospectively confirmed as a molecular biomarker of oral cancer risk 172 . An effective and tolerable chemoprevention agent against HPV-negative HNSCC remains an elusive but noble ambition. Modern trials of chemoprevention of tobacco-related cancers now focus on the cytoprotective, anti-inflammatory or immunomodulatory potential of repurposed pharmaceutical and nutraceutical compounds that are known to be well-tolerated during prolonged exposure. Ongoing secondary prevention trials include the evaluation of aspirin and other non-steroidal anti-inflammatory drugs to reduce cyclooxygenase 2 (COX2) signalling 173 ; the study of metformin, an anti-hyperglycaemic biguanide that might block mTOR signalling in transforming epithelial cells 174 ; and trials of ‘green chemoprevention’ agents derived from cruciferous vegetables rich in isothiocyanates, which are thought to induce carcinogen detoxication and, possibly, innate immunity 175 , 176 .

The treatment approach to every individual patient is guided by anatomical subsite, stage, disease characteristics, functional considerations and patient wishes. Although natural history is different for HPV-related than for tobacco-related HNSCC, and intensive therapy is more difficult for elderly patients, these considerations do not lead to absolute differences in how patients should be managed. Surgery, radiation and chemotherapy The principal modalities of curative therapy for locally or locoregionally confined HNSCC are resection, radiation and systemic therapy. Treatment planning should aim for the most highly curative approach, while optimizing preservation of function. For patients with a small primary cancer with no clinical nodal involvement, or involvement of only a single node, cure rates of over 80% can be achieved with single modality intervention (resection or radiation) 177 . Surgery is commonly elected for oral cavity cancers, whereas radiation might be more commonly employed for pharyngeal and laryngeal cancers. For laryngeal cancers, a moderately hypo-fractionated radiation schedule results in better locoregional control and survival than standard radiation therapy 178 , 179 . Advances in minimally invasive resection, including transoral robotic or laser resection and larynx-preserving partial laryngectomy, as well as improved reconstructive techniques, have extended the indications for primary surgical management in the hands of high-volume head and neck surgical oncologists 180 , 181 . Occult metastases in the draining cervical lymph nodes might be present even with small, invasive primary tumours, and use of elective neck dissection improves survival 182 . In the event of treatment failure after single modality radiation or surgery, salvage with the alternate modality offers a high chance of cure 181 , 183 . For tumours with more advanced tumour or nodal stage, post-operative radiation or chemoradiation, guided by pathological risk factors, reduces the risk of recurrence and improves survival 184 , 185 . Pathological features indicative of increased risk of occurrence include extra-nodal extension, close or involved surgical margins, or perineural invasion; when these are present, administration of high-dose cisplatin chemotherapy concurrent with radiation further improves disease-free survival and impacts survival in the highest risk groups 184 , 185 . The use of tri-modality therapy (that is, the addition of CRT following surgery) is known to increase the late toxicities of radiation, including chronic dysphagia and aspiration, and might increase the risk of non-cancer mortality in survivors 186 . For this reason, it is considered important to accurately predict the extent of disease, including the presence of extra-nodal extension, prior to initiation of definitive therapy, to avoid the need to add CRT after what was initially projected to be single modality surgical therapy, as currently happens in 65% of node-positive HPV-associated oropharyneal cancer that are managed primarily with resection 187 . Deep-learning neural networks, other radiomics approaches and functional imaging with PET offer promise in improving pre-operative diagnostic accuracy 188 , 189 . Furthermore, there is a >50% likelihood of distant metastases in patients with HPV-positive oropharyngeal cancer and >5 nodes involved — such patients are also poor candidates for initial surgical management, given the potential positive impact of chemotherapy on micro-metastases 177 . Definitive treatment with CRT is recommended as non-surgical treatment for patients with advanced T stage (≥T3), more than one involved node, a single bulky node and for function preservation. The standard chemotherapy regimen is single agent cisplatin given at 100 mg/m 2 every 3 weeks 190 , with a 3-year survival of 37% in a predominantly HPV-negative population; however, in patients who are poor candidates for high-dose cisplatin owing to pre-existing hearing loss or renal injury, weekly administration of 40–mg/m 2 cisplatin might lead to a comparable outcome 191 . Although patients with T4 laryngeal cancer have previously been excluded from trials of larynx-preservation strategies because of the concern that even complete response would not lead to restoration of larynx function 183 , in patients who respond to a single cycle of induction chemotherapy and retain good laryngeal function, larynx preservation may be considered 192 . The EGFR-directed antibody cetuximab is also an effective radiation sensitizer 4 ; however, survival is reduced when cetuximab is substituted for cisplatin in HPV-positive oropharyngeal cancer 5 , 6 . EBV-related nasopharyngeal cancer is treatment-responsive but associated with increased risk of distant metastases. Additional chemotherapy exposure after the completion of CRT, or as induction therapy, leads to an ~6% improvement in survival and should be considered the standard of care for locally advanced dis

Patient health and supportive care Given the complex nature of everyday functions within the head and neck area, the inherent consequences of HNSCC and its treatment and the increasing choices of treatments have a large effect on the health-related QOL (HRQOL) of patients with HNSCC. The wide array and combinations of treatments all have their specific sequelae, including physical, emotional, functional, social, and occupational dysfunction, as well as a profound effect on the families of patients with HNSCC 214 . Furthermore, HRQOL is significantly associated with survival 215 , 216 . For example, a clinically meaningful association exists between HRQOL scores measured at diagnosis and overall survival of patients after treatment (HR = 0.90, CI 0.86–0.94, p <0.001) 217 . Depending on the primary tumour site, patients with HNSCC might be confronted with specific symptoms, such as oral dysfunction and swallowing and speech problems, during treatment, which often improve 6 months after treatment 218 . However, long-term reduction in QOL in HNSCC survivors (at 10-year follow up) is common 219 . On average, overall HRQOL deteriorated by 11% when compared with pre-treatment, and by 15% when compared with years 1 and 2 post-treatment 219 . To provide individualized (supportive) care, monitoring HRQOL in a structured manner in clinical research and practice is important. HRQOL is typically assessed using patient-reported outcome measures (PROMs) 220 . Widely used PROMs among patients with HNSCC include the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ-C30 and QLQ-HN35 or QLQ-HN43) 221 and the Functional Assessment of Cancer Therapy - Head & Neck Cancer (FACT-H&N) 222 .

An integrated approach to survivorship care in HNSCC survivors, including (early) rehabilitation, psychosocial care, lifestyle interventions and self-management, will likely be implemented in the next 5–10 years 229 . In addition, peer support can be important to address the general and specific survivorship needs of individual patients 230 . Substantial efforts are being made to improve HRQOL for patients with HNSCC by developing e-health applications, including self-monitoring of HRQOL and self-help interventions 231 . These innovations carry the promise of sustainably improving supportive care and empowerment of HNSCC survivors 232 . Measurement precision of HRQOL by PROMs can benefit from other data sources as biomarkers and from objective measures (collected using, for example, wearable devices, such as a smart watch, that record and analyse physical activity) 233 . Furthermore, emerging data-driven analytics can be used to study and improve forecasts of HRQOL 233 . One of the current major challenges is to make collected HRQOL data universally available to patients and clinicians in a meaningful way that will facilitate the design of treatment regimens and post-therapy decisions and indicate appropriate supportive care for the individual patient.

Substantial progress has been made over the past decade in the molecular characterization of both HPV-positive and HPV-negative HNSCC, culminating in The Cancer Genome Atlas (TCGA) 59 , 71 , 72 . These collective efforts have confirmed the preponderance of TP53 mutations, identified previously unknown NOTCH1 mutations and provided a platform to test precision medicine approaches in HNSCC. Success stories include the recognition that HRAS mutations may serve as predictive biomarkers for treatment with farnesyl transferase inhibitors, such as tipifarnib 239 , and evidence that oncogenic PIK3CA mutations are common and could be used to identify patients with HNSCC who are most likely to benefit from PI3K pathway inhibitors 69 , 240 . Although some centres are routinely evaluating the mutational profile of HNSCC tumours, the tumours in the majority of patients with HNSCC remain uncharacterized, even when these patients present with recurrent or metastatic disease. Furthermore, the role of tumour mutational burden as a predictive biomarker for immunotherapy remains incompletely understood and efforts are underway to establish guidelines that are designed to harmonize tumour mutation burden evaluation and reporting 241 . Prospective, targeted sequencing, supported by efforts such as the American Association for Cancer Research Project Genie, aim to provide a publicly accessible international cancer registry of real-world data assembled through data sharing 242 . Importantly, single-cell transcriptomic analysis represents a powerful new tool for defining diverse intratumoral expression programmes and differences among tumours from different patients, as has been demonstrated in HNSCC 137 , 243 . In addition, increased use of relevant preclinical models, including patient-derived xenografts 244 , 245 and organoids 246 , should facilitate the translation of laboratory discoveries to patients with HNSCC.