Head and neck squamous cell carcinoma

Abstract

Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.

Figure 1.. Anatomical sites of HNSCC development.

Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium of the oral cavity (lips, buccal mucosa, hard palate, anterior tongue, floor of mouth and retromolar trigone), nasopharynx, oropharynx (palantine tonsils, lingual tonsils, base of tongue, soft palate, uvula and posterior pharyngeal wall), hypopharynx (the bottom part of the throat, extending from the hyoid bone to the cricoid cartilage) and larynx. Human papilloma virus-associated HNSCCs arise primarily from the palantine and lingual tonsils of the oropharynx, whereas tobacco-associated HNSCCs arise primarily in the oral cavity, hypopharynx and larynx.

Figure 2.. Global incidence of head and neck squamous cell carcinoma.

The estimated age-standardized rate (ASR) of HNSCC incidence worldwide is shown for men and women combined^–. Data from GLOBOCAN, 2018 . Map was generated using the GLOBOCAN website mapping tool (https://gco.iarc.fr/today/online-analysis-map) by selecting the ‘hypopharynx’, ‘larynx’, ‘lip, oral cavity’, ‘nasopharynx’ and ‘oropharynx’ cancer sites.

Figure 3.. Progression of HNSCC and key genetic events.

The mucosal epithelium lining the oral cavity, pharynx, larynx and sinonasal tract is the site of origin for head and neck squamous cell carcinoma (HNSCC). In a model of ordered histological progression of HNSCC, mucosal epithelial cell hyperplasia is followed by dysplasia, and carcinoma in situ precedes the development of invasive carcinoma. Specific genetic events have been found to be enriched at each stage of progression and are indicated. Of note, unlike in most cancers in which oncogenic mutations typically drive tumorigenesis, HNSCC formation usually involves the inactivation of tumour suppressor genes, such as CDKN2A and TP53 (encoding p16INK4A and p53, respectively) in early stages and PTEN (encoding phosphatase and tensin homologue (PTEN)) at later stages. LOH, loss of heterozygosity. Histopathology images of hyperplasia, dysplasia, carcinoma in situ and invasive carcinoma are reprinted from ref. 250, Springer Nature Limited. Histopathology image of normal mucosa courtesy of R. Jordan, University of California, San Francisco.

Figure 4.. Development of carcinogen-associated, HPV-negative HNSCC.

Consumption of tobacco products or betel quid (the leaf of Piper betle) and areca nut (Areca catechu), exposure to environmental pollutants or excessive alcohol consumption are primary factors in the development of human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). Tobacco and tobacco smoke, in particular, are rich in polycyclic aromatic hydrocarbons and nitrosamines, which are known human carcinogens and are associated with a strongly increased risk of HNSCC. Metabolic activation of carcinogens results in the formation of reactive metabolites, which, if not detoxified and excreted, can damage DNA, typically by generating bulky DNA adducts. If the DNA damage is faithfully and accurately repaired, there may be no lasting consequences. However, if the damaged DNA is not promptly repaired, or is repaired errantly by lower fidelity repair mechanisms, then permanent damage in the form of mutations, deletions and amplifications can occur. The accumulation of alterations in key tumour suppressor genes (such as TP53 and CDKN2A, which encode p53 and p16^INK4A, respectively) or signalling pathways (such as PI3K–AKT–mTOR and RAS–MAPK pathway genes) is associated with the onset, progression and poor prognosis of HPV-negative HNSCC.

Figure 5.. HPV infection of the tonsil crypt and development of HPV-positive HNSCC.

a | Throughout the tonsil epithelium, proliferating basal epithelial cells constitute the cell layer adjacent to the basement membrane. Differentiation of basal epithelial cells leads to their detachment from the basement membrane and upward migration, with progressively increasing differentiation leading to the sloughing off of terminally differentiated, non-proliferating cells. The palatine and lingual tonsils are also characterized by numerous tissue invaginations, commonly termed crypts, which are particularly enriched in stem cells at their base. A unique, reticulated squamous epithelium lines the crypt structure and gaps or fissures in the basement membrane and basal layer also occur. The presence of these fissures allows lymphocytes to enter the crypts and directly interact with foreign, external antigens. b | During infection with human papilloma virus (HPV), the reticulated and disrupted nature of the crypt squamous epithelium allows viral access to stem cells, proliferating basal cells and the basement membrane. Infiltrating immune cells also make contact with the viral particles. In the case of a productive infection, distinct viral genes and proteins are induced and/or activated during the different stages of epithelial cell differentiation, culminating in the production and shedding of new viral particles. c | Stem cells or proliferating basal cells represent probable cells of origin for HPV-positive head and neck squamous cell carcinoma (HNSCC). Stable integration of the viral genome into the host genome, and the concerted action of HPV E6 and E7 proteins on cellular p53 and RB levels, respectively, acts to promote cellular transformation. The accumulation of additional genetic alterations is needed to induce full transformation, including the acquisition of invasive and metastatic phenotypes.

Figure 6.. Histopathology of HNSCC.

a | Well-differentiated squamous cell carcinoma of the oral tongue, demonstrating mature cells with semi-organized keratinization and featuring a ‘keratin pearl’ (10x). b | A poorly differentiated squamous cell carcinoma of the base of tongue (10x). Inset shows immature cells with nuclear polymorphism and atypical mitoses without apparent stratification or keratinization (40x). c | A p16^INK4A-positive oropharyngeal squamous cell carcinoma characterized by diffuse nuclear and cytoplasmic staining for the cell-cycle protein p16^INK4A by immunohistochemistry, indicative of HPV-positive disease (10x). d | A p16^INK4A-negative oropharyngeal squamous cell carcinoma demonstrates minimal staining by the same anti-p16^INK4A antibody, a staining intensity that is indicative of HPV-negative disease (40x). In parts a and b, staining is with haematoxylin and eosin. HNSCC, head and neck squamous cell carcinoma.

Figure 7.. Algorithm for treatment-decision making for recurrent and/or metastatic HNSCC.

After a diagnosis of recurrent disease or distant metastasis, patients with disease that is amenable to local therapy receive resection, radiation or limited volume irradiation and are then subject to observation. However, in patients who are not amenable to these therapies, systemic therapy is indicated. Pembrolizumab is chosen for those with expression of programmed cell death 1 ligand 1 (PDL1) expression (composite positive score (CPS)>1; CPS is: (the number of PDL1-staining tumor and immune cells/total number of viable tumour cells counted)X100), given alone for those with high expression and asymptomatic disease (CPS>20), or given with platinum-based chemotherapy for those with lower PDL1 expression (CPS 1–19) or higher symptom burden. If PDL1 expression is absent (CPS<1), platinum doublet chemotherapy with cetuximab is appropriate first-line therapy. Patients who relapse after platinum-based therapy are candidates for nivolumab or pembrolizumab.