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Head and Neck Squamous Cell Carcinomas (HNSCCs) are malignant epithelial tumors arising from the mucosal linings of the upper aerodigestive tract, including the oral cavity, oropharynx, hypopharynx, and larynx. They account for over 90% of all head and neck malignancies.

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https://www.youtube.com/watch?v=rKUOUkjD-FQ

Etiopathogenesis

Major risk factors:

Risk Factor Mechanism
Tobacco use Direct mucosal carcinogen exposure; synergistic with alcohol
Alcohol consumption Mucosal damage and solvent effect for carcinogens
HPV (Human Papillomavirus) Strongly associated with oropharyngeal SCC (especially HPV-16)
EBV (Epstein-Barr virus) Linked to nasopharyngeal carcinoma
Additional contributing factors Additional contributing factors

Pathogenesis:

![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 from Shah, F. D. et al. A review on salivary genomics and proteomics biomarkers in oral cancer. Indian. J. Clin. Biochem. 26, 326–334 (2011). Histopathology image of normal mucosa courtesy of R. Jordan, University of California San Francisco. Johnson, D.E., Burtness, B., Leemans, C.R. et al. Head and neck squamous cell carcinoma. Nat Rev Dis Primers 6, 92 (2020). https://doi.org/10.1038/s41572-020-00224-3](attachment:61441341-55a0-42a1-a641-2b606cb1ac0d:image.png)

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 from Shah, F. D. et al. A review on salivary genomics and proteomics biomarkers in oral cancer. Indian. J. Clin. Biochem. 26, 326–334 (2011). Histopathology image of normal mucosa courtesy of R. Jordan, University of California San Francisco. Johnson, D.E., Burtness, B., Leemans, C.R. et al. Head and neck squamous cell carcinoma. Nat Rev Dis Primers 6, 92 (2020). https://doi.org/10.1038/s41572-020-00224-3

Classification

Site Subsites
Oral cavity Lips, tongue, buccal mucosa, floor of mouth, hard palate
Oropharynx Soft palate, tonsils, base of tongue, pharyngeal walls
Hypopharynx Pyriform sinuses, postcricoid area, posterior pharyngeal wall
Larynx Supraglottis, glottis, subglottis
Nasopharynx (Distinct epidemiologically and pathologically; often EBV-related)

![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 (palatine 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 papillomavirus-associated HNSCCs arise primarily from the palatine and lingual tonsils of the oropharynx, whereas tobacco-associated HNSCCs arise primarily in the oral cavity, hypopharynx and larynx.

Johnson, D.E., Burtness, B., Leemans, C.R. et al. Head and neck squamous cell carcinoma. Nat Rev Dis Primers 6, 92 (2020). https://doi.org/10.1038/s41572-020-00224-3](attachment:757d71ff-f2ea-4415-90c1-7e1e2fd79428:41572_2020_224_Fig1_HTML.webp)

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 (palatine 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 papillomavirus-associated HNSCCs arise primarily from the palatine and lingual tonsils of the oropharynx, whereas tobacco-associated HNSCCs arise primarily in the oral cavity, hypopharynx and larynx.

Johnson, D.E., Burtness, B., Leemans, C.R. et al. Head and neck squamous cell carcinoma. Nat Rev Dis Primers 6, 92 (2020). https://doi.org/10.1038/s41572-020-00224-3

Clinical presentation