Background: Squamous Cell Carcinoma of the Head and Neck (SCCHN) are neoplasms arising from
the epithelium of the first aero-digestive tract. They are very heterogeneous both clinically and biologically.
Classic and well acknowledged risk factors are alcohol and tobacco consumption and other forms of smokeless
tobacco assumption, although lately the incidence of Human Papilloma Virus (HPV)-related SCCHN is rapidly
increasing. HPV-related tumors are very different from their alcohol and tobacco-associated counterpart, as they
show strong chemo and radio sensitivity and thus can often be treated with conservative treatment strategies.
Moreover, peculiar biologic features characterize HPV-related tumors, such as wild type TP53, low expression
of Epidermal Growth Factor Receptor (EGFR), wild type CCND1 and high expression of P16. In contrast,
alcohol and tobacco related SCCHN show opposite features, together with higher number of chromosomal and
genetic abnormalities, conferring them chemo and radio resistance.
Methods: We have performed a narrative review of the PubMed database with the aim to study the mutational
landscape of SCCHN.
Results: Several lines of evidence support the existence of at least two genetically different types of SCCHN,
one virus-related and the other alcohol and/or tobacco-related, characterized by both clinical and biological
opposite features. Virus related SCCHN are very chemo and radiosensitive, so suitable for organ preserving
strategy, which in the near future may be induction chemotherapy followed by association of chemotherapy and
underpowered radiotherapy. Alcohol and tobacco related SCCHN are themselves strongly heterogeneous and
can be divided in different entities on the basis of the “Driver” genetic aberration, responsible for carcinogenesis.
The most frequently mutated genes in alcohol and tobacco-related SCCHN are TP53, NOTCH1, CCND1,
CDKN2A, EGFR and PI3KCA.
Conclusions: Virus-related SCCHN can be managed with chemo-radiotherapy. Alcohol and tobacco-related
tumors should be further characterized on the basis of their “Driver Mutations” in order to select effective targeted