Squamous cell carcinoma of the head and neck (SCCHN) represent a group of malignancies arising from the first tract of both respiratory and digestive ways. Being very similar with regard to pathology, etiology and clinical outcome, SCCHN have been often approached with similar therapy strategies in clinical trials. Recent studies have demonstrated the existence of different entities among the SCCHN, in particular, some neoplasms have been shown to behave differently from others. Human papilloma virus (HPV) related SCCHN show very peculiar features, as like good prognosis and good response to both chemo and radiotherapy. On the other hand, alcohol and tobacco related ones show the opposite features. Immunoistochemistry (IHC) and polymerase chain reaction (PCR) methodologies may help us to identify the biological characteristics which strongly divide HPV related SCCHN from the tobacco and alcohol related ones.

Moreover, another subgroup of SCCHN may be recognized, namely those related to a loco-regional immune suppression status. Some oral cavity and soft palate carcinomas often recur after standard treatment and this feature may be related to a local immune system impairment, often due to the microenvironment and tumour characteristics.

On the basis of these findings, we can conclude that the very heterogeneous category of SCCHN should be better studied and divided in several subgroups, characterized by different biological and clinical features. A step forward may be to administer a well shaped therapy starting from these biological features.