Oropharyngeal squamous cell carcinomas (OPSCC) are categorized as head and neck squamous cell carcinoma (HNSCC) together with squamous cell carcinoma of the oral cavity, larynx and hypopharynx. OPSCC account for approximately 50,000 incident cases [1, 2], and together with hypopharyngeal squamous cell carcinomas they account for about 1.1% of all malignancies worldwide . Tobacco smoking and alcohol consumption are recognized as major risk factors but infection with Human papillomaviruses (HPV) has been identified as a causal factor for an increasing number of OPSCC, particularly in Waldeyer’s tonsillar ring [4, 5].
Among the 51 mucosal HPV types known so far, 12 have been classified as carcinogenic (class I) for cervical cancer (CxCa) . While HPV type 16 is the most prevalent type in CxCa worldwide (61%), the other carcinogenic types, i.e. HPV18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 (here referred to as non-HPV16 types) are responsible for approximately another 33% of CxCa, with HPV58 specifically accounting for 2% of CxCa. HPV58 in cervical cancer has the highest prevalence in Asia (4%), followed by North- and South-America (2% each), Europe (1%) and Africa (<1%) .
In contrast to CxCa, an even larger majority of HPV DNA-positive OPSCC are associated with HPV16 (89% - 97%), and DNA of other carcinogenic non-HPV16 types has been detected only rarely in OPSCC tissues [8–10]. A recent metanalysis of HPV DNA prevalence in head and neck cancers (Ndiaye C, Alemany L et al., in preparation) identified 11 (0.8%) HPV58 DNA positives among a total of 1466 HPV DNA positive oropharyngeal cancer cases that had been analysed for presence of HPV58 DNA [5, 11–15].
Intriguingly, only a subset of HPV16 DNA-positive OPSCC display HPV16 carcinogenic activity in the tumor tissue, i.e. are HPV-driven (HPV DNA-positive RNA-positive) OPSCC, particularly in populations with low HPV DNA prevalence in OPSCC such as Western Europe. This indicates that presence of HPV DNA alone is not sufficient proof for causal involvement of any HPV DNA found in an OPSCC tissue. For non-HPV16 types found in OPSCC molecular proof of causality is largely lacking.
Over the last 25 years a rather detailed model of HPV-driven transformation of human tumor cells has been established. Truly HPV-transformed tumor cells contain at least one viral genome copy per cell and express the viral oncogenes E6 and E7. Interaction of the E6 and E7 oncoproteins with key regulators of cell cycle and apoptosis leads to upregulation of cellular protein p16INK4a and downregulation of tumor suppressor proteins pRb and p53. In patients with invasive HPV-driven cervical, penile and oropharyngeal SCC overexpression of E6 and E7 oncoproteins frequently leads to strong antibody responses against these viral proteins [4, 16–24].
This model has been extensively verified in cervical carcinoma for all HPV types classified by IARC/WHO as carcinogenic, probably and possibly carcinogenic . It has also been fully or partially verified for HPV16 in squamous cell carcinoma of the oropharynx [8, 26], larynx , oral cavity , penis  and anus .
Here, we present the first case of an OPSCC driven by HPV58, a carcinogenic HPV type with low prevalence in CxCa, as demonstrated by a broad variety of HPV transformation markers. The present case is part of an ongoing prospective multicentric study of head and neck cancer patients from North-East Italy.