29
evaluate the possibility of de-escalation of radiotherapy doses in the treatment of
HPV-associated oropharyngeal cancers [ 46 ].
3.5.3 HPV and Anal, Penile, and Vulvovaginal Cancers
Similar to the cervix, the anus has a transformation zone that is highly susceptible
to HPV infection. The association of HPV is well documented in the development
of anal cancers. Of anal cancer cases, 97% are HPV positive, mostly with HPV16
(75%) followed by HPV18 (3%) [ 47 ]. The incidence of this relatively uncommon
cancer has been reported increasing over the last few decades. The risk for anal
carcinoma is increased among men having sex with men (MSM) and in the immu-
nocompromised population (individuals with AIDS and organ graft recipients) [ 26 ].
Though there is emerging evidence that anal intraepithelial neoplasia (AIN) is a
precursor of anal cancer unlike cervical cancer, the evidence is mainly from small
studies with a follow-up duration of only 5–10 years. Larger studies are required to
evaluate the progression of AIN to anal cancers and to study its impact on treatment
outcome [ 48 ].
HPV contribution in penile cancer is 45%, mostly attributed to the two mostcommon HR HPV types, HPV16 (60%) and 18 (13%), but also to the two most
common LR HPV types, 6 and 11 (together 8%) [ 49 ].
Most vulvar and vaginal cancers are squamous cervical cancer in older women,and mechanisms similar to those of cervical cancer development have been docu-
mented. A systematic review has reported a progression rate of 3.3% from vulval
intraepithelial neoplasia to SCC of the vulva [ 50 ]. The HPV contribution in vulvar
cancer is 40%, mostly HPV16 (32%) and then HPV18 (4%) [ 49 ]. In vaginal cancer,
the HPV contribution is higher, being 70% and mostly HPV16 (54%) followed by
HPV18 (8%) [ 49 ].
3.5.4 HPV and Skin Cancers
In addition to the HR α-HPV types, several β-HPV types, notably HPV types 5 and
8, are associated with skin cancer and are thus considered possibly carcinogenic.
The clinical relevance of β-HPV infection has clearly been demonstrated in patients
suffering from epidermodysplasia verruciformis (EV). EV is a rare genetically het-
erogeneous disease, either autosomal recessive or X linked, but also associated with
a high risk for nonmelanoma skin cancer [ 51 ]. EV is a unique model where genetic
susceptibility to HPVs is demonstrated [ 52 ]. In the normal population, beta-PV is
suspected to have an etiologic role in skin carcinogenesis as well, but this is still
controversially discussed. Their oncogenic potency has been investigated in mouse
models and in vitro. In 2009, the International Agency for Research on Cancer
3 HPV-Related Cancers