Two target cells for HPV infection at the cervix?

In the 1980s human papilloma virus (HPV) was identified as the cause of nearly all squamous cell cervical cancers (SCC), and the primary site of HPV infection at the cervix was long believed to be the basal cells of mature squamous epithelium. Considerable evidence now points to subcolumnar reserve cells (RC) nested in the endocervical epithelium as an alternative HPV target. Proof of the RC concept are i) HPV E6/E7 mRNA transcripts in histologically bland appearing p16 overexpressing thin HSIL, ii) similar genomic alterations in RC thin HSIL and invasive cervical SCC, and iii) HPV E6/E7 mRNA in endocervical RC adjacent to the preneoplastic regions. Even to date both the IARC and IPVS focus almost exclusively on HPV-associated cervical carcinogenesis originating in mature squamous cervical epithelium. The concept of dual carcinogenesis with distinct target cells for HPV at the cervix better explains most of the observations related to the natural history of cervical SCC. Further experimental substantiation of the RC as target cells for HPV and cell of origin of squamous (pre)cancer and the regulation of E6/7 expression in HPV infected proliferating RC and active metaplasia in the development of HSIL is needed. Furthermore, prospective in vivo studies of p16-positive thin HSIL lesions are necessary to document the risk of progression, but may be difficult to conduct for ethical reasons.