CHAPTER 3 Pathology of HPV infection at the cytologic and histologic levels: Basis for a 2-tiered morphologic classification system.

Over the last 2 decades the pathogenesis and natural history of cervi-cal cancer has become clearer. As a result, the cytologic and histologic terminol-ogy used to refer to cervical cancer precursors has needed to change. Today we recognize that almost all cervical cancers are due to infection with specific high-risk types of human papillomavirus (HPV). Most women become infected with these viruses within several years of initiating sexual intercourse and a productive HPV in-fection frequently results in characteristic morphologic changes within the infected cervical squamous cells. Cells demonstrating the morphologic changes associated with a productive HPV infection are referred to as low-grade squamous intraepi-thelial lesions (LSIL) when observed in cytologic specimens and low-grade cervical intraepithelial neoplasia (CIN 1) when observed in histologic specimens. In some women, HPV gene expression becomes unlinked to the state of differentiation of the infected epithelial cells and deregulated expression of the early region of the viral genome results in a dramatic increase in expression of two HPV oncoproteins (E6 and E7). This results in loss of normal cell cycle control of the epithelium and genetic instability. When this occurs the epithelium develops characteristic mor-phologic features, with immature "basaloid-type" squamous cells and mitotic fig-ures in the upper half of the cervical epithelium. Such lesions are felt to represent "true" neoplasia and are referred to as high-grade squamous intraepithelial lesions (HSIL) when observed in cytologic specimens and high-grade cervical intraepithelial neoplasia (CIN 2,3) when observed in histologic specimens.