Page 33 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Figure 1. Histopathological findings in productive and transforming HPV infections
A. productive HPV infection, characterized by koilocytosis and other minor cellular reactions. B. CIN 3 lesion, characterized by an increased number of mitotic figures, actively replicating cells throughout the thickness of the epithelium and an increased nucleus to cytoplasm ratio. Both figures are hematoxylin and eosin stained. Adapted from Litjens et al. (86)
Transforming infection
High-grade intraepithelial neoplasia of the cervix occurs when the normal viral gene expression is deregulated.(28, 29) Expression of E6 and E7 in the basal cell layers is increased, initiating uncontrolled cell proliferation and immortalization and making the cell susceptible to chromosomal instability. This type of infection is known as a ‘transforming infection’ and is associated almost exclusively with high-risk HPV types. A transforming infection is the basis for cervical oncogenesis. Transforming infections are cytologically and histologically characterized by increased numbers of mitotic figures, actively replicating cells throughout the thickness of the epithelium and an increased nucleus to cytoplasm ratio, which are diagnosed as high-grade CIN (figure 1). Several hypotheses have evolved as to the origin of the cervical transforming infections: they could be the result of a persisting and deregulating productive infection or originate as primary transforming infections. An interesting new concept was recently introduced by Herfs et al.(30) They found that the removal of squamocolumnar junction (SCJ) cells decreased disease recurrence. This empowered a recently introduced hypothesis that specific SCJ cells may be the origin of high-grade CIN and that these cells may not regenerate after excision. They showed that most high-grade CIN lesions developed in SCJ cells, whereas most low-grade CIN lesions developed in other cells populations, such as metaplastic epithelium of the cervix or the ectocervix. They concluded that SCJ cells may be more susceptible to HPV infection and dysplastic changes. Following on this hypothesis, one may imagine two pathways to high-grade CIN: some high- grade CIN lesions occur as a result of a primary transforming infection of the SJC cells, whereas other high-grade CIN lesions may occur as a result of a persistent and deregulated productive infection of other cervical cells. This concept was recently elegantly illustrated by Steenbergen et al.(21)
A review of prognostic biomarkers
31
2