General introduction and thesis outline 19 1 and prevention of apoptosis provides a mechanism of malignant transformation. Through a series of interactions and pathways, activation of E6 and E7 leads to the upregulation of Ki-67 and increased p16INK4A levels. Ki-67 is a marker of proliferation and has been suggested as a sensitive biological indicator of CIN progression 61. p16INK4A is involved in regulation of the cell cycle and is used to guide CIN grading as expression increases with increasing severity of disease 62. The College of American Pathologists and the American Society for Colposcopy and Cervical Pathology recommended in the LAST criteria the use of p16INK4A as an adjunct to morphologic assessment for differentiation between HSIL and a disease state mimicking HSIL. CIN2 lesions can be further differentiated based on their p16INK4A status, where p16INK4A-positive CIN2 lesions are classified into HSIL and p16INK4A-negative CIN2 lesions into LSIL 12, 63, 64. The concept of cervical carcinogenesis is summarised in Figure 1.5. Viral infection Original concept TZ Productive CIN hrHPV New concept Type of hrHPV infection Morphological appearance Normal CIN1/2 CIN2/3 Cancer Onset of cervical carcinogenesis Viral persistence • E ▪ E6 and E7 expression in proliferating cells ▪ Viral transformation Development of precancerous lesions Progression to invasive cancer Transforming CIN Cancer Transient (latent) infection Productive (permissive) infection Transforming (non-permissive) infection 20-30 years Productive CIN SCJ cells Ectocervix or TZ Transforming CIN Cancer Figure 1.5 The concept of HPV-mediated cervical carcinogenesis. Schematic representation of several outcomes of a high-risk (hr) human papillomavirus (HPV) infection in cervical epithelial cells. Most HPV infections (~80%) are transient and are cleared by the immune system without causing cellular abnormalities. If HPV persists, the (reversible) progression of a productive CIN1/2 towards a transforming CIN2/3 reflects the onset of cervical carcinogenesis. Transforming infections are characterised by deregulated E6 and E7 expression in proliferating cells. Transforming CIN is a heterogeneous disease with variable duration of lesion existence and includes both progressive and regressive lesions. Only a very small proportion of infections will eventually lead to the development of cervical cancer, which can take up to 20-30 years. Adapted from Steenbergen et al., Nat Rev Cancer, 2014 25. Abbreviations: TZ, transformation zone; CIN, cervical intraepithelial neoplasia; SCJ, squamous columnar junction; hr, high-risk; HPV, human papillomavirus
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