Page 13 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Cervical Intraepithelial Neoplasia 1
Cervical Intraepithelial Neoplasia (CIN) is the term used to describe dysplastic lesions of the uterine cervix. It is the precursor of cervical cancer.[1] CIN is caused by infection with human papillomavirus (HPV).[2] CIN lesions originate at the squamocolumnar junction (SCJ) of the uterine cervix, which is the border between two types of epithelium covering the cervix: the glandular columnar epithelium of the endocervix and the squamous epithelium of the ectocervix. [3] Recent evidence has shown that a particular population of cells in the SCJ may be the origin of CIN lesions: these are single layered, cuboidal epithelial cells of embryonic origin.[4] CIN lesions are classified as low-grade (CIN1) or high-grade (CIN2-3), based on the degree and extension of histopathological abnormalities. Low grade CIN is characterized by minor cellular atypia confined to the lower 1/3 of the epithelial thickness. In high-grade CIN, histopathological abnormalities are more pronounced and extensive: increased numbers of mitotic figures, actively replicating cells and an increased nucleus to cytoplasm ratio is seen in the lower 2/3 of the epithelium (CIN2) or the complete thickness of the epithelium (CIN3).
Epidemiology of CIN
Genital infection with HPV is very common: it likely affects nearly all sexually active individuals. [5] However, most infections are successfully cleared by the immune system, leaving a small subset of approximately 10–20% of infected women with a persistent HPV infection, susceptible to development of CIN lesions.[5] In the western world, the incidence of high-grade CIN is estimated at 1.5/1000 women, with a peak incidence between the ages of 25-30 years (8.1/1000). [6] In the Netherlands, approximately 5000 women are treated for high-grade CIN lesions every year.[7] Most CIN lesions are asymptomatic and are diagnosed as a result of population screening for cervical cancer. This population screening program enables early treatment of cervical precancerous lesions and as a result, the incidence of cervical cancer is much lower than CIN: 6/100 000 women in the Netherlands.[7]
Human papillomavirus and oncogenesis
CIN is caused by cervical infection with HPV, which is sexually transmitted.[2] More than 150 different HPV types (genotypes) have been identified, out of which approximately one-third infect the human genital tract. HPV genotypes are classified into risk categories according to their oncogenic potential. Twelve HPV genotypes have been classified as ‘high-risk’ and are associated with the development of high-grade CIN and cervical carcinoma. Among these, HPV16 and HPV- 18 are the most common.[3] HPV contains eight genes: six early genes (E1, E2, E4, E5, E6 and E7) regulate viral replication and DNA transcription. Of these, E6 and E7 are considered oncogenic. Two late genes (L1 and L2) encode for the virus capside proteins. Cervical HPV infection occurs at the basal cell layers of the SCJ. After entry of the virus in the host cell, the viral oncogenes E6 and E7 are expressed and induce viral replication through activation of the host DNA replication machinery. The E7 protein binds to the retinoblastoma tumor suppressor protein (pRB) and inhibits binding of pRB to E2F, which leads to S-phase entry of the infected cell, inducing DNA
Introduction
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