14 Chapter 1 different candidates qualify as stem cells 7. Different target cells of lesion formation and transformation towards cervical cancer have been described, but it has been suggested that specific cell populations of epithelial stem cells (reserve cells, located at the transformation zone, and cuboidal cells, located at the SCJ) are particularly vulnerable to neoplastic transformation by the human papillomavirus (HPV; further detailed in section 2) and are considered to be the cells of origin for cervical cancer 5, 8. 1.1.3 CERVICAL CANCER AND ITS PRECURSOR LESIONS Cervical cancer is classified into different histological types, with squamous cell carcinoma (SCC) and adenocarcinoma (ACC) being the two main histotypes. SCC accounts for about 80% of cervical cancers, while ACC accounts for about 15%. The remaining 5% of cervical cancers comprise rare types, including neuro-endocrine carcinoma and HPVindependent adenocarcinoma (i.e., clear-cell, mesonephric, gastric or endometrioid type) 2, 9-11. Cervical SCC and ACC develop through precursor lesions. The development of SCC is preceded by premalignant lesions called cervical intraepithelial neoplasia (CIN). CIN can be histologically classified into three grades based on the extent of immature dysplastic cells in the epithelium (Figure 1.3): CIN1 (mild dysplasia), in which atypical cells are limited to the lower one third of the epithelial layer, CIN2 (moderate dysplasia), in which the lower two thirds of the epithelium contain atypia and CIN3 (severe dysplasia), in which atypical cells affect more than two-third of the epithelial layer. When atypical squamous cells extend through the basal membrane, a lesion is defined as cervical cancer. In the United States, an alternative two-tiered system, the Lower Anogenital Squamous Terminology (LAST), is used, which recognises low-grade squamous intraepithelial lesions (LSIL), equivalent to HPV-related epithelial changes without CIN (CIN0) and CIN1, and high-grade squamous intraepithelial neoplasia (HSIL), equivalent to CIN2 and CIN3 12. Clinical management of CIN depends on the classification of the lesion. Treatment of CIN aims to prevent cancer. In general, a conservative approach is recommended for CIN1, as the majority of these lesions will spontaneously regress (~80%). Treatment is indicated for women with a CIN3 lesion due to their high risk for progression into cancer (~31%) 13. Management guidelines for CIN2 lesions vary, as these lesions represent a heterogeneous group of disease with a highly variable clinical course. Premalignant lesions of ACC are less well-defined 14. The clinical significance of minor endocervical glandular dysplasia in the development of ACC is not known and the diagnosis is poorly reproducible. The only reproducible precursor stage of ACC is
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