Page 32 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 2
results can be used in individualized medical decision making, it is crucial to know their accuracy in predicting the behaviour of high-grade CIN lesions. Each biomarker will be evaluated according to established criteria to determine applicability of diagnostic and prognostic candidate biomarkers: the prospective-specimen-collection, retrospective-blinded-evaluation (PROBE) design.(20) Selected biomarkers may function as prognostic biomarkers in individual high-grade CIN lesions. This enables a more individualized treatment plan for patients, with the option of watchful waiting in those patients in which spontaneous regression is likely.
HPV: infection and oncogenesis
Papillomaviruses are species-specific, double strand DNA viruses. To date, over 150 different types have been identified that infect human beings and of these, approximately one third infect squamous epithelia of the genital tract (http://pave.niaid.nih.gov/#home). The virus contains eight coding genes. Six early genes (E1, E2, E4, E5, E6 and E7) regulate viral replication and DNA transcription, of which E6 and E7 are considered oncogenic. Two late genes (L1 and L2) encode for the virus capside proteins. Human papillomaviruses are categorized according to their oncogenic potential. Although the individual oncogenic potential shows a gradient pattern, all viruses are categorized into either high risk, intermediate risk or low risk types. Twelve HPV-types have been consistently classified as high-risk.(21) High-grade CIN and cervical carcinoma are predominantly associated with high-risk HPV types.(22) High risk types HPV16 and HPV-18 are the most prevalent virus types in cervical carcinoma. Either of these types are identified in approximately 70% of cervical malignancies.(23)
Infection
Infection of the anogenital tract with HPV is very common: up to 80% of the female population may be infected at least once in a lifetime.(24, 25) Most infections are successfully cleared, leaving a small subset of approximately 10-20% of infected women with a persistent HPV infection, susceptible to development of CIN.(24, 26, 27). The biology and life-cycle of HPV and its role in cervical oncogenesis has been extensively reviewed by others.(28, 29) A short summary will be provided here, as a basis for biomarker selection
Productive infection
HPV infection results primarily in a productive infection of the cervical epithelium in which new viruses are produced. Infection occurs at the basal cell layers of the squamocolumnar junction, after which viral DNA is present in an episomal form and expression of E6 and E7 is limited. Viral replication is facilitated by the host replication apparatus and leads to abundant expression of viral genes, including E6 and E7, in differentiating cells in the upper cell layers. Viral replication occurs, capside proteins are produced and new viruses are formed, which are shed from the upper cell layers. Productive infections are cytologically and histologically characterized by koilocytosis and other minor cellular reactions, which are roughly diagnosed as CIN 1 or CIN 2 at the most (figure 1).
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