Oncogenic human papillomavirus genotypes and the diagnosis of cervical intraepithelial neoplasia

Abstract

Cervical cancer is the fourth most common cancer in women, with more than half a million new cases worldwide each year. In the majority of cervical cancers a persistent infection with high-risk (hr) Human papillomavirus (HPV) types has been proven to be the causative agent. Prevention of cervical cancer can be improved by studying the detection of cervical precancer by colposcopy and by understanding the natural history of different HPV genotypes. This thesis addresses different approaches to improve colposcopic accuracy. Furthermore, the biology of different hrHPV genotypes is studied in premalignant lesions.

Despite the important role of colposcopy in detecting high-grade disease, sensitivity is relatively low. We studied whether colposcopic accuracy can be improved by hrHPV genotyping and by studying colposcopic characteristics systematically. In a population following European screening practice, HPV16 related lesions were detected at younger age and showed similar colposcopic impression as non-16 hrHPV high-grade lesions. There was no relation between any of the colposcopic characteristics and HPV16 status. To further investigate improvement of colposcopic diagnostic accuracy, we evaluated improved detection of high-grade lesions by taking multiple lesion-directed biopsies. We showed that a second lesion-directed biopsy is associated with a significant increase in disease detection. We suggest that performing an additional lesion-directed biopsy should become the standard practice of colposcopy.

Atypical immature metaplasia (AIM) is an equivocal category used to describe changes in immature metaplasia (IM) suggestive of high-grade neoplasia which causes diagnostic and management problems. The relative infrequency of HPV18 in high-grade disease and its importance in cervical cacner might be explained by infection of glandular cells or IM cells . The role of hrHPV infected AIM in cervical neoplasia was studied. AIM was a particular feature of HPV18 infection in women with high-grade lesions. Women with high-grade lesions frequently present with multiple cervical lesions and multiple concomitant HPV genotype infections. Studying causal genotype attribution to cervical disease is important to measure the effect of vaccination and to study HPV types to be included in HPV assays for cervical screening. We performed molecular mapping of cervical disease in a small pilot study in women with high-grade CIN to elucidate HPV genotype attribution in different regions on the cervix. HPV16 was identified as the causal type in all women with HPV16 in cytology. In this US population we were able to attribute an individual HPV type to each area of CIN. We demonstrated that HPV16 is even more etiologically dominant than previously thought, based on various genotype attribution models.

Genotype attribution to high-grade CIN was also evaluated in a large population based study of 257 women with high-grade lesions. We confirmed that only 9% of the lesions are associated with multiple hrHPV types, much less than cytology would indicate, and each lesion was associated with a single hrHPV infection