Human papillomavirus type 18 variants: Histopathology and E6/E7 polymorphisms in three countries

In cervical cancer, human papillomavirus type 18 (HPV 18) and HPV 16 are predominantly related to adenocarcinomas (ADCs) and squamous cell carcinomas (SCCs), respectively. Here, we studied whether the geographically distributed HPV intratypic variants are also associated with histologically different tumors. A total of 44 HPV 18-positive and 91 HPV 16-positive cervical carcinomas from Indonesian, Surinamese and Dutch patients were histologically classified using hematoxilin and eosin, periodic acid Schiff plus and Alcian Blue staining. Samples were sequenced and intratypic variants were classified into the known phylogenetic branches. The Asian Amerindian HPV 18 variant was observed in 56% of ADCs compared to 15% of SCCs (p < 0.006). The African HPV 18 variant was exclusively found in SCCs. By sequencing the HPV 18 E6 and E7 open reading frames, we found predicted amino acid changes only in 8 samples. Two amino acid changes were consistent throughout the African branch. In HPV 16-positive tumors, we did not find a specific linkage between intratypic variants and histopathology. We conclude that HPV 18 intratypic variants are differentially associated with adenocarcinoma and squamous cell carcinoma of the cervix. The findings described here stress the biologic significance of intratypic HPV variants and might help explaining differences in the pathogenesis of cervical ADCs and SCCs.