Human Papillomaviruses (HPVs) are non-enveloped double-stranded DNA viruses. The most extensively studied group of HPVs is the α-HPV group. Distinguished from low-risk α-HPVs by their oncogenic potential, high-risk α-HPVs are well-know for being the etiological agents of certain cancers diagnosed in the anogenital tract and oropharyngeal region. While the link between HPV and cancer is established in the cervix (>90%), vulva (≈40%), vagina (≈70%), penis (≈50%), anus (≈85%), and upper aerodigestive tract (≈30%), the involvement of HPV infections in esophageal carcinogenesis (both squamous and glandular) remains highly controversial. This observation is also true for the different subtypes of cervical adenocarcinoma. The objectives of this thesis are : 1) to histopathologically characterize esophageal cancers (squamous and glandular) and gain a better understanding of the potential involvement of α-HPVs in their initiation/progression ; 2) to conduct a systematic review and meta-analysis in order to comprehensively assess HPV positivity in various subtypes of cervical adenocarcinoma.
In the first part of this study, in collaboration with Belgian and European biobanks, a cohort of 230 patients with squamous carcinoma and 119 patients diagnosed with esophageal adenocarcinoma was collected. The HPV status of each sample was analyzed through genotyping and confirmed using In Situ Hybridization. Viral transcriptional activity was also verified using both RT-qPCR and RNAscope. This process allowed us to classify the samples into three categories: HPV-negative, HPV DNA+/RNA-, and HPV DNA+/RNA+. These three subgroups were then compared based on various criteria: tumor differentiation, p53 status, proliferation index (Ki67), positivity for p16ink4a, as well as the density of CD8+ and PD1+ cells. Clinical data was also collected and patient survival analyses were conducted. Despite a 26% HPV infection rate (DNA+/RNA+) found in the adenocarcinoma cohort (31/119, 26%), HPV does not appear to be implicated in their carcinogenesis given the low percentage of virus-infected cells (as seen in RNAscope) and the unchanged patient survival with a positive HPV status. Conversely, the study focusing on squamous carcinomas shows HPV involvement in 14% of tumors (32/230, 14%), and this HPV DNA+/RNA+ category presents close characteristics with HPV+ tumors located in the oropharyngeal region. Furthermore, several features support the causal role of HPV in this subset of tumor: 100% of tumor cells are infected (RNAscope), validation of these latter results using the indirect HPV biomarker (p16ink4a), and the significantly improvement of patient disease-free survival in case of HPV positivity (p=0.0365).
The second part of this project focused on the prevalence and distribution of HPV genotypes in different subtypes of cervical adenocarcinoma. To address the lack of a comprehensive understanding of HPV involvement in this heterogeneous tumor group, a systematic review and meta-analysis was conducted. A total of 379 studies comprising 17 129 cases of cervical adenocarcinoma were collected. An HPV prevalence of 78.4% in these tumors was highlighted, with significant heterogeneity between geographical regions (72.5% in Asia versus 86.8% in Oceania) and studied histological subtypes of cancer (9.8% in the gastric subtype versus 85% in the classic/usual subtype). This analysis demonstrates the presence of HPV across all subtypes of adenocarcinoma but to a varying degree. Developing a classification system for these tumors based on precise morphological and viral features could be an interesting evolution of the current “mutually exclusive” WHO 2020 classification.