Oncogenesis by HPV is the main interest of Annarosa Del Mistro. High-risk HPV (hrHPV) types are the necessary cause of all cervical carcinomas and most high-grade lesions, and a subset of oropharyngeal carcinomas. Since 2002, she is actively contributing to the studies of the Italian multicentric randomized trial NTCC (New Technologies In Cervical Cancer screening), a very large trial that evaluated the performance of HPV testing as primary screening test in comparison to cytology. The NTCC longitudinal results (Lancet Oncol 2010) and its data pooled with other European trials (Lancet 2014) have demonstrated the higher efficacy of HPV testing in the prevention of cervical cancer, while the pilot projects on the use of HPV testing in routine screening programmes (BJOG 2013 & 2017 & 2019; J Med Screen 2014) have demonstrated the feasibility of the new protocol. All the Regions are now implementing HPV testing as primary test for cervical screening. By the use of NTCC stored samples, viral (JCM 2013; JCV 2014; IJC 2018 & 2020) and cellular (Lancet Oncol 2008) characteristics are being studied as molecular biomarkers for a more precise definition of cancer risk in women with infection by hrHPV types. A new multicentric trial (NTCC2) on the role of mRNA-HPV and p16/Ki67 testing as triage is ongoing. Studies of HNSCC in North-Italian patients have shown a low but increasing over time prevalence of HPV-driven OPSCC, as evaluated by several biomarkers (J Cancer Res Clin Oncol 2009; Papillomavirus Res 2016; Scientific Reports, 2020).
Dr. Annarosa Del Mistro, MD
HPV TESTING AND NOVEL BIOMARKERS IN PREVENTION AND DIAGNOSIS OF CERVICAL AND OROPHARYNGEAL HPV-DRIVEN CARCINOMAS
The definition and clinical assessment of viral and cellular biomarkers will allow more effective protocols for cervical cancer prevention and for the management of patients with HPV-driven oropharyngeal cancer.
Studies on natural history and determinants of cervical carcinogenesis by HPV aimed at improving cervical cancer prevention by a more precise cancer risk assessment, larger participation of the target population to organized cervical cancer screening programmes and tailored treatment. Studies on oropharyngeal cancer (OPSCC) and oral infection to assess the causal involvement of HPV and the clinical correlates.
A subset of HPV types, defined as high-risk HPV (hrHPV), are the causal agents of all cervical carcinomas and a subgroup of OPSCC. Cervical cancer is now preventable by effective primary (prophylactic vaccines) and secondary (organized screening programmes) measures. Evidence-based protocols for more effective and tailored risk assessment of women with cervical hrHPV infection and treatment of potentially progressive high-grade pre-neoplastic lesions, as well as how to best screen vaccinated women, are being actively investigated by several groups. On the other hand, HPV-driven OPSCC is a recently identified new entity, characterized by a better prognosis than classic (driven by smoking and alcohol) OPSCC, large variations in geographic distribution and an increase over time trend; the assessment of HPV causal involvement is clinically relevant for the management of the patients, and the diagnostic work-out needs the demonstration of HPV causal involvement.
The studies conducted by the team, mostly as multicentric trials (the most important being NTCC, New Technologies in Cervical Cancer screening, started in 2002), have assessed the geographical distribution of cervical, anal and oral type-specific HPV infections and related lesions; have demonstrated the higher efficacy of HPV testing in the prevention of cervical cancer (leading to the reccomendation by the Ministry of Health to implement HPV testing as primary test for cervical screening in all the Italian regions by 2018, and the team is one of the three centralized laboratories in Veneto); have defined the screening protocol (women’s age, screening interval, HPV assays to be used and laboratory quality control requirements, triage assays); have assessed the prevalence of HPV-driven HNSCC in North-East Italy and defined a diagnostic algorythm. These studies have also led the team to collaborate with external Italian (i.e., CPO, Torino; ISPO, Firenze) and international research groups (i.e., IARC, Lyon, France; DKFZ, Heidelberg, Germany).
Conclusions and perspectives
The ongoing studies are evaluating HPV genotyping, and methylation of cellular and viral genes as new biomarkers for cervical cancer prevention on NTCC stored samples (with long-term longitudinal assessment of their clinical utility); mRNA HPV testing in comparison to cytology and p16/ki67 expression as triage tools in a new randomized multicentric trial (NTCC2); the same biomarkers are being evaluated as prognostic parameters to conservatively manage CIN2 lesions in young women. HPV-driven OPSCCs have been increasing over time in the last two decades also in North-East Italy, and the prospective study is ongoing to evaluate possible predictive biomarkers.
- Del Mistro A, Adcock R, Carozzi F, Gillio-Tos A, De Marco A, Girlando S, Rizzolo R, Frayle H, Trevisan M, Sani C, Burroni E, Giorgi Rossi P, Cuzick J, Ronco G. HPV genotyping for the cross-sectional and longitudinal probability of developing CIN2+. Int J Cancer 2018;143:333-342. doi:10.1002/ijc.31326
- Boscolo-Rizzo P, Zorzi M, Del Mistro A, et al. The evolution of the epidemiological landscape of head and neck cancer in Italy: is there evidence for an increase in the incidence of potentially HPV-related carcinomas? PLoS ONE 2018;13(2):e192621.
- Del Mistro A, Giorgi Rossi P, Frayle H, Pasquale L, Campari C, Ronco G, Zorzi M. Five-year risk of CIN3 after short-term HPV-DNA negativity in cytology-negative women: a population-based cohort study. BJOG 2019;126:1365-1371.