Dr. Annarosa Del Mistro, MD
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. Studies on the presence and characterization of HPV sequences in cervical carcinomas and preneoplastic lesions have provided insights into HPV epidemiology in Italy (EJC 2001; Inf Agents Cancer 2006). 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; J Med Screen 2014) have demonstrated the feasibility of the new protocol. As a consequence, 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) 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. Studies of HNSCC in North-Italian patients have shown a low prevalence of HPV-driven OPSCC, as evaluated by several biomarkers (J Cancer Res Clin Oncol 2009; Papillomavirus Res 2016).
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 methylation of cellular and viral genes and microRNAs as new biomarkers for cervical cancer prevention on NTCC stored samples (with long-term longitudinal assessment of their clinical utility), and mRNA HPV testing in comparison to cytology and p16 expression as triage tools in a new randomized multicentric trial (NTCC2).
- Rossana Trevisan
- Helena Frayle
- Martina Rizzi
- Silvia Gori
- Zorzi M, Del Mistro A, Farruggio A, de’ Bartolomeis L, Frayle Salamanca H, Baboci L, Bertazzo A, Cocco P, Fedato C, Gennaro M, Marchi N, Penon MG, Cogo C, Ferro A. Use of high-risk Human Papillomavirus DNA test as primary test in a cervical cancer screening programme: a population-based cohort study. BJOG 2013, 120:1260-7.
- Del Mistro A, Frayle H, Ferro A, Callegaro S, Del Sole A, Stomeo A, Cirillo E, Fedato C, Pagni S, Barzon L, Zorzi M, on behalf of the Veneto HPV-screening Working Group. Cervical cancer screening by high risk HPV testing in routine practice: results at one year recall of high risk HPV-positive and cytology-negative women. J Med Screen 2014;21:30-37.
- Carozzi FM, Del Mistro A, Cuschieri K, Frayle H, Sani C, Burroni E. HPV testing for primary cervical screening: Laboratory issues and evolving requirements for robust quality assurance. J Clin Virol 2016;76:S22-S28.