Radiomic Analysis for Human Papillomavirus Assessment in Oropharyngeal Carcinoma: Lessons and Pitfalls for the Next Future  
[PERSON]  
1 Department of Experimental and Clinical Biomedical Sciences \"[PERSON]\", University of Florence, 50121 Florence, Italy; [EMAIL_ADDRESS] (M.J.); [EMAIL_ADDRESS] (M.B. ); [EMAIL_ADDRESS] (M.V. ); [EMAIL_ADDRESS] (N.B. ); [EMAIL_ADDRESS] (I.M. ); [EMAIL_ADDRESS] (I.L. );
2 Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, 50134 Florence, Italy; [EMAIL_ADDRESS] (C.B. ); [EMAIL_ADDRESS] (M.L. ); [EMAIL_ADDRESS] (G.F.); [EMAIL_ADDRESS] (V.S. ); [EMAIL_ADDRESS] (P.B.) [PERSON], [PERSON], [PERSON], [PERSON], J.  
Oropharyngeal Squamous Cell Carcinoma (OPSCC) is a specific subtype which arises most frequently from the tonsils, followed by the base-tongue, the soft palate and the uvula. Human Papillomavirus (HPV) infection is strictly related to the development of OPSCC and is responsible for its growing incidence [2], despite a reduction in tobacco smoking and alcohol consumption in Western countries. HPV-positive (HPV+) and HPV-negative (HPV\(-\)) OPSCC present as different entities, with peculiar clinical presentation, pathogenetic mechanisms and prognosis. HPV+ patients are usually younger, with no smoking history and fewer comorbidities [3]; HPV+ disease is typically related to nodal spread with cystic neck masses at onset, whereas HPV\(-\) cancer symptoms are usually associated with local primary growth. Hence, HPV+ OPSCC is characterized by earlier detection, better prognosis and response rate to Chemoradiotherapytherapy (CRT) [4], which is classified in the 8 th edition of TNM staging according to the American Joint Committee on Cancer (AJCC). Five-year overall survival rates account for 80% in HPV-positive patients versus 50% in HPV-negative ones [5]. Therefore, de-escalation strategies have been investigated to minimize treatment-related adverse events in the former group, even if any modification in treatment regimens is not supported by current clinical data yet [6]. Regardless of HPV status, in early-stage disease, conservative surgery or radiotherapy (either external beam or brachytherapy for selected stage I) give similar rates of locoregional control. Post-operative (chemo-)radiation can be required to decrease the risk of local recurrence in case of pT3-4 (UICC TNM 8 th edition), positive margin (tumor at 1 mm from the margin), close resection margin (between 1 and 5 mm), perineural infiltration, lymphovascular spread, >1 invaded lymph node and the presence of extracapsular nodal infiltration. For locally advanced disease (cT3-4 cN0 cM0, cT1-4 cN1-3 cM0), the standard of care is represented by concomitant platinum-based chemoradiotherapy, whereas surgery followed by (C)RT may be an alternative option [7]. HPV infection is most frequently assessed by p16 Immunohistochemistry (IHC) on biopsied tissue or by testing for the presence of HPV DNA or mRNA in the tumor by using Polymerase Chain Reaction (PCR) or in situ hybridization [8]. p16 is routinely used as a surrogate marker; however, in approximately 17% of p16-positive patients, PCR results are negative, with almost the same inferior survival rates of those with p16-negative disease [9]. In addition, surgical biopsy may expose patients to complications such as bleeding, especially in those with hemorrhagic diathesis. Also, immunostaining sensitivity can be influenced by inflammatory changes in the specimen [10]. Moreover, IHC and PCR are time-consuming, expensive and not always available [11]. Therefore, the development of a non-invasive tool to determine HPV status could prove useful. For what concerns diagnostic imaging, HPV-related disease has peculiar growth patterns and nodal involvement which differ from HPV-negative OPSCC; for example, [PERSON] et al. showed that poorly defined borders of the primary tumor and invasion of adjacent muscles are characteristic for HPV-negative disease [12].