MERVA S. 17, DANICA . 18, ELKABETZ M. 7, BENZERDJEB N. 2, HUNTER K. 9, SHAW R. 9, BOSSI P. 4,10, MARINE H. 1, MARTINEZ P. 1, KOLJENOVIC S. 19, SAINTIGNY P. 1, VARRAZZANI A. 2, COSTEA D. 3, MARTIN J. 20, SAPKOTA D. 5, LOPEZ JORNET P. 6, ALLON I. 7, SHLAPOBERSKY M. 7, INGRIDA ?. 8, SHAW V. 9, FRANCESCA G. 4,10, MARTINA I. 4,10, ROSA MARÍA . 11, AMARAL MENDES R. 12, CSÜRY D. 1, BENGT H. 13, OOFT M. 21, KHURRAM S. 15, FERNANDO S. 12, MATTI S. 16
1 Univ Lyon, Université Claude Bernard Lyon 1, Inserm 1052, Cnrs 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France., Lyon, France; 2 Hospices Civils de Lyon, Lyon-Sud Hospital, Lyon, France., Lyon, France; 3 Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway., Bergen, Norway; 4 Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan, Italy., Milan, Italy; 5 Institute of Oral Biology, Faculty of Dentistry, University of Oslo, 0313 Oslo, Norway., Oslo, Norway; 6 Dentistry Clinic, Department of Dermatology, Stomatology, Radiology and Physical Medicine, Faculty of Medicine, Hospital Morales Meseguer, University of Murcia, Marques Velez S/N, 30008 Murcia, Spain., Murcia, Spain; 7 Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Institute of Pathology, Barzilai University Medical Center, Ashqelon, Israel., Beer-Sheva, Israel; 8 Department of Oral and Maxillofacial Surgery and Oral Medicine, Riga Stradi? University, 16 Dzirciema Str., LV-1007 Riga, Latvia., Riga, Latvia; 9 University of Liverpool, Liverpool, United Kingdom, Liverpool, United Kingdom; 10 IRCCS Humanitas Research Hospital, Milan, Italy., Milan, Italy; 11 Department of Dental Clinical Specialties, ORALMED Research Group, Complutense University of Madrid, Madrid, Spain., Madrid, Spain; 12 RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal., Porto, Portugal; 13 Department of Oral Medicine and Pathology, Institute of Odontology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Gothenburg, Sweden; 14 Pathology-DNA, Rijnstate Hospital, Arnhem, the Netherlands., Arnhem, Netherlands; 15 School of Clinical Dentistry, Faculty of Health, University of Sheffield, Sheffield, UK., Sheffield, United Kingdom; 16 Hals-Nasen-Ohrenklinik, Kopf- und Halschirurgie, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstrasse 1, 91054, Erlangen, Deutschland., Erlangen, Germany; 17 Department of Oral Pathology, Faculty of Dentistry, Ankara University, Ankara, Türkiye., Ankara, Turkey; 18 Department of Oral Medicine, University of Zagreb School of Dental Medicine, Gunduli?eva 5, Zagreb, 10000, Croatia., Zagreb, Croatia; 19 Department of Pathology, Antwerp University Hospital (UZA), Edegem, Belgium., Edegem, Belgium; 20 Institut Curie, Paris, France; 21 Pathology-DNA, Rijnstate Hospital, Arnhem, the Netherlands., Arnhem, Netherlands
Background: Oral potentially malignant disorders (OPMD), including oral leukoplakia, erythroplakia, and erythroleukoplakia, affect an estimated 4–5% of the global population and account for a substantial proportion of oral squamous cell carcinomas (OSCC) arising through malignant transformation. To date, dysplasia is routinely classified by grade which is not a reliable predictor of outcomes, because it is a subjective assessment, very much related to pathologists training and experience. Improving early risk assessment in OPMD is a key unmet need in OSCC prevention, particularly in view of marked geographic heterogeneity in incidence, clinical practices, and access to specialized care across Europe.
Objectives: The ISEBIO study (Immune-based Stratification and Evolutionary Biomarkers in OPMD) aims to improve oral cancer prevention by identifying immune-based and molecular biomarkers able to improve malignant transformation risk assessment beyond conventional histopathology. The primary objective is to identify biological features associated with progression from OPMD to OSCC. Secondary objectives include characterizing the molecular and immunological heterogeneity of OPMD and promote informed prevention strategies applicable across diverse European healthcare settings.
Methods: ISEBIO is a retrospective, multicentric, pan-European study conducted within the INTERCEPTOR (Interception of oral cancer) COST Action (CA21140). Adult patients diagnosed with oral leukoplakia, erythroplakia, or erythroleukoplakia are included based on the availability of formalin-fixed paraffin-embedded (FFPE) tissue and adequate longitudinal follow-up, enabling classification as progressors or non-progressors. All samples undergo centralized processing, quality control and pathological assessment by an international group of expert pathologists within the newly implemented OPMD Board developed within the INTERCEPTOR framework. This international virtual board enables harmonized reassessment of OPMD cases and contributes to a consensus-based evaluation of dysplasia patterns across participating countries (see Senada Koljenovic et al. abstract). Analyses include standardized histopathological review, CK13/CK17 immunohistochemistry, RNA sequencing using a 3’ Tag-Seq approach, and targeted DNA sequencing combining a whole-genome backbone and a head and neck cancer driver gene panel. The planned cohort size is approximately 246 patients, with an expected progressor-to-non-progressor ratio of 1:3.
Results: As of early 2026, 11 clinical sites in 7 European countries and affiliated regions are actively contributing in providing clinical data and biological materials. Additional centers from 5 further countries are currently in the process of activation. Expert pathological review is undergoing through the international OPMD Board. To date, 157 cases have successfully passed quality control, with 65 additional cases currently being qualified. Recruitment is ongoing to ensure adequate representation of progressing lesions and balanced geographic coverage.
Conclusions: ISEBIO constitutes a major collaborative effort to advance biomarker-driven oral cancer prevention in Europe. By integrating pathological features, immune, transcriptomic, and genomic data within a harmonized data model, the study aims to support evidence-based risk stratification for patients with OPMD. Beyond its scientific objectives, ISEBIO represents an important step toward pan-European harmonization of data generation, interpretation, and sharing for OPMD, contributing to more consistent prevention strategies and reduced disparities in oral cancer outcomes. Funded by INTERCEPTOR COST Action CA21140.