Oral epithelial dysplasia (OED) poses a significant clinical challenge due to its potential for malignant transformation and the lack of reliable prognostic markers. Current grading systems for OED may not be reliable for prediction of malignant transformation and suffer from considerable inter- and intra-rater variability, potentially leading to suboptimal treatment decisions. Recent studies have highlighted the potential prognostic significance of peri-epithelial lymphocytes (PELs) in malignant transformation, with suggestions that intra-epithelial lymphocytes (IELs) may also play a role. In this study, we propose a novel artificial intelligence (AI) based IEL score from Haematoxylin and Eosin (H&E) stained Whole Slide Images (WSIs) of OED tissue slides. We further determine the prognostic value of our IEL score on a large digital dataset of 219 OED WSIs (acquired using three different scanners), compared to pathologist-led clinical grading. Notably, despite IELs not being incorporated into the current WHO grading system for OED, our findings suggest that IEL scores carry significant prognostic value that were shown to further improve both the Binary/WHO grading systems in multivariate analyses. This underscores the potential importance of IELs, and by extension our IEL score, as prognostic indicators in OED. Further validation through prospective multi-centric studies is warranted to confirm the clinical utility of the proposed IEL score and its integration into existing grading systems for OED.

NMR is the co-founder, CEO and CSO of Histofy Ltd., UK. He is also the GSK Chair of Computational Pathology and is in receipt of research funding from GSK and AstraZeneca. SAK is a shareholder of Histofy Ltd. All other authors have no competing interests to declare.

This study was supported by a Cancer Research UK Early Detection Project Grant, as part of the ANTICIPATE study (grant no. C63489/A29674) in addition to funding from the National Institute for Health Research (award no. NIHR300904).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical approval was obtained by the NHS Health Research Authority West Midlands (Ref: 18/WM/0335) and experiments were conducted in compliance with the Declaration of Helsinki.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

We are unable to share the whole slide images and clinical data used in this study due to restrictions in the ethics applications.