oral cancer clinical presentations

Textbook of Oral Cancer pp 47–54 Cite as

Clinical Presentation and Differential Diagnosis of Oral Cancer

• Jose V. Bagan 3 &
• Leticia Bagan-Debon 4  
• First Online: 23 February 2020

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Part of the book series: Textbooks in Contemporary Dentistry ((TECD))

Over 90% of oral cancers are squamous cell carcinomas (OSCCs) which are of epithelial origin. Other types of malignancies account for the small remaining 10%. In this chapter, we describe the clinical characteristics of early- and advanced-stage OSCC and also consider the differential diagnosis of early-stage OSCC. The priority concern is to establish an early diagnosis, in order to secure the best possible prognosis and highest survival rate among oral cancer patients.

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Oral Medicine and Service of Stomatology and Maxillofacial Surgery, University of Valencia and University General Hospital, Valencia, Spain

Jose V. Bagan

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Bagan, J.V., Bagan-Debon, L. (2020). Clinical Presentation and Differential Diagnosis of Oral Cancer. In: Warnakulasuriya, S., Greenspan, J. (eds) Textbook of Oral Cancer. Textbooks in Contemporary Dentistry. Springer, Cham. https://doi.org/10.1007/978-3-030-32316-5_5

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Molecular diagnostics in oral cancer and oral potentially malignant disorders-A clinician's guide

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• 1 Melbourne Dental School, University of Melbourne, Melbourne, Victoria, Australia.
• 2 Australian Centre for Oral Oncology Research & Education, Nedlands, Western Australia, Australia.
• PMID: 31309636
• DOI: 10.1111/jop.12920

Current risk stratification of individuals for the development of oral squamous cell carcinoma (OSCC), including those with oral potentially malignant disorders (OPMD), remains based on clinical detection of visibly abnormal mucosa and tissue biopsy with histological assessment for the presence of OSCC or oral epithelial dysplasia (OED). In OPMD, the presence of OED remains the only prognostic tool used in standard care for the development of future OSCC, despite its ample limitations. There is assured potential that the analysis of the genome, transcripts and proteome can provide insight into what is occurring at a cellular level preceding the appearance of clinically observable change. The landscape of the role of the genome and its transcriptome on the development of OSCC and relationships with OPMDs are immense with exploration occurring on several fronts. For clinicians involved in the diagnosis and care of patients with OSCC and OPMD, understanding of commonly used molecular diagnostic techniques is imperative to gain useful insight from the expanding literature investigating the development of OSCC and the relationship with the clinical presentations which encompass OPMDs. Here we present an introduction to molecular diagnostic methods used in the study of OSCC and OPMD.

Keywords: biomarkers; molecular diagnostics; oral cancer; potentially malignant oral mucosal disorders; prognosis.

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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• Carcinoma in Situ
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• Mouth Neoplasms*
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• Abdulhameed Alsarraf, Roqaya Alrumaih. Oral Cancer Clinical Presentations – An Illustrative Review. International Journal of Dental Sciences and Research . Vol. 12, No. 2, 2024, pp 19-24. https://pubs.sciepub.com/ijdsr/12/2/1 ">Normal Style
• Alsarraf, Abdulhameed, and Roqaya Alrumaih. 'Oral Cancer Clinical Presentations – An Illustrative Review.' International Journal of Dental Sciences and Research 12.2 (2024): 19-24. ">MLA Style
• Alsarraf, A. , & Alrumaih, R. (2024). Oral Cancer Clinical Presentations – An Illustrative Review. International Journal of Dental Sciences and Research , 12 (2), 19-24. ">APA Style
• Alsarraf, Abdulhameed, and Roqaya Alrumaih. 'Oral Cancer Clinical Presentations – An Illustrative Review.' International Journal of Dental Sciences and Research 12, no. 2 (2024): 19-24. ">Chicago Style

Oral Cancer Clinical Presentations – An Illustrative Review

Oral cancer (OC) is a global health burden with a 5-year survival rate of 50%. It is traditionally defined as oral squamous cell carcinoma due to more than 90% of oral cancers histologically originating in the squamous cells. Early detection of OC improves morbidity accompanying its treatment therefore it is vital for clinicians to recognise the various clinical presentations of OC to facilitate prompt referral and early management. OC has a wide range of presentations with a spectrum ranging from a small asymptomatic lump, red or white, or mixed red and white patch to a large extensive ulcer or growth. In locally advanced cases, pain is usually present accompanied by referred pain to the ear, halitosis, trismus, dysphagia and odynophagia, intra-oral bleeding, weight loss and neck swelling. Due to the wide variation in clinical presentation, general dental practitioners and dental specialists may be unsure of suspicious lesions and the urgency of referrals required in such cases. This review aims to illustrate the clinical presentations of OC using representative clinical photographs from patients attending our Oral Medicine Clinic.

1. Introduction

One of the most significant causes of mortality and morbidity worldwide is cancer 1 . Oral cancer (OC) represents 2% of the cancer burden worldwide with an annual number of new cases exceeding 377,000 and 177,000 mortalities 2 . It most commonly presents as oral squamous cell carcinoma (OSCC) in 90% of the cases 3 . The mucosal lining epithelium is the site at which OSCC originates 3 . OSCC is a tumour involving invasive epithelial cells with a ranging degree of squamous differentiation 4 . OC most commonly presents in males between the ages of 60-79 5 . The incidence of OC has a diverse geographic variation, and a greater burden is observed in low- and middle-income countries such as Latin America, South-East Asia, and Western Europe 6 . This diverse incidence rate seems to be linked to the adaptation of different OC behavioural risk factors 7 .

The modality of management of OC is primarily through surgical resection of the tumour site and may include radiotherapy or chemotherapy 2 . Cancer treatment usually leads to the development of oral symptoms including dysphagia, salivary gland dysfunction, and mucositis 7 . Salivary gland dysfunction may result in altered taste, difficulty swallowing and infections of fungal origin 7 . Patients who undergo radiotherapy or chemotherapy may end up with mucositis which is inflammation of the tissues, resulting in sores and ulcers in 40% of the cases 7 .

Table 1. Anatomical subsites derived from the International Classification of Diseases for Oncology

• Tables index View option Full Size

The management of oral cancer through surgery and radiotherapy may not only result in disfigurement but may also interfere with daily activities such as talking, eating, and drinking 8 . Changes in appearance may follow even with successful reconstructive surgery and patients may end up with an increased risk of airway obstruction, hence may require a tracheostomy and a feeding tube 2 . Anatomical sites in which OC presents are listed in Table 1 . These sites are important for speech, swallowing, and taste, therefore OC and its treatment may have considerable functional sequelae with subsequent impairment of quality of life. This review illustrates a plethora of clinical features of oral cancer presenting in different oral cavity subsites.

2. Clinical Presentations

OC may arise in any oral cavity subsite ( Table 1 ). According to the affected subsite, clinical features may vary. OC may be detected at its early stages where lesions may appear as asymptomatic small ulcers or lumps. The size of initial OC lesions can range from a few millimeters to several centimeters as the lesions progress. Lesions may appear as erythroleukoplakias with central ulcerations indicating suspicion for carcinoma in situ or invasive squamous cell carcinoma at the time of detection ( Figure 1 ). Late-stage disease however appears as large growths with rolled margins and surface ulcerations ( Figure 2 ). The tongue is a common oral cavity subsite for the development of OC ( Figure 3 ). Suspicious tongue lesions may present as a small growth-like lesion ( Figure 4 ) to a larger ulcerative lesion extending to the ventral surface ( Figure 5 ). Some tumours present within large non-homogenous leukoplakias ( Figure 6 -8). In advanced cases, tumours present as ulceroproliferative growths with areas of necrosis and extension to surrounding structures such as muscle, bone, and layers of the skin with neck metastasis ( Figure 9 ). The floor of mouth represents the second most common site for the development of OC ( Figure 10 ). Lesions are likely to arise from a pre-existing leukoplakia or erythroplakia ( Figure 11 ). The palate may also be affected with OC when lesions present as non-healing indurated ulcers with a depressed alveolar mucosa ( Figure 12 ). It is worth noting that appropriate retraction of oral tissues aids in the detection of suspicious lumps presenting in edentulous spaces such as the lower posterior alveolar ridge ( Figure 13 ).

3. Risk factors

Risk factors for the development of OC include alcohol abuse, tobacco consumption and betel-quid chewing 10 . Individuals who are heavy smokers and binge drinkers are 38 times more likely to develop OC in comparison to abstainers 6 . This may be due to acetaldehyde, a metabolite of alcohol and a component of tobacco, which is classed as a carcinogen 6 . Acetaldehyde prevents the synthesis of DNA and its repair 2 . Heavy smokers are three times more likely to develop OC than their non-smoking counterparts 2 . Tobacco and alcohol together have a synergistic effect on the risk of developing OC 1 . Smokeless tobacco such as betel quid is sometimes combined with ground areca nut 2 . Areca nut alone without its combination with tobacco is associated with the development of OC as it causes cytotoxic damage of the mucosa through hypoxia and inflammation of the tissues 2 . These behavioural risk factors are thought to cause OC as they interfere with cellular processes and alter genetics 7 . Human Papilloma Virus (HPV) also seems to be linked to the development of OC 10 . A study from 27 countries examining head and neck squamous cell carcinoma revealed a greater risk in those with a low educational background and income regardless of behavioural risk factors such as alcohol consumption and smoking 11 . This shows the independent effect of one’s socioeconomic status on their OC development risk 11 .

• Figure 1. (Tongue) A large erythroleukoplakia with central ulceration (arrow) suspicious for OSCC

• Fig ure 2. (Tongue) An extensive growth-like lesion highly suspicious for OSCC

• Figure 3. (Tongue) A large growth-like lesion with surface ulceration suspicious for OSCC

• Figure 4. (Tongue) Growth-like lesion with a red ulcerative surface suspicious for OSCC

• Figure 5. (Tongue) Large ulcerative lesion extending from the lateral to ventral surface of tongue

• Figure 6. (Tongue) Suspicious tumour in the left aspect (arrow) of the dorsum surface surrounded by an extensive verrucous leukoplakia

• Figure 7. (Tongue) Large erythroleukoplakia suspicious for OSCC

• Figure 8. (Tongue) Highly suspicious growth-like lesion (arrow) presenting superior to a non-homogenous leukoplakia

• Figure 9. (Neck) Metastasis from primary oral cancer

• Figure 10. (Floor of mouth) Suspicious growth-like lesion

• Figure 11. (Floor of mouth) High-risk non-homogenous leukoplakia

• Figure 12. (Palate) A large suspicious ulcer with indurated margins and depressed alveolar mucosa

• Figure 13. (Lower alveolar ridge) A soft tissue lump with irregular surface texture recently developed (arrow), suspicious for carcinoma in situ or OSCC

4. Advanced Stages

In advanced stages of OC, ulceration is one of the most common features presenting with an irregular floor and margins, elevation, and induration. With large lesions, the pain is severe and usually radiates to the ipsilateral ear 12 . Less common presentations include paraesthesia of the chin or delayed healing following a dental extraction or sometimes a lump with abnormal blood vessel supply, dysphagia, or weight loss. In these advanced cases, neck metastases and cervical lymph node enlargement can be seen ( Figure 8 ). Large OC lesions (Stages T3-T4) with lymph node involvement (N2a-N2b) were most associated with mortality in a study on 216 patients over a period of 5 years 13 . Despite advances in medicine, OC has high rates of mortality with a global five-year survival rate of 50% 10 . Treatment leaves patients with high rates of morbidity 14 . In comparison to other cancers such as breast or colon, OC has worse survival rates due to failure of thorough screening, low index of suspicion, and poor dental attendance which all delay the diagnosis 14 . When the diagnosis is delayed, patients present late with more advanced disease which is more challenging to treat and hence a greater negative impact on their quality of life is observed. Cancer survival is heavily dependent on the stage of diagnosis 6 . More than half of patients (60%) with OC present in stages three and four, hence more complex treatment is required 6 . Higher survival rates are seen in patients treated with early stages of OC, hence early disease detection and referral improve survival 5 . A higher incidence of OC is seen in patients with a low socio-economic background and those patients tend to have worse outcomes such as worse survival rates 10 . OC seems to be closely linked to economic and social deprivation, with the highest incidence of disease occurring in those most deprived 6 . Cancer survival trends revealed a gap in survival rates between the most deprived and affluent groups 5 . This may be due to several factors including barriers to access and inadequate awareness 1 .

5. Clinical Significance

At the time of diagnosis, approximately half of OC patients present with metastases either regional or distant, leading to greater rates of mortality 15 . Late presentation is also associated with more complex treatment of an increased cost and increased morbidity 3 . In order to detect disease at early stages, a comprehensive oral examination should be routinely carried out by clinicians and if a potentially malignant lesion is present, referral to a specialist is required for a definitive diagnosis 14 . Malignant transformation is determined after histopathological grading of a specimen is completed to determine the presence and extent of oral epithelial dysplasia 15 . OSCC is usually preceded by oral potentially malignant disorders such as leukoplakia, erythroplakia and submucous fibrosis 16 . On some occasions, OSCC may develop from sound epithelium free of dysplastic changes 14 . However, a visible pre-clinical phase of dysplasia precedes most OSCC cases 17 . Screening could prevent malignant changes or ensure that disease is diagnosed at earlier stages 18 . It is the process of identifying individuals at increased risk of a disease from an apparently healthy population 18 . Screening is seen in multiple forms such as screening an entire population, or selectively where the focus is only on high-risk individuals, or opportunistically when individuals are screened after attending for other reasons 6 . OC screening is a straightforward, quick, cheap procedure that involves good lighting, gloves, and gauze in comparison to breast cancer screening which involves mammograms 3 . The incidence and mortality rates have been significantly improved after screening programmes have been introduced for common cancers such as breast and bowel cancer 6 . Screening programmes may allow for early disease detection and improved survival 3 . Clinicians are also encouraged to keep a detailed record of a lesion including the site, size, texture, borders, colour, and clinical photography is advised to monitor the lesion.

Guidelines on practices and treatment enhance outcomes as they set the standards for managing patients 1 . It is encouraged that local guidelines are developed for the referral of patients with potentially malignant lesions. In the United Kingdom, a 2 week wait pathways has been developed to ensure patients with a red/white patch, ulcer, or a new growth present in the mouth for more than three weeks are referred urgently to specialist services 14 . Having a clear referral system reduces error and ensures that patients are seen in a timely manner. Developing national guidelines may bridge the gap between general practitioners and specialists, hence minimising abuse of the system with unnecessary referrals and maximising effectiveness.

It is important to emphasise the crucial role of disease prevention in which General Dental Practitioners (GDP) identify risk factors through history taking and address them appropriately as part of the holistic treatment plan. Cultural barriers should be overcome especially when taking a social history. GDPs are expected to give smoking cessation and alcohol advice or signpost patients to the appropriate services. Managing those risk factors will not only reduce the risk of OC, but of other diseases as well. HPV vaccinations have been introduced globally. Patients should be encouraged to take the vaccine at appropriate ages. Governments tend to place resources on cancer treatment with a low emphasis on prevention 1 . According to the World health Organization, it is advised that measures are put in place for prevention of OC as part of local cancer control programmes 3 . Hence campaigns should be developed to shed light on risk factors, signs, and symptoms of OC. Policy makers could work on initiatives to address risk factors such as taxing tobacco.

Additionally, the awareness of General Medical Practitioners and medical disciplines including otolaryngologists, gastroenterologists, and dermatologists with regards to OC is important. Many patients with oral diseases present to otolaryngology departments since patients consider the oral cavity to be within the realm of the throat, while many gastroenterologists assume oral lesions develop due to gastrointestinal disease 19 . The ultimate aim is to enhance early detection thereby improving prognosis for patients presenting with OC.

6. Conclusion

Oral cancer is a preventable disease and early detection can reduce cancerous transformation hence potentially improve survival rates. General dental practitioners and medical disciplines have an important role in giving advice on risk factors implicated in OC and to recognise and promptly refer suspicious lesions. This review illustrates a plethora of clinical features of OC presenting in different oral cavity subsites. Knowledge of the various clinical features facilitates prompt referral to specialist services for diagnosis and management.

ACKNOWLEDGEMENTS

The authors wish to thank the patients for giving consent to obtain clinical photographs.

Published with license by Science and Education Publishing, Copyright © 2024 Abdulhameed Alsarraf and Roqaya Alrumaih

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Briacell announces oral and poster presentations at asco 2024.

• Oral presentation by Mayo Clinic Professor and Principal Investigator, Saranya Chumsri, MD
• Two poster presentations include Drs. Hurvitz (Fred Hutchinson Cancer Center), Brufsky (UPMC), and Cristofanilli (Weill Cornell) as authors

PHILADELPHIA and VANCOUVER, British Columbia, April 24, 2024 (GLOBE NEWSWIRE) -- BriaCell Therapeutics Corp. (Nasdaq: BCTX, BCTXW) (TSX: BCT) (“BriaCell” or the “Company”), a clinical-stage biotechnology company that develops novel immunotherapies to transform cancer care, is pleased to announce an oral presentation on the clinical data of the randomized Phase 2 study evaluating Bria-IMT™ in patients with advanced metastatic breast cancer at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting taking place May 31 – June 4 at McCormick Place, Chicago, IL. Principal Investigator and Professor of Oncology, Mayo Clinic, Saranya Chumsri, MD, will be giving the presentation.

BriaCell will also have two poster presentations. The first poster will describe the Company’s ongoing pivotal Phase 3 registrational study in advanced metastatic breast cancer. BriaCell is excited to collaborate on this important program with authors and BriaCell medical advisory board members Sara A. Hurvitz, MD, Professor of Medicine, Fred Hutchinson Cancer Center, Adam M. Brufsky, MD, PhD, Professor of Medicine, University of Pittsburgh School of Medicine, and Massimo Cristofanilli, MD, Professor of Medicine, Weill Cornell Medical College, Cornell University. The other poster will describe clinical data of Bria-IMT™ in metastatic breast cancer patients who failed antibody drug conjugates (ADCs) and is spearheaded by Chaitali Nangia, MD, Partner, Hoag Medical Group, and Carmen Calfa, MD, Professor of Medicine, University of Miami.

The details are listed below.

Oral Presentation Session Temporary Abstract Submission ID: 461296 Abstract Number for Publication: 1022 Title: Outcomes of advanced/metastatic breast cancer (aMBC) treated with Bria-IMT™, an allogeneic whole cell immunotherapy. Session Type and Title: Rapid Oral Abstract – Breast Cancer—Metastatic Session Date and Time: 6/3/2024; 11:30 AM-1:00 PM CDT

Poster Presentation Session Temporary Abstract Submission ID: 458176 Abstract Number for Publication: TPS1137 Title: Study of the Bria-IMT™ regimen and CPI vs physicians' choice in advanced metastatic breast cancer (BRIA-ABC). Session Type and Title: Poster Session – Breast Cancer—Metastatic Session Date and Time: 6/2/2024, 9:00 AM-12:00 PM CDT Temporary Abstract Submission ID: 461256 Abstract Number for Publication: 1087 Abstract Title: SV-BR-1-GM after progression on ADC in patients with metastatic breast cancer. Session Type and Title: Poster Session – Breast Cancer—Metastatic Session Date and Time: 6/2/2024, 9:00 AM-12:00 PM CDT

Following the presentations, copies of the presentations will be posted on https://briacell.com/scientific-publications/ .

About BriaCell Therapeutics Corp.

BriaCell is a clinical-stage biotechnology company that develops novel immunotherapies to transform cancer care. More information is available at https://briacell.com/ .

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This press release contains “forward-looking statements” that are subject to substantial risks and uncertainties. All statements, other than statements of historical fact, contained in this press release are forward-looking statements. Forward-looking statements contained in this press release may be identified by the use of words such as “anticipate,” “believe,” “contemplate,” “could,” “estimate,” “expect,” “intend,” “seek,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “target,” “aim,” “should,” “will,” “would,” or the negative of these words or other similar expressions, although not all forward-looking statements contain these words. Forward-looking statements, including those about Dr. Saranya Chumsri’s delivery of an oral presentation outlining BriaCell’s clinical data regarding the Company’s Phase 2 study evaluating Bria-IMT™ in patients with advanced metastatic breast cancer; BriaCell’s two poster presentations with one poster describing the Company’s ongoing pivotal Phase 3 registrational study in advanced metastatic breast cancer, and its collaboration with authors and BriaCell medical advisory board members Sara A. Hurvitz, MD, Professor of Medicine, Fred Hutchinson Cancer Center, Adam M. Brufsky, MD, PhD, Professor of Medicine, University of Pittsburgh School of Medicine, and Massimo Cristofanilli, MD, Professor of Medicine, Weill Cornell Medical College, Cornell University; BriaCell’s second poster describing clinical data of Bria-IMT™ in metastatic breast cancer patients who failed antibody drug conjugates (ADCs) and it being spearheaded by Chaitali Nangia, MD, Partner, Hoag Medical Group, and Carmen Calfa, MD, Professor of Medicine, University of Miami; and the contents of all such oral and poster presentations are based on BriaCell’s current expectations and are subject to inherent uncertainties, risks, and assumptions that are difficult to predict. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate. These and other risks and uncertainties are described more fully under the heading “Risks and Uncertainties” in the Company's most recent Management’s Discussion and Analysis, under the heading "Risk Factors" in the Company's most recent Annual Information Form, and under “Risks and Uncertainties” in the Company's other filings with the Canadian securities regulatory authorities and the U.S. Securities and Exchange Commission, all of which are available under the Company's profiles on SEDAR+ at www.sedarplus.ca and on EDGAR at www.sec.gov . Forward-looking statements contained in this announcement are made as of this date, and BriaCell Therapeutics Corp. undertakes no duty to update such information except as required under applicable law.

Neither the Toronto Stock Exchange nor its Regulation Services Provider (as that term is defined in the policies of the Toronto Stock Exchange) accepts responsibility for the adequacy or accuracy of this release.

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Company Contact: William V. Williams, MD President & CEO 1-888-485-6340 [email protected]

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Medicenna Announces Oral Presentation of MDNA11 Data from the Phase 1/2 ABILITY-1 Study at the 2024 ASCO Annual Meeting

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Oral presentation of MDNA11’s Phase 1/2 ABILITY-1 Study will feature new and updated clinical data

Medicenna Announces Oral Presentation of MDNA11 Data from the Phase 1/2 ABILITY-1 Study at the 2024 ASCO Annual Meeting Back to video

Updated bizaxofusp survival results from the Phase 2b recurrent glioblastoma trial versus propensity matched external control arm will also be presented as a poster

TORONTO and HOUSTON, April 24, 2024 (GLOBE NEWSWIRE) —  Medicenna Therapeutics Corp. (“Medicenna” or the “Company”) (TSX: MDNA, OTCQB: MDNAF), a clinical-stage immunotherapy company focused on the development of Superkines, announced today that it will be presenting two abstracts, including an oral podium presentation, at the Annual Meeting of the American Society of Clinical Oncology (“ASCO”) to be held in Chicago from May 31 – June 4, 2024.

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The oral podium presentation will include new clinical data from the ongoing Phase 1/2 ABILITY-1 Study evaluating MDNA11, a long-acting ‘beta-enhanced not-alpha’ interleukin-2 (IL-2) super-agonist, as both a monotherapy and in combination with pembrolizumab (KEYTRUDA®) in patients with advanced or metastatic solid tumors.

Details of the podium presentation are as follows:

Title: “Results from ABILITY-1 Monotherapy Dose Escalation Study with MDNA11, an Engineered Long-acting IL-2 agonist, in patients with advanced solid tumors” Abstract #: 2508 Abstract Session: Developmental Therapeutics – Immunotherapy Date and Time: June 3, 2024; 11:30 AM-2:30 PM CDT Presenter: Dr Victoria G. Atkinson, MBBS, FRACP, Gallipoli Medical Research Foundation, Greenslopes Private Hospital, and Princess Alexandra Hospital, University of Queensland, Australia.

The second abstract will provide new data analyses for bizaxofusp (formerly known as MDNA55) survival outcomes compared to a propensity matched external control arm (ECA) in nonresectable recurrent glioblastoma (rGBM).

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Details of the poster presentation are as follows:

Title: “Phase 2 Study of Bizaxofusp, an IL-4R Targeted Toxin Payload, in Nonresectable Recurrent GBM: Comparison of Overall Survival with Contemporaneous Eligibility-Matched and Propensity Score Balanced External Control Arm” Abstract #: 2709 Abstract Session: Poster Session – Central Nervous System Tumors Date and Time: June 1, 2024; 9:00 AM-12:00 PM CDT Presenter: Dr. John Sampson, MD, PhD, MBA, Robert H. and Gloria Wilkins Distinguished Professor of Neurosurgery, School of Medicine, Duke University, Durham, North Carolina, USA

The full text of the published abstracts will be available on the 2024 ASCO Annual Meeting website on May 23 rd , 2024 at 5:00 PM EDT.

About MDNA11

MDNA11 is a long-acting ‘beta-enhanced not-alpha’ interleukin-2 (IL-2) Superkine specifically engineered to overcome the shortcomings of aldesleukin and other next generation IL-2 variants by preferentially activating immune effector cells (CD4 + T, CD8 + T and NK cells) responsible for killing cancer cells, with minimal or no stimulation of immunosuppressive Tregs. These unique proprietary features of the IL-2 Superkine have been achieved by incorporating seven specific mutations and genetically fusing it to a recombinant human albumin scaffold to improve the pharmacokinetic (PK) profile and pharmacological activity of MDNA11 due to albumin’s natural propensity to accumulate in highly vascularized sites, in particular tumor and tumor draining lymph nodes. MDNA11 is currently being evaluated in the Phase 1/2 ABILITY-1 study as both a monotherapy and in combination with pembrolizumab (KEYTRUDA®).

About the ABILITY-1 Study

The ABILITY-1 study ( NCT05086692 ) is a global, multi-center, open-label study that assesses the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of MDNA11 as monotherapy or in combination with pembrolizumab (KEYTRUDA®). In the combination dose escalation of the Phase 2 study, approximately 6-12 patients are expected to be enrolled and administered ascending doses of MDNA11 intravenously once every two weeks in combination with pembrolizumab. This portion of the study includes patients with a wide range of solid tumors with the potential for susceptibility to immune modulating therapeutics. Upon identification of an appropriate dose regimen for combination, the study will proceed to a combination dose expansion cohort.

About Bizaxofusp

Bizaxofusp (formerly known as MDNA55) is Medicenna’s IL-4 Empowered Superkine that has been studied in 5 clinical trials in over 130 patients, including a Phase 2b trial in patients with recurrent glioblastoma (rGBM), the most common and uniformly fatal form of brain cancer. Results from the Phase 2b study, which were published in the journal Neuro-Oncology® (Sampson, et al. June 2023), demonstrated that bizaxofusp more than doubled the median survival in end-stage rGBM patients when compared to a well-matched external control arm. Medicenna has obtained agreement from the U.S. FDA on the study design for the registrational Phase 3 LIGHT™ ( L ocalized I nfusion for the treatment of recurrent G lioblastoma with H igh-dose bizaxofusp T herapy) trial and the Company is actively pursuing potential partnerships to conduct the LIGHT trial, and if approved, bizaxofusp’s commercialization in key global markets. Bizaxofusp has been granted FastTrack and Orphan Drug status from the FDA and FDA/EMA, respectively.

About Medicenna

Medicenna is a clinical-stage immunotherapy company focused on developing novel, highly selective versions of IL-2, IL-4 and IL-13 Superkines and first-in-class Empowered Superkines. Medicenna’s long-acting IL-2 Superkine, MDNA11, is a next-generation IL-2 with superior affinity toward CD122 (IL-2 receptor beta) and no CD25 (IL-2 receptor alpha) binding, thereby preferentially stimulating cancer-killing effector T cells and NK cells. Medicenna’s IL-4 Empowered Superkine, bizaxofusp (formerly MDNA55), has been studied in 5 clinical trials enrolling over 130 patients, including a Phase 2b trial for recurrent GBM, the most common and uniformly fatal form of brain cancer. Bizaxofusp has obtained FastTrack and Orphan Drug status from the FDA and FDA/EMA, respectively. Medicenna’s early-stage BiSKITs™ (Bifunctional SuperKine ImmunoTherapies) and the T-MASK™ (Targeted Metalloprotease Activated SuperKine) programs are designed to enhance the ability of Superkines to treat immunologically “cold” tumors.

For more information, please visit  www.medicenna.com , and follow us on  Twitter and  LinkedIn .

KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Forward-Looking Statements

This news release contains forward-looking statements within the meaning of applicable securities laws. Forward-looking statements include, but are not limited to, express or implied statements regarding the future operations of the Company, estimates, plans, strategic ambitions, partnership activities and opportunities, objectives, expectations, opinions, forecasts, projections, guidance, outlook or other statements that are not historical facts, such as statements on the Company’s clinical performance and potential, of MDNA11 and bizaxofusp (MDNA55). Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical studies may not be indicative of full results or results from later stage or larger scale clinical studies and do not ensure regulatory approval. You should not place undue reliance on these statements or the scientific data presented. Forward-looking statements are often identified by terms such as “will”, “may”, “should”, “anticipate”, “expect”, “believe”, “seek”, “potentially” and similar expressions. Forward-looking statements are based on a number of assumptions believed by the Company to be reasonable at the date of this news release. Although the Company believes that the expectations reflected in such forward-looking statements are reasonable, there can be no assurance that such statements will prove to be accurate. These statements are subject to certain risks and uncertainties and may be based on assumptions that could cause actual results and future events to differ materially from those anticipated or implied in such statements. Important factors that could cause actual results to differ materially from the Company’s expectations include the risks detailed in the latest Annual Report on Form 20-F of the Company and in other filings made by the Company with the applicable securities regulators from time to time in Canada.

The reader is cautioned that assumptions used in the preparation of any forward-looking information may prove to be incorrect. Events or circumstances may cause actual results to differ materially from those predicted, as a result of numerous known and unknown risks, uncertainties, and other factors, many of which are beyond the control of the Company. The reader is cautioned not to place undue reliance on any forward-looking information. Such information, although considered reasonable by management, may prove to be incorrect and actual results may differ materially from those anticipated or implied in forward-looking statements. Forward-looking statements contained in this news release are expressly qualified by this cautionary statement. The forward-looking statements contained in this news release are made as of the date hereof and except as required by law, we do not intend and do not assume any obligation to update or revise publicly any of the included forward-looking statements.

This news release contains hyperlinks to information that is not deemed to be incorporated by reference in this news release.

Investor and Media Contact:

Christina Cameron Investor Relations, Medicenna Therapeutics [email protected] (647) 953-0673

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Merus Announces Abstracts Accepted for Presentation at the 2024 ASCO Annual Meeting

Petosemtamab in combination with pembrolizumab in 1L HNSCC initial interim clinical data selected for rapid oral session presentation

MCLA-145 as monotherapy or in combination with pembrolizumab in solid tumors initial interim clinical data selected for rapid oral session presentation

MCLA-129 in NSCLC with c-MET exon 14 skipping mutations initial interim clinical data selected for poster presentation

Rapid oral presentation:

Title: Petosemtamab (MCLA-158) with pembrolizumab as first-line (1L) treatment of recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC): Phase 2 study

Abstract #: 6014

Session Title: Head and Neck Cancer

Session Date and Time: June 3, 2024, 8:00-9:30 a.m. CT

The presentation concerns petosemtamab evaluated in combination with pembrolizumab in patients with untreated advanced PD-L1+ HNSCC.

Title: Phase I study of MCLA-145, a bispecific antibody targeting CD137 and PD-L1, in solid tumors, as monotherapy or in combination with pembrolizumab

Abstract #: 2520

Session Title: Developmental Therapeutics—Immunotherapy

Session Date and Time: June 2, 2024, 11:30 a.m.-1:00 p.m. CT

The presentation concerns MCLA-145 evaluated as monotherapy or in combination with pembrolizumab in patients with solid tumors.

Poster presentation:

Title: Efficacy and safety of MCLA-129, an anti-EGFR/c-MET bispecific antibody, in non-small-cell lung cancer (NSCLC) with c-MET exon 14 skipping mutations (METex14)

Abstract #: 8583

Session Title: Lung Cancer—Non-Small Cell Metastatic

Session Date and Time: June 3, 2024, 1:30-4:30 p.m. CT

The presentation concerns MCLA-129 evaluated as monotherapy in patients with locally advanced/metastatic METex14 NSCLC.

The abstracts will be available on the ASCO website on May 23, 2024 at 5:00 p.m. ET. The full presentations will be available on the Merus website at the start of each session.

About Petosemtamab

Petosemtamab, or MCLA-158, is a bispecific Biclonics® low-fucose human full-length IgG1 antibody targeting the epidermal growth factor receptor (EGFR) and the leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5). Petosemtamab is designed to exhibit three independent mechanisms of action including inhibition of EGFR-dependent signaling, LGR5 binding leading to EGFR internalization and degradation in cancer cells, and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activity.

About MCLA-145

MCLA-145 is a Biclonics® T-cell agonist that binds with high affinity and specificity to human PD-L1 and CD137 in preclinical models. The unique immunostimulatory profile of MCLA-145 derives from the potential to potently activate immune effector cells in the context of the tumor microenvironment while blocking inhibitory signals among T-cells within the same immune cell population.

About MCLA-129

MCLA-129 is an antibody-dependent cellular cytotoxicity-enhanced Biclonics® that is designed to inhibit the EGFR and c-MET signaling pathways in solid tumors. Preclinical data have shown that MCLA-129 can effectively treat TKI-resistant NSCLC in xenograft models of cancer. MCLA-129 is designed to have two complementary mechanisms of action: blocking growth and survival pathways to stop tumor expansion and recruitment and enhancement of immune effector cells to eliminate the tumor.

About Merus N.V.

Merus is a clinical-stage oncology company developing innovative full-length human bispecific and trispecific antibody therapeutics, referred to as Multiclonics®. Multiclonics® are manufactured using industry standard processes and have been observed in preclinical and clinical studies to have several of the same features of conventional human monoclonal antibodies, such as long half-life and low immunogenicity. For additional information, please visit Merus’ website, X, and LinkedIn.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the clinical development of petosemtamab, MCLA-145 and MCLA-129, future clinical trial results or interim data, clinical activity and safety profile in the on-going trials and planned abstracts and presentation. These forward-looking statements are based on management’s current expectations. These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our need for additional funding, which may not be available and which may require us to restrict our operations or require us to relinquish rights to our technologies or Biclonics®, Triclonics® and multispecific antibody candidates; potential delays in regulatory approval, which would impact our ability to commercialize our product candidates and affect our ability to generate revenue; the lengthy and expensive process of clinical drug development, which has an uncertain outcome; the unpredictable nature of our early stage development efforts for marketable drugs; potential delays in enrollment of patients, which could affect the receipt of necessary regulatory approvals; our reliance on third parties to conduct our clinical trials and the potential for those third parties to not perform satisfactorily; impacts of the market volatility; we may not identify suitable Biclonics® or bispecific antibody candidates under our collaborations or our collaborators may fail to perform adequately under our collaborations; our reliance on third parties to manufacture our product candidates, which may delay, prevent or impair our development and commercialization efforts; protection of our proprietary technology; our patents may be found invalid, unenforceable, circumvented by competitors and our patent applications may be found not to comply with the rules and regulations of patentability; we may fail to prevail in potential lawsuits for infringement of third-party intellectual property; and our registered or unregistered trademarks or trade names may be challenged, infringed, circumvented or declared generic or determined to be infringing on other marks.

These and other important factors discussed under the caption “Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2023 filed with the Securities and Exchange Commission, or SEC, on February 28, 2024, and our other reports filed with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change, except as required under applicable law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release.

Biclonics®, Triclonics® and Multiclonics® are registered trademarks of Merus N.V.

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Sapience therapeutics announces oral presentation at the upcoming 2024 asco annual meeting featuring st101 phase 2 results in gbm.

-Presentation to include clinical efficacy and biomarker data-

TARRYTOWN, N.Y. , April 24, 2024 /PRNewswire/ -- Sapience Therapeutics, Inc., a clinical-stage biotechnology company focused on the discovery and development of peptide therapeutics to address oncogenic and immune dysregulation that drive cancer, today announced that data from its Phase 2 study of ST101 will be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 31-June 4, 2024, in Chicago, IL and online.

ST101 is a first-in-class antagonist of C/EBPβ, currently being evaluated in patients with recurrent and newly diagnosed GBM in the Phase 2 portion of an ongoing Phase 1-2 clinical study ( NCT04478279 ).

Presentation details:

Abstract Title:  " Efficacy and biomarker analysis of phase 2 (P2) and window-of-opportunity (WoO) cohorts of patients with glioblastoma (GBM) treated with ST101, an inhibitor of the transcription factor C/EBP β"

Abstract Number for Publication:  2011

Session Type and Title: Clinical Science Symposium – Advancing Trial Design: Illuminating Tumor Evolution in Central Nervous System Cancer

Date and Time: 6/1/2024, 3:00 PM-4:30 PM CDT

Presenting Author: Fabio M. Iwamoto , MD, Division of Neuro-Oncology, New York-Presbyterian/Columbia University Medical Center

More information can be found on the 2024 ASCO  website . The presentation described here will be made available on the Sapience Therapeutics website following the conference.

About ST101

ST101, a first-in-class antagonist of C/EBPβ, is currently being evaluated in patients with newly diagnosed and recurrent GBM (ndGBM and rGBM) in the Phase 2 portion of an ongoing Phase 1-2 clinical study ( NCT04478279 ). In an ongoing window-of-opportunity sub-study, ST101 is being evaluated as a monotherapy in rGBM and in combination with radiation and temozolomide in ndGBM, with patients receiving ST101 before and after surgical resection. ST101 has been granted Fast Track designation for rGBM from the U.S. FDA and orphan designations for glioma from the U.S. FDA and the European Commission.

About Sapience Therapeutics

Sapience Therapeutics, Inc. is a privately held, clinical-stage biotechnology company focused on discovering and developing peptide therapeutics to address oncogenic and immune dysregulation that drive cancer.  With in-house discovery capabilities, Sapience has built a pipeline of therapeutic candidates called SPEARs™ (Stabilized Peptides Engineered Against Regulation) that disrupt intracellular protein-protein interactions, enabling targeting of transcription factors which have traditionally been considered undruggable. Sapience is advancing its lead programs, ST316, a first-in-class antagonist of β-catenin, and ST101, a first-in-class antagonist of C/EBPβ, through Phase 1-2 clinical trials.

For more information on Sapience Therapeutics, please visit  www.sapiencetherapeutics.com  and engage with us on  LinkedIn .

Cautionary Note on Forward-Looking Statements

This press release contains forward-looking statements. Any statements herein other than statements of historical fact could be deemed to be forward-looking statements. These forward-looking statements may include, among other things, statements regarding future events that involve significant risks and uncertainties (including with respect to Sapience's preclinical and clinical development programs). These forward-looking statements are based on management's current expectations, and actual results and future events may differ materially as a result of certain factors, including, without limitation, our ability to obtain additional funds, and meet applicable regulatory standards and receive required regulatory approvals. Forward-looking statements speak only as of the date of this press release. Sapience does not undertake any obligation to update any forward-looking statements as a result of new information, future events, changed assumptions or otherwise, except as required by law.

Media and Investor Contact: Amy Conrad Juniper Point (858) 366-3243 [email protected]

View original content to download multimedia: https://www.prnewswire.com/news-releases/sapience-therapeutics-announces-oral-presentation-at-the-upcoming-2024-asco-annual-meeting-featuring-st101-phase-2-results-in-gbm-302126199.html

SOURCE Sapience Therapeutics, Inc.

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Unmet Needs and Perspectives in Oral Cancer Prevention

Jebrane bouaoud.

1 Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, CNRS 5286, INSERM 1052, Université Claude Bernard Lyon 1, University Lyon, F-69008 Lyon, France; [email protected]

2 Department of Translational Research and Innovation, Centre Léon Bérard, Université Claude Bernard Lyon 1, University Lyon, F-69008 Lyon, France; [email protected] (V.G.); [email protected] (C.B.)

3 Department of Maxillo-Facial Surgery, Assistance Publique des Hôpitaux de Paris, Sorbonne Université, Hôpital Pitié-Salpêtrière, F-75013 Paris, France

Paolo Bossi

4 Medical Oncology, ASST Spedali Civili Brescia, I-25064 Brescia, Italy; [email protected]

5 Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, I-25123 Brescia, Italy

Moshe Elkabets

6 The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel; li.ca.ugb@eehsom (M.E.); li.ca.ugb.tsop@seedagaj (S.J.)

7 Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel

Sandra Schmitz

8 Department of Medical Oncology and Head and Neck Surgery, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), UCLouvain, 1200 Brussels, Belgium; [email protected] (S.S.); [email protected] (J.-P.M.)

Léon C. van Kempen

9 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9712 CP Groningen, The Netherlands; [email protected]

Pierre Martinez

Sankar jagadeeshan, ingrid breuskin.

10 Department of Head and Neck Oncology, Gustave Roussy Cancer Campus, F-94805 Villejuif, France; [email protected]

Gerwin J. Puppels

11 Department of Dermatology, Erasmus MC, University Medical Center Rotterdam, Room Ee-1691, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; moc.drevir@sleppupg

Caroline Hoffmann

12 INSERM U932 Research Unit, Department of Surgery, Institut Curie, PSL Research University, F-75006 Paris, France; [email protected]

Keith D. Hunter

13 Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, UK; [email protected]

Christian Simon

14 Department of Otolaryngology and Head and Neck Surgery, Lausanne University Hospital, 1011 Lausanne, Switzerland; [email protected]

Jean-Pascal Machiels

Vincent grégoire.

15 Radiation Oncology Department, Centre Léon Bérard, Université Claude Bernard Lyon 1, University Lyon, F-69008 Lyon, France

Chloé Bertolus

Ruud h. brakenhoff.

16 Cancer Center Amsterdam, Section Head and Neck Cancer Biology & Immunology, Otolaryngology and Head and Neck Surgery, Vrije Universiteit Amsterdam, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands; [email protected]

Senada Koljenović

17 Department of Pathology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; [email protected]

Pierre Saintigny

18 Department of Medical Oncology, Centre Léon Bérard, Université Claude Bernard Lyon 1, University Lyon, 28 Promenade Léa et Napoléon Bullukian, F-69008 Lyon, France

Simple Summary

Oral cavity is the most common site of head and neck cancer which is ranked as the eighth most common cancer worldwide. Oral cancer treatment is often associated with significant morbidity and is sometimes ineffective. These cancers, mainly due to tobacco and alcohol consumption, can develop from oral potentially malignant disorders, the most common of which is oral leukoplakia. Some of these oral potentially malignant disorders disappear, while others will transform to oral cancer. Patients may also develop cancer in the field of cancerization. Unfortunately, except for the surgical excision of lesions with dysplasia, there is no effective intervention to effectively prevent transformation or cancer development in the field of cancerization. Moreover, no standardized biomarker has been clearly identified as sufficient to predict malignant transformation. In this article, several experts discuss the main challenges in oral cancer prevention, in particular the need (i) to define new a new classification system integrating cellular and molecular features aiming (ii) at better identifying patients at high risk of malignant transformation, and (iii) at developing treatment strategies to prevent their malignant transformation of oral potentially malignant disorders.

Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation.

1. Introduction

Oral cavity is the most common site of Head and Neck Squamous Cell Carcinoma (HNSCC), which is ranked as the eight most common cancer worldwide [ 1 ]. Oral SCC (OSCC) is a major cause of morbidity and mortality [ 2 , 3 ]. OSCC are preceded by mucosal precancerous changes that might be visible as white (leukoplakia) or red (erythroplakia) lesions, but are mostly not macroscopically visible, which explains that most OSCC seem to develop de novo . However, the preceding precancerous changes can present under the microscope as abnormal mucosal epithelium, also indicated as dysplasia, graded as mild moderate and severe, or they can be identified by genetic markers. In 2017, the World Health Organization (WHO) defined oral potentially malignant disorders (OPMD) as “clinical presentations that carry a risk of cancer development in the oral cavity, whether in a clinically definable precursor lesion or in clinically normal mucosa” [ 4 ]. Thus, OPMD may precede OSCC, and may be visible or not [ 5 ]. While it is traditionally assumed that OPMD and OSCC are associated with similar risk factors (e.g., alcohol, tobacco, betel quid), a proportion of OPMD and OSCC cases occur in the complete absence of any identifiable risk factor, particularly in young patients who have never been drinkers or smokers [ 6 , 7 , 8 , 9 ]. The overall worldwide prevalence of OPMD is about 4.5% [ 10 ]. The main risk factors of malignant transformation of OPMD described to date are patient-related, clinical (e.g., female, >50 years; non-smoker with a nonhomogeneous red lesion of the tongue and floor of mouth >200 mm 2 and existing for several years; history of previous OSCC; diabetes mellitus), tumor-related, histological (i.e., severe dysplasia), and molecular factors (i.e., aneuploidy, loss of heterozygosity [LOH]). The reported malignant transformation rates range from 3 to 66%, indicating that variable definitions may be used, data with different follow-up periods have been collected and the existence of histological and, in particular, molecular heterogeneity of OPMD [ 11 , 12 , 13 , 14 , 15 ]. For OPMDs that are visible, standard policy is to take multiple, repeated, and deep incision biopsies to check for invasive growth and dysplasia. Treatment of the OPMD may prevent malignant transformation and improve outcome [ 6 , 11 ]. The surgical excision of OPMD can decrease the risk of malignant transformation at the same site, but it does not eliminate the risk of subsequent development of SCC at other sites [ 16 ]. To date, no standard therapy has been shown to be effective in patients with OPMD to prevent OSCC development in the entire field of cancerization [ 17 ].

The main challenges are (i) to define an OPMD classification system integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop prevention strategies that would treat both the visible lesion and the entire field of cancerization [ 18 , 19 ]. Large longitudinal studies of OPMD cases with malignant transformation, as the most relevant clinical outcome, are required.

2. Pathological Perspective

As defined in the recent OPMD WHO classification, OPMD include fifteen disorders affecting the oral mucosa (e.g., leukoplakia, erythroplakia, proliferative verrucous leukoplakia, oral submucous fibrosis…) and which are either secondary to genetic aberrations, exposure to exogenous factors such as tobacco and/or immune-mediated disorders or related to rare inherited diseases [ 4 , 20 ]. The different histologic features, especially those usually used to grade dysplasia (architectural and cytologic changes…) have been reviewed elsewhere [ 21 ].

The histopathological diagnosis and grading of dysplasia are the gold standard in guiding OPMD management. Unfortunately, especially in the oral cavity, it is challenging due to the high degree of inter and intra-observer variability, resulting in limited value of grading of dysplasia as a predictive factor for OPMD malignant transformation [ 22 , 23 ]. The WHO classification postulates that the more advanced the degree of dysplasia, the higher the likelihood of developing oral squamous cell carcinoma (OSCC). However, the literature reports that OSCC may also arise from seemingly non-dysplastic epithelium. The histology of these lesions is subtle and easily underdiagnosed. In particular, by studying the abnormalities in the mucosa surrounding OSCC, it was recently shown that the dysplastic changes are most commonly subtle (70%, with the features of so-called differentiated dysplasia) and therefore may easily be undervalued by the pathologist [ 24 ]. To improve the dysplasia diagnosis, authors proposed refined histopathological criteria, and have shown that immunohistochemistry with antibodies against cytokeratin 13, cytokeratin 17, and Ki67 is a useful diagnostic adjunct. It has been shown that, compared to the classic histologic criteria (Who 2017), differentiated dysplasia improves the prediction of oral leukoplakia at increased risk of malignant progression [ 25 ]. To address the issues in histological diagnosis and grading of dysplasia, we should develop refined and standardized histopathological criteria encompassing the various histological appearances for reliable diagnosis of OPMD and implement validated immunohistochemical and molecular biomarkers.

In addition, Artificial Intelligence methods are becoming a powerful diagnostic adjunct [ 26 ]. In particular, machine learning and deep learning algorithms are promising for diagnostic support (enhance laboratory efficiency and quality assurance), as disruptive technology to standard biomarkers, and to derive patterns not achievable by a human observer [ 27 ]. Although this field is rapidly evolving, currently very few algorithms have reached clinical implementation [ 28 ].

3. Biomarkers, Prospective High-Risk Cohorts with Embedded Trials

Besides the clinical and histological characteristics of OPMD [ 4 ], several biomarkers have been proposed to identify patients with OPMD at high risk of OSCC development [ 29 ]. LOH at specific chromosomal sites (3p14 or 9p21) has been validated prospectively [ 30 ]. LOH was also found to be a biomarker predicting the development of second oral malignancies in patients with an OPMD, subsequent to the treatment of a OSCC [ 31 , 32 ]. Prospective cohorts with long-term follow-up of patients with OPMD are needed to identify other predictive biomarkers that may be used for clinical practice.

4. Biology of Precancerous Changes

In 1953, Slaughter et al., concluded from histopathological studies of oral cancer specimen: “From the foregoing observations it would appear that epidermoid carcinoma of the oral stratified squamous epithelium originates in a process of “field cancerization,” in which an area of epithelium has been preconditioned by an as-yet-unknown carcinogenic agent. Such a carcinogenic influence if operative enough in time and intense enough in exposure produces an irreversible change in cells and cell groups in the given area, so that change of the process toward cancer becomes inevitable” [ 33 ]. It is remarkable that this model was already reported before tobacco and alcohol were identified as the major culprits of OSCC, and before the scientific world had any clue on molecular carcinogenesis and the role of mutated cancer genes. At present, we know that cancer arises by the accumulation of genetic and epigenetic changes, causing a changed circuitry of many signal transduction routes and invoking the acquired capabilities of cancer cells characterized as the “hallmarks of cancer” [ 34 ]. Hence, the onset and driving force of carcinogenesis is the accumulation of genetic changes, albeit stroma interactions likely play a role in parallel. The genetic changes occurring during oral carcinogenesis are now well defined [ 33 , 35 , 36 , 37 , 38 ]. Typical chromosomal changes such as loss of 3p, 9p, and 17p that are frequently found in invasive HNSCC are also found in precancerous changes and are in fact the most accurate predictors of malignant transformation of the OPMD, as discussed above [ 30 ].

Given the causal role of genetic changes in carcinogenesis, the upper aerodigestive tract field cancerization may be explained, at least partially, by the accumulation of genetic changes in the mucosal keratinocytes. There are no specific markers of stem cells in the mucosa, but we may assume that these exist in the basal layer of the mucosal epithelium. The stemness of such cells is not intrinsic and fixed, but most likely the result of a dynamic process as it is in the intestine [ 39 ]. These stem cells form the basis of the mucosal units of transit, amplifying cells and differentiating cells in areas of approximately 200 cells wide, which together make up the mucosal epithelium. This clonal unit was demonstrated in mouse epidermis using Axin2 lineage tracing experiments [ 40 ]. A somatic mutation in such a cell with stemness properties will give rise to a mutated clonal unit as first described in 2002 using TP53 mutations as a molecular marker [ 41 ]. These rare somatic mutations in cells have since been shown in numerous tissues and are studied using next generation sequencing approaches [ 42 , 43 ]. The mutated cells compete with the wild type cells. In the skin, UV-induced cell death of normal cells supports the extension of the preneoplastic cells [ 44 ]. In the oesophagus, oxidative stress has been identified as a potential factor that supports the proliferation of TP53-mutated cells over the wild type cells [ 45 ]. When applying N-acetylcysteine (NAC) as oxidative stress reducing agent, the balance was shifted in advantage of wild type cells. However, no effect of NAC to prevent recurrent cancer or second primary tumours in both lung and head and neck cancer patients was seen in the EUROSCAN trial [ 46 ].

Besides environmental factors that may favour the growth of genetically damaged cells, the accumulation of subsequent genetic alterations may induce a growth advantage and change the balance between normal cells and genetically damaged cells, the latter displacing the normal mucosa by so far unresolved mechanisms. It is likely not related to proliferation rate as normal keratinocytes, precancer and cancer cells may have comparable cell division times, at least in vitro [ 47 ].

5. Field of Cancerization

A field should be defined as a group of cells with tumour-associated somatic genetic alterations. Irrespective of the underlying biology and cellular interaction, the preneoplastic fields will develop in time and can reach dimensions greater than 10 cm in diameter. As explained above, the minority is clinically visible as an asymptomatic persistent white or red lesion that cannot be rubbed off [ 20 ]. The clinical aspect is poorly specific of OPMD, given that not all lesions harbour histologically proven dysplasia [ 25 ]. Hence, the visible lesions form the tip of the iceberg. Indeed, some normal surgical margins of oral cancer specimen showed genetic changes, indicating that not all precancerous fields are recognized by histology, and that we must rely on genetic markers to identify all potentially malignant fields. However, with the introduction of differentiated dysplasia as novel morphological entity [ 24 , 25 ], this may change soon. Whether they are visible or not, these potentially malignant changes may transform into invasive cancers. The tumours are diagnosed and treated, but particularly when these fields are not visible to the naked eye, they may stay behind and cause local relapses clinically diagnosed either as local recurrence or second primary tumour, depending on the distance (2 cm and/or different subsite) and the time interval (3 years) [ 35 , 36 ]).

In vitro cultures of visible lesions were reported in 2002 [ 48 ]. More recently, 98 2D cultures from normal appearing mucosa of the surgical margins of patients with primary HNSCC were generated and characterized for their molecular alterations and the number of population doublings (PDs) [ 47 ]. Cultures with more than 20 PDs and a random selection of nine other cultures with a normal life span (<20 PDs) were analysed for copy number changes and for mutations of the ten key HNSCC driver genes using target-enrichment sequencing. Irrespective of the lifespan of < or >20 PD, in 50% of the cultures somatic genetic changes were identified with a large variety in type and number. Despite many genetic alterations in some cultures and an apparent immortal lifespan, none formed tumours in immunodeficient mice, demonstrating the lack of invasive capacity and confirming the precancerous state [ 48 ]. This supports that acquisition of immortality is an earlier event during OSCC progression than acquisition of invasive properties. Most frequently mutated genes were TP53 , NOTCH1 and FAT1 , whereas CDKN2A showed frequent copy number losses. Most intriguingly, in four cultures copy number changes were found but no mutations in key driver genes, suggesting that carcinogenesis may start with copy number changes, although such precancerous cells may never transform.

In summary, field cancerization has been well characterized in genetic terms, the cells can be cultured and even used for therapeutic target screening [ 49 , 50 ]. A field should be defined as a group of cells with tumour-associated somatic genetic alterations. A field should be larger than the clonal unit and, consequently, larger than at least 200 cells wide and can reach dimensions of up to 10 cm in diameter. Some fields present as dysplasia under the microscope, and some are macroscopically visible as a non-specific persistent white or red lesion. These fields contain a variety of genetic changes, but typically also mutations in the cancer driver genes of head and neck cancer. They develop by a process of somatic mutation in relation to aging and carcinogen exposure. The reason as to why the normal epithelium is displaced remains an enigma. Enhanced proliferation seems logical but is likely not the cause, and biological processes perhaps stimulated by environmental cues may be more likely.

6. The OPMD Immune Microenvironment (IME)

The interplay between OPMD and IME has been poorly explored, while it appears as a promising and actionable target [ 51 , 52 ]. Briefly, compared to OPMD that transformed into OSCC, patients with dysplastic OPMD and no subsequent malignant transformation had significantly more infiltrating CD3+, CD4+ and CD8+ T-cells and decreased T-regulatory cells [ 53 , 54 , 55 , 56 ]. Furthermore, the progression from OPMD to OSCC has shown increased number of CD163+ cells (M2 Macrophages), PD-L1 expression and a decreased number of CD8+ cells [ 52 , 53 , 56 , 57 , 58 , 59 ]. More recently, the Saintigny Team (JB, PS) studied the dynamic of the IME in the 4-NQO murine model of oral carcinogenesis [ 60 ], an accepted model for the human disease in particular at early steps of tumorigenesis [ 61 ]. They found that changes in the composition of immune infiltrate (T-cells, B-cells, M1/M2 macrophages) can already be observed in histologically proven premalignant stages. Transcriptomic changes revealed activation of immune related processes at early steps of oral carcinogenesis. On the other hand, when the gene expression data of 86 patients with OPMD were challenged with transcriptomic features coming from HNSCC patients, the lesions could be stratified in several clusters, and the OPMD from the mesenchymal, hypoxia and classical molecular subgroups showed a higher risk of malignant transformation in comparison with the immune-related ones [ 62 ].

It is tempting to speculate on OPMD within the concept of “immunoediting”, hypothesizing that these lesions are in the equilibrium phase of a dynamic process between the malignant transformation and surveillance of the immune system. One hypothesis is that malignancy will develop in the presence of an immunosuppressive microenvironment. Another hypothesis is that OPMD do not elicit a sufficient immune response, and that for two main reasons: (i) OPMD highly resemble “self” and are not detected as non-self by the immune system; (ii) OPMD barely induce local tissue-damage and therefore insufficiently release the immune-attracting damage-associated molecular patterns.

Overall, while promising, our knowledge of the complex and dynamic nature of the OPMD IME remains incomplete, which might explain the failure of immunoprevention strategies [ 63 , 64 ]. Thus, further characterization of the dynamic changes in immune response during oral carcinogenesis is required [ 51 , 52 ], especially differences between OPMD that subsequently transformed into OSCC and those that did not.

7. Oral Microbiome

The study of the potential contribution of the microbiome in the carcinogenesis of different cancer types including OSCC is emerging [ 65 ]. Regarding the very few studies which have reported the microbiome composition associated with OPMD, results are heterogeneous and difficult to compare because of diversity in microbiota and methodological heterogeneity [ 66 , 67 ]. Briefly, it was suggested that the microbiota may contribute to tumorigenesis, both directly (production of microbial genotoxin inflicting DNA damages), and indirectly through its interplay with the immune system (stimulation of chronic inflammation alters the immune responses and aberrant immune responses facilitate dysbiosis, especially in aging context) [ 68 ]. Moreover, the dysregulation by the microbiome of some physiological activities that are critical for oral carcinogenesis (nitrogen transport, response to stress, interspecies interactions, Wnt pathway modulation, and amino acid and lipid biosynthesis) were identified using the 4-NQO mice model [ 69 ]. Overall, the understanding of the role of the oral microbiome in carcinogenesis is still an area of investigation [ 67 ].

8. Early Diagnosis of OPMD

The early detection of OPMD serves the purpose of secondary prevention of oral cancer [ 70 ]. Examination of the oral cavity (visual inspection and palpation) is the conventional method for identifying and monitoring OPMD. However, clinical recognition of OPMD is challenging [ 5 ]. Thus, methods to enhance the early detection of OPMD are required [ 4 , 5 , 71 ].

In 2008, the International Agency for Research in Cancer (IARC) published a digital manual to help physicians in this aim. Furthermore, non-invasive in vivo optical imaging provides unique opportunities for real-time diagnosis of oral pre-malignancies. These techniques are mainly autofluorescence imaging (AFI), targeted fluorescence imaging (TFI), high-resolution microendoscopy (HRME), narrow band imaging (NBI) and Raman spectroscopy (RS) ( Table 1 ) [ 72 , 73 ].

Main in vivo optical imaging methods that could be used as an adjunct to conventional oral examination in oral premalignant disorders screening are autofluorescence imaging (AFI), targeted fluorescence imaging (TFI), high-resolution microendoscopy (HRME), narrow band imaging (NBI), Raman spectroscopy (RS). For each method, basic principles, advantages and inconvenient are described as well as references.

Using AFI, altered and dysplastic tissues appear darker compared to the healthy surrounding tissue (autofluorescence loss). AFI devices displayed superior accuracy levels in the identification of OPMD compared to clinical examination [ 74 ]. AFI devices evaluated for early diagnosis of OPMD are practical and cost-effective but suffer from low specificity [ 5 ]. Moreover, mucosa with hyperkeratinisation such as some oral leukoplakia can demonstrate increased autofluorescence when compared to normal mucosa, which limits the ability to detect malignant change within such lesions [ 75 ]. TFI utilizes a targeting fluorescence probe which can specifically target some elements by approved antibodies (targeted immune-fluorescence imaging). However, the lesion heterogeneity could decrease the TFI sensitivity.

NBI visualizes the angiogenic patterns within and surrounding lesions. NBI as an endoscopic system is widely available and easy to use [ 5 , 76 , 77 ]. Moreover, the neoangiogenesis-related morphological changes, especially the abnormal intraepithelial capillary loops (ICPL) patterns, have been widely reported [ 5 , 75 ]. Unfortunately, IPCL patterns characterization is subjective and the visualization of microvessel architecture may be affected by various factors. Artificial intelligence may make the prediction of malignant transformation more objective and with greater accuracy [ 26 ].

HRME is cost effective, non-invasive and provides real-time high-resolution microscopic images (in situ “optical biopsy”) [ 78 ]. HRME has demonstrated high sensitivity and specificity. However, HRME is not commercially available, its contrast agent is not yet approved, and the field of view is limited [ 5 ].

RS is a non-destructive vibrational spectroscopic technique [ 79 , 80 , 81 ]. Raman spectra represent the overall molecular composition of the tissue and can be used to distinguish healthy tissue from (pre-)malignant tissue [ 5 ]. RS is a promising tool for early diagnosis/biopsy guidance and follow up (optical biopsy) of OPMD but required further development [ 82 ].

Other imaging techniques to detect OPMD are optical coherence tomography, elastic scattering spectroscopy, diffuse reflectance spectroscopy, confocal laser endomicroscopy and confocal reflectance microscopy, but they are not widely developed [ 5 , 83 ]. Vital staining (toluidine blue, Methylene blue, Rose Bengal and Ludo’s iodine) are sensitive, simple, rapid, efficient and low-cost techniques [ 5 , 77 , 84 ] but false positive results are frequent, and their application is not without issues.

In summary, the previously described techniques are promising with high sensitivity to detect OPMD but suffer from poor specificity. This is not only due to inherent limitations of the techniques, but also to the lack of a good histological gold standard, which renders the development of predictive algorithms based on optical methods very difficult [ 5 , 75 , 84 ]. To overcome the technical part of the problem, a combination of techniques, e.g., combining AFI and HRME, are interesting [ 85 , 86 ]. Further investigations (large randomized clinical trial with long follow-up) are needed.

9. Preclinical Models

9.1. in vitro tissue culture models, 9.1.1. 2d culture of cell lines.

There are many reports of cell lines being established from OPMD biopsies ( Table 2 ). These OPMD cell line model systems recapitulate the key characteristics of the clinical lesions closely and have been used to study the early stages of oral cancer and malignant transformation of oral keratinocytes in vitro [ 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 ]. However, the major limitation of cell line models is that these cells fail to grow in vivo , thereby prohibiting the study of the involvement of the oral microenvironments.

Available cell lines to study oral premalignant disorders. (PMID: PubMed identification Member; ISSN: International Standard Serial Number).

9.1.2. 3D Culture of Organotypic Co-Culture

In this method, keratinocytes are cultured at an air-to-liquid interface on a fibroblast-containing collagen type I matrix. While several refinements have been proposed to overcome the major limitations of the classically used collagen-based connective tissue equivalent (deficit of complex structural heterogeneity and collagen fibre crosslinking present in mature connective tissue, induction of artificial epithelial invasion by lose of biostability over a long period of culture and lack of a well-defined continuous basement membrane between the epithelium and connective tissue) [ 95 ], to date, most organoids lacked vasculature, fibroblasts and immune cell components that are known to influence malignant transformation, which make them not a true representation of in vivo transformation of OPMD to OSCC.

Recently, to mimic the oral mucosal complexity, progress has been achieved in designing more complex tissue engineering techniques in organotypic co-cultures that includes the incorporation of blood capillaries to the cell surface [ 96 ], culturing oral keratinocytes with fibroblasts [ 97 ], immune cells [ 98 ], and oral microbiota [ 99 , 100 ]. As protocols and analysis methods continue to improve, these 3D techniques will become more accessible within the said field.

9.1.3. In Vivo Rodent Models

• Carcinogen-induced models

Several agents, including coal tar, cigarette smoke, benzo[a]pyrene (B[a]P), 3-methylcholanthrene, 7,12-dimethylbenz(a)anthracene (DMBA) and 4-nitroquinoline-1-oxide (4-NQO) have been used to induce OSCC in rodent models. In particular, the 4-NQO-induced oral carcinogenesis murine model closely resembles human OSCC in terms of pathogenesis, pathological changes, host immune activity, and molecular levels, thus making this model widely acceptable to study OSCC, especially for the identification of biomarkers for early diagnosis and the transformation of the epithelium [ 61 ]. The major limitations of the carcinogen-induced models are (i) the requirement of prolonged animal and carcinogen handling, making them laborious and time-consuming, (ii) the resulting tumours do not recapitulate the tumours in patients, and (iii) it is not possible to study specific gene alterations in the development and malignant transformation process.

• 2. Genetically engineered mouse models (GEMMs)

GEMMs that allow oncogene activation and/or tumour suppressor inactivation solely in stratified epithelia of the oral cavity under the control of inducible promoters are extensively used to study OPMD [ 101 ]. While promising, there are still several barriers to their full application in understanding the OPMD malignant transformation. The main limitation is that these models do not reflect human oral pathogenesis in terms of the degree of gene expression during the transformation process. Secondly, these models have low specificity to form premalignant lesions by gene activation or inactivation and appear in sites other than the oral cavity. Thirdly, the introduction of exogenous genes or the knockout of endogenous genes in GEMM will occur in almost every cell which does not recapitulate the normal oral microenvironment of OPMD. Lastly, the potentially induced changes or disruptions to the oral microbiome limit the use of GEMMs for understanding the relationship between the oral microbiome and OPMD.

10. Prevention Strategies

10.1. current clinical management of opmd.

To date, there has been a general consensus for the most appropriate management of OPMD [ 75 ]. Primary prevention remains the first management measure. In all cases, tobacco and alcohol consumption cessation is required to limit the risk of malignant progression, as well as the screening of whole upper aero-digestive tract mucosa for OPMD [ 20 ]. Furthermore, the histological assessment of the biopsy, especially the grading of dysplasia, should be performed both at baseline and in case of clinical modifications (macroscopic, clinic) because of its high prognostic value [ 12 ]. Surgical resection is applied when possible and certainly indicated for OPMD with moderate or severe dysplasia [ 20 ]. When surgery is not feasible (patient not operable or surgery excessively mutilating), the two available options are either destruction of the lesion (cryosurgery, carbon dioxide laser, photodynamic therapy) and/or the close surveillance with repeated biopsies. Finally, a recent Cochrane database review indicated no useful medical treatments to prevent OPMD malignant transformation [ 17 ].

10.2. Systemic Strategies to Prevent Malignant Transformation of OPMD

Treatment of the lesion and prevention of malignant transformation of OPMD may improve patient outcome [ 11 ]. Hence, inhibitors that eradicate the lesion, or chemopreventive agents that prevent the malignant transformation of OPMD must be developed. Several systemic agents have been tested such as bleomycin, Vitamin E, retinoids, beta carotene, lycopene and mixtures of tea [ 31 , 75 , 102 ]. However, these agents showed limited benefits. Although they caused macroscopic regression of OPMD, recurrences occurred frequently after discontinuation of treatments, and they were not shown to prevent OPMD malignant transformation [ 11 , 17 ].

It has been proposed to leverage premalignant biology for precision-based and more specifically immune-based cancer prevention [ 103 , 104 ]. Unfortunately, targeted therapies have failed to prevent malignant transformation of OPMD [ 31 ]. On the other hand, the IME is an attractive therapeutic target [ 51 , 52 ]. The development of multimodal immune-prevention strategies to halt OSCC progression, including immune check point inhibitors, vaccines, adjuvants activating the innate immune system and in combination with some chemopreventive agents that impact positively the tumour IME, is an interesting option [ 105 ]. In recent clinical trials evaluating PD-1- and PD-L1 targeting monoclonal antibodies (pembrolizumab and avelumab) patients with OPMD at high-risk of oral cancer development based on LOH status have been enrolled ( {"type":"clinical-trial","attrs":{"text":"NCT02882282","term_id":"NCT02882282"}} NCT02882282 and {"type":"clinical-trial","attrs":{"text":"NCT04504552","term_id":"NCT04504552"}} NCT04504552 ), but the results are still awaited.

11. Conclusions and Discussion

Given the knowledge gaps in OPMD clinical management, classification, and risk stratification, as well as the lack of standardized procedures for biospecimen collection (i.e., mucosal biopsy; oral brushes; saliva), the lack of efficient, acceptable, and approved interventions to treat the whole cancerization field and the lack of a network of cooperating centres for clinical research in this area, several European experts in the field give their opinions and perspectives.

Joint efforts of academic teams and societies, clinical cancer research organizations, biotechs and pharmaceutical companies should be engaged to decipher the full temporal spectrum of the disease that may evolve to OSCC. There is need to define standardized procedures for sample collection, to refine OPMD classification and improve patients’ stratification. A biologically-driven classification of OPMD may identify clusters with actionable biology, allowing the development of prevention strategies that treat the entire field of cancerization.

There is a critical need for standardized protocols for the clinical screening and diagnosis of OPMD, in particular to encourage systematic biopsies, and for patient follow-up and treatment. Minimally invasive technologies for OPMD detection should be prioritized. For pathological diagnosis, the current gold standard, we should (i) develop standardized histopathological criteria encompassing the various histological appearances for reliable diagnosis of OPMD; (ii) implement validated immunohistochemical and molecular biomarkers; (iii) incorporate artificial intelligence for diagnostic support; and (iv) develop and implement objective detection techniques as well as non-invasive alternatives to biopsies (buccal brushes, saliva, buccal rinses, optical techniques) [ 83 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 ].

Prospective population-wide studies of longitudinal disease trajectories to interrogate the general medical histories of patients with cancer represent a recently developed concept to improve healthcare monitoring and reduce costs. Analysis of national or regional data hubs (e.g., clinical data warehouses, cancer registries, social security databases, hospital electronic medical records etc.) may identify disease associations occurring prior to OSCC diagnosis.

Electronic health (eHealth) interventions and patient-reported outcome tools (PROMs) dedicated to patients with OPMD to monitor disease progression, to identify early signs of transformation and to monitor the lifestyle and psychological impact of being at risk (uncertainty, anxiety and depression) [ 111 ] should be developed and evaluated. This may spare unnecessary visits and exams, while providing the best possible care.

Finally, there is a need to evaluate the socio-economic impact of preventive medicine and to perform generalizable health technology assessment; a network of centres gathering cost- and patient-related data should be built. Eventually, the aim here would be to decrease the economic burden of OSCC.

Author Contributions

Conceptualization: J.B., P.B., R.H.B., M.E., L.C.v.K., K.D.H., S.K. and P.S.; writing—original draft preparation J.B., P.B., R.H.B., M.E., L.C.v.K., S.K. and P.S.; writing—review and editing, J.B., P.B., R.H.B., M.E., L.C.v.K., K.D.H., S.S., L.C.v.K., P.M., S.J., I.B., G.J.P., C.H., C.S., J.-P.M., V.G., C.B., S.K. and P.S.; supervision, J.B., P.B., S.K. and P.S.; funding acquisition, J.B., P.B. and P.S. All authors have read and agreed to the published version of the manuscript.

This research was funded by the following grant: ITMO Cancer 2020, “Formation à la Recherche Fondamentale et Translationnelle en Cancérologie” (JB); CLARA 2020 “Soutien à la mobilité des jeunes chercheurs en oncologie, [N° CVPPRCAN000198]” (JB); Fondation de France 2020 “Aide à la mobilité international de médecins et pharmaciens, [N° 00112162]” (JB); Ligue contre le Cancer 2020 (PS); INCa SIRIC-LYriCAN INCa-DGOS-Inserm_12563” (PS); Région Auvergne-Rhône-Alpes “AAP Amorçage Europe 2021” [n°21 018082 01 6 22472] (PS); “INCa [n°2021-160-AAP PREV-BIO21-008]–Projet ISEBIO” (PS); “AIRC IG [nr 21740]” (PB).

Conflicts of Interest

The authors declare no conflict of interest.

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