[Oral cavity cancer: A distinct entity]. / Le cancer de la cavité orale : une entité spécifique ?

Oral Squamous cell carcinoma represent the 17th most frequent cancer in the world. The main risk factors are alcohol and tobacco consumption but dietary, familial, genetic, or oral diseases may be involved in oral carcinogenesis. Diagnosis is made on biopsy, but detection remains late, leading to a poor prognosis. New technologies could reduce these delays, notably Artificial Intelligence and the quantitative evaluation of salivary biological markers. Currently, management of oral cancer consists in surgery, which can be mutilating despite possible reconstructions. In the future, immunotherapies could become a therapeutic alternative and the immune microenvironment could constitute a source of prognostic markers.

Title: Le cancer de la cavité orale : une entité spécifique ? Abstract: Les carcinomes épidermoïdes de la cavité orale sont le 17e cancer le plus fréquent dans le monde. Les facteurs de risque principaux sont l'alcool et le tabac mais des facteurs alimentaires, familiaux, génétiques ou certaines maladies orales peuvent intervenir dans la genèse de ces cancers. Le diagnostic est tardif, entraînant un pronostic sombre. De nouvelles approches, comme l'utilisation de l'intelligence artificielle ou de marqueurs biologiques salivaires pourraient réduire ces délais. La prise en charge actuelle de ces cancers repose sur la chirurgie, la chimiothérapie et la radiothérapie, mais avec une iatrogénie importante. Les immunothérapies pourraient devenir une alternative à ces traitements et certaines caractéristiques du microenvironnement immunitaire pourraient constituer un/des marqueurs pronostiques.

Artificial intelligence for oral squamous cell carcinoma detection based on oral photographs: A comprehensive literature review.

INTRODUCTION: Oral squamous cell carcinoma (OSCC) presents a significant global health challenge. The integration of artificial intelligence (AI) and computer vision holds promise for the early detection of OSCC through the analysis of digitized oral photographs. This literature review explores the landscape of AI-driven OSCC automatic detection, assessing both the performance and limitations of the current state of the art. MATERIALS AND METHODS: An electronic search using several data base was conducted, and a systematic review performed in accordance with PRISMA guidelines (CRD42023441416). RESULTS: Several studies have demonstrated remarkable results for this task, consistently achieving sensitivity rates exceeding 85% and accuracy rates surpassing 90%, often encompassing around 1000 images. The review scrutinizes these studies, shedding light on their methodologies, including the use of recent machine learning and pattern recognition approaches coupled with different supervision strategies. However, comparing the results from different papers is challenging due to variations in the datasets used. DISCUSSION: Considering these findings, this review underscores the urgent need for more robust and reliable datasets in the field of OSCC detection. Furthermore, it highlights the potential of advanced techniques such as multi-task learning, attention mechanisms, and ensemble learning as crucial tools in enhancing the accuracy and sensitivity of OSCC detection through oral photographs. CONCLUSION: These insights collectively emphasize the transformative impact of AI-driven approaches on early OSCC diagnosis, with the potential to significantly improve patient outcomes and healthcare practices.

An Unusual Case of Recurrent Gingival Epstein-Barr Virus-Positive B-Cell Lymphoproliferation.

Epstein-Barr virus (EBV)-positive mucocutaneous ulceration commonly presents as a B-cell lymphoproliferative process with manifold aspects. There is scarce data on its oral manifestation in the scientific literature. We report the case of a 57-year-old male immunocompromised renal transplant patient who developed recurrent chronic and symptomatic mucosal ulceration facing the mandibular incisor teeth. Pathological examination with microscopic and immunohistochemistry studies revealed a B plasma cell infiltration as well as positive staining for EBV, leading to a diagnosis of EBV-positive mucocutaneous ulceration with B-cell lymphoproliferation after extensive workup. Treatment with rituximab was implemented and led to the healing of the lesion. This lesion develops in geriatric and immunodeficient patients and may require oncological therapies. While it is generally associated with an excellent prognosis, it may be indicative of underlying immunosuppression, and hence oral cavity specialists must be aware of this particular entity.

A Giant Posterior Maxillary Intra-Sinusal Complex Odontoma: A Clinical Case.

Odontomas are the most common odontogenic neoplasms. They are generally small and asymptomatic. This article presents an unusual case of a giant maxillary complex odontoma, which obscured a part of the maxillary antrum and impacted a tooth. This was discovered during an episode of maxillofacial cellulitis. In this case, surgical excision of the lesion was performed under general anesthesia, and the closure was performed with a fat pad pedicled flap. A brief review of the literature was performed to analyze the characteristics of this clinical entity and their implication in the treatment.

"Plasma cell gingivitis" encompasses multiple entities: a retrospective series of 37 cases.

BACKGROUND: Plasma cell gingivitis is defined as gingival inflammation comprised of plasma cell infiltrates. This diagnostic criterion is non-specific and underlying mechanisms remain unknown. OBJECTIVES: We performed a multidisciplinary clinico-pathological review of cases previously identified as "gingivitis with plasma cell infiltrates", with assessment of putative contributing factors and critical appraisal of the final diagnosis. MATERIALS & METHODS: Cases previously identified as "gingivitis with plasma cell infiltrates" between 2000 and 2020 were included from archives from the GEMUB group, a French multidisciplinary network of physicians with expertise on oral mucosa. RESULTS: Among the 37 included cases, multidisciplinary clinico-pathological review allowed differential diagnosis in seven cases (oral lichen planus n=4, plasma cell granuloma n=1, plasmacytoma n=1, and mucous membrane pemphigoid n=1). The remaining cases were classified as "reactive plasma cell gingivitis" (induced by drugs, trauma/irritation or periodontal disease) (n=18) or "idiopathic plasma cell gingivitis" when no contributing factors were identified (n=12). Clinico-pathological characteristics did not differ significantly between "reactive" and "idiopathic" cases, preventing us from identifying specific features of "idiopathic" plasma cell gingivitis. CONCLUSION: "Plasma cell gingivitis" is a polymorphous, non-specific entity with various aetiologies, of which the diagnosis requires multidisciplinary anatomo-clinical correlation for exclusion of secondary causes of plasma cell infiltration. Although our study was limited by its retrospective design, most cases of "plasma cell gingivitis" appeared to be associated with an underlying cause. We propose a diagnostic algorithm to properly investigate such cases.

Oral Lichen Planus in Patients With Good's Syndrome: A Literature Review.

Good's syndrome is defined as the association of a thymoma with an immune deficiency. Many patients with Good's syndrome also have oral lichen planus involvement, and some authors have even considered it to be one of the clinical signs of Good's syndrome. In the literature, to our knowledge, clinical forms of oral lichen planus associated with Good's syndrome have not been described. We therefore aimed to characterize the forms of oral lichen planus occurring in the context of Good's syndrome. To this end, we carried out a scoping review of the literature according to the Joanna Briggs Institute guide and included 17 articles on the theme of "the forms and clinical locations of oral lichen planus associated with Good's syndrome". A total of 17 articles were selected, and 19 patients with Good's syndrome including oral lichen planus were identified. Most of them were women aged 60 years with erosive oral lichen planus of the tongue and inner cheeks. The treatments used were thymectomy, to which immunoglobulin infusions were added in some cases. All these treatments resulted in improvement of the oral lichen planus in 70.6% of cases. The management of Good's syndrome allows the improvement of oral lichen. In patients over 50 years of age with acute erosive oral lichen planus refractory to conventional therapies, Good's syndrome should be investigated.

Multiple oral papillomas after antiretroviral treatment resumption.

Lesions of the oral mucosa due to human papillomavirus (HPV) present in various clinical forms. The case of a man in his 50s is reported. This patient was referred for multiple whitish oral lesions, unresponsive to antifungal drugs, in a context of pneumocystis having revealed a therapeutic break of an HIV antiretroviral treatment. The lesions had appeared a few days after treatment resumption. Clinical examination revealed multiple lesions on the lips, the inner sides of the cheeks and lips and on the tongue. The patient reported burning sensations in the mouth. The diagnosis of multiple papillomas was made in view of the characteristic clinical picture and history of the disease: appearance of oral papular lesions with multiple locations, which may reveal a context of severe immunodeficiency. HPV lesions are more frequent in HIV-positive patients and may increase on initiation of antiretroviral therapy.

PD-L1 and ICOSL discriminate human Secretory and Helper dendritic cells in cancer, allergy and autoimmunity.

Dendritic cells (DC) are traditionally classified according to their ontogeny and their ability to induce T cell response to antigens, however, the phenotypic and functional state of these cells in cancer does not necessarily align to the conventional categories. Here we show, by using 16 different stimuli in vitro that activated DCs in human blood are phenotypically and functionally dichotomous, and pure cultures of type 2 conventional dendritic cells acquire these states (termed Secretory and Helper) upon appropriate stimuli. PD-L1highICOSLlow Secretory DCs produce large amounts of inflammatory cytokines and chemokines but induce very low levels of T helper (Th) cytokines following co-culturing with T cells. Conversely, PD-L1lowICOSLhigh Helper DCs produce low levels of secreted factors but induce high levels and a broad range of Th cytokines. Secretory DCs bear a single-cell transcriptomic signature indicative of mature migratory LAMP3+ DCs associated with cancer and inflammation. Secretory DCs are linked to good prognosis in head and neck squamous cell carcinoma, and to response to checkpoint blockade in Melanoma. Hence, the functional dichotomy of DCs we describe has both fundamental and translational implications in inflammation and immunotherapy.

Defining biomarkers in oral cancer according to smoking and drinking status.

Introduction: Oral Squamous Cell Carcinomas (OSCC) are mostly related to tobacco consumption eventually associated to alcohol (Smoker/Drinker patients: SD), but 25-30% of the patients have no identified risk factors (Non-Smoker/Non-Drinker patients: NSND). We hypothesized that these patients have distinguishable immune profiles that could be useful for prognosis. Materials and Methods: Cells present in immune tumor microenvironment (TME) and blood from 87 OSCC HPV-negative patients were analyzed using a multiparameter flow cytometry assay, in a prospective case-control study. Cytokine levels in tumor supernatants and blood were determined by a cytometric bead array (CBA) assay. Results: Normal gingiva and blood from healthy donors (HD) were used as controls. A significant increase of granulocytes (p<0.05 for blood), of monocytes-macrophages (p<0.01 for blood) and of CD4+ T cells expressing CD45RO and CCR6 (p<0.001 for blood; p<0.0001 for TME) as well as higher levels of IL-6 (p<0.01 for sera, p<0.05 for tumor supernatant) were observed in SD patients as compared to NSND OSCC patients and HD. High percentages of CD4+ T cells expressing CD45RO and CCR6 cells in tumor tissue (p=0.05) and blood (p=0.05) of SD OSCC patients were also associated with a poorer prognosis while a high percentage of regulatory T cells (Treg) in tumor tissue was associated with a more favorable prognostic factor (p=0.05). Also, a higher percentage of blood CD8+ T lymphocytes among CD45+ cells in NSND patients was associated with a better disease-free survival (p=0.004). Conclusion: Granulocytes, monocytes-macrophages, and CD4+ T cells expressing CD45RO and CCR6 in blood and TME as well as serum IL-6 can therefore distinguish OSCC SD and NSND patients. Quantifying the proportion of CD4+ T cells expressing CD45RO and CCR6 and of Treg in SD patients and CD8+ T cells in NSND patients could help defining the prognostic of OSCC patients.

Tumor-Associated Tertiary Lymphoid Structures: From Basic and Clinical Knowledge to Therapeutic Manipulation.

The tumor microenvironment is a complex ecosystem almost unique to each patient. Most of available therapies target tumor cells according to their molecular characteristics, angiogenesis or immune cells involved in tumor immune-surveillance. Unfortunately, only a limited number of patients benefit in the long-term of these treatments that are often associated with relapses, in spite of the remarkable progress obtained with the advent of immune checkpoint inhibitors (ICP). The presence of "hot" tumors is a determining parameter for selecting therapies targeting the patient immunity, even though some of them still do not respond to treatment. In human studies, an in-depth analysis of the organization and interactions of tumor-infiltrating immune cells has revealed the presence of an ectopic lymphoid organization termed tertiary lymphoid structures (TLS) in a large number of tumors. Their marked similarity to secondary lymphoid organs has suggested that TLS are an "anti-tumor school" and an "antibody factory" to fight malignant cells. They are effectively associated with long-term survival in most solid tumors, and their presence has been recently shown to predict response to ICP inhibitors. This review discusses the relationship between TLS and the molecular characteristics of tumors and the presence of oncogenic viruses, as well as their role when targeted therapies are used. Also, we present some aspects of TLS biology in non-tumor inflammatory diseases and discuss the putative common characteristics that they share with tumor-associated TLS. A detailed overview of the different pre-clinical models available to investigate TLS function and neogenesis is also presented. Finally, new approaches aimed at a better understanding of the role and function of TLS such as the use of spheroids and organoids and of artificial intelligence algorithms, are also discussed. In conclusion, increasing our knowledge on TLS will undoubtedly improve prognostic prediction and treatment selection in cancer patients with key consequences for the next generation immunotherapy.

CCR2 Influences T Regulatory Cell Migration to Tumors and Serves as a Biomarker of Cyclophosphamide Sensitivity.

The CCL2 chemokine receptor CCR2 drives cancer by mediating the recruitment of monocytes and myeloid-derived suppressor cells to the tumor microenvironment. In this study, we extend the significance of CCR2 in this setting by identifying a new role for it in mediating recruitment of CD4+ T regulatory cells (Treg). Following tumor initiation, an expanded population of CCR2+ Tregs required CCR2 expression to traffic between draining lymph nodes (dLN) and the tumor. This Treg subset was enriched in the fraction of tumor antigen-specific cells in the dLN, where they displayed an activated immunosuppressive phenotype. Notably, in mouse models, low-dose cyclophosphamide treatment preferentially depleted CCR2+ Treg, enhancing priming of tumor-specific CD8+ T cells. In the MMTV-PyMT transgenic mouse model of breast cancer and in oral squamous cell carcinoma patients, tumor development was associated with decreased blood frequency and inversely increased tumor frequency of CCR2+ Tregs. Our results define a novel subset of CCR2+ Treg involved in tumoral immune escape, and they offer evidence that this Treg subset may be preferentially eradicated by low-dose cyclophosphamide treatment. Cancer Res; 76(22); 6483-94. ©2016 AACR.

Intra-cheek immunization as a novel vaccination route for therapeutic vaccines of head and neck squamous cell carcinomas using plasmo virus-like particles.

Despite current therapy, head and neck squamous cell carcinomas (HNSCCs) arising from various mucosal sites of the upper aero-digestive tract frequently relapse in a loco-regional manner and have a poor prognosis. Our objective was to validate an innovative mucosal route of vaccination using plasmo virus-like particles (pVLPs) in a pre-clinical orthotopic model of HNSCCs. For this purpose, we used pVLP-E7, that are plasmid DNA encoding retroviral virus-like particles carrying a truncated E7 oncoprotein from HPV-16 as antigen model, to vaccinate mice bearing pre-established TC-1 tumors implanted into the buccal mucosa. pVLP-E7 were combined with clinical grade TLR agonists (Imiquimod and CpG-ODN). In this pre-clinical orthotopic model, whose tumor microenvironment resembles to those of human HNSCCs, different mucosal vaccination routes were tested for their ability to elicit efficient immune and antitumoral responses. Results showed that mucosal intra-cheek (IC) vaccinations using pVLP-E7, comparatively to intradermic vaccinations (ID), gave rise to higher mobilization of mucosal (CD49a(+)) CD8(+) specific effector T cells in both tumor draining lymph nodes (TdLNs) and tumor microenvironment resulting in better antitumor effects and in a long-term protection against tumor rechallenge. In vivo CD8(+) depletion demonstrated that antitumoral effects were fully dependent upon the presence of CD8(+) T cells. Validation of IC mucosal vaccinations with pVLPs combined with adjuvants using a pre-clinical orthotopic model of HNSCC provides valuable pre-clinical data to rapidly envision the use of such therapeutic vaccines in patients with HNSCCs, inasmuch as vaccinal components and adjuvants can be easily obtained as clinical grade reagents.