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Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy 2.0

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: 30 April 2025 | Viewed by 22226

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Dr. Elena Varoni

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Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
Interests: oral medicine; biomaterials; nutrition; oral health
Special Issues, Collections and Topics in MDPI journals

Dr. Lia Rimondini

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Guest Editor

Department of Health Sciences, University of Piemonte Orientale “UPO”, Vercelli, Italy
Interests: biomaterials; dental materials; tissue regeneration; tissue engineering; oral medicine; bacterial biofilm; anti-infective technologies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue, “Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy”, will focus on the pathophysiology, diagnosis, prognosis, and therapy of malignant and potentially malignant disorders of the oral cavity, but will not be limited to only these aspects.

This Special Issue is open to both clinical and pre-clinical research using multi-disciplinary approaches and is open to both original articles and reviews.

Oral squamous cell carcinoma (OSCC) represents the most frequent malignant tumor of the oral cavity, with an estimated annual incidence of 529,000 new cases (including cases in the oral cavity and pharynx) and more than 300,000 deaths. Recent trends highlight an increasing incidence in young women. Alcohol and smoking habits are still the main risk factors, although the role of Human Papilloma Virus has recently been debated. At advanced stages, the five-year survival is about 50%, so prevention is strongly recommended. New trends in therapy at advanced stages, such as immunotherapy, have also been introduced in the last few years.

Often, OSCC derives from oral potentially malignant disorders (OPMD), including mucosal lesions, which have a greater chance of transforming into cancer, e.g., oral leukoplakia, oral erythroplakia, palatal lesions in reverse smokers, oral lichen planus, oral submucous fibrosis, actinic keratosis, and discoid lupus erythematosus. No reliable prognostic factor nor treatment is currently available to avoid their risk of malignant transformation, and the need to clarify the “field cancerization” process is urgent.

Oral conditions and their associations with other systemic malignant and chronic inflammatory diseases will be considered as well.

Dr. Elena Varoni
Dr. Lia Rimondini
Guest Editors

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Keywords

oral squamous cell carcinoma
leukoplakia
erythroplakia
immunotherapy
smoking
human papilloma virus
field cancerization
oral microbiome

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Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy in Biomedicines (11 articles)

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19 pages, 7213 KiB

Open AccessArticle

The Protective Role of Troxerutin (Trox) in Counteracting Anaplastic Thyroid Carcinoma (ATC) Progression

by Valentina Bova, Rossella Basilotta, Giovanna Casili, Marika Lanza, Alessia Filippone, Michela Campolo, Anna Paola Capra, Giulia Vitale, Giulia Chisari, Cristina Colarossi, Dario Giuffrida, Irene Paterniti and Emanuela Esposito

Biomedicines 2024, 12(8), 1755; https://doi.org/10.3390/biomedicines12081755 - 5 Aug 2024

Cited by 1 | Viewed by 1017

Abstract

Anaplastic thyroid carcinoma (ATC) is a rare thyroid neoplasm characterized by aggressiveness and a high mortality rate. Troxerutin (Trox) is a bioflavonoid widely found in various fruits and vegetables with numerous protective effects, including anticancer activities. To evaluate the anti-oxidant and anti-inflammatory effect of Trox, in vitro and in vivo studies were conducted in a model of ATC. Human ATC 8305C cell lines were treated with increasing concentrations of Trox (10 μg/mL, 30 μg/mL, 100 μg/mL, 300 μg/mL), and our results revealed that Trox treatment was able to reduce the viability of ATC cells and migratory capacity, reducing the expression of anti-apoptotic factors, such as B-cell lymphoma (bcl-2), and increasing the expression of pro-apoptotic factors, such as Caspase-3 and BID, activating oxidative stress mediators, such as manganese superoxide dismutase (MnSOD), heme oxygenase-1 (HO-1), glutathione (GSH) and reactive oxygen species modulator 1 (ROMO-1). Furthermore, Trox modulates NF-κB pathway markers, such as NIK and TRAF-6. Further confirmation was obtained through in vivo studies, in which Trox treatment, at doses of 12.5, 25 and 50 mg/kg, reduced morphological alteration, decreasing mast cell accumulation. Therefore, the use of Trox could be considered a promising strategy to counteract the progression of ATC. Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy 2.0)

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14 pages, 5226 KiB

Open AccessArticle

Anti-Cancer Activities of Nano Amorphous Calcium Phosphates toward Premalignant and Oral Cancer Cells

by Evelina Herendija, Milica Jakšić Karišik, Jelena Milašin, Miloš Lazarević and Nenad Ignjatović

Biomedicines 2024, 12(7), 1499; https://doi.org/10.3390/biomedicines12071499 - 5 Jul 2024

Viewed by 1493

Abstract

Despite advancements in treatment, the squamous cell carcinoma (OSCC) patient survival rate remains stagnant. Conventional therapies have limited effectiveness, necessitating novel agents. Our study aims to synthesize and characterize amorphous calcium phosphate nanoparticles (nACPs), assess their potential cytotoxic effects on premalignant and malignant OSCC cells, and investigate possible mechanisms of action. The morphological features of nACP were investigated by field emission scanning coupled with energy dispersive spectroscopy (EDS), Fourier transform infrared spectroscopy (FTIR), and particle size distribution (PSD). Then, we examined the effect of nACPs on nanoparticle uptake, cell adhesion, viability, invasion ability, cell cycle, and gene expression. nACP uptake was dose-dependent, induced limited selectivity in cytotoxicity between healthy and malignant cells, and affected cellular adhesion and invasion. Early apoptosis was the predominant type of cell death. The nACP effect on viability was verified by alterations in the genes associated with apoptosis and proliferation. A high concentration of nACP was shown to arrest the cell cycle progression in the G0/G1 phase of both malignant and premalignant cells. This type of nACP justifies the development of a strategy for its potential use as an anti-cancer agent and/or anti-cancer active carrier for various drugs in oral cancer treatments. Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy 2.0)

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14 pages, 4145 KiB

Open AccessArticle

Clinicopathological Significance of Cancer Stem Cell Markers (OCT-3/4 and SOX-2) in Oral Submucous Fibrosis and Oral Squamous Cell Carcinoma

by Divyambika Catakapatri Venugopal, Cynthia Leslie Caleb, Nandhini Priyadarshini Kirupakaran, Vidyarani Shyamsundar, Soundharya Ravindran, Madhavan Yasasve, Arvind Krishnamurthy, Thamizhchelvan Harikrishnan, Sathasivasubramanian Sankarapandian and Vijayalakshmi Ramshankar

Biomedicines 2023, 11(4), 1040; https://doi.org/10.3390/biomedicines11041040 - 28 Mar 2023

Cited by 4 | Viewed by 2781

Abstract

Oral submucous fibrosis (OSMF) is highly prevalent in South East Asia with higher rates of malignant transformation in Indian subcontinent. Numerous biomarkers are now being studied to predict disease prognosis and detect malignant alterations at an early stage. Patients with clinically and biopsy-proven oral submucous fibrosis and oral squamous cell carcinoma were included in the study as the experimental group, while patients without a tobacco or betel nut habit who had their third molars surgically removed were included as the healthy control group. For the immunohistochemistry (IHC) investigation, 5-μm slices from formalin-fixed, paraffin-embedded tissue blocks (FFPE) were obtained. Fresh tissues (n = 45) from all three groups were collected and gene expression was studied using relative quantitation-based qPCR. The protein expression of octamer-binding transcription factor 3/4 (OCT 3/4) and sex-determining region Y-box 2 (SOX 2) was evaluated in the experimental group and compared with healthy controls. The IHC results showed a significant correlation with the expression of OCT 3/4 (p value = 0.000; χ2 = 20.244) and SOX 2 (p value = 0.006; χ2 = 10.101) among OSCC and OSMF patients in comparison to healthy controls. Both OCT 3/4 and SOX 2 showed overexpression of four-fold and three-fold in OSMF when compared to OSCC and healthy controls, respectively. This study shows the significant importance of cancer stem cell markers OCT 3/4 and SOX 2 to assess the disease prognosis in OSMF. Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy 2.0)

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16 pages, 2864 KiB

Open AccessArticle

Growth Conditions Influence Lactobacillus Cell-Free Supernatant Impact on Viability, Biofilm Formation, and Co-Aggregation of the Oral Periodontopathogens Fusobacterium nucleatum and Porphyromonas gingivalis

by Paola Zanetta, Diletta Francesca Squarzanti, Alessia di Coste, Angela Amoruso, Marco Pane and Barbara Azzimonti

Biomedicines 2023, 11(3), 859; https://doi.org/10.3390/biomedicines11030859 - 11 Mar 2023

Cited by 4 | Viewed by 2828

Abstract

Fusobacterium nucleatum and Porphyromonas gingivalis human periodontopathogens play a leading part in oral squamous cell carcinoma through cell proliferation, invasion, and persistent inflammation promotion and maintenance. To explore how the activity of Lactobacillus-derived cell-free supernatants (CFSs) can be influenced by growth medium components, CFSs were produced both in the standard MRS and the novel animal-derivative-free “Terreno Industriale Lattobacilli” (TIL) media, and in vitro screened for the containment of F. nucleatum and P. gingivalis both single and co-cultured and also for the interference on their co-aggregation. The viability assay demonstrated that the Limosilactobacillus reuteri LRE11 and Ligilactobacillus salivarius LS03 MRS-produced CFSs were significantly more effective against single and co-cultured pathogens. All the other CFSs significantly improved their efficacy when produced in TIL. Both MRS- and TIL-produced CFSs significantly inhibited the single and co-cultured pathogen biofilm formation. Only Levilactobacillus brevis LBR01 CFS in MRS specifically reduced F. nucleatum and P. gingivalis co-aggregation, while viable LBR01, LS03, and LRE11 in MRS significantly co-aggregated with the pathogens, but only LS03 cultivated in TIL improved this effect. This work paves the way to better consider environmental growth conditions when screening for probiotic and postbiotic efficacy as crucial to pathogen aggregation, adhesion to the host’s niches, and exclusion. Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy 2.0)

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13 pages, 4032 KiB

Open AccessArticle

Arsenic Trioxide Triggers Apoptosis of Metastatic Oral Squamous Cells Carcinoma with Concomitant Downregulation of GLI1 in Hedgehog Signaling

by Raphael Luís Rocha Nogueira, Taís Bacelar Sacramento de Araújo, Ludmila Faro Valverde, Viviane Aline Oliveira Silva, Bruno Raphael Ribeiro Cavalcante, Erik Aranha Rossi, Kyan James Allahdadi, Mitermayer Galvão dos Reis, Thiago Almeida Pereira, Ricardo D. Coletta, Daniel Pereira Bezerra, Bruno Solano de Freitas Souza, Rosane Borges Dias and Clarissa A. Gurgel Rocha

Biomedicines 2022, 10(12), 3293; https://doi.org/10.3390/biomedicines10123293 - 19 Dec 2022

Cited by 4 | Viewed by 2508

Abstract

Given the lack of advances in Oral Squamous Cell Carcinoma (OSCC) therapy in recent years, pharmacological strategies to block OSCC-related signaling pathways have gained prominence. The present study aimed to evaluate the therapeutic potential of Arsenic Trioxide (ATO) concerning its antitumoral effects and the inhibition of the Hedgehog (HH) pathway in OSCC. Initially, ATO cytotoxicity was assessed in a panel of cell lines. Cell viability, cell cycle, death patterns, and cell morphology were analyzed, as well as the effect of ATO on the expression of HH pathway components. After the cytotoxic assay, HSC3 cells were chosen for all in vitro assays. ATO increased apoptotic cell death and nuclear fragmentation in the sub-G1 cell cycle phase and promoted changes in cell morphology. In addition, the reduced expression of GLI1 indicated that ATO inhibits HH activity. The present study provides evidence of ATO as an effective cytotoxic drug for oral cancer treatment in vitro. Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy 2.0)

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13 pages, 2082 KiB

Open AccessReview

Preventive Photobiomodulation for Chemotherapy-Induced Oral Mucositis: A Systematic Review of Randomized Clinical Trials

by Susell Parra-Rojas, Rocío Trinidad Velázquez-Cayón, Maria Elena Ciortan-Pop, Manoela Domingues Martins and Juliana Cassol Spanemberg

Biomedicines 2025, 13(2), 268; https://doi.org/10.3390/biomedicines13020268 - 22 Jan 2025

Viewed by 443

Abstract

Background/Objectives: Oral mucositis (OM) is the most common acute complication among cancer patients. It initially manifests as an inflammatory process, beginning with erythema and edema of the oral mucosa, progressing to erosive lesions, and ultimately leading to highly painful ulcers. This systematic review seeks to evaluate the efficacy of preventive PBM protocols in mitigating chemotherapy-induced OM. Methods: The PRISMA guidelines were followed. The search was conducted in August 2024 in the following databases: Pubmed/Medline, Scopus, WoS, Cochrane, SciELO, BDTD, and BVS/IBECS. Only randomized clinical trials that utilized preventive photobiomodulation protocols in chemotherapy patients were included. All studies involving patients previously treated with radiation therapy were excluded. The Joanna Briggs Institute tool was employed for risk of bias analysis. Results: The total sample size consisted of 828 patients aged between 1 and 84 years. There was no predisposition based on gender or age. When the patients were evaluated under preventive protocols, some cases of mucositis manifested in a total of 339 cases. Of the total number of patients in the 13 selected studies (n = 828), 40.94% developed oral mucositis over the course of chemotherapy cycles. Comparing the experimental and control groups, 211 patients who did not receive preventive laser treatment developed oral mucositis; in contrast, only 128 in the experimental group did. Eighty-five percent of the studies exhibited a low risk of bias. Conclusions: Preventively applied photobiomodulation proves effective in minimizing or even preventing the manifestation of oral mucositis and reducing the severity of lesions that arise during oncological treatment. Registration PROSPERO (CRD42023465329). Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy 2.0)

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18 pages, 2424 KiB

Open AccessReview

Oral Surgery and Osteoradionecrosis in Patients Undergoing Head and Neck Radiation Therapy: An Update of the Current Literature

by Giulia Corrao, Giovanni Carlo Mazzola, Niccolò Lombardi, Giulia Marvaso, Alberto Pispero, Elisa Baruzzi, Sem Decani, Marco Tarozzi, Luca Bergamaschi, Chiara Lorubbio, Ilaria Repetti, Anna Starzyńska, Daniela Alterio, Mohseen Ansarin, Roberto Orecchia, Fiorella D’Amore, Roberto Franchini, Andrea Nicali, Paolo Castellarin, Andrea Sardella, Giovanni Lodi, Elena Maria Varoni and Barbara Alicja Jereczek-Fossa Show full author list Hide full author list

Biomedicines 2023, 11(12), 3339; https://doi.org/10.3390/biomedicines11123339 - 18 Dec 2023

Cited by 2 | Viewed by 2886

Abstract

Osteoradionecrosis (ORN) is a serious long-term complication of head and neck radiotherapy (RT), which is often triggered by dental extractions. It results from avascular aseptic necrosis due to irradiated bone damage. ORN is challenging to treat and can lead to severe complications. Furthermore, ORN causes pain and distress, significantly reducing the patient’s quality of life. There is currently no established preventive strategy. This narrative review aims to provide an update for the clinicians on the risk of ORN associated with oral surgery in head and neck RT patients, with a focus on the timing suitable for the oral surgery and possible ORN preventive treatments. An electronic search of articles was performed by consulting the PubMed database. Intervention and observational studies were included. A multidisciplinary approach to the patient is highly recommended to mitigate the risk of RT complications. A dental visit before commencing RT is highly advised to minimize the need for future dental extractions after irradiation, and thus the risk of ORN. Post-RT preventive strategies, in case of dento-alveolar surgery, have been proposed and include antibiotics, hyperbaric oxygen (HBO), and the combined use of pentoxifylline and tocopherol (“PENTO protocol”), but currently there is a lack of established standards of care. Some limitations in the use of HBO involve the low availability of HBO facilities, its high costs, and specific clinical contraindications; the PENTO protocol, on the other hand, although promising, lacks clinical trials to support its efficacy. Due to the enduring risk of ORN, removable prostheses are preferable to dental implants in these patients, as there is no consensus on the appropriate timing for their safe placement. Overall, established standards of care and high-quality evidence are lacking concerning both preventive strategies for ORN as well as the timing of the dental surgery. There is an urgent need to improve research for more efficacious clinical decision making. Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy 2.0)

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12 pages, 279 KiB

Open AccessReview

Oral Cavity Squamous Cell Carcinoma: An Update of the Pharmacological Treatment

by Martina Imbesi Bellantoni, Giacomo Picciolo, Igor Pirrotta, Natasha Irrera, Mario Vaccaro, Federico Vaccaro, Francesco Squadrito and Giovanni Pallio

Biomedicines 2023, 11(4), 1112; https://doi.org/10.3390/biomedicines11041112 - 7 Apr 2023

Cited by 24 | Viewed by 6707

Abstract

Oral cavity squamous cell carcinoma (OCSCC) represents a serious health and socio-economic problem in different geographical areas of the world. It is characterized by a high rate of mortality, recurrence and metastasis. Despite the therapeutic strategies implemented for its management and resolution, currently the survival estimate for locally advanced disease is about 50%. The available therapeutic options comprise surgery and pharmacological treatment. Recently, an increased emphasis has been placed on the drugs that might be of benefit in this life-threatening disease. Therefore, the aim of this present review was to offer a general survey of the current available pharmacological treatment for OCSCC. The PubMed database was used to retrieve the papers using “OCSCC” as the search terms. We limited our search to the last 5 years to give a more updated and recent picture of the state of the art, including preclinical and clinical investigations. We found that 77 out of 201 papers were on the surgical treatment of OCSCC, 43 out of 201 focused on the radiotherapy and 81 out of 201 underwent evaluation for the aim of our review. We excluded the case reports, editorial letters, observational studies and papers written in languages other than English. A total of 12 articles were included in the final review. Our results showed that nanotechnologies use to enhance the efficacy of anticancer drugs such as: cisplatin, paclitaxel, cetuximab, EGFR antagonists, MEK1/2 and immune check inhibitors combination could have promising anti-cancer activity. However, the paucity of available data on drugs suggests the urgent need to improve the pharmacological armamentarium for OCSCC treatment. Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy 2.0)

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