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Oral Cancer: The Latest Advances in Clinical and Basic Research (Second Edition)

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Clinical Research of Cancer".

Deadline for manuscript submissions: 31 July 2026 | Viewed by 10628

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Prof. Dr. Kenji Yamagata

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Department of Oral and Maxillofacial Surgery, Kochi Medical School, Kochi University, Kochi, Japan
Interests: oral cancer; orthognathic surgery; cleft lip and palate; implantology; traumatology
Special Issues, Collections and Topics in MDPI journals

Dr. Fumihiko Uchida

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Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
Interests: signal transduction; oral diseases; oral surgery; cancer biology apoptosis
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Dear Colleagues,

The number of patients with oral cancer has been growing in recent years. Generally speaking, diagnosis at a low stage is beneficial for a good prognosis, and recently, a new molecular target drug and immune checkpoint inhibitor were found to prolong survival after recurrence and distant metastasis.

Although treatment results can be improved through chemoradiotherapy and surgery with wide resection and reconstruction, some patients suffer from poor prognosis. We must always consider the appropriateness of new treatments and conduct basic research based on each patient's cancer prognosis.

In this Special Issue, we welcome the submission of original research articles and reviews on the latest advances in clinical and basic research related to oral cancer.

We look forward to receiving your contributions.

Prof. Dr. Kenji Yamagata
Dr. Fumihiko Uchida
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

oral cancer
clinical research
basic research
surgery
radiotherapy
chemotherapy
molecular biology
immune checkpoint inhibitor

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Published Papers (6 papers)

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Research

15 pages, 1167 KB

Open AccessArticle

Metabolic Predictors in Risk Stratification for Oral Cavity and Oropharyngeal Cancer Patients Undergoing Free Flap Tissue Transfer: A Retrospective Study

by Darko Solter, Andro Koren, Luciana Koren, Emili Dragaš, Alan Pegan, Goran Geber, Davor Vagić and Andro Košec

Cancers 2026, 18(4), 698; https://doi.org/10.3390/cancers18040698 - 20 Feb 2026

Viewed by 2995

Abstract

Background/Objectives: Oral and oropharyngeal cancers are highly prevalent and associated with a high mortality. The primary treatment modality is surgery with free flap reconstruction becoming the gold standard. Our study aimed to assess the anthropometric and metabolic predictors of the occurrence of postoperative complications after free flap reconstruction, and to present a PRISM (Predictive Reconstructive Index for Soft-tissue Microflaps) scoring system. Methods: This retrospective cohort study included 92 patients with advanced oral and oropharyngeal squamous cell carcinoma who underwent primary surgical treatment with microvascular free flap reconstruction between 2020 and 2024. Clinical, surgical, and biochemical parameters (operative and flap ischemia time, BMI; serum albumin, total protein, and calcium) were analyzed in relation to postoperative complications. Associations were assessed using correlation analyses and binary logistic regression. Based on the key predictive variables, the PRISM scoring system was developed to estimate perioperative risk. Results: Underweight or overweight patients showed higher complication rates (Kruskal–Wallis, p = 0.019). Longer surgeries were associated with a higher incidence of SIRS, which in turn correlated with increased flap ischemia (Man-Whitney, p = 0.032 and 0.039). Lower albumin and total protein levels on the second postoperative day were linked to more complications (Kruskal–Wallis, p = 0.001 and 0.010), as were lower calcium levels on the first postoperative day (p = 0.033). Additionally, longer hospitalization was significantly associated with complication severity (p = 0.031). The PRISM score stratified patients into low-, moderate-, and high-risk groups. Conclusions: Free flap outcomes in oral and oropharyngeal cancer are influenced by SIRS, nutritional status, and surgical factors. Longer surgeries, flap ischemia, low albumin, protein, calcium, and abnormal BMI increased the complication risk. Careful preoperative assessment, optimization of patient condition, and strategies to minimize operative time and ischemia are essential. The PRISM score may help stratify patients and guide clinical decisions. Full article

(This article belongs to the Special Issue Oral Cancer: The Latest Advances in Clinical and Basic Research (Second Edition))

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18 pages, 1478 KB

Open AccessArticle

Non-Smoking, Non-Drinking Oral Squamous Cell Carcinoma Is Associated with an Immune-Modulated Clinical Phenotype

by Marko Tarle, Marina Raguž, Koraljka Hat, Igor Čvrljević, Davor Brajdić and Ivica Lukšić

Cancers 2026, 18(4), 553; https://doi.org/10.3390/cancers18040553 - 8 Feb 2026

Viewed by 875

Abstract

Background: Non-smoking, non-drinking (NSND) oral squamous cell carcinoma (OSCC) is increasingly recognized, yet its clinicopathologic and immune-related correlates remain incompletely defined. Methods: We retrospectively studied 243 surgically treated patients with previously untreated primary OSCC (2011–2020). Patients were classified as NSND or smoking and/or drinking (SD). Immune-modulating conditions and preoperative systemic immune–inflammatory indices (NLR, LMR, SIRI, AISI) were assessed, and overall (OS) and disease-specific survival (DSS) were analyzed. Results: Eighty-five patients (35.0%) were NSND. NSND patients were more often female (58.8% vs. 12.7%) and slightly older (median 54 vs. 50 years). Subsite distribution differed (p < 0.001): tongue (52.9%), buccal mucosa (15.3%), and floor of mouth (3.5%) in NSND versus a predominance of floor of mouth tumors in SD (34.8%). NSND tumors showed smaller diameter, lower depth of invasion, less perineural invasion (40.5% vs. 55.1%), and more frequent inflammatory infiltrate (73.8% vs. 60.1%). Immune-modulating conditions were enriched in NSND (67.1% vs. 17.7%; p < 0.001; adjusted OR 6.25, 95% CI 3.23–12.11), particularly among NSND patients >50 years (79.2%). NSND patients showed lower NLR (p = 0.01), lower SIRI and AISI (p < 0.001), and higher LMR (p < 0.001). Median OS was 81.2 months; NSND showed a trend toward improved OS (p = 0.083) and improved OS after age/sex adjustment (HR 0.64, 95% CI 0.42–0.98), but not after full clinicopathologic adjustment; DSS did not differ (p = 0.59). Conclusions: NSND OSCC exhibits a distinct clinicopathologic presentation and is strongly associated with immune-modulating comorbidity and lower tumor-associated systemic inflammatory indices, consistent with an immune-modulated clinical phenotype. Full article

(This article belongs to the Special Issue Oral Cancer: The Latest Advances in Clinical and Basic Research (Second Edition))

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11 pages, 578 KB

Open AccessArticle

Sentinel Lymph Node Biopsy Versus Elective Neck Dissection in Carcinoma of the Tongue and Floor of the Mouth

by Carolin Naegeli-Pullankavumkal, Tamara Manser, Tarun Mehra, Niels Jan Rupp, Thomas Gander, Martin W. Huellner and Martin Lanzer

Cancers 2025, 17(19), 3098; https://doi.org/10.3390/cancers17193098 - 23 Sep 2025

Cited by 1 | Viewed by 1745

Abstract

Background/Objectives: Lymph node metastases represent the most important prognostic factor for survival in patients with localized squamous cell carcinoma (SCC) of the oral cavity. In patients with carcinoma of the tongue or floor of the mouth, elective neck dissection (END) has been the standard of care, but it has been replaced at many centers by sentinel lymph node biopsy (SLNB). This study’s purpose was to measure and compare recurrence rates between END and SLNB in patients with early SCC of the oral cavity. Methods: Patients were included in this retrospective monocenter cohort study, performed at the University Hospital of Zürich, if they underwent either END or SLNB for oral squamous cell carcinoma (OSCC) of the tongue or floor of the mouth between January 2008 and December 2018. Only patients with early-stage tumors and a clinically negative neck (T1 or T2; cN0) who had a follow-up period of at least 5 years were included. Patients with a T3 or T4 tumor or a clinically positive neck were excluded, as were those who previously underwent therapy for another head and neck carcinoma. The predictor variable was the surgical treatment used, with subjects divided into two groups: END and SLNB. The main outcome variable was the time to recurrent disease, defined as the time between the primary surgical treatment and the diagnosis of recurrence. The covariates were primary tumor location, pT status, pN status, histopathological grade and postoperative radiotherapy. We used descriptive analysis, univariate analysis and the logrank test, with a p-value < 0.05 considered statistically significant. We deliberately refrained from multivariate analysis due to insignificant statistical results in the univariate analysis. Results: In total, 82 patients (46 male, 36 female; median age at the time of surgery: 58.9 years) were included, with a median observation period of 4.3 years. The main primary tumor location was the floor of the mouth (62.2%). The SLNB cohort had smaller primary tumors in comparison to the END cohort (20% vs. 37% pT2, respectively). Furthermore, pN+ disease was more prevalent in the END group in comparison to the SLNB group (81.8% vs. 74.1% pN0, respectively). Recurrence-free survival was not significantly different between the two groups. Subgroup analysis demonstrated a higher risk of recurrent disease in pN+ groups undergoing SLNB compared to those undergoing END. Conclusions: We demonstrate that SLNB is a useful tool for assessing lymph nodes of the neck. In cases of pN+ necks after SLNB and subsequent neck dissection, patients need to be closely followed up with due to the risk of recurrent disease. Full article

(This article belongs to the Special Issue Oral Cancer: The Latest Advances in Clinical and Basic Research (Second Edition))

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22 pages, 2763 KB

Open AccessArticle

PIAS1 Shapes a Tumor-Suppressive Microenvironment by Suppressing Immune Evasion in Oral Squamous Cell Carcinoma

by Parisa Ghahremanifard, Jinsu An, Ayan Chanda, Angela M. Y. Chan, Steven C. Nakoneshny, T. Wayne Matthews, Shamir P. Chandarana, Robert D. Hart, Martin D. Hyrcza, Joseph C. Dort, Shirin Bonni and Pinaki Bose

Cancers 2025, 17(17), 2905; https://doi.org/10.3390/cancers17172905 - 4 Sep 2025

Viewed by 1766

Abstract

Background: The SUMO E3 ligase PIAS1 (Protein Inhibitor of Activated STAT1) regulates pathways such as TGFβ signaling and has been implicated in multiple cancers. However, its role in the tumor microenvironment (TME), particularly in non-malignant stromal and immune cells, remains poorly understood. This study aimed to characterize the expression and functional relevance of PIAS1 within the TME of oral squamous cell carcinoma (OSCC). Methods: PIAS1 protein expression was assessed via immunohistochemistry (IHC) on OSCC tissue microarrays. Single-cell RNA-sequencing (scRNA-seq) datasets from OSCC tumors and normal tissues were analyzed to map cell-type-specific PIAS1 expression. Downstream effects were evaluated using differential gene expression, Ingenuity Pathway Analysis (IPA), gene set enrichment analysis (GSEA), and cell–cell communication inference. Results: IHC analysis revealed that higher stromal PIAS1 levels correlated with improved survival. scRNA-seq analysis showed an increase in the proportion of PIAS1-expressing cells across most stromal and immune cell populations within OSCC-derived tumors compared to their counterparts in adjacent normal tissue. However, when comparing PIAS1-positive cells, expression levels were significantly reduced in cancer cells, CAFs, TAMs, T cells, and endothelial cells within the TME. PIAS1-positive CAFs, TAMs, and T cells exhibited activation of apoptotic and tumor-suppressive pathways, while PIAS1-negative counterparts showed enrichment of immunosuppressive signaling and immune checkpoint expression. Cell–cell communication analyses indicated that PIAS1 fosters an immune-activated TME by promoting pro-inflammatory signaling, M1-like TAM polarization, and T cell activation. Conclusions: PIAS1 expression in stromal and immune cells is associated with tumor-suppressive reprogramming of the OSCC microenvironment. These findings position PIAS1 as a potential modulator of anti-tumor immunity and candidate target for therapeutic intervention. Full article

(This article belongs to the Special Issue Oral Cancer: The Latest Advances in Clinical and Basic Research (Second Edition))

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16 pages, 555 KB

Open AccessArticle

Surgery for T1/2N0 Oropharyngeal Carcinoma Is a Better Treatment Option than Radiotherapy—A Long-Term Follow-Up Study from a Single Japanese High-Volume Cancer Center

by Masahiro Rokugo, Takeshi Shinozaki, Ryo Ishii, Yusuke Ito, Shingo Sakashita, Genichiro Ishii, Takenori Ogawa, Yukio Katori, Kazuto Matsuura and Ryuichi Hayashi

Cancers 2025, 17(11), 1862; https://doi.org/10.3390/cancers17111862 - 31 May 2025

Cited by 1 | Viewed by 1401

Abstract

Background: The proportion of oropharyngeal cancers, especially those that are HPV-associated, is increasing, and both surgery and RT are considered effective initial treatments for early-stage oropharyngeal cancer, regardless of p16 status. However, there are still many unknowns regarding the long-term prognosis after initial treatment, the incidence rate of multiple cancers, and the relationship with p16 status. Methods: We retrospectively analyzed 94 cases of T1/2N0 oropharyngeal squamous cell carcinomas (OPSCCs) treated with surgery or radiotherapy between January 2000 and December 2012 at the Japan National Cancer Center Hospital East. The study items include long-term prognosis, p16 status, and the proportion of patients with multiple cancers after receiving treatment for oropharyngeal cancer. Results: The patients included 80 men and 14 women, whose median age was 68 (35–92). The median follow-up time was 2131 days. T1N0 cancer was observed in 34 patients and T2N0 in 60 patients. Surgery was performed for 74 patients, and radiotherapy for 20 patients. Of the patients who underwent surgery, 57 underwent transoral surgery, and 17 underwent pharyngectomy via transcervical approach. Nine of the 17 patients underwent partial pharyngectomy with free-flap reconstruction. The 5-year overall survival rates were 74.9 and 51.0% (p = 0.035); the 5-year disease-specific survival rates were 86.0 and 64.5% (p = 0.116); and the 5-year local control rates, 76.5 and 59.1% (p = 0.106) for the surgery and radiotherapy groups, respectively. Furthermore, 54 (57.4%) of the 94 cases suffered from multiple primary cancers, of which 29 (30.9%) were in the head and neck region and all were metachronous. Conclusions: Initial surgery for T1/2N0 OPSCCs is a proper therapeutic strategy considering the better overall survival and high incidence of multiple primary cancers. Full article

(This article belongs to the Special Issue Oral Cancer: The Latest Advances in Clinical and Basic Research (Second Edition))

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15 pages, 1351 KB

Open AccessArticle

The Association Between Skeletal Muscle Mass and Surgical Site Infection and Prognosis in Patients Undergoing Free Flap Reconstructive Surgery for Oral Squamous Cell Carcinoma: A Single-Center, Retrospective Study

by Atsuro Noguchi, Kenji Yamagata, Satoshi Fukuzawa, Kaoru Sasaki, Shohei Takaoka, Fumihiko Uchida, Naomi Ishibashi-Kanno, Mitsuru Sekido and Hiroki Bukawa

Cancers 2025, 17(10), 1729; https://doi.org/10.3390/cancers17101729 - 21 May 2025

Viewed by 980

Abstract

Background/Objectives: Local and systemic factors, including nutritional status, influence the prognosis of oral squamous cell carcinoma (OSCC). Skeletal muscle mass (SMM) loss is a poor prognostic factor in older patients and those with cancer. Herein, we examined the SMM index (SMI), rates of surgical site infection (SSI), and prognosis of 92 patients (59 males and 33 females) who underwent resection and free flap reconstructive surgery (FFRS) between 2013 and 2021. Methods: Preoperative computed tomography was performed to measure SMM at L3. The median SMI was 45.94 and 38.03 cm²/m² in males and females, respectively. Patients were classified into low and high SMI groups based on median SMI, and overall survival (OS) was analyzed. Results: Overall, 47 (51.1%) and 45 (48.9%) patients had low and high SMIs, respectively. SSI occurred in 11 (12.0%) patients; wound dehiscence and delayed wound healing were observed in 22 (23.9%). SSI rates were not significantly different between the low and high SMI groups. Conversely, OS was significantly associated with age, pathological N (pN), extranodal extension (ENE), and SMI (high, 81.1%; low, 60.2%). Univariate analyses revealed significant associations between OS and age (≥65 vs. <65 years), SMI (low vs. high), pN (present vs. none), ENE (present vs. none), and albumin (<4.0 vs. ≥4.0 mg/dL). Cox multivariate analysis included SMI (low vs. high; hazard ratio [HR]: 2.339, 95% confidence interval [CI]: 1.008–5.429; p = 0.015) and ENE (present vs. none; HR: 7.727, 95% CI: 3.083–19.368; p < 0.001). Conclusions: SMI and ENE were identified as independent predictive factors of OS in patients with OSCC undergoing FFRS. Full article

(This article belongs to the Special Issue Oral Cancer: The Latest Advances in Clinical and Basic Research (Second Edition))

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