Early-Onset Oral Tongue Squamous Cell Carcinoma in the Absence of Traditional Risk Factors: A Case Report with Whole-Exome Sequencing Analysis

Changing patterns in tongue, oral cavity, laryngeal and hypopharyngeal squamous cell carcinomas in New Zealand: Incidence, trends and survival from 2006 to 2022.

This work demonstrates that a comprehensive strategy of proteomics identification combined with further validation and detailed functional analysis should be adopted in the field of cancer biomarker discovery. A comparative proteomics approach was utilized to identify differentially expressed proteins in 10 oral squamous carcinoma samples paired with their corresponding normal tissues. A total of 52 significantly and consistently altered proteins were identified with eight of these being reported for the first time in oral squamous carcinoma. Of the eight newly implicated proteins, RACK1 was chosen for detailed analysis. RACK1 was demonstrated to be up-regulated in cancer at both the mRNA and protein levels. Immunohistochemical examination showed that the enhanced expression of RACK1 was correlated with the severity of the epithelial dysplasia as well as clinical stage, lymph node involvement, and recurrence, which are known indicators of a relatively poor prognosis in oral squamous carcinoma patients. RNA interference specifically targeted to silence RACK1 could initiate apoptosis of oral squamous carcinoma cells. Taken together, the results indicate that RACK1 is up-regulated in oral squamous carcinoma, not only being closely related to cell proliferation and apoptosis but also linked to clinical invasiveness and metastasis in carcinogenesis. The observations suggest that RACK1 may be a potential biomarker for early diagnosis, prognosis, and monitoring in the therapy of oral squamous carcinoma. Further this comprehensive strategy could be used for identifying other differentially expressed proteins that have potential to be candidate biomarkers of oral squamous carcinoma.

Human Leukocyte Antigen G (HLA-G) is a molecule involved in the tumor immunosuppression and also in the generation of regulatory T (Treg) cells, thus leading to evasion to the immune system host, and consequently, contributing to tumor progression in several cancers. The aim of this study was to evaluate the immunoexpression of HLA-G by tumor cells and FoxP3+ Treg cells in 25 oral tongue squamous cell carcinomas (SCCs) and 25 lower lip SCCs and analyze their relationship with clinical parameters. HLA-G expression was higher in oral tongue SCCs than in lower lip SCCs. In oral tongue SCCs and lower lip SCCs, no association between HLA-G expression and clinical parameters (tumor size, lymph node status, distant metastasis, and clinical stage) was verified (P>0.05). FoxP3+ Treg cells were detected along the tumor invasive front in all cases of oral tongue and lower lip SCCs. In oral tongue SCC cases, the number of Treg cells tended to be higher in smaller tumors, tumors without regional lymph node metastasis, and tumors in early clinical stages, but the difference was not statistically significant (P>0.05). A significant positive correlation was found between the expression of HLA-G by neoplastic cells and Treg cells in lower lip SCCs (p = 0.008). Our findings suggest the involvement of HLA-G and Treg cells in the modulation of immune responses in oral tongue and lower lip SCCs. This interaction between HLA-G and Treg cells may represent an evasion mechanism in these malignancies.

Nerve Growth Factor and Tyrosine Kinase A Receptor in Oral Squamous Cell Carcinoma: Is There an Association With Perineural Invasion?

T1 oral tongue squamous cell carcinoma: Local and regional failures

The aim of this study was to define the biomarkers of lymphatic spread which facilitate the appropriate therapy for oral tongue squamous cell carcinoma (OTSCC) patients at early stage. Here, we investigated the expression levels of seven biomarkers in oral squamous cell carcinoma (OSCC) tissues as well as their associations with the clinicopathologic features of OTSCC patients. The OTSCC samples were obtained from 138 patients undergoing tumor resection. Immunohistochemical staining was performed by using ColIA, ColIVA, Fn1, MMP-1, MMP-2, uPA, and D2-40 antibodies. Expression level of theses biomarkers in normal and tumor tissues were compared. Risk factors of lymphatic dissemination were evaluated by logistic regression equation. LVD, MMP-1, MMP-2, and uPA in cancer tissues were significantly higher than those in normal tissue, and ColIA, ColIVA, and Fn1 in cancer tissue were significantly lower than those in normal tissue. Similar results were obtained from the comparison between metastatic tumor and non-metastatic tumor. All biomarker expressions were closely related with lymph node status and clinical stage. Additionally, the regression equation demonstrated that LVD is the risk factor of lymphatic metastasis in OTSCC patients (OR = 1.732; 95% CIs: 1.167-2.057; P < 0.05). Down-regulation of ColIA, ColIVA, and Fn1 and up-regulation of LVD, MMP-1, MMP-2, and uPA might be important features of OSCC progression, which may exert their functions and favorably predict lymphatic dissemination for OSCC patients at relatively early stage. Among these biomarkers, increased LVD is an independent risk factor of lymphatic metastasis, which could better predict whether metastasis will occur or not.

Oral squamous cell carcinoma (OSCC) is currently a highly prevalent disease worldwide. Cisplatin (CDDP) is widely used for the chemotherapy of OSCC. Yet, the molecular mechanisms responsible for cisplatin resistance have not been fully elucidated. In this study, we showed that overexpression of p21 (RAC1) activated kinase 1 (PAK1) induced epithelial to mesenchymal transition (EMT) and significantly promoted the invasion and migration of oral squamous cell carcinoma SCC25 cells. Emerging evidence indicates a strong link between resistance to therapy and the induction of EMT in cancer. We showed that overexpression of PAK1 induced cisplatin resistance in SCC25 cells. ERCC1 and YAP can promote cisplatin resistance in human OSCC. We showed that ERCC1 and YAP protein were upregulated by PAK1 in SCC25 cells. We found that miR-485-5p inhibited PAK1 protein expression in the SCC25 cells. Contrary to PAK1, we demonstrated that overexpression of miR-485-5p reversed EMT and significantly inhibited invasion and migration. Moreover, its overexpression sensitized SCC25-CR cells (cisplatin-resistant cells) to cisplatin. Thus, we conclude that miR-485-5p reverses EMT and promotes cisplatin-induced cell death by targeting PAK1 in oral tongue squamous cell carcinoma. This study suggests that PAK1 plays an essential role in the progression of OSCC and it is a potential therapeutic target for OSCC.

Oral tongue cancer incidence has increased among whites in the United States; however, the cause remains unknown. If an infectious agent is implicated, then elevated risk would be expected among immunosuppressed individuals. By using population-based registry linkage information from the US Transplant Cancer Match and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) Cancer Match studies, the authors examined the risk of oral tongue squamous cell carcinoma (SCC) among immunocompromised transplantation recipients and HIV-infected individuals. In addition, the risks of oropharyngeal SCC (strongly related to human papillomavirus infection; modestly affected by immunosuppression), other tobacco/alcohol-related oral cavity SCCs (not thought to be infection/immunosuppression-related), and non-Hodgkin lymphoma of oral cavity/pharynx (strongly related to Epstein-Barr virus; profoundly affected by immunosuppression) were evaluated. Compared with the general population, the risk of non-Hodgkin lymphoma was strongly increased (standardized incidence ratio [SIR] > 8.0). The risk of all SCCs was modestly and similarly elevated among transplantation recipients (SIR range, 2.2-2.7; Pheterogeneity = .2); whereas, among HIV-infected individuals, the risk of oral tongue SCC was higher compared with the risk of other SCCs (SIR, 3.0 vs 1.7 [for oropharyngeal SCCs] and 2.3 [for other oral cavity SCCs]; Pheterogeneity < .001). The risk of SCCs was significantly higher among men, older individuals, and whites; and risk increased with the time since transplantation/AIDS onset. The risk of oral tongue SCC was significantly higher among HIV-infected men who have sex with men compared with the average risk in HIV-infected individuals (adjusted incidence rate ratio = 2.0). Similar modest increases in the risk of oral tongue and other oral cavity SCCs do not suggest that an infectious agent or exposure profoundly affected by immunosuppression underlies the increase in oral tongue cancer. Cancer 2018;124:2515-22. © 2018 American Cancer Society.

Oral squamous cell carcinoma (OSCC) is associated with substantial mortality and morbidity, and oral tongue squamous cell carcinoma (SCC) is representative in OSCC. Early detection of oral premalignant lesions (OPLs) that will develop into invasive tumors is necessary to improve the poor prognosis of this cancer. To identify potential biomarkers that could be used for early detection, we compared the gene expression of incident primary oral tongue SCC, severe dysplasia, mild and moderate dysplasia. For this, we used three expression datasets obtained from a public database and selected chromosomal locations related with the progress of oral tongue cancer from a dataset. We then evaluated the gene set, which is included in the selected chromosomal locations, using out of bag (OOB) error and plots in two validation datasets. Sixty-two chromosomal locations were detected, and most genomic aberrations were shown in chromosome 3. We identified 62 genes included in those locations, and three precancerous and SCC groups were well classified with low OOB error rates. These were also discriminative in the two validation datasets. The selected probes with genomic alteration in low-grade dysplasia can be used as an effective predictor for disease progression.

Rising incidence of oral tongue squamous cell carcinoma in young women: Emerging non-traditional etiologic factors and clinical implications: A structured narrative review.

DPM1 expression as a potential prognostic tumor marker in oral squamous cell carcinoma.

Introduction: Oral tongue squamous cell carcinoma (OTSCC) is the most common cancer of the oral cavity. Contradictory results have been observed on the involvement of herpes simplex virus 1 (HSV-1) in oral squamous cell carcinomas. Here, we aimed to study the predominance of HSV-1 or HSV-2 in oral HSV infections and to investigate the presence of HSV-1 in OTSCC and its effect on carcinoma cell viability and invasion. Methods: The distribution of HSV types one and two in diagnostic samples taken from suspected oral HSV infections was determined from the Helsinki University Hospital Laboratory database. We then analysed 67 OTSCC samples for HSV-1 infection using immunohistochemical staining. We further tested the effects of HSV-1 using six concentrations (0.00001-1.0 multiplicity of infection [MOI]) on viability and two concentrations (0.001 and 0.1 MOI) on invasion of highly invasive metastatic HSC-3 and less invasive primary SCC-25 OTSCC cell lines using MTT and Myogel-coated Transwell invasion assays. Results: Altogether 321 oropharyngeal samples were diagnosed positive for HSV during the study period. HSV-1 was the predominant (97.8%) HSV type compared with HSV-2 (detected in 2.2% of samples). HSV-1 was also detected in 24% of the OTSCC samples and had no association with patient survival or recurrence. OTSCC cells were viable even after 6days with low viral load (0.00001, 0.0001, 0.001 MOI) of HSV-1. In both cell lines, 0.001 MOI did not affect cell invasion. However, 0.1 MOI significantly reduced cell invasion in HSC-3 cells. Discussion: HSV-1 infection is predominant compared with HSV-2 in the oral cavity. HSV-1 is detected in OTSCC samples without clinical significance, and OTSCC cell survival or invasion was not affected at low doses of HSV-1.

BackgroundResistance to anticancer agents is a major obstacle for successful chemotherapy in tongue squamous cancer. Sam68 is an oncogenic-related protein in oral tongue squamous cell carcinoma functions as a signaling molecule mediating apoptosis, whose over-expression is associated with the clinicopathologic characteristics and prognosis of patients. The present study was to examine the effect of Sam68 on chemotherapeutics-induced apoptosis in oral tongue squamous cell carcinoma, and its clinical significance in oral tongue squamous cell carcinoma progression.MethodsThe effect of Sam68 on apoptosis induced by cisplatin was examined both in vitro and in vivo, using Annexin V staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays. Real-time PCR and Western blotting analysis were used to detect mRNA and protein expression levels.ResultsUpregulation of Sam68 significantly inhibited cisplatin-induced apoptosis in oral tongue squamous cell carcinoma cells, associated with induction of anti-apoptotic proteins caspase-9, caspase-3, and PARP. In contrast, Silencing Sam68 expression significantly enhanced the sensitivity of oral tongue squamous cell carcinoma cells to apoptosis induced by cisplatin both in vitro and in vivo.ConclusionsThe current study suggests that Sam68 could enhance the anti-apoptosis activity of oral tongue squamous cell carcinoma cells. Sam68 is a potential pharmacologic target for the treatment of oral tongue squamous cell carcinoma and inhibition of Sam68 expression might represent a novel strategy to sensitize oral tongue squamous cell carcinoma to chemotherapy.

The objective of this study was to compare survival in patients with squamous cell carcinoma (SCC) of the oral tongue with that in patients with SCC in other oral cavity subsites. Patients with stage I and II (T1-T2N0M0) SCC of the oral cavity diagnosed between 1988 and 2004 were queried by using the Surveillance, Epidemiology, and End Results (SEER) database. The log-rank test was used to compare the overall survival (OS) and cause-specific survival (CSS) of patients who had oral tongue SCC with those of patients who had SCC of other oral cavity subsites. A Cox proportional hazards multivariate analysis was performed to evaluate the influence of covariates on the risk of CSS and OS. Between 1988 and 2004, 6791 patients with stage I and II SCC of the oral cavity were identified. Among them, 40% had oral tongue SCC, and 60% had SCC of other oral cavity subsites. The median patient age was 64 years. The 5-year OS and CSS rates were 60.9% and 83.5%, respectively, for patients with oral tongue SCC versus 64.7% and 94.1%, respectively, for patients with SCC of other oral cavity subsites (OS: hazard ratio, 1.24; P< .0001; CSS: hazard ratio, 3.04; P< .0001). On multivariate analysis, OS and CSS were influenced significantly by T classification, age, sex, and oral tongue subsite. The CSS for patients who had stage I and II oral tongue SCC also was unfavorable compared with the CSS for stage-matched patients who had SCC of other head and neck sites. Oral tongue SCC was associated with poor survival compared with other oral cavity and head and neck sites. These data suggested a potential benefit for multimodality therapy in this cohort of patients.

Oral tongue squamous cell carcinoma (SCC) is characterized by early metastasis and poor prognosis. Interleukin-17F (IL-17F) plays a protective role in many tumors. However, IL-17F expression in oral tongue SCC tissue has not been investigated. Immunostaining of 83 oral tongue SCC specimens and blinded-scoring were used to map IL-17F expression, location, and distribution. Survival curves were constructed according to Kaplan-Meier method. The Cox proportional hazard model was applied for univariate and multivariate survival analyses. Mast cells are the major source of IL-17F in oral tongue SCC. In multivariate analysis, only the extracellular mast cell-derived IL-17F at the tumor invasion front was associated with better disease-specific survival in patients with all-stages and early-stages of oral tongue SCC. Extracellular mast cell-derived IL-17F is antitumorigenic in oral tongue SCC. It separates patients with early-stage disease who are at high risk from patients who are at low risk. Furthermore, when analyzing tentative prognostic molecules, we conclude that in addition to the staining intensity, attention must be paid to the cellular source, distribution, and location of the molecule.