Oral Tongue Squamous Cell Carcinoma Research Articles

Prognostic significance of tumor budding thresholds in oral tongue squamous cell carcinoma.

Oral tongue squamous cell carcinoma (OTSCC) represents the most common malignancy of the oral cavity. Tumor budding (TB) is a reliable prognostic factor in OTSCC; however, a standardized scoring system is not still validated. The study aims to evaluate the prognostic role of TB in 211 OTSCC patients treated between 1997 and 2018. TB was evaluated on hematoxylin and eosin-stained sections in the hotspot area of the infiltrative front (×200-magnification). It was scored using a two-tier system, a three-tier system, and according to BD-model and revised-Grading system. Univariate and multivariate Cox regression analyses of disease-specific survival (DSS) and disease-free survival (DFS) were performed. A p<0.05 was considered as statistically significant. The two-tier and three-tier systems resulted an independent prognostic factor of DSS. High-risk patients had a 2.21 and 3.08 times increased probability of poor DSS compared with low-risk group. It is significantly increased even for intermediate-risk group. No significant differences emerged classifying patients according to BD-model and revised-Grading system. These data confirm the prognostic value of TB in predicting DSS in OTSCC. Classifying patients into two groups using the 5-bud cutoff significantly discriminates their outcomes. Since the established role of DOI and the poor prognostic value of grading, TB could be considered an independent prognostic marker.

The prognostic role of combining Krüppel-like factor 4 score and grade of inflammation in a Norwegian cohort of oral tongue squamous cell carcinomas.

Krüppel‐like factor 4 (KLF4) is a zinc‐finger transcription factor involved in inflammation, cancer development, and progression. However, the relationship between KLF4, inflammation, and prognosis in oral cancer is not fully understood. KLF4 expression levels were examined in a multicenter cohort of 128 oral squamous cell carcinoma (OSCC) specimens from the tongue (OTSCC) using immunohistochemistry. In two external KLF4 mRNA datasets (The Cancer Genome Atlas/The Genotype‐Tissue Expression Portal), lower KLF4 mRNA expression was found in OSCC and head and neck squamous cell carcinomas (HNSCC) than in control oral epithelium. These data indicate that down‐regulation of KLF4 mRNA is linked to OSCC/HNSCC progression. Using Cox‐multivariate analysis, a significantly favorable 5‐year disease‐specific survival rate was observed for a subgroup of patients with a combination of high levels of KLF4 expression and inflammation. OSCC cell lines exposed to IFN‐γ showed a significant upregulation of nuclear KLF4 expression, indicating a link between inflammation and KLF4 expression in OSCC. Overall, the current data suggest a functional link between KLF4 and inflammation. The combination of high KLF4 nuclear expression and marked/moderate stromal inflammation might be useful as a favorable prognostic marker for a subgroup of OTSCC patients.

Oral tongue carcinoma: prognostic changes according to the updated 2020 version of the AJCC/UICC TNM staging system.

SUMMARYBackgroundThis study aimed to evaluate the performance of the 2017 8th TNM edition and the latest update in 2020 compared to the 7th in a large cohort of patients affected by oral tongue squamous cell carcinoma (OTSCC), considering all stages.Materials and methodsThe cohort involved 300 patients affected by OTSCC treated with surgery. All cases were classified according to the 7th, 8th (2017), and the latest updated TNM edition (October 2020),. Patients were grouped based on the shift in tumour (T) category, lymph nodal (N) category and final pathological stage. Overall survival (OS) and disease-free survival (DFS) were calculated with the Kaplan-Meier method. Univariate and multivariate analyses were carried out.ResultsAccording to the 7th edition, multivariate analysis OS revealed that stage IV patients had an almost 4-fold risk of death compared to stage I (HR = 3.81 95% CI: 2.32-6.25; p < 0.001). Regarding DFS, stage IV patients had a 2-fold greater risk of relapses, or second primary, than patients in stage I (HR = 2.51 95% CI: 1.68-3.74; p < 0.001). According to 2017 8th edition for OS, stage IV patients presented a 5-fold higher risk of death compared to patients in stage I (HR = 5.18 95% CI: 2.96-9.08; p < 0.001) and almost 4-old greater risk of relapses or second primary compared to patients in stage I considering DFS (HR = 3.61 95% CI: 2.28-5.71; p < 0.001). Regarding the recent edition of 8th TNM (2020), stage IV patients had an almost 5-fold greater risk of death compared to patients in stage I considering OS (HR = 4.84 95% CI: 2.74-8.55; p < 0.001), while for DFS they had 3-fold greater risk of relapse or second primary compared to patients in stage I (HR = 3.13 95% CI: 1.99-4.91; p < 0.001).ConclusionsThis study confirmed that the recent update of the 8th edition of the TNM (2020) improves stratification and identification of advanced tumours, reducing the number of T3 compared to the 2017 edition and increasing the number of patients with pT4. This improvement made by the updated edition may reduce the risk of skipping adjuvant therapy.

Radiomics Metrics Combined with Clinical Data in the Surgical Management of Early-Stage (cT1-T2 N0) Tongue Squamous Cell Carcinomas: A Preliminary Study.

Simple SummaryThe purpose of this study is to predict the risk of metastatic lymph nodes related to oral tongue squamous cell carcinoma (OTSCC) and tumor grading through the combination of clinical data with radiomics metrics extracted from computed tomography (CT) images. We aimed to develop a supportive approach in the management of lymphatic cervical areas, with particular attention given to the early stages (T1−T2). Specifically, we evaluated the effectiveness of the radiomics and clinical features in the study of OTSCC and in the prediction of occult laterocervical metastatic lymph nodes. We concluded that radiomics features and clinical parameters have an important role in identifying tumor grading and metastatic lymph nodes. Machine learning approaches can be used as an easy-to-use tool to stratify patients with early-stage OTSCC, based on the identification of metastatic and non-metastatic lymph nodesObjective: To predict the risk of metastatic lymph nodes and the tumor grading related to oral tongue squamous cell carcinoma (OTSCC) through the combination of clinical data with radiomics metrics by computed tomography, and to develop a supportive approach in the management of the lymphatic cervical areas, with particular attention to the early stages (T1−T2). Between March 2016 and February 2020, patients with histologically confirmed OTSCC, treated by partial glossectomy and ipsilateral laterocervical lymphadenectomy and subjected to computed tomography (CT) before surgery, were identified by two centers: 81 patients (49 female and 32 male) with 58 years as the median age (range 19–86 years). Univariate analysis with non-parametric tests and multivariate analysis with machine learning approaches were used. Clinical, hematological parameters and radiological features extracted by CT were considered individually and in combination. All clinical parameters showed statistically significant differences (p < 0.05) for the Kruskal−Wallis test when discriminating both the tumor grading and the metastatic lymph nodes. DOI, PLR, SII, and SIRI showed an accuracy of 0.70 (ROC analysis) when identifying the tumor grading, while an accuracy ≥ 0.78 was shown by DOI, NLR, PLR, SII, and SIRI when discriminating metastatic lymph nodes. In the context of the analysis of radiomics metrics, the original_glszm_HighGrayLevelZoneEmphasis feature was selected for identifying the tumor grading (accuracy of 0.70), while the wavelet_HHH_glrlm_LowGrayLevelRunEmphasis predictor was selected for determining metastatic lymph nodes (accuracy of 0.96). Remarkable findings were also obtained when classifying patients with a machine learning approach. Radiomics features alone can predict tumor grading with an accuracy of 0.76 using a logistic regression model, while an accuracy of 0.82 can be obtained by running a CART algorithm through a combination of three clinical parameters (SIRI, DOI, and PLR) with a radiomics feature (wavelet_LLL_glszm_SizeZoneNonUniformityNormalized). In the context of predicting metastatic lymph nodes, an accuracy of 0.94 was obtained using 15 radiomics features in a logistic regression model, while both CART and CIDT achieved an asymptotic accuracy value of 1.00 using only one radiomics feature. Radiomics features and clinical parameters have an important role in identifying tumor grading and metastatic lymph nodes. Machine learning approaches can be used as an easy-to-use tool to stratify patients with early-stage OTSCC, based on the identification of metastatic and non-metastatic lymph nodes.

IDO1 Inhibition Reduces Immune Cell Exclusion Through Inducing Cell Migration While PD-1 Blockage Increases IL-6 and -8 Secretion From T Cells in Head and Neck Cancer.

BackgroundImmune checkpoint inhibitors (ICIs), primarily anti-PD-1, are currently used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, only a minority of patients benefit from these costly therapies. Therefore, there is an unmet need to better understand the effect of ICIs on immune effector cells. This study aimed to investigate the effect of a PD-1 antibody and an IDO1 inhibitor on different lymphocyte populations (NK, CD4+, and CD8+ T cells) in term of migration, cytotoxicity, and cytokine release in the presence of HNSCC cells.MethodsUsing a microfluidic chip, we injected HSC-3 cells (an oral tongue squamous cell carcinoma cell line) embedded in a human tumor-derived matrix “myogel/fibrin” together with NK, CD4+, and CD8+ T cells in separate channels. The two channels were connected with microchannels. The PD-1 antibody nivolumab and IDO1 inhibitor epacadostat were added to the microfluidic chips. Lymphocyte migration and cytotoxicity were examined under fluorescent microscopy and cytokine release was measured using a FirePlex Human Discovery Cytokines Immunoassay.ResultsEpacadostat significantly increased the migration and infiltration of NK and CD4+ T cells, but not CD8+ T cells, towards the cancer cells. Nivolumab did not exhibit a similar effect. While CD8+ T cells alone showed near to no migration, adding CD4+ T cells enhanced migration towards the cancer cells. There was a mild nonsignificant increase in apoptosis of HSC-3 cells after adding epacadostat to lymphocytes. In contrast, HSC-3 proliferation was not affected by lymphocytes regardless of ICIs. Nivolumab significantly increased release of MIP1-α, IL-6, and IL-8 from NK, CD4+, and CD8+ T cells, respectively.ConclusionsThis study revealed that each subpopulation of lymphocytes respond differently to ICIs. We also revealed the subpopulation of lymphocytes responsible for the increases in specific serum cytokines after ICI treatment.

Dosimetric Comparison of Intensity Modulated Radiotherapy (IMRT) and Intensity Modulated Proton Therapy (IMPT) for Novel Oral Tongue Avoidance Concept in Low-Risk Squamous Cell Carcinoma of the Oral Tongue

<h3>Purpose/Objective(s)</h3> A subset of favorable oral tongue squamous cell carcinoma patients who undergo adequate surgical resection are at low risk of local recurrence to the primary site. Since irradiation of the primary site is the major cause of treatment morbidity during adjuvant radiotherapy, avoidance of this target while still treating the at-risk lymph nodes including the intervening lymphatics between the tongue and neck is an attractive potential treatment strategy. Prior to initiation of an investigator-initiated trial, we sought to quantify the dosimetric advantage of this strategy, hypothesizing intensity modulated proton therapy (IMPT) may further reduce dose to organs at risk (OAR) when avoiding the oral tongue compared to intensity modulated radiation therapy (IMRT). <h3>Materials/Methods</h3> Five consecutive patients with oral tongue cancer treated with postoperative radiation therapy from 8/2020 to 9/2021 were retrospectively reviewed. Novel Clinical Target Volume (CTV) contours were generated that excluded the oral tongue while maintaining coverage of at-risk lymph nodes. Comparison IMRT (X) and IMPT (PBT) plans were generated using both standard treatment volumes (Control) and oral tongue avoidance volumes (Study) (n=4 plans per patient). Dosimetric variables for critical OARs were compared using the paired t-test. <h3>Results</h3> Patients had T1-2 and N0-N2b disease with complete margin-negative partial or hemiglossectomy and bilateral neck dissections. The prescribed dose was 60 Gy in 30 fractions. D95% CTV coverage was similar between X and PBT plans for both Control and Study target volumes. Comparing Control to Study plans, both X (58.9 Gy vs. 38.3 Gy, p=0.007) and PBT (60.2 Gy vs. 26.1 Gy, p<0.001) decreased the mean dose to the oral cavity (OC). Similar results were demonstrated for mean pharyngeal constrictor dose with X (47.7 Gy vs. 44.6 Gy, p=0.003) and PBT (45.0 Gy vs. 34.9 Gy, p=0.001). There was no difference between Control and Study plans for larynx (p>0.19) or parotid (p>0.11) mean dose, or mandible max dose (p>0.59). Comparing the Study plans alone, PBT resulted in a significant reduction in mean OC dose (38.3 Gy vs. 26.1 Gy, p=0.007) and reduction in mean parotid dose (23.3 Gy vs.19.3 Gy, p=0.03) compared to X. For Control plans, there was no difference in OC dose using PBT compared to X but an improvement in mean parotid dose (26.6 Gy vs 19.7 Gy, p=0.02). <h3>Conclusion</h3> This study quantifies the dosimetric advantage of avoiding the oral tongue while still treating the at-risk intervening lymphatics and the bilateral necks during adjuvant radiotherapy for oral tongue cancer. The dosimetric difference between PBT and X was most prominent with an oral tongue avoidance strategy. Prospective studies are warranted to evaluate the clinical efficacy of oral tongue avoidance for favorable oral tongue cancer patients with indications for elective nodal irradiation.

Mass Spectrometry-Based Differentiation of Oral Tongue Squamous Cell Carcinoma and Nontumor Regions With the SpiderMass Technology.

Oral cavity cancers are the 15th most common cancer with more than 350,000 new cases and ~178,000 deaths each year. Among them, squamous cell carcinoma (SCC) accounts for more than 90% of tumors located in the oral cavity and on oropharynx. For the oral cavity SCC, the surgical resection remains the primary course of treatment. Generally, surgical margins are defined intraoperatively using visual and tactile elements. However, in 15–30% of cases, positive margins are found after histopathological examination several days postsurgery. Technologies based on mass spectrometry (MS) were recently developed to help guide surgical resection. The SpiderMass technology is designed for in-vivo real-time analysis under minimally invasive conditions. This instrument achieves tissue microsampling and real-time molecular analysis with the combination of a laser microprobe and a mass spectrometer. It ultimately acts as a tool to support histopathological decision-making and diagnosis. This pilot study included 14 patients treated for tongue SCC (T1 to T4) with the surgical resection as the first line of treatment. Samples were first analyzed by a pathologist to macroscopically delineate the tumor, dysplasia, and peritumoral areas. The retrospective and prospective samples were sectioned into three consecutive sections and thaw-mounted on slides for H&E staining (7 μm), SpiderMass analysis (20 μm), and matrix-assisted laser desorption ionization (MALDI) MS imaging (12 μm). The SpiderMass microprobe collected lipidometabolic profiles of the dysplasia, tumor, and peritumoral regions annotated by the pathologist. The MS spectra were then subjected to the multivariate statistical analysis. The preliminary data demonstrate that the lipidometabolic molecular profiles collected with the SpiderMass are significantly different between the tumor and peritumoral regions enabling molecular classification to be established by linear discriminant analysis (LDA). MALDI images of the different samples were submitted to segmentation for cross instrument validation and revealed additional molecular discrimination within the tumor and nontumor regions. These very promising preliminary results show the applicability of the SpiderMass to SCC of the tongue and demonstrate its interest in the surgical treatment of head and neck cancers.

Emerging histopathologic markers in early-stage oral tongue cancer: A systematic review and meta-analysis.

Although there are many histopathologic prognosticators, grading of early oral tongue squamous cell carcinoma (OTSCC) is still based on morphological cell differentiation which has low prognostic value. Here we summarize the emerging histopathological markers showing powerful prognostic value, but are not included in pathology reports. Using PubMed, Scopus, Ovid Medline, and Web of Science databases, a systematic literature search was preformed to identify early OTSCC studies that investigated the prognostic significance of hematoxylin–eosin‐based histopathologic markers. Our meta‐analysis showed that tumor budding was associated with overall survival (hazard ratio [HR] 2.32; 95% CI 1.40–3.84; p < 0.01) and disease‐specific survival (DSS) (1.89; 95% CI 1.13–3.15; p = 0.02). Worst pattern of invasion was associated with disease‐free survival (DFS) (1.95; 95% CI 1.04–3.64; p = 0.04). Tumor–stroma ratio was also associated with DFS (1.75, 95% CI 1.24–2.48; p < 0.01) and DSS (1.69; 95% CI 1.19–2.42; p < 0.01). Tumor budding, worst pattern of invasion, and tumor–stroma ratio have a promising prognostic value in early OTSCC. The evaluation and reporting of these markers is cost‐effective and can be incorporated in daily practice.

Significance of Pattern of Invasion in Tongue Squamous Cell Carcinoma-A Retrospective Study from a Regional Cancer Center of North-East India.

Introduction Many multiparametric models and scoring systems had been proposed in oral tongue squamous cell carcinoma (OTSCC) to predict the survival and recurrence, out of which pattern of invasion (POI) is gaining focus recently. Objective We conducted a retrospective study with the aim to see the prognostic significance of the POI and other parameters such as depth of invasion, perineural invasion (PNI), and lymph node status in OTSCC. Materials and Methods The slides of already diagnosed OTSCC cases were prepared from January 2015 to December 2017 records and studied by two pathologists for different patterns using Brandwein-Gensler scoring system. The different clinicopathologic parameters were compared with different POI. Statistical analysis was performed to present cumulative survival outcomes and for comparison. Results Most of our patients were > 40 years of age with male preponderance. Tumor differentiation pattern was assessed using Broders' system of grading that showed 85% of tumors were well, 12.5% tumors were moderately differentiated, and 2.5% tumors were poorly differentiated. The worst POI was predominantly pattern III (50%) followed by pattern II (32.5%) and pattern IV (13.8%). Most patients were in stage II (33.8%) followed by stage III (32.5%), stage IV (26.3%), and stage I (7.5%). There was an inverse relationship between POI with tumor stage and recurrence. A strong statistically significant association was found between POI with perineural infiltration and lymph node metastasis. Conclusion We concluded from our study that worst POI is significantly associated with number of lymph nodes metastasis and perineural infiltration and hence can be used as an independent prognostic factor.

Clinicopathological Difference Between Gingivobuccal and Oral Tongue Cancers: A Cross-Sectional Observational Study from a Tertiary Healthcare Centre in Northern India.

Gingivobuccal and oral tongue squamous cell carcinomas are commonly considered together as a single clinical entity for staging and treatment purposes. Though there is data suggesting a significant difference between SCC of various oral cavity subsites, very few studies have compared clinicopathological characteristics between the tongue and gingivobuccal primaries. We retrospectively analysed 225 patients with biopsy-proven gingivobuccal (GB) and oral tongue (OT) SCC operated between April 1, 2018 and April 30, 2021 in All India Institute of Medical Sciences, Rishikesh, India to compare their clinicopathological characteristics. Demographic, clinical and histopathological data were collected from electronic medical records. An independent sample t-test was used to compare means and Pearson chi-square test or Fisher exact test was applied to compare the distribution of categorical variables. A relative male preponderance (12:1 vs. 5:1, p = 0.036) and increased smokeless tobacco consumption (82% Vs. 69%, p = 0.003) was seen in GB-SCC. Significantly higher proportion of patients with OT-SCC presented with early primaries (T1/T2) (54.1% vs. 24.8%, p < 0.001). Similarly, a higher proportion of GB-SCC patients presented with palpable neck nodes (cN +) (81% Vs. 67%, p = 0.02). Due to early primary tumours at presentation, stage I/II disease was also significantly higher in cases of OT-SCC (36.5% Vs.13.7%, p < 0.001). No difference was noticed in age at presentation, neck node status, and other clinicopathological parameters. GB-SCC has a higher male preponderance than OT-SCC due to relatively higher consumption of smokeless tobacco in males. Oral tongue cancers presented at an earlier stage than gingivobuccal malignancies. No difference in neck node status, however, suggests a relatively aggressive disease behaviour and early regional metastasis in tongue cancers. Follow up data regarding recurrence and survival is required to further characterise the differences between these two common OSCC subsites.

The Usefulness of Intraoral Ultrasonography and Post-Contrast Three-Dimensional Fast Field Echo Imaging in the Evaluation of Radiological Depth of Invasion of Oral Tongue Squamous Cell Carcinoma: Comparison with Pathological Depth of Invasion Assessment

Aim Squamous cell carcinoma (SCC) is the most common malignancy in the oral tongue. Depth of invasion (DOI) of the tongue SCC is known as a predictor of recurrence and survival in patients. Both intraoral ultrasonography (ioUS) and post-contrast three-dimensional fast field echo (3D-FFE) imaging are useful for predicting pathological DOI and can contribute to effective treatment plans and a positive prognosis. The purpose of this study was to evaluate the usefulness of ioUS in comparison with post-contrast 3D-FFE imaging for assessing radiological DOI and compare radiological DOI and pathological DOI in patients with oral tongue SCC. Methods Fifteen patients were included in this study conducted between August 2018 and March 2020. Spearman's rank correlation coefficient was used to compare radiological DOI with pathological DOI. Results Both ioUS-derived DOI (9.98 mm) and 3D-FFE-derived DOI (9.86 mm) were larger than pathological DOI (5.7 mm). The Pearson’s correlation coefficient (PCC) between ioUS-derived DOI and pathological DOI was 0.63 and between 3D-FFE-derived DOI and pathological DOI was 0.58.

KIF18A is a potential prognostic factor and promotes tumor progression in oral tongue squamous cell carcinoma

The kinesin family member 18A protein was dysregulated in several human cancers and involved in cancer progression. However, the significance in oral tongue squamous cell carcinoma (OTSCC) has not been studied. The present study was intended to explore the functions of KIF18A in oral tongue squamous cell carcinoma. The immunohistochemistry (IHC) assay was performed to assess the relationships between the KIF18A protein expression level and clinical-pathological features of the patients. The biological functions of KIF18A in OTSCC cells were investigated by the experiments in vitro and in vivo. Based on immunohistochemistry, we found that KIF18A was correlated with the clinical-pathological features of OTSCC patients. High expression of KIF18A was associated with the lymph node metastasis, and clinical stages. In vitro experiments revealed that silencing of KIF18A significantly inhibited the expression of the proliferation and migration related proteins such as Ki67, proliferating cell nuclear antigen, matrix metalloproteinase-7 and matrix metalloproteinase-9, and thereby inhibiting the proliferation, migration and invasion of tumor cells. In vivo, knocking-down of KIF18A could inhibit the tumor growth in nude mice. In conclusion, we found KIF18A promoted tumor progression in vivo and in vitro and might become an effective target for the treatment of OTSCC.

Results of sequential swallowing assessments in patients undergoing upfront surgery for oral tongue squamous cell carcinoma

BackgroundThe swallowing outcomes in patients undergoing glossectomy have been inconsistently reported in the literature owing to variable follow up times, different tools for assessment and lack of single institution large scale studies. The aim of our study was to assess the patterns of swallowing outcomes over time and identify factors affecting nasogastric tube dependency at 1-year post-surgery. Materials and MethodsThis was a retrospective study of treatment naïve patients with oral tongue carcinoma who underwent surgery and attended the speech and swallow clinic between January 2016 and December 2019 at our institute were included in the study. The findings of swallowing assessment by a speech language pathologist at three time points were recorded. ResultsA total of 606 patients were found eligible for the study. The median age of the patients was 50 years with the 211 (34.8%) patients having T3/T4 disease. The swallowing outcomes in terms of tube dependence and the spectrum of diet tolerance seem to improve over time with an increasing number of patients switching over to a solid diet by 1 year. A higher defect class (HR = 24.43 [3.48–171.27]) and presence of co-morbidities (HR = 4.17 [1.59–10.92]) were associated with sustained feeding tube dependency status at 1 year. A nomogram was developed based on these findings. ConclusionThe swallowing outcomes in terms of tube dependence and the spectrum of diet tolerance seem to improve over time. A higher defect class and presence of co-morbidities were associated with NGT dependency at 1 year.

Immunoexpression of REGγ and apoptosis-related proteins in oral tongue squamous cell carcinoma

The aim of this study was to investigate the immunohistochemical expression of REGγ, p53, MDM-2, Bcl-2, and Bax in oral tongue squamous cell carcinoma (OTSCC), and to correlate the findings with clinicopathological parameters. Fifty-eight OTSCC cases were selected for the study. The percentages of nuclear (REGγ, p53, and MDM-2) and cytoplasmic (Bcl-2 and Bax) staining in epithelial cells were determined and correlated with clinicopathological parameters (regional lymph node metastasis, clinical stage, clinical outcome, and histopathological grade of malignancy). Expression of REGγ was observed in all cases studied. Significantly lower percentages were observed in tumours with lymph node metastasis (P = 0.036) and in high-grade tumours (P = 0.013). No significant differences in p53, MDM-2, or Bax expression were observed according to the clinicopathological parameters. Lower percentages of Bcl-2 staining were found in high-grade OTSCC (P = 0.040) and in cases of disease-related death (P = 0.032). The expression of REGγ showed a weak positive correlation with the expression of MDM-2 (P = 0.001) and Bcl-2 (P = 0.014). The results of this study suggest that lower expression of REGγ may contribute to the progression of OTSCC. The role of REGγ in the development of OTSCC does not appear to be primarily related to the modulation of apoptosis in neoplastic cells.

Depth of Invasion as an Independent Predictor of Survival in Patients of Stage III Squamous Cell Carcinoma of the Oral Tongue.

Depth of invasion (DOI) has been incorporated in the new AJCC 8th classification. However, even with this new AJCC classification stage III oral tongue squamous cell carcinoma (OTSCC) remains a heterogenous group. The study aims at finding a discreet group within stage III using DOI as a cut-off of 10 mm. The institutional database was reviewed from 2012 to 2018 for postoperative stage III OTSCC patients who subsequently received postoperative radiotherapy. Ninety-six patients matched the inclusion criteria. Two groups were created using a DOI cut-off of 10 mm (superficial and deep groups). The groups were analyzed for overall survival (OS) and relapse-free survival (RFS). The baseline and treatment characteristics were comparable between the groups except for the higher number of extensive surgeries, endophytic configuration, pT3 and, DOI in the deep group. For a median follow-up of 40.5 (range: 4-139) months, the median OS and RFS for the superficial group were not reached. The median OS and RFS for the deep group were 101 (range: 73.7-128.3) and 60 (range: 46.6-73.4) months, respectively. The difference was statistically significant for median RFS (P=.008) and trended toward significance for median OS (P=.066) for the superficial group. Multivariate Cox regression analysis showed DOI cut-off as a significant predictor for RFS but not for OS. DOI significantly predicts poor RFS. However, showed a trend toward poor OS. This study hints toward a possibility of sub-dividing stage III OTSCC based on DOI cut-off. 3 (Retrospective cohort study) Laryngoscope, 132:1594-1599, 2022.

The Role of Arginine Metabolism in Oral Tongue Squamous Cell Carcinoma.

Simple SummaryCancers that are ‘arginine auxotrophic’ rely on extracellular arginine as a crucial substrate for proliferation and growth. Capitalizing on this vulnerability, there are numerous clinical trials evaluating the therapeutic benefits of depleting arginine in multiple types of cancer, including those occurring in the head and neck. However, head and neck cancers are different and are nonauxotrophic for arginine. Here, we explored the intricacies of arginine metabolism in tongue cancer in order to better understand the therapeutic potential of this biological vulnerability. We showed that reprogramming arginase 1 (ARG1) expression in tongue cancer cells inhibits growth compared with controls. Further, RNA-sequencing showed that HIFα, natural killer cell and interferon signaling were concordantly deregulated.Early diagnosis and treatment do not prevent the high morbidity and poor prognosis of oral tongue squamous cell carcinoma (TSCC). Earlier studies have shown that ARG1 signaling is deregulated in TSCC. Here, we investigated the complexity of ARG1 metabolism in this cancer subsite to appreciate the therapeutic potential of this potential biological vulnerability. Various functional studies show that ARG1 overexpression in oral cancer cells inhibits cell proliferation and invasion compared with controls. Further, RNA-sequencing revealed numerous differentially expressed genes (DEGs) and associated networks were dysregulated by ARG1 overexpression, including hypoxia-inducible factor (HIFα) signaling, the natural killer cell signaling pathway and interferon signaling. Our work provides a foundation for understanding the mechanism of action of disrupted arginine metabolism in oral tongue squamous cell carcinoma. This may impact the community for developing further therapeutic approaches.

Subnetwork representation learning for discovering network biomarkers in predicting lymph node metastasis in early oral cancer

Cervical lymph node metastasis is the leading cause of poor prognosis in oral tongue squamous cell carcinoma and also occurs in the early stages. The current clinical diagnosis depends on a physical examination that is not enough to determine whether micrometastasis remains. The transcriptome profiling technique has shown great potential for predicting micrometastasis by capturing the dynamic activation state of genes. However, there are several technical challenges in using transcriptome data to model patient conditions: (1) An Insufficient number of samples compared to the number of genes, (2) Complex dependence between genes that govern the cancer phenotype, and (3) Heterogeneity between patients between cohorts that differ geographically and racially. We developed a computational framework to learn the subnetwork representation of the transcriptome to discover network biomarkers and determine the potential of metastasis in early oral tongue squamous cell carcinoma. Our method achieved high accuracy in predicting the potential of metastasis in two geographically and racially different groups of patients. The robustness of the model and the reproducibility of the discovered network biomarkers show great potential as a tool to diagnose lymph node metastasis in early oral cancer.

Nomogram based on clinical characteristics and serological inflammation markers to predict overall survival of oral tongue squamous cell carcinoma patient after surgery

BackgroundOral tongue squamous cell carcinoma (OTSCC) is a prevalent malignant disease that is characterized by high rates of metastasis and postoperative recurrence. The aim of this study was to establish a nomogram to predict the outcome of OTSCC patients after surgery.MethodsWe retrospectively analyzed 169 OTSCC patients who underwent treatments in the Cancer Hospital of Shantou University Medical College from 2008 to 2019. The Cox regression analysis was performed to determine the independent prognostic factors associated with patient’s overall survival (OS). A nomogram based on these prognostic factors was established and internally validated using a bootstrap resampling method.ResultsMultivariate Cox regression analysis revealed the independent prognostic factors for OS were TNM stage, age, lymphocyte-to-monocyte ratio and immunoglobulin G, all of which were identified to create the nomogram. The Akaike Information Criterion and Bayesian Information Criterion of the nomogram were lower than those of TNM stage (292.222 vs. 305.480; 298.444 vs. 307.036, respectively), indicating a better goodness-of-fit of the nomogram for predicting OS. The bootstrap-corrected of concordance index (C-index) of nomogram was 0.784 (95% CI 0.708–0.860), which was higher than that of TNM stage (0.685, 95% CI 0.603–0.767, P = 0.017). The results of time-dependent C-index for OS also showed that the nomogram had a better discriminative ability than that of TNM stage. The calibration curves of the nomogram showed good consistency between the probabilities and observed values. The decision curve analysis also revealed the potential clinical usefulness of the nomogram. Based on the cutoff value obtained from the nomogram, the proposed high-risk group had poorer OS than low-risk group (P < 0.0001).ConclusionsThe nomogram based on clinical characteristics and serological inflammation markers might be useful for outcome prediction of OTSCC patient.

Role of plasminogen activator inhibitor-1 in oral tongue squamous cell carcinoma: An immunohistochemical and in vitro analysis

ObjectiveTo evaluate the influence of plasminogen activator inhibitor-1 (PAI-1) on the biological behavior and prognosis of oral tongue squamous cell carcinoma (OTSCC). MethodsImmunoexpression of PAI-1 was analyzed in 60 OTSCC specimens and classified as low-expression (≤50% of positive cells) or high-expression (>50%). In vitro effects of recombinant human PAI-1 (rhPAI-1) were assessed through functional assays on the OTSCC-derived cell line SCC-25. Three cell groups were evaluated: G0 (control), G10 (10 nM rhPAI-1), and G20 (20 nM rhPAI-1). ResultsHigh membrane expression of PAI-1 was associated with tumor budding (p = 0.046) and high-risk cases (p = 0.043). Cytoplasmic and membrane expression of PAI-1 was not associated with patient survival. Cell viability (p = 0.020) and progression to the S-phase of the cell cycle (p = 0.024) were higher in G10 and G20 at 24 h. The percentages of apoptotic/necrotic cells were not affected by rhPAI-1. The presence of rhPAI-1 increased cell migration (p = 0.039) and invasion (p = 0.039) after 24 and 72 h, respectively. ConclusionOur findings indicate the involvement of PAI-1 in the biological behavior of OTSCC, although its expression may not predict patient survival. The in vitro results suggest that PAI-1 stimulates cell proliferation, migration and invasion and may contribute to the aggressive phenotype of OTSCC.

Population-based comparative survival analysis of surgery with or without adjuvant radiotherapy and non-operative primary radiotherapy in patients with early-stage oral tongue squamous cell carcinoma.

PurposeAlthough recent clinical guidelines do allow primary radiotherapy for selected patients with early-stage oral tongue cancer, there has been little knowledge on the treatment outcomes of non-operative radiotherapy using modern treatment techniques. This study evaluated recent prognostic differences between primary radiotherapy and surgical resection in T1‒2N0 oral tongue squamous cell carcinoma.MethodsPatients diagnosed with T1‒2N0 oral tongue squamous cell carcinoma were identified from the Surveillance, Epidemiology, and End Results database. After propensity score matching, the disease-specific survival of primary radiotherapy and surgery was compared.ResultsFrom a total of 8,458 patients initially identified, we defined matched cohorts: cohort A, comparing surgery alone vs. primary radiotherapy (n = 230 vs. 230), and cohort B, comparing surgery plus adjuvant radiotherapy vs. primary radiotherapy (n = 230 vs. 230). The 7-year disease-specific survival rates were 77% vs. 35% (cohort A) and 65% vs. 35% (cohort B) (P < 0.001 for all comparisons). Primary radiotherapy was independently associated with worse disease-specific survival in both cohorts A (hazard ratio 4.06; 95% confidence interval 2.53‒6.52) and B (hazard ratio 2.81; 95% confidence interval 1.96‒4.04). Time-course hazard rate function plots showed a distinct short-term risk increment in disease-specific mortality in the primary radiotherapy group.ConclusionIn the contemporary treatment era, the use of radiotherapy as a definitive treatment resulted in an inferior prognosis in patients with T1‒2N0 oral tongue squamous cell carcinoma. The present population-based data suggest that primary radiotherapy cannot be used as an alternative to surgical management and it needs to be avoided as much as possible in early-stage tumors.