Squamous Cell Carcinoma Of The Oral Tongue Research Articles

Predicting nodal metastases in squamous cell carcinoma of the oral tongue using artificial intelligence

ObjectiveThe presence of occult nodal metastases in patients with squamous cell carcinoma (SCC) of the oral tongue has implications for treatment. Upwards of 30% of patients will have occult nodal metastases, yet a significant number of patients undergo unnecessary neck dissection to confirm nodal status. This study sought to predict the presence of nodal metastases in patients with SCC of the oral tongue using a convolutional neural network (CNN) that analyzed visual histopathology from the primary tumor alone. MethodsCases of SCC of the oral tongue were identified from the records of a single institution. Only patients with complete pathology data were included in the study. The primary tumors were randomized into 2 groups for training and testing, which was performed at 2 different levels of supervision. Board-certified pathologists annotated each slide. HALO-AI convolutional neural network and image software was used to perform training and testing. Receiver operator characteristic (ROC) curves and the Youden J statistic were used for primary analysis. ResultsEighty-nine cases of SCC of the oral tongue were included in the study. The best performing algorithm had a high level of supervision and a sensitivity of 65% and specificity of 86% when identifying nodal metastases. The area under the curve (AUC) of the ROC curve for this algorithm was 0.729. ConclusionA CNN can produce an algorithm that is able to predict nodal metastases in patients with squamous cell carcinoma of the oral tongue by analyzing the visual histopathology of the primary tumor alone.

Squamous cell carcinoma of the mobile tongue in young adults: A Swedish head & neck cancer register (SweHNCR) population-based analysis of prognosis in relation to age and stage

Increased incidence of squamous cell carcinoma (SCC) of the tongue has been reported in young adults (YA) in several countries since the 1980s and confirmed in later studies. The etiology is unclear, the prognosis has been debated, and conflicting results have been published. Some studies show better survival in young adults than in older patients, some worse, and others no difference. Most studies are based on selected series or include other sites in the oral cavity. The definition of “YA” is arbitrary and varies between studies. It is thus difficult to use in general conclusions.This work uses data from the population-based Swedish Head and Neck Cancer register (SweHNCR), which has > 98% coverage. SweHNCR data includes age, gender, TNM, treatment intention, treatment given, lead times, performance status, and to a lesser degree, smoking habits. The current Swedish population is around 10 million.We analyzed outcomes for 1416 patients diagnosed with SCC of the oral tongue from 2008 to 2017 using 18–39 years to define YA age because it is the range most commonly used.We found no significant difference in relative survival (a proxy for diagnosis-specific survival) between age groups of patients treated with curative intent for SCC of the oral tongue. The stage at time of diagnosis was equally distributed among the age groups. Excess mortality rate correlated mainly with stage, subsite of the tongue, performance status, and lead time to treatment.

Early detection of squamous cell carcinoma of the oral tongue using multidimensional plasma protein analysis and interpretable machine learning

AbstractBackgroundInterpretable machine learning (ML) for early detection of cancer has the potential to improve risk assessment and early intervention.MethodsData from 261 proteins related to inflammation and/or tumor processes in 123 blood samples collected from healthy persons, but of whom a sub‐group later developed squamous cell carcinoma of the oral tongue (SCCOT), were analyzed. Samples from people who developed SCCOT within less than 5 years were classified as tumor‐to‐be and all other samples as tumor‐free. The optimal ML algorithm for feature selection was identified and feature importance computed by the SHapley Additive exPlanations (SHAP) method. Five popular ML algorithms (AdaBoost, Artificial neural networks [ANNs], Decision Tree [DT], eXtreme Gradient Boosting [XGBoost], and Support Vector Machine [SVM]) were applied to establish prediction models, and decisions of the optimal models were interpreted by SHAP.ResultsUsing the 22 selected features, the SVM prediction model showed the best performance (sensitivity = 0.867, specificity = 0.859, balanced accuracy = 0.863, area under the receiver operating characteristic curve [ROC‐AUC] = 0.924). SHAP analysis revealed that the 22 features rendered varying person‐specific impacts on model decision and the top three contributors to prediction were Interleukin 10 (IL10), TNF Receptor Associated Factor 2 (TRAF2), and Kallikrein Related Peptidase 12 (KLK12).ConclusionUsing multidimensional plasma protein analysis and interpretable ML, we outline a systematic approach for early detection of SCCOT before the appearance of clinical signs.

Ultrasound-assisted resection of oral tongue cancer

Background In surgical resection of squamous cell carcinoma of the oral tongue (SCCOT), achieving clear margins is important for prognosis. Insufficient histopathological margins are common, particularly deep margins. Aims/objectives The aim of the present study was to determine whether ultrasound (US)-assisted resection could decrease the proportion of insufficient histopathological deep margins in SCCOT. Material and methods 34 patients with SCCOT undergoing US-assisted resection (study group) were compared to 76 whose resections were performed without US (conventional group). Outcome measures were insufficient deep histopathological resection margins and mean difference in deep margins. Results Insufficient deep resection margins (<5.0 mm) were seen in 8 of 34 (23.5%) in the study group, compared to 31 of 76 (40.8%) in the conventional group, unadjusted RR 0.58 [95% CI 0.30–1.12; p = .11], adjusted RR 0.82 [95% CI 0.35–1.92; p = .64]. Unadjusted mean difference was 1.4 mm (95% CI 0.1–2.7, p = .04), adjusted mean difference 1.1 mm (95% CI −2.7 to 0.5, p = .19). Conclusions Intraoperative US can visualize the deep resection margins in T1/T2 SCCOT. US-assisted resection seems to decrease the number of insufficient histopathological deep margins, though the results are not statistically significant. Comparatively good results in the conventional group is one explanation for the lack of significance. Clinicaltrials.gov ID NCT04059861

Antigen peptide transporters are upregulated in squamous cell carcinoma of the oral tongue and show sex-specific associations with survival.

Transporter associated with antigen processing 1 (TAP1) and TAP2 serve pivotal roles in adaptive immunity. Tumor cells often show reduced antigen presentation on their surface as one mechanism to escape immune recognition. Whether downregulation of TAPs is a common mechanism of tumor immune evasion in squamous cell carcinoma of the oral tongue (SCCOT) is unclear. In the present study, samples from 78 patients with SCCOT and 17 patients with benign hyperplastic tongue lesions were analyzed for TAP1 and TAP2 expression by immunohistochemistry. The percentage of positive cells and staining intensity were scored. Associations with clinicopathological variables and survival outcome were also investigated. The results demonstrated that TAP1 and TAP2 levels were highly associated with each other in individual samples and were upregulated in SCCOT compared with benign lesions (P<0.001). The proportion of TAP1- or TAP2-positive tumor cells was >80% in all but two of the tumors, whereas 25.6 and 23.0% of the tumors showed weak intensity of TAP1 and TAP2, respectively. There were no significant associations with clinicopathological variables or survival outcomes between TAP-intermediate/strong and TAP-weak tumors. However, in patients <70 years old and with early stage SCCOT, male patients had better outcomes than female patients (log-rank P<0.05), and the best outcome was observed in male patients with intermediate/strong TAP expression. In conclusion, loss of TAP was not a frequent event in SCCOT and stronger TAP expression in male patients was associated with improved survival, providing further evidence for sex-specific immune modulation in cancer.

Ultrasound accurately assesses depth of invasion in T1-T2 oral tongue cancer.

BackgroundDepth of invasion (DOI) is important for the T‐classification of squamous cell carcinoma of the oral tongue (SCCOT) and incorporated in the TNM 8 classification of oral cavity cancer. To determine DOI clinical palpation is performed, but the preferred radiological modality remains controversial. The aim of this study was to investigate the assessment of DOI using ultrasound (US‐DOI).MethodsThe DOI was assessed in 40 patients with T1–T3 SCCOT by ultrasound, palpation, computed tomography and magnetic resonance imaging (MRI). Histopathological DOI (H‐DOI) was gold standard. Bland–Altman analysis was used to compare mean difference and 95% limits of agreement (LOA).ResultsThe mean difference of US‐DOI was −0.5 mm (95% LOA −4.9–4.0) compared to H‐DOI and the mean difference for MRI was 3.9 mm (95% LOA −2.3–10.2). In the subgroup analysis of cT1‐T2 the US‐DOI mean difference was 0.1 mm and the 95% LOA limits −2.5–2.7.ConclusionsUltrasound seems to be the most accurate method to assess DOI in T1‐T2 SCCOT. MRI overestimates DOI and cannot assess a substantial proportion of the tumors.Level of Evidence2c.

High Failure Rates in Young Nonsmoker Nondrinkers With Squamous Cell Carcinoma of the Oral Tongue.

There has been a disproportionate increase in the incidence of young patients with squamous cell carcinoma of the oral tongue (SCCOT). The purpose of this study was to compare young patients to older patients with SCCOT without prior drinking or smoking history as this population is poorly characterized in the literature. A retrospective review of patients presenting to our institution with SCCOT was performed. The clinical and pathologic characteristics, as well as, outcomes were compared between younger patients (age ≤45) and older patients (age >45). Outcome analysis was performed using Kaplan Meier method. Multivariable Cox proportional hazard models were performed for age and stage. Eighty-two patients (38 young, 44 old) were included in this study. Median follow-up was 29.4 months. When compared to the older cohort (age >45), the younger cohort (age ≤45) demonstrated lower rates of 5-year locoregional control (LC) (79.6% vs. 52.5%, p=0.043) and distant metastasis-free survival (88.1% vs. 61.8%, p=0.006). Both cohorts demonstrated similar overall survival rates (55.5% vs. 58.1%) and disease-specific survival (66.2% vs. 58.1%). Of patients experiencing locoregional failure with available radiation therapy plans and PET scans in younger cohorts (n=7), 100% demonstrated in-field failures. Multivariable Cox proportional hazards demonstrated age was an independent predictor of DMFS (p=0.004) and the advanced stage was a predictor of DSS (p=0.03). Young, nondrinker, nonsmokers with SCCOT demonstrate high rates of locoregional recurrence, distant metastasis, and in-field failures. Future studies are warranted to determine underlying mechanisms driving pathogenesis in this unique cohort. 3 Laryngoscope, 133:1110-1121, 2023.

Variation in Plasma Levels of TRAF2 Protein During Development of Squamous Cell Carcinoma of the Oral Tongue.

As early detection is crucial for improvement of cancer prognosis, we searched for biomarkers in plasma from individuals who later developed squamous cell carcinoma of the oral tongue (SCCOT) as well as in patients with an already established SCCOT. Levels of 261 proteins related to inflammation and/or tumor processes were measured using the proximity extension assay (PEA) in 179 plasma samples (42 collected before diagnosis of SCCOT with 81 matched controls; 28 collected at diagnosis of SCCOT with 28 matched controls). Statistical modeling tools principal component analysis (PCA) and orthogonal partial least square - discriminant analysis (OPLS-DA) were applied to provide insights into separations between groups. PCA models failed to achieve group separation of SCCOT patients from controls based on protein levels in samples taken prior to diagnosis or at the time of diagnosis. For pre-diagnostic samples and their controls, no significant OPLS-DA model was identified. Potentials for separating pre-diagnostic samples collected up to five years before diagnosis (n = 15) from matched controls (n = 28) were seen in four proteins. For diagnostic samples and controls, the OPLS-DA model indicated that 21 proteins were important for group separation. TNF receptor associated factor 2 (TRAF2), decreased in pre-diagnostic plasma (< 5 years) but increased at diagnosis, was the only protein showing altered levels before and at diagnosis of SCCOT (p-value < 0.05). Taken together, changes in plasma protein profiles at diagnosis were evident, but not reliably detectable in pre-diagnostic samples taken before clinical signs of tumor development. Variation in protein levels during cancer development poses a challenge for the identification of biomarkers that could predict SCCOT development.

Low potential of circulating interleukin 1 receptor antagonist as a prediction marker for squamous cell carcinoma of the head and neck.

Circulating markers are attractive molecules for prognosis and management of cancer that allow sequential monitoring of patients during and after treatment. Based on previous protein profiling data, circulating interleukin 1 receptor antagonist (IL-1Ra) was evaluated as a potential diagnostic and prognostic marker for squamous cell carcinomas of the head and neck (SCCHN). In this study, we aimed at confirming the clinical relevance of plasma IL-1Ra in SCCHN and exploring its potential as a prediction marker for SCCHN. Plasma from 87 patients with SCCHN, control plasma from 28 healthy individuals and pre-diagnostic plasma from 44 patients with squamous cell carcinoma of the oral tongue (SCCOT) and 88 matched controls were analysed with IL-1Ra electrochemiluminescence immunoassays from mesoscale diagnostics. Plasma IL-1Ra was found to be up-regulated in patients with oral tongue, gingiva and base of tongue tumours compared to healthy individuals (p<0.01). IL-1Ra levels positively correlated with tumour size (p<0.01) and body mass index (p=0.013). Comparing pre-diagnostic plasma to the matched controls, similar IL1-Ra levels were seen (p=0.05). The anti-inflammatory cytokine IL-1Ra could be a diagnostic marker for SCCHN, whereas its potential as a cancer prediction marker was not supported by our data.

Are Oral Pain and Otalgia Predictive of Perineural Invasion in Squamous Cell Carcinoma of the Oral Tongue?

Squamous cell carcinoma of the oral tongue (SCCOT) has been reported as the most common cancer found in the oral cavity.1 Tongue cancer is often associated with pain and perineural invasion, which is typically defined by tumor cells invading perineural tissues, tracking along nerves, and/or surrounding at least one-third the circumference of nerves.2 The purpose of this study was to determine the association between tongue pain and otalgia and the microscopic identification of perineural invasion in patients with squamous cell carcinoma of the tongue. A retrospective cohort study was performed of patients diagnosed with squamous cell carcinoma of the tongue from January 2013 through June 2019. Patients without a prior history of head and neck cancer, diagnosed and operated for squamous cell carcinoma of the oral tongue by a single surgeon, were included in the study. The primary predictor variables were tongue pain and otalgia (presence vs absence of both). Other variables were patient demographics and TNM staging. The primary outcome variable was the histologic presence of perineural invasion. Chi-square analysis was performed to test for any significant associations between pain, T stage, and overall stage in relation to perineural invasion outcome, and multivariate logistic regression analysis was used to control for cancer staging variables when testing the association between pain and perineural invasion. The sample was composed of 128 subjects of which 76 were male and the mean age was 60 years. Most patients, n = 97 (75.8%), complained of tongue pain, while a minority n = 50 (39.1%) complained of otalgia. Patients with otalgia had 3.15 times higher odds of perineural invasion when controlling for T stage, P = .016, and 3.68 times higher odds of perineural invasion when controlling for overall stage, P = .007. Increasing T stage and overall stage – with the exception of stage II – were also significantly associated with perineural invasion, P = < .05. Our study demonstrates a statistically significant association between preoperative otalgia and perineural invasion in a consecutive group of patients presenting with newly diagnosed tongue cancer.

Downregulation of TAP1 in Tumor-Free Tongue Contralateral to Squamous Cell Carcinoma of the Oral Tongue, an Indicator of Better Survival.

Oral cancers are surrounded by epithelium that histologically might seem normal, but genetically has aberrations. In patients with squamous cell carcinoma of the oral tongue (SCCOT), it is therefore important to study not only the tumor but also the clinically tumor-free contralateral tongue tissue that remains in the patient after treatment to map changes of prognostic and/or diagnostic value. The transporter associated with antigen processing (TAP) dimer is a key factor in the process of activating cytotoxic T cells. By downregulating the expression of TAP, tumor cells can escape cytotoxic T cell recognition. Biopsies from tumor and clinically tumor-free contralateral tongue tissue in 21 patients with SCCOT were analyzed together with tongue biopsies from 14 healthy individuals, which served as the control group. Dividing patients into TAP1-high and TAP1-low groups according to the median TAP1 level in tumor-free samples showed that patients with lower TAP1 mRNA levels in tumor-free samples had better overall (p = 0.003) and disease-free survival (p = 0.002). The results showing that TAP1 levels in tumor-free tongue tissue contralateral to the SCCOT correlate with survival is an important contribution to early diagnosis and follow up of SCCOT.

PD-L1 in squamous cell carcinoma of the oral tongue shows gender-specific association with prognosis.

To use alternative quantitation approaches to clarify the clinical implication of programmed cell death ligand 1 (PD-L1) in squamous cell carcinoma of the oral tongue (SCCOT). Ventana SP263 immunohistochemistry assay and a multiplicative QuickScore method were applied to quantify PD-L1 in tumor and surrounding immune cells from 101 patients with SCCOT. Tumor-infiltrating immune cells were estimated from bulk tissue transcriptional profiles of 25 patients. Circulating PD-L1 levels were measured in serum from 30 patients using an electrochemiluminescence assay platform. We found higher tumor cell PD-L1 levels in females than males (p=.019). For patients with low PD-L1 in tumor cells, better survival was seen in males than females (overall survival p=.021, disease-free survival p=.020). Tumor-infiltrating natural killer T cells, immature dendritic cells, and M1 macrophages were positively associated with tumor cell PD-L1 (p<.05). Our data confirmed the significance of gender on tumor cell PD-L1 expression and demonstrated combined effects of gender and PD-L1 levels on clinical outcome in patients with SCCOT. The data also indicated the involvement of specific immune cell types in PD-L1-regulated immune evasion.

Levels of MUC1 in tumours and serum of patients with different sub-types of squamous cell carcinoma of the head and neck.

Mucin 1 (MUC1) is a membrane-bound and secreted glycoprotein that has a protective role in surface epithelia. We recently demonstrated that MUC1 mRNA expression was upregulated in tumour-free tongue tissues adjacent to squamous cell carcinoma of the oral tongue (SCCOT) compared with that in the tumour tissues. The present study investigated MUC1 protein in SCCOT tissue and serum from patients with squamous cell carcinoma of the head and neck (SCCHN) at different sub-sites. The results from immunohistochemistry demonstrated that all SCCOT tissues expressed MUC1; however, the protein levels were not correlated with MUC1 mRNA levels in the same tumours. Furthermore, serum MUC1 level was lower in patients with SCCOT, tonsil SCC and gingival SCC compared with that in healthy subjects; however, the difference was only significant for patients with SCCOT (P=0.0421). No correlation was seen between MUC1 level in tumour tissues and MUCI level in serum from the same patients. The absence of correlation between MUC1 protein and mRNA levels in SCCOT tissues emphasized the importance of validating genomic data in clinical samples. Although significant MUC1 downregulation was observed in the serum of patients with SCCOT, there was a large variation within the groups, suggesting that MUC1 may not be used as a biomarker for these types of tumors.

Radiomics of apparent diffusion coefficient maps to predict histologic grade in squamous cell carcinoma of the oral tongue and floor of mouth: a preliminary study.

Histologic grade assessment plays an important part in the clinical decision making and prognostic evaluation of squamous cell carcinoma (SCC) of the oral tongue and floor of mouth (FOM). To assess the value of apparent diffusion coefficient (ADC)-based radiomics in discriminating between low- and high-grade SCC of the oral tongue and FOM. We included data from 88 patients (training cohort: n = 59; testing cohort: n = 29) who underwent diffusion-weighted imaging with a 3.0-T magnetic resonance imaging scanner before treatment. A total of 526 radiomics features were extracted from ADC maps to construct a radiomics signature with least absolute shrinkage and selection operator logistic regression. Receiver operating characteristic curves and areas under the curve (AUCs) were used to evaluate the performance of radiomic signature. Five features were selected to construct the radiomics signature for predicting histologic grade. The ADC-based radiomics signature performed well for discriminating between low- and high-grade tumors, with AUCs of 0.83 in both cohorts. Based on the cut-off value of the training cohort, the radiomics signature achieved accuracies of 0.78 and 0.79, sensitivities of 0.65 and 0.71, and specificities of 0.85 and 0.82 in the training and testing cohorts, respectively. ADC-based radiomics can be a useful and promising non-invasive method for predicting histologic grade of SCC of the oral tongue and FOM.

SMARCD1 is a transcriptional target of specific non-hotspot mutant p53 forms.

Though primarily a tumor suppressor, TP53 harboring specific missense mutations located in the region encoding the DNA binding domain exhibits a gain of function by transcriptional activation of oncogenes. We performed microarray-based messenger RNA profiling of squamous cell carcinoma of the oral tongue (SCCOT) and identified significant elevation of SMARCD1 in samples exhibiting p53 nuclear stabilization. Activation of SMARCD1 by mutant p53 was confirmed by evaluation of additional tongue cancer samples as well as The Cancer Genome Atlas expression datasets. SMARCD1 knockdown in HNSCC cells resulted in a significant reduction in several tumorigenic characteristics including cell viability, ability to form colonies in liquid and solid media and cell migration. We identified significantly increased SMARCD1 transcript levels in tumor versus matched normal samples in SCCOT as well as in other cancer types. Increased SMARCD1 expression predicted poor survival in HNSCC tumors harboring missense p53 mutations. Our results suggest SMARCD1 to be a novel transcriptional target of mutant p53.

Altered mRNA Expression of Genes Involved in Endocannabinoid Signalling in Squamous Cell Carcinoma of the Oral Tongue

Little is known about the endocannabinoid (eCB) system in squamous cell carcinoma of the oral tongue (SCCOT). Here we have investigated, at the mRNA level, expression of genes coding for the components of the eCB system in tumour and non-malignant samples from SCCOT patients. Expression of NAPEPLD and PLA2G4E, coding for eCB anabolic enzymes, was higher in the tumour tissue than in non-malignant tissue. Among genes coding for eCB catabolic enzymes, expression of MGLL was lower in tumour tissue while PTGS2 was increased. It is concluded that the eCB system may be dysfunctional in SCCOT.

Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue.

BackgroundThe incidence of squamous cell carcinoma of the oral tongue (SCCOT) is increasing in people under age 40. There is an urgent need to identify prognostic markers that help identify young SCCOT patients with poor prognosis in order to select these for individualized treatment.Materials and methodsTo identify genetic markers that can serve as prognostic markers for young SCCOT patients, we first investigated four young (≤40 years) and five elderly patients (≥50 years) using global RNA sequencing and whole‐exome sequencing. Next, we combined our data with data on SCCOT from the cancer genome atlas (TCGA), giving a total of 16 young and 104 elderly, to explore the correlations between genomic variations and clinical outcomes.ResultsIn agreement with previous studies, we found that SCCOT from young and elderly patients was transcriptomically and also genomically similar with no significant differences regarding cancer driver genes, germline predisposition genes, or the burden of somatic single nucleotide variations (SNVs). However, a disparate copy number variation (CNV) was found in young patients with distinct clinical outcome. Combined with data from TCGA, we found that the overall survival was significantly better in young patients with low‐CNV (n = 5) compared to high‐CNV (n = 11) burden (P = 0.044).ConclusionsCopy number variation burden is a useful single prognostic marker for SCCOT from young, but not elderly, patients. CNV burden thus holds promise to form an important contribution when selecting suitable treatment protocols for young patients with SCCOT.

Challenging the Requirement to Treat the Contralateral Neck with >4-Mm Tumor Thickness in Patients Receiving Postoperative Radiation Therapy for Squamous Cell Carcinoma of the Oral Tongue or Floor of Mouth

In patients with oral tongue or floor of mouth squamous cell carcinoma (SCC), the policy at our institution for many years has been to limit postoperative radiotherapy (RT) to the ipsilateral side when the primary tumor does not cross the midline, regardless of tumor thickness or depth of tumor invasion. We report the rate of contralateral neck failure in this group. We retrospectively reviewed the medical records of patients with T1-4 N1-N2b SCC of the oral tongue or floor of mouth who underwent postoperative RT to the primary site +/− ipsilateral neck RT between 1998 and 2014. No patients received radiation to the contralateral neck. All patients received resection of the primary site with or without ipsilateral and/or bilateral neck dissection. Our study population was 32 patients: 75% with close (<5 mm) or positive margins; 38% with perineural invasion. No patient had a tumor that crossed the midline. Tumor thickness was ≥4 mm in 75% of patients. Depth of invasion was >5 mm in 68% of patients. The rate of isolated contralateral neck recurrence was 3% (1/32). When delivering postoperative RT for oral tongue or floor of mouth cancer, the risk of not irradiating the contralateral neck is very low when the primary tumor does not cross the midline, regardless of other factors at the primary site, including tumor thickness and depth of invasion.

Expression of urokinase-type plasminogen activator and its receptor in squamous cell carcinoma of the oral tongue.

Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) act in the proteolysis of basement membrane and extracellular matrix structures, facilitating tumor invasion. The purpose of this study was to evaluate the relationship between these proteins and clinicopathological parameters in squamous cell carcinoma of the oral tongue (SCCOT). Sixty cases of SCCOT were submitted to immunohistochemistry and analyzed semiquantitatively at the invasion front and in the tumor core. The results were associated with lymph node metastasis, clinical stage, locoregional recurrence, clinical outcome and histological grade of malignancy. A higher expression of uPA was observed in cases of tumors of high-grade versus low-grade malignancy (p = 0.010). Moreover, the cases with the worst pattern of invasion presented an overexpression of uPA (p = 0.011). The presence of locoregional recurrence was associated with uPAR (p = 0.039), and the expression of both biomarkers was much higher at the invasion front than in the tumor core (p < 0.001). The results suggest uPA and uPAR are involved in the progression and aggressiveness of SCCOT, mainly at the tumor-host interface.

Comparative Analysis of MicroRNA Expression among Benign and Malignant Tongue Tissue and Plasma of Patients with Tongue Cancer.

Identification of a microRNA (miRNA) pattern to be used as a biomarker for HNSCC is challenging given the heterogeneity of the disease and different methodologies used. To better define the field, we performed a prospective analysis of blood, tumor, and paired benign tissues in tongue squamous cell carcinoma (SCC) patients. Plasma samples were collected prior to surgery, and paired tumor and benign tissue blocks were collected from tongue cancer resections. Circulating free and exosomal miRNA, and paired tumor and benign tissues miRNA were analyzed. TaqMan-based miRNA arrays were used to quantitate the expression of 747 human miRNAs. The comparative Ct method assessed the miRNA profile results, and Student's t-test determined statistical significance between tumor and benign samples. Sixteen of 359 miRNAs detected were differentially expressed between paired tumor and benign tissue. Nine were upregulated, and seven downregulated in tumor tissue. All nine upregulated and six of seven downregulated tumor miRNAs were expressed in circulating exosomes. In contrast, eight of nine upregulated and four of seven downregulated tumor miRNAs were circulating free in the plasma. An aberrantly expressed pattern of miRNA was identified in both tumor and plasma of patients with tongue SCC, suggesting this may be a biomarker for SCC of the oral tongue. Circulating exosomes appear to be a more reliable method for evaluation of circulating tumor-miRNA expression. Further studies with a larger cohort of patients and serial blood samples are needed to validate our findings.