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Background: Long-term smoking and drinking are known to contribute to the onset of tongue cancer (TC). However, the increasing incidence of TC in younger adults has been suggested to be associated with other factors., Objectives: The present study investigated the relationship between TC and human papillomavirus (HPV) infection., Material and Methods: Clinical records and surgically resected specimens from 86 patients (<40-years-old, n = 12; ≥40-years-old, n = 74) with TC were analyzed. Strong nuclear and cytoplasmic p16 staining was considered positive. HPV DNA (high-risk subtypes: 16, 18, 31, 33, 35, 52b, and 58; low-risk subtypes: 6 and 11) was detected using consensus primer-mediated polymerase chain reaction., Results: Strong p16 expression was observed in 10 (11.6%) patients. HPV DNA was detected in 9 (10.5%) patients (high-risk subtypes, n = 2; low-risk subtypes, n = 7). Strong p16 expression was observed more frequently among younger adults than among older adults (33.3% vs. 8.1%; p = .045). p16 staining did not correlate with the detection of HPV DNA (correlation coefficient, 0.113; p = .300)., Conclusions and Significance: In TC, p16 expression was not associated with HPV infection, suggesting that it may be caused by a different mechanism.

Objective: LncRNA MALAT1 has been proved to be involved in the development of various types of human cancers while the involvement of MALAT1 in tongue squamous cell carcinoma has not been reported. In view of this, our study aimed to investigate the functionality of MALAT1 in tongue squamous cell carcinoma., Patients and Methods: The expression of MALAT1 in tumor tissues and adjacent healthy tissues of tongue cancer patients, and the serum from tongue cancer patients as well as healthy controls, were detected by quantitative Real Time-PCR (qRT-PCR). ROC curve analysis was performed to analyze the diagnostic value of plasma MALAT1 for tongue cancer. Survival curves were plotted using the Kaplan-Meier method to evaluate the prognostic value of plasma MALAT1 for tongue cancer. CCK-8 assay, transwell migration and invasion assay were performed to investigate the effects of MALAT1 knockdown on the proliferation, migration and invasion of tongue cancer cells, respectively. The effects of MALAT1 overexpression on the PI3K/Akt pathway and MMP-9 expression were detected by Western blot., Results: The expression level of MALAT1 was remarkably higher in tumor tissues than that in adjacent healthy tissues. Serum MALAT1 was significantly higher in tongue cancer patients than in healthy controls. MALAT1 knockdown markedly inhibits the proliferation, migration and invasion of tongue cancer cells. MALAT1 knockdown also reduced the phosphorylation level of Akt as well as the expression level of MMP-9. It showed no significant effects on Akt expression, while PI3K activator treatment reduced the inhibitory effects of MALAT1 knockdown on the proliferation, migration and invasion of tongue cancer cells., Conclusions: LncRNA MALAT1 expression inhibition can inhibit the proliferation, migration and invasion of tongue cancer cells by inactivating the PI3K/Akt pathway and downregulating MMP-9. MALAT1 may serve as a target for the treatment of tongue squamous cell carcinoma.

Background: The 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 Methods: To 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., Results: In 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)., Conclusions: Copy 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., (© 2018 The Authors. Journal of Oral Pathology & Medicine Published by John Wiley & Sons Ltd.)

Objective: To determine if adjuvant radiation therapy for patients with pT2N0 oral cavity tongue cancer affects overall survival., Study Design: Retrospective cohort study., Setting: National Cancer Database., Subjects and Methods: Cases diagnosed between 2004 and 2013 with pathologic stage pT2N0 oral cavity tongue cancer with negative surgical margins were extracted from the National Cancer Database. Data were stratified by treatment received, including surgery only and surgery + postoperative radiation therapy. Univariate analysis was performed with a 2-sample t test, chi-square test, or Fisher exact test and log-rank test, while multivariate analysis was performed with Cox regression models adjusted for individual variables as well as a propensity score., Results: A total of 934 patients were included in the study, with 27.5% of patients receiving surgery with postoperative radiation therapy (n = 257). In univariate analysis, there was no significant difference in 3-year overall survival between the patient groups ( P = .473). In multivariate analysis, there was no significant difference in survival between the treatment groups, with adjuvant radiation therapy having a hazard ratio of 0.93 (95% CI, 0.60-1.44; P = .748). Regarding tumors with a depth of invasion >5 mm, there was no survival benefit for the patients who received postoperative radiation therapy as compared with those who received surgery alone (hazard ratio = 0.93; 95% CI, 0.57-1.53; P = .769)., Conclusion: An overall survival benefit was not demonstrated for patients who received postoperative radiation therapy versus surgery alone for pT2N0 oral cavity tongue cancer, irrespective of depth of tumor invasion.

Objective: To evaluate outcomes and survival in young patients with oral tongue cancer (OTC)., Methods: Retrospective chart review of patients aged 18-40 with OTC treated between 2000 and 2016. Tumor characteristics of p16 expression, perineural invasion (PNI), and lymph-vascular invasion (LVI) were evaluated. Recurrence-free (RFS) and overall survival (OS) data were analyzed according to Kaplan-Meier method with univariate analysis., Results: A total of 23 patients were identified: 12 with early stage disease (ESD, stage I), and 11 with advanced stage disease (ASD, stage III or IV), (17 men and 6 women). Mean age at presentation was 34.5 years (±5 months) and mean follow-up was 46.6 months. For all patients, 5-year RFS was 62% and OS 66%. RFS for ESD was 73% and ASD 25% (log rank p = 0.011). OS for ESD was 100% and ASD 55% (log rank p = 0.012). 22% indicated tobacco use >5 pack-years and 9% heavy alcohol use. Factors associated with worse OS were neck disease (log rank p = 0.073), positive margins (log rank p = 0.001), and LVI (log rank p = 0.002). Factors associated with worse RFS were chemotherapy or radiation therapy prior to surgery (log rank p = 0.002), neck disease (log rank p = 0.047), positive margins (log rank p = 0.039), and PNI (log rank p = 0.001). Expression of p16 was observed in five cases and was not significantly associated with OS or RFS., Conclusion: In young patients with OTC, factors associated with worse outcomes are similar to known predictors in older patients. Expression of p16 was not statistically associated with improved OS. OS in patients with ESD was excellent (100%), and significantly worse for ASD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hypothesis: While treating patients with postoperative radiotherapy (RT) for squamous cell carcinoma of the oral tongue or floor of mouth, we hypothesized a low risk of tumor recurrence in the contralateral neck in the absence of contralateral neck RT when the primary tumor is >1 cm from the midline regardless of tumor thickness (TT) or depth of invasion (DOI)>4 mm., Objective: The policy at our institution for many years has been to limit postoperative RT to the ipsilateral side when the primary tumor does not cross the midline, regardless of TT or DOI. We report the rate of isolated contralateral neck failure in this group., Materials and Methods: We retrospectively reviewed all patients treated with postoperative RT at our institution between 1998 and 2014 for pathologic stage T1-T4 N1-N2b squamous cell carcinoma of the oral tongue or floor of mouth that did not cross the midline and thus were treated with RT limited to the primary site +/- ipsilateral neck., Results: Our study population included 32 patients: 75% with close (<5 mm) or positive margins and 38% with perineural invasion. No patients had a tumor that crossed the midline. TT was ≥4 mm in 75% of patients. DOI was >5 mm in 68% of patients. There were no isolated contralateral neck recurrences with a median follow-up of 5 years., Conclusion: While delivering postoperative RT for oral tongue or floor of mouth cancer with pathologic neck stage N0-2b, 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, such as TT and DOI.

Background: Oral tongue/floor of mouth squamous cell carcinoma (OTFMSCC) with a depth of invasion (DOI) > 10 mm involves extrinsic muscles and lingual neurovascular/lymphatic bundles. "Compartmental" hemiglossopelvectomy (CHGP) was developed to improve loco-regional control by "en bloc" removal of tumor and its pathways of spread., Methods: We conducted a retrospective observational study on 45 CHGPs performed at a single institution for OTFMSCC with a DOI > 10 mm at CT/MR. Group A (n = 35) included naïve patients, and group B (n = 10) recurrent cancers. We evaluated 2-year overall survival (OS), disease-free survival (DFS), local control (LC), and loco-regional control (LRC)., Results: Two-year OS, DFS, LC, and LRC were 80%, 91%, 100%, and 94% for group A, and 27%, 26%, 67%, and 36% for group B, respectively. Salvage surgery and positive margins were significantly associated with worse prognosis., Conclusion: CHGP is a reliable oncologic approach in primary surgery for advanced OTFMSCC. In recurrent cancers, survival remains poor., (© 2018 Wiley Periodicals, Inc.)

The management of the node negative neck in patients with tongue cancer remains a complex and controversial issue, especially in those with early stage tumors. Patients with negative cervical lymph nodes generally have a good prognosis. However, in patients without neck dissection, neck recurrences may occur after excision of the primary tumor due to occult cervical metastases. It often results in poor salvage therapy options and short survival. We used Surveillance, Epidemiology, and End Results data from 2004 to 2013 to investigate the association of neck dissection with survival among early stage tongue cancer patients with negative lymph node metastasis. A total of 4274 eligible patients were subdivided into 2 groups according to their neck management strategies: neck dissection and observation. Univariate and multivariate Cox proportional hazards regression models were used to determine the independent factors of survival. The Kaplan-Meier method was employed for survival analysis. In the overall cohort, patients who underwent neck dissection had better survival than those who were managed with observation in both tongue cancer specific survival and overall survival. After adjusting for confounding variables, neck dissection strategy remains an independent prognostic factor for better survival. When stratifying the patients according to age, gender, race, marital status, histologic grade, stage and radiotherapy, patients in the neck dissection group had significantly better survival than those in the observation group. Neck dissection may improve survival for early stage tongue cancer patients with negative lymph node metastasis. These results may assist clinicians in selecting the most appropriate neck management strategy for individual patients.

Aims : Immunohistochemistry of PD-L1 has been recently established as a surrogate method to predict if immunotherapy targeting PD-L1/PD-1 has a significant effect on suppression of cancers such as lung non-small cell carcinoma, melanoma, and renal cell carcinoma. Here we performed immunohistochemistry for PD-L1 expression in squamous cell carcinoma (SCC) of the tongue to investigate the potential correlation between PD-L1 expression and clinicopathological factors and whether PD-L1 expression would be associated with prognosis. Methods: Tissue microarray cores of paraffin-embedded blocks from 135 cases with surgically resected tongue SCC were immunohistochemically analysed for PD-L1 expression. Results: We observed a positive correlation between PD-L1 expression and tongue SCC pT1 and pT2 tumours, but a negative correlation with pT2, pT3 and pT4 tumours. We also observed a positive correlation with lymph node metastasis. However, no positive correlation was demonstrated between PD-L1 expression and overall survival. Conclusions: PD-L1 tends to be overexpressed at the early stage of tongue SCC, showing a close correlation with initial development of tongue. However, PD-L1 expression may not affect prognosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: The treatment failure for oral squamous cell carcinoma (SCC) frequently takes the form of local and regional recurrences. We investigated the role of lingual lymph nodes (LLNs) in the recurrence of SCC of the tongue and the floor of the mouth., Methods: A total of 111 patients with SCC of the tongue and the floor of the mouth who received treatment between 2012 and 2017 were included in this study. The patients with lingual lymph nodes that were confirmed to be metastasis on pathological examination were classified into the LNN group. The demographic and clinical data differences between the No-LLN group and the LLN group were compared. Statistical analyses were performed using the Pearson chi-square test RESULTS: The total incidence of LLNs was 17.12% (19/111) and 5 patients (4.5%) demonstrated LLN metastases. All the patients with LLN metastases had a neck lymph node status of N2 classification. The incidence and metastasis of the LLNs were associated with pathological classifications of SCC of the tongue and the floor of the mouth., Conclusions: LLNs are rare in patients with SCC of the tongue and the floor of the mouth, and they would be ready to be omitted. The dissection of these LLNs would be of benefit to those patients with advanced pathological grade., (© 2018 Wiley Periodicals, Inc.)

Background: The purpose of this study was to determine the factors affecting local control in patients with T1N0 squamous cell carcinoma (SCC) of the tongue., Methods: We conducted a retrospective analysis of 144 patients with pT1N0 SCC of the tongue who underwent wide excision and neck dissection without adjuvant therapy., Results: The adverse pathological features associated with local control were least margin 5 mm (P = .004), infiltrative margin (P = .403), depth >4 mm (P = .136), lymphovascular invasion (P = .301), and perineural invasion (P = .342). We derived a scoring system of 10 points based on the hazard ratio for local failure; those with scores >5 points had a 5-year local control of <60%., Conclusion: This study suggests patients having a margin of 5 mm need revision, however, if they do not have additional adverse pathological features (score ≤4), local control is 88% at 5 years, and they may be observed. Those who have margins over 5 mm with a total score >5 may still benefit from adjuvant therapy. Those with margins over 5 mm have improved local control (P = .029)., (© 2018 Wiley Periodicals, Inc.)

One of the main changes in the 8th edition of the American Joint Committee on Cancer (AJCC) for staging of oral cancer is the inclusion of depth of invasion (DOI) in the T category. However, cancers in different oral subsites have variable behavior, with oral tongue squamous cell carcinoma (OTSCC) being the most aggressive one even at early stage. Thus, it is necessary to evaluate the performance of this new T category in homogenous cohort of early OTSCC. Therefore, we analyzed a large cohort of patients with a small (≤ 4 cm) OTSCC to demonstrate the differences in T stage between the AJCC 7th and 8th editions. A total of 311 early-stage cases (AJCC 7th) of OTSCC were analyzed. We used 5 mm and 10 mm DOI for upstaging from T1 to T2 and from T2 to T3 respectively, as in the AJCC 8th. We further reclassified the cases according to our own proposal suggesting 2 mm to upstage to T2 and 4 mm to upstage to T3. According to AJCC 7th, there were no significant differences in the survival analysis. When we applied the 8th edition, many cases were upstaged to T3 and thus associated with worse disease-specific survival (HR 2.37, 95% CI 1.12-4.99) and disease-free survival (HR 2.12, 95% CI 1.09-4.08). Based on our proposal, T3 cases were associated with even worse disease-specific survival (HR 4.19, 95% CI 2.27-7.74). The 8th edition provides better survival prediction for OTSCC than the 7th and can be further optimized by lowering the DOI cutoffs.

Background: To identify the difference of surgical margin and recurrence status of early stage tongue carcinoma via wide excision in a single institution with and without free flap reconstruction., Objective: Survey whether the reconstruction methods for early tongue cancer affects disease control, survival outcomes., Methods: This was a retrospective study and patients with early tongue cancer underwent surgery via tumor ablation with (group 1 = 56) or without free flap reconstruction (group 2 = 291)., Results: The percentage of patients with free margin less than 5 mm was higher in the group 2 than in group 1 (49.48% vs. 19.64%, p < .001), as the mean free margin was significantly larger in group 1 than in group 2 (7.88 mm vs. 5.68 mm; p < .001). Despite higher number of T2 stage patients in group 1 (89.29%), the group 1 resulted in a significant lower recurrence rate (p = .024)., Conclusions: The utilization of free flap reconstruction for early stage tongue cancer achieved a large pathologic free margin and had relative lower recurrence and good survival rates.

Background: With the introduction of new American Joint Committee on Cancer (AJCC) classifications for head and neck cancers few cases are upgraded from T2 to T3 based only on depth of invasion. The role of adjuvant therapy in this particular subset of patients is still not defined., Methods: This is a retrospective analysis of data from 2009 to 2015, of patients with histopathology of pT1, T2, and N0. A total of 375 patients were subdivided into 3 groups per the new AJCC classification depth of invasion <5 mm, 6 to 10 mm, and >10 mm. Survival analyses of patients receiving adjuvant therapy and those who did not were compared with specific emphasis on patients who were upstaged from T2 to T3 based on depth of invasion., Results: Depth of invasion is a poor prognostic factor and addition of adjuvant therapy based on depth of invasion did not have significant survival benefits., Conclusion: Addition of adjuvant therapy based on depth of invasion does not influence survival in patients with early carcinoma of the tongue., (© 2018 Wiley Periodicals, Inc.)

Background: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2018 Wiley Periodicals, Inc.)

Background: Early detection of oral cancer is the most effective means of reducing morbidity, complexity, and extent of treatment. This study evaluated the clinicopathological profile of epidermoid carcinoma of the tongue, including treatment and survival., Material and Methods: This observational, retrospective cross-sectional study evaluated patients with squamous cell carcinoma of the tongue treated at the Dr. Luiz Antônio Hospital, Natal, Brazil, from January 2001 to December 2011. Survival variables were calculated using the Kaplan-Meier method and compared by log rank tests., Results: Of the 412 patients diagnosed in this period, 298 (72.3%) were men; their mean age was 60.5 years, and 69.2% were diagnosed with stage III/IV tumours. Improved survival was associated with early stage diagnosis, absence of affected lymph nodes at diagnosis, and treatment with surgery alone., Conclusions: Late stage diagnosis of oral cancer negatively affects patient survival. In addition, the general public should be made aware of the prognostic factors for oral SCC of the tongue and of the importance of periodic examinations of the oral cavity.

Background: Our aim was to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in operable tongue cancer patients., Methods: The presence of CD3 + , CD4 + , CD8 + , and forkhead box protein P3-positive (FOXP3 + ) TILs in tumor tissues obtained from 93 patients during surgery was examined using immunohistochemistry., Results: The 3-year overall survival (OS) of patients with a low CD8/FOXP3 ratio was significantly lower than that of patients with a high CD8/FOXP3 ratio (63.8% vs. 87.3%, p = 0.001). Patients with high FOXP3 had a significantly lower 3-year regional recurrence-free survival (RRFS) than did patients with low FOXP3 (49.3% vs. 87.3%, univariate log rank p = 0.000). A low CD4/FOXP3 ratio (68.4% vs. 93.7%, univariate log rank p = 0.002) was significantly unfavorable prognostic factors for 3-year distant metastasis-free survival (DMFS)., Conclusions: In addition to clinicopathological characteristics, TIL markers represent prognosticators for clinical outcomes.

Background: Tongue squamous cell carcinoma (SCC) contains a cell subpopulation referred to as cancer stem cells (CSCs), which are responsible for tumor growth, metastasis, and resistance to chemotherapy and radiotherapy. The CSC markers have been used to isolate these cells and as biomarkers to predict overall survival., Methods: The CSC markers CD44, NANOG, OCT4, and BMI1 were investigated using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry and correlated with clinicopathological parameters., Results: The CD44 overexpression was associated with disease-related death (P = 0.02) and worst prognosis. NANOG was upregulated in nontumoral margins and associated with T1/T2 classification, lymph node metastasis, and worst prognosis. OCT4 was associated with lymph node metastasis and worst overall survival. BMI1 and CD44v3 were overexpressed in tongue SCC. Coexpression of CD44 ++ /NANOG ++ was associated with worst overall survival when compared with patients with CD44 -/+ /NANOG -/+ ., Conclusion: The CSC markers might play an important role not only in CSC trait acquisition but also in tongue SCC development and progression., (© 2018 Wiley Periodicals, Inc.)

Background: As per TNM classification, superficial tumors with a favorable prognosis are fallaciously clubbed together with unfavorable, deeply infiltrating lesions in the same classification., Methods: This is a retrospective study of 588 patients with treatment-naive oral tongue cancers. Binary logistic regression was used to identify predictors of nodal metastasis and extracapsular spread (ECS) using tumor volume and thickness as separate models. The C-index was generated to quantify predictive accuracy of T classification, thickness, and tumor volume for survival., Results: Compared to T classification, tumor volume and thickness were better predictors of nodal metastasis and ECS. Predictive accuracy for disease-free survival (DFS) and overall survival (OS) given by C-index was equal and better for thickness (0.60 and 0.69) and tumor volume (0.61 and 0.69) as compared to T classification (0.59 and 0.64, respectively). For early-stage T1 to T2 oral tongue cancer, thickness is a better predictor of nodal metastasis as compared to tumor volume and T classification., Conclusion: Concordance between the tumor thickness and volume proves that tumor thickness can be taken as a surrogate and reliable predictor of outcomes instead of calculating the tumor volume., (© 2018 Wiley Periodicals, Inc.)

Aims: Oral tongue squamous cell carcinoma (OTSCC) has a relatively poor outcome, and there is a need to identify better prognostic factors. Recently, tumour-stroma ratio (TSR) has been associated with prognosis in several cancers. The aim of this multi-institutional study was to evaluate the prognostic value of TSR from original haematoxylin and eosin (HE)-stained tumour-resection slides in a series of early-stage (cT1-2N0) OTSCC patients., Methods and Results: A TSR cutoff value of 50% was used to divide the patients into stroma-rich (≥50%) and stroma-poor (<50%) groups. The relationships between TSR and clinicopathological characteristics of 311 early-stage OTSCC cases were analysed. The prognostic value of TSR in OTSCC was calculated separately and in combination with a previously published cancer cell budding and depth of invasion (BD) prognostic model. A total of 89 cases (28.6%) belonged to the stroma-rich group. In a multivariate analysis, the stroma-rich group had worse disease-free survival, with a hazard ratio (HR) of 1.81 [95% confidence interval (CI) 1.17-2.79, P = 0.008], and higher cancer-related mortality (HR 1.71, 95% CI 1.02-2.86, P = 0.03). The combination of the highest-risk parameter scores of TSR and the BD model showed significant correlations with recurrence rate (HR 3.42, 95% CI 1.71-6.82, P = 0.004) and cancer-related mortality (HR 11.63, 95% CI 3.83-35.31, P < 0.001)., Conclusions: We conclude that TSR is a simple histopathological feature that is useful for prognostication of early-stage OTSCC, and suggest that TSR analyses in association with BD score could be included in routine clinical pathology reports for HE-stained slides., (© 2018 John Wiley & Sons Ltd.)

Background: Although perineural invasion (PNI) is recognized as an adverse prognostic factor in oral tongue squamous cell carcinoma (SCC), the patterns of failure are poorly defined., Methods: Patients with oral tongue SCC who received primary surgical treatment were identified. Specimens were reviewed by head and neck pathologists. Disease-specific survival (DSS) and locoregional recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS) were calculated. The PNI and PNI characteristics were analyzed as predictors of outcome. The utility of grading the extent of PNI was assessed by quantifying the number of PNI foci per slide reviewed, nerve caliber, and percent circumference involved., Results: Patients with PNI had a decreased DSS; however, PNI was not predictive of LRFS or RRFS. Patients with PNI were more likely to develop a distant recurrence and 19.40 (confidence interval [CI] 6.70-56.14; P < .001) times more likely to develop a distant recurrence if PNI foci density was >1., Conclusion: The presence of PNI in oral tongue SCC predicts worse DSS, with distant recurrence as the most common pattern of failure. High PNI foci density is associated with worse DRFS., (© 2018 Wiley Periodicals, Inc.)

Background: Tongue squamous cell carcinoma (TSCC) is one of the most common malignancies of oral squamous cell carcinomas. Cellular retinol binding protein-1 (CRBP-1) as a carrier protein transports retinol from the liver storage site to peripheral tissue. Up-regulated expression of CRBP-1 is associated with some tumor types such as prostate cancer, breast cancer and ovarian cancer as reported, but its role in TSCC remains uncertain., Methods: In this study, an integrated bioinformatics analysis based on the multiple cancer microarray data sets available from Oncomine database was conducted to view the differential expression of CRBP-1 between TSCC and the adjacent non-tumorous tissues. Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB) and immunohistochemical (IHC) assays were performed to investigate CRBP-1 expression in 101 paraffin-embeded TSCC tissues and 48 pairs of freshly frozen tissues. Kaplan-Meier curve and univariate and multivariate Cox-regression analysis were used to estimate the association between CRBP-1 expression and patients' prognosis. Then western blotting, MTT, transwell migration and invasion assays were performed in TSCC cell lines to investigate the effects of CRBP-1 on cellular proliferation and invasion., Results: Compared with the matched adjacent non-tumorous tissues, the expression of CRBP-1 was significantly up-regulated in TSCC tissues, which correlated with the differentiation state (P = 0.003), N classification (P = 0.048), the clinical stage (P = 0.048) and death (P = 0.001). The Kaplan-Meier curve showed that TSCC patients with higher CRBP-1 expression levels had lower overall survival rates than those with lower CRBP-1 expression levels. A univariate and multivariate analysis demonstrated that CRBP-1 was an independent prognostic factor (P < 0.05). Furthermore, we knocked down CRBP-1 expression and observed that TSCC cell proliferation and invasion in vitro were significantly blocked, as determined by MTT and transwell assays., Conclusions: Up-regulated expression of CRBP-1 is associated with poor prognosis in TSCC, so it might potentially serve as an additional prognostic marker, and the inhibition of CRBP-1 might provide new therapeutic approaches for TSCC.

Objective: The purposes of the study was to evaluate for the functional improvement of outcomes of patients undergoing surgical management for tongue cancer at varying periods after surgery., Design: Case series with intervention., Participants: Thirty consecutive patients, from 2011 to 2015, with carcinoma of the tongue undergoing surgical resection and reconstruction with a radial forearm free flap., Main Measures: The Speech Intelligibility Test (SIT) is used for objective evaluation of speech function. The 7-point ordinal scale Functional Oral Intake Score (FOIS) was used to estimate the swallowing function., Results: The patients included were 25 men and 5 women with a mean age of 50.4 years (range - 27-65). All tumors were squamous cell carcinomas and all patients underwent a hemiglossectomy. There were two complete flap failures, with a resultant flap success rate of 93.3%. The initial mean speech intelligibility scores at 1-month increased from 72.3 ± 0.2 to 77.7 ± 8.9 at 6-months after surgery (p = 0.05). Similarly, the mean score of swallowing function improved from 6.1 at 1-month to 6.8 at 6-months after surgery (p = 0.05)., Conclusion: Reconstruction of hemiglossectomy defects with a radial forearm free flap offers functional benefits in speech and deglutition that demonstrate progressive improvement when 1- and 6-month post-surgical assessments are compared., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To determine the factors affecting outcomes in surgically salvaged, locoregionally recurrent squamous cell carcinoma of the tongue (SCCT)., Materials and Methods: In a retrospective cohort of patients who underwent successful salvage of locoregionally recurrent SCCT, we performed this observational analytical study to determine survival and its determinants. Details extracted from our database were patient characteristics (age, gender, tobacco use), treatment characteristics, and characteristics of recurrent disease (stage and adverse pathologic features [APFs] such as grade, perineural invasion, and lymphovascular invasion). Overall survival (OS) curves were plotted using the Kaplan-Meier method. A Cox proportional hazards model was used to determine the impact of patient, disease, and treatment characteristics on OS., Results: Of 52 patients with locoregional recurrences of surgically treated SCCT, 25 (48.1%) underwent surgical salvage with curative intent. The median overall OS for this cohort was 26 months. Factors predictive of worse OS were previous adjuvant therapy (P = .016) and increasing APFs in recurrent tumor histology (P = .008). Lymphovascular invasion in recurrent tumor histology and patients with a disease-free interval of less than 6 months showed worse survival (P = .008 and P = .058, respectively)., Conclusions: Among patients with locoregional recurrence, the number who are eligible for curative-intent surgical salvage is small. Those who received previous adjuvant therapy and those with increasing APFs in recurrent tumors had poor outcomes despite attempts at surgical salvage, particularly patients with early recurrence., (Copyright © 2018 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to present the outcomes of oropharyngeal cancers treated with intensity-modulated radiotherapy (IMRT) especially the differences between tonsillar and base of tongue (BOT) primaries., Methods: Retrospective analysis of 124 patients with biopsy proven squamous cell carcinomas of the oropharynx, treated with IMRT., Results: Human papillomavirus (HPV) association correlated with improvement in survivals in both tonsillar and BOT primaries. At the 2-year median follow-up, the cumulative incidences of locoregional recurrences were 8% in both the tonsil and BOT groups (P = .76) but the distant metastases were 8% in the tonsil group versus 26% in the BOT group (P = .009). Thirty percent of tonsil primaries has ≥N2c neck disease as compared to 54% of BOT. Incidence of distant metastases increases with advanced nodal classification, especially >N2c., Conclusion: Even though the locoregional controls are excellent with IMRT and chemotherapy, these patients continue to fail distantly, particularly significant for the BOT group and for nodal stage >N2c., (© 2018 The Authors Head & Neck Published by Wiley Periodicals, Inc.)

Purpose: Squamous cell carcinoma of tongue (SCCT) is the most common type of oral cavity carcinoma. Chemoresistance in SCCT is common, and the underlying mechanism remains largely unknown. We aimed to identify key molecules and signaling pathways mediating chemoresistance in SCCT. Experimental Design: Using a proteomic approach, we found that the HSP27 was a potential mediator for chemoresistance in SCCT cells. To further validate this role of HSP27, we performed various mechanistic studies using in vitro and in vivo models as well as serum and tissue samples from SCCT patients. Results: The HSP27 protein level was significantly increased in the multidrug-resistant SCCT cells and cell culture medium. Both HSP27 knockdown and anti-HSP27 antibody treatment reversed chemoresistance. Inversely, both HSP27 overexpression and recombinant human HSP27 protein treatment enhanced chemoresistance. Moreover, chemotherapy significantly induced HSP27 protein expression in both SCCT cells and their culture medium, as well as in tumor tissues and serum of SCCT patients. HSP27 overexpression predicts a poor outcome for SCCT patients receiving chemotherapy. Mechanically, extracellular HSP27 binds to TLR5 and then activates NF-κB signaling to maintain SCCT cell survival. TLR5 knockdown or restored IκBα protein level disrupts extracellular HSP27-induced NF-κB transactivation and chemoresistance. Moreover, intracellular HSP27 binds to BAX and BIM to repress their translocation to mitochondrion and subsequent cytochrome C release upon chemotherapy, resulting in inhibition of the mitochondrial apoptotic pathway. Conclusions: HSP27 plays a pivotal role in chemoresistance of SCCT cells via a synergistic extracellular and intracellular signaling. HSP27 may represent a potential biomarker and therapeutic target for precision SCCT treatment. Clin Cancer Res; 24(5); 1163-75. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Appropriate selection of tongue cancer patients considering surgery is critical in ensuring optimal outcomes. The American College of Surgeons' National Surgical Quality Improvement Program ('ACS-NSQIP') risk calculator was developed to assess patients' 30-day post-operative risk, providing surgeons with information to guide decision making., Method: A retrospective review of 30-day actual mortality and morbidity of tongue cancer patients was undertaken to investigate the validity of this tool for South Australian patients treated from 2005 to 2015., Results: One hundred and twenty patients had undergone glossectomy. Predicted length of stay using the risk calculator was significantly different from actual length of stay. Predicted mortality and other complications were found to be similar to actual outcomes., Conclusion: The American College of Surgeons' National Surgical Quality Improvement Program risk calculator was found to be effective in predicting post-operative complication rates in South Australian tongue cancer patients. However, significant discrepancies in predicted and actual length of stay may limit its use in this population.

Background: The purpose of this study was to determine an appropriate cutoff value for the resection margin according to the initial T classification., Methods: The medical records of 151 patients treated by surgery for tongue cancer were retrospectively reviewed to identify the significant perioperative parameters and appropriate cutoff value associated with disease-specific survival (DSS) and recurrence-free survival (RFS)., Results: The posterior resection margin was significantly correlated with survival and local recurrence (P = .020 and .016, respectively), whereas the deep resection margin was correlated with overall recurrence (P = .047). The cutoff values of the posterior and deep resection margins for survival and recurrence were different and larger in the advanced-stage T classification group (0.45 cm vs 0.95 cm and 0.25 cm vs 0.80 cm, respectively)., Conclusion: Posterior and deep resection margins are significant prognosticators in tongue cancer. A larger resection margin may be needed in advanced-stage T classification., (© 2017 Wiley Periodicals, Inc.)

Background: Long non-coding RNA (lncRNA) actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) is oriented in an antisense direction to the protein-coding gene AFAP1 in the opposite strand. Previous studies showed that lncRNA AFAP1-AS1 was upregulated and acted as an oncogene in a variety of tumors. However, the expression and biological functions of lncRNA AFAP1-AS1 in tongue squamous cell carcinoma (TSCC) are still unknown., Methods: The expression level of AFAP1-AS1 was measured in 103 pairs of human TSCC tissues and corresponding adjacent normal tongue mucous tissues. The correlation between AFAP1-AS1 and the clinicopathological features was evaluated using the chi-square test. The effects of AFAP1-AS1 on TSCC cells were determined via a CCK-8 assay, clone formation assay, flow cytometry, wound healing assay and transwell assay. Furthermore, the effect of AFAP1-AS1 knockdown on the activation of the Wnt/β-catenin signaling pathway was investigated. Finally, CAL-27 cells with AFAP1-AS1 knockdown were subcutaneously injected into nude mice to evaluate the effect of AFAP1-AS1 on tumor growth in vivo., Results: In this study, we found that lncRNA AFAP1-AS1 was increased in TSCC tissues and that patients with high AFAP1-AS1 expression had a shorter overall survival. Short hairpin RNA (shRNA)-mediated AFAP1-AS1 knockdown significantly decreased the proliferation of TSCC cells. Furthermore, AFAP1-AS1 silencing partly inhibited cell migration and invasion. Inhibition of AFAP1-AS1 decreased the activity of the Wnt/β-catenin pathway and suppressed the expression of EMT-related genes (SLUG, SNAIL1, VIM, CADN, ZEB1, ZEB2, SMAD2 and TWIST1) in TSCC cells. In addition, CAL-27 cells with AFAP1-AS1 knockdown were injected into nude mice to investigate the effect of AFAP1-AS1 on tumorigenesis in vivo. Downregulation of AFAP1-AS1 suppressed tumor growth and inhibited the expression of EMT-related genes (SLUG, SNIAL1, VIM, ZEB1, NANOG, SMAD2, NESTIN and SOX2) in vivo., Conclusions: Taken together, our findings present a road map for targeting the newly identified lncRNA AFAP1-AS1 to suppress TSCC progression, and these results elucidate a novel potential therapeutic strategy for TSCC.

Background: The purpose of this study was to determine whether the pull-through resection is better than the mandibular lip-split for advanced tongue/floor of mouth (FOM) cancers, which remains inconclusive., Methods: A retrospective cohort study was performed on 91 patients with T4a tongue/FOM cancers from 2009 to 2014. Cases with mandibular resection were excluded. The pull-through resection was used when the mouth opening was ≥15 mm; otherwise the mandibular lip-split was used., Results: Fifty-eight patients received pull-through resections and 33 underwent mandibular-lip splits and the mean follow-up periods were 42 and 45 months, respectively. Surgical margin, locoregional recurrence, and 5-year survival were similar between the 2 groups. The pull-through approach had a significantly shorter operation time, lower rates of flap infection, osteoradionecrosis, metal plate exposure, loss of tooth vitality, and better aesthetics., Conclusion: Our data suggest that the pull-through resection does not compromise disease control for advanced tongue/FOM cancers and is superior to the mandibular lip-split in terms of operation time, postoperative complications, and aesthetics., (© 2017 Wiley Periodicals, Inc.)

Purpose: The aims of this study were to evaluate the pattern of distribution of cervical metastasis in tongue cancer and to analyze the various therapeutic options available. Moreover, numerous histological features were analyzed to assess the impact of each factor on overall survival., Materials and Methods: A retrospective analysis was conducted using the records of patients diagnosed with oral tongue cancer between 2004 and 2010 in the Virgen de las Nieves University Hospital (HUVN). A total of 117 patients with squamous cell carcinoma of the tongue treated with glossectomy and selective neck dissection were included in the study. The pattern of distribution of cervical metastases and numerous histological features such as T-stage, N stage, surgical margins, tumor thickness, extracapsular spread (ECS) and vascular invasion were analyzed., Results: Level IIA was the most affected, followed by level III. The rate of skip metastasis was 7,4%. T and N stage, tumor thickness, ECS, surgical margins and nerve and vascular invasion were associated with poorer outcomes in terms of overall survival (p < 0,001)., Conclusion: Cervical nodal involvement represents the major prognostic factor in tongue cancer. A total of 51,2% of N+ patients presented T1 and T2 tumors in this series. We recommend performing neck dissection at the early stages in clinically N0 patients when a tumor thickness >0,4 cm is suspected. Level IV should be included in the neck dissection of clinically N0 tongue cancer., (Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Total glossectomy remains a controversial procedure as it often leads to notorious sequalae in swallowing and speaking functions. Disease entities indicating total glossectomy tend to have poor prognosis. We evaluated whether this type of surgery can be concidered justified based on our national series. We reviewed all total and subtotal glossectomies with laryngeal preservation performed in Finland between 2005 and 2014 in terms of overall survival (OS), disease-specific survival (DSS), locoregional control (LRC), and functional outcome as assessed by gastric tube or tracheostomy dependence and ability to produce intelligible speech. Of the 29 eligible patients, 15 had undergone total and 14 subtotal glossectomy with curative intent. In eight patients, total/subtotal glossectomy was performed as salvage procedure after the previous treatment. One-year estimates for OS, DSS, and LRC were 48, 59, and 66%, and corresponding 3-year estimates were 31, 46, and 46%, respectively. The gastrostomy and tracheostomy dependence rates at 1 year after operation were 77 and 15%, respectively. Fifty-nine percent of the patients were assessed to be able to communicate verbally. As in most other published studies, we found unsatisfactory survival figures after subtotal or total glossectomy and most patients remained dependent on gastrostomy tube. This surgery is, however, presumably the best and often only chance for cure in a selective patient population, and according to our opinion, it is indicated as a primary or salvage treatment provided that the reconstruction is planned optimally to guarantee a reasonable quality of life after surgery.

The purpose of this study was to determine the prognostic value and oncogenic pathways associated to miRNA expression in squamous cell carcinoma of the oral tongue and to link these miRNA candidates with potential gene targets. We performed a miRNA screening within our institutional cohort (n = 58 patients) and reported five prognostic targets including a cluster of four co-expressed miRNAs (miR-18a, miR-92a, miR-103, and miR-205). Multivariate analysis showed that expression of miR-548b (p = 0.007) and miR-18a (p = 0.004, representative of co-expressed miRNAs) are independent prognostic markers for squamous cell carcinoma of the oral tongue. These findings were validated in The Cancer Genome Atlas (TCGA) cohort (n = 131) for both miRNAs (miR-548b: p = 0.027; miR-18a: p = 0.001). Bioinformatics analysis identified PTEN and ACTN4 as direct targets of the four co-expressed miRNAs and miR-548b, respectively. Correlations between the five identified miRNAs and their respective targeted genes were validated in the two merged cohorts and were concordantly significant (miR-18a/PTEN: p < 0.0001; miR-92a/PTEN: p = 0.0008; miR-103/PTEN: p = 0.008; miR-203/PTEN: p = 0.019; miR-548b/ACTN4: p = 0.009)., (© 2017 UICC.)

Background: The survival outcomes for surgery + postoperative radiotherapy (S+RT) or surgery + postoperative chemoradiation (S+CRT) was compared in patients having oral tongue cancers with intermediate-risk pathological features., Methods: Using the National Cancer Database (NCDB), overall survival (OS) for S+RT or S+CRT was estimated using the Kaplan-Meier methods and Cox proportional hazard models in the entire population (n = 2803) and in a propensity-matched cohort (n = 1136)., Results: The 3-year OS was 73.3% for S+CRT versus 66.7% for S+RT (P = .02). The S+CRT improved the 3-year OS for patients with 2 or more involved metastatic lymph nodes (≥2 MLNs; P = .01) but not for patients with <2 MLNs (P = .73). Undergoing S+CRT improved the 3-year OS for patients with pathologic T classification (pT) pT3-pT4 disease (P = .01) but not for patients with pT1-pT2 disease (P = .18)., Conclusion: Undergoing S+CRT was associated with improved survival for patients with tongue cancers with ≥2 MLNs and/or pT3-pT4 suggesting that specific intermediate-risk pathological features benefit from treatment intensification., (© 2017 Wiley Periodicals, Inc.)

In clinical N0 early oral tongue carcinoma, treatment of occult lymph node metastasis is controversial. The purpose of this study was to assess the histopathological risk factors for predicting late lymph node metastasis in early oral tongue carcinoma. We retrospectively reviewed 48 patients with early oral tongue squamous cell carcinoma. Associations between the histopathological factors (depth of tumor, differentiation, blood vessel invasion, lymphatic invasion, and tumor budding) and late lymph metastasis were analyzed. Although the univariate analysis identified blood vessel invasion, lymphatic invasion, and high-grade tumor budding as predictive factors for neck recurrence (p < 0.001), the Cox proportional hazards model identified high-grade tumor budding as an independent predictive factor (p < 0.01). The combination of a tumor depth ≥ 3 mm and high-grade tumor budding yielded high diagnostic accuracy. Tumor depth and budding grade were identified as histopathological risk factors for late neck recurrence in clinical N0 early oral tongue carcinoma.

Purpose: The National Cancer Data Base was analyzed to evaluate the patterns of care and impact of brachytherapy (BT) boost on overall survival (OS) for patients with squamous cell carcinoma of the base of tongue., Methods and Materials: Patients with nonmetastatic squamous cell carcinoma of the base of tongue between 2004 and 2012 who received concurrent external beam radiation therapy (EBRT) and chemotherapy with or without BT boost in the definitive setting were queried. Overall survival was assessed by the Kaplan-Meier method. Cox regression analysis was used to identify covariates that affected OS., Results: There were 15,934 patients included in this study; 137 (0.9%) received EBRT + BT and the remaining received EBRT only. Median followup was 41.2 months. The utilization of BT boost declined from 2.1% in 2004 to 0.2% in 2012 (p < 0.0001), whereas intensity-modulated radiation therapy use increased from 22.8% in 2004 to 69.2% in 2012 (p < 0.0001). The three- and 5-year OS was 83.2% and 78.3% for patients receiving EBRT + BT compared with 77.4% and 69.0% for those receiving EBRT only (p = 0.03). The difference in survival was significantly better among patients with T3-4 tumors with EBRT + BT boost (p = 0.009) however, there was no survival benefit among patients with T1-2 tumors (p = 0.72). The analysis was repeated with patients who received intensity-modulated radiation therapy vs. EBRT with BT boost and the survival difference was sustained only for those with T3-4 tumors (p = 0.02)., Conclusions: Brachytherapy boost has decreased in its utilization even though it was associated with favorable survival outcomes particularly among patients with higher T-stage tumors., (Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: The clinicopathological features and outcomes of squamous cell carcinoma (SCC) of the tongue in patients of different age groups remain debatable., Methods: Medical records of 457 patients with tongue SCC were reviewed, grouped by age, followed up, and compared., Results: Sex and TNM stage showed no intergroup differences. Tongue SCC in patients ≤30 years had the most advanced TNM classification and greatest proportion of poorly differentiation tumors. Both disease-free survival (DFS) and disease-specific survival (DSS) showed no statistically significant difference between the youngest and the oldest groups (P = .605 and P = .520). However, there was a tendency of higher death rate caused by recurrence or metastasis in the youngest group compared with the others (91.7% vs 75.4% and 77.4%)., Conclusion: Young patients had a tendency of higher death rate caused by recurrence or metastasis than middle-age and older patients; therefore, a larger case sample is needed for further confirmation., (© 2017 Wiley Periodicals, Inc.)

Purpose: Locally advanced tongue carcinomas (LATCs) in inoperable lesions are managed with external beam radiation therapy (EBRT) and chemotherapy. In our institution, the boost to the gross tumor volume is delivered with high-dose-rate brachytherapy (HDR-BT) after EBRT. We review the outcome of these patients when HDR-BT is added as a boost., Methods and Materials: From May 2000 to December 2014, a total of 24 patients with LATC, nonsurgical oral tongue, and base of tongue carcinomas were treated with EBRT and with interstitial plastic tubes for brachytherapy; median dose was 18-24 Gy in 6-8 fractions after 50-60 Gy of EBRT. Mean age was 60 years, 20 men and 4 women. The distribution by stages was 11 patients in Stage III and 13 patients in Stage IV. All cases but one received chemotherapy., Results: With a median followup of 44 months, local control (LC) rate at 4 years was 80% for the entire group, 78% in Stage III, and 90% in Stage IV. The cause-specific survival was 68% at 4 years; the regional control was 76%. Four patients developed distant metastasis with disease free from distant metastasis of 77% at 4 years. The overall survival was 68% at 4 years., Conclusions: HDR-BT yields similar results to low dose rate in treatment of patients with LATC, with better results than those reported with exclusive EBRT. HDR-BT allows to increase the local dose, with good LC rates. In patients with large tumors requiring very mutilating surgery and patients who refuse surgery, EBRT with HDR-BT boost is a good option to increase the LC and cause-specific survival while keeping a better functional outcome., (Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: c-MYC is a potent oncoprotein with roles in a wide range of cellular processes such as differentiation, apoptosis and growth control. Deregulation of the MYC gene is commonly seen in human tumours resulting in overexpression of the protein. Here we studied expression of c-MYC in correlation to clinical outcome in patients with primary squamous cell carcinoma of the mobile tongue., Methods: Immunohistochemistry was used to identify c-MYC in a group of 104 tongue squamous cell carcinomas with an antibody directed against the N-terminal part of the protein. Staining was evaluated by multiplying the percentage of c-MYC-expressing cells with staining intensity, giving a quick score for each tumour., Results: All 104 tumours expressed c-MYC at varying levels. Quantitation according to per cent of positive cells and staining intensity revealed that most (15/21; 71%) high-expressing tumours were seen in males. Within the group of high c-MYC-expressing tumours, the majority were alive 2 and 5 years after treatment., Conclusions: The present findings show that expression of c-MYC has prognostic value in squamous cell carcinoma of the tongue, and could be useful in choice of therapy., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The objectives were to determine the prevalence of human papillomavirus (HPV) in mobile tongue cancer (MTC) and evaluate associations and survival., Materials and Methods: Patients who underwent surgical resection as primary treatment for MTC (n = 127) were retrospectively evaluated. Formalin-fixed paraffin-embedded (FFPE) specimens were assessed for p16 and p53 by immunohistochemistry; for HPV DNA by nested multiplex polymerase chain reaction (PCR) using two pairs of consensus primers (MY09-MY11 and GP5+-GP6+); and for E6 and E7 oncogenes from 13 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 52, 56, 58, 59, 66, and 68) by real-time reverse transcription PCR (RT-PCR)., Results: There were 18 (14.2%) p16-positive, 45 (35.4%) p53-positive, 9 (7.1%) HPV DNA-positive, and 7 (5.5%) E6 and/or E7 mRNA-positive tumors, but the correlation of all pairs was poor. There was no demographic or histopathologic association with HPV status. Cause-specific survival was significantly better with p16-positive than with p16-negative tumors (p = .037)., Conclusions: The prevalence of HPV and p16 positivity was relatively low and p16 status was a poor surrogate marker for HPV status. The results showed the importance of p16 expression in prognosticating mobile tongue cancer.

Background: Identifying informative prognostic biomarkers for oral tongue squamous cell carcinoma (OTSCC) is of great importance in order to better predict tumour behaviour and to guide treatment planning. Here, we summarise existing evidence regarding immunohistochemical prognostic biomarkers for OTSCC., Methods: A systematic search of the literature was performed using the databases of Scopus, Ovid Medline, Web of Science and Cochrane Library. All studies which had investigated the prognostic significance of immunohistochemical biomarkers in OTSCC during the period from 1985 to 2015 were retrieved. For the five most often evaluated biomarkers a random-effects meta-analysis on overall survival was performed, including those studies that provided the necessary statistical results., Results: A total of 174 studies conducted during the last three decades were found, and in these 184 biomarkers were evaluated for the prognostication of OTSCC. The five biomarkers most frequently assessed were p53, Ki-67, p16, VEGFs and cyclin D1. In the meta-analyses, the most promising results of the prognostic power for OTSCC were obtained for cyclin D1. For studies of VEGF A and C the results were equivocal, but the pooled analysis of VEGF A separately showed it to be a useful prognosticator for OTSCC. There was no sufficient evidence to support p53, Ki-67 and p16 as prognostic biomarkers for OTSCC. Limitations in the quality of the published studies (e.g., small cohorts, lack of compliance with REMARK guidelines) are widespread., Conclusions: Numerous biomarkers have been presented as useful prognosticators for OTSCC, but the quality of the conduct and reporting of original studies is overall unsatisfactory which does not allow reliable conclusions. The value of two biomarkers (VEGF-A and cyclin D1) should be validated in a multicentre study setting following REMARK guidelines.

Background: Concurrent chemoradiation (CCRT) and upfront surgery followed by adjuvant therapy both are recommended treatment options for patients with advanced stage squamous cell carcinoma (SCC) of the tonsil. To the authors' knowledge, the question of whether surgical-based treatments can achieve better survival compared with CCRT has never been compared in a clinical trial. The authors analyzed the National Cancer Data Base to measure the impact of different treatment modalities on overall survival (OS)., Methods: All patients aged ≤70 years diagnosed with clinical stage III to IVB (excluding T4B) SCC of the tonsil from 1998 through 2011 were selected. Analysis was limited to patients receiving CCRT, surgery plus CCRT, or surgery followed by adjuvant radiotherapy (RT). OS was compared using the Kaplan-Meier method and log-rank test. Univariable and multivariable hazards analyses were performed to identify factors significant for survival. Propensity score matching was performed., Results: There were 16,891 patients who met the inclusion criteria. The most common treatment was CCRT (8123 patients; 48.1%), followed by surgery plus CCRT (5249; 31.1%) and surgery plus RT (3519 patients; 20.8%). Patients treated with surgery plus CCRT were found to have the highest 3-year OS rate (88.5%) followed by those treated with surgery plus RT (84%) and CCRT (74.2%) (P<.0001). In a propensity score-matched subpopulation of 4962 patients, the 3-year OS rate was 90.2% for those treated with surgery plus CCRT, 84.9% for those treated with surgery plus RT, and 82.1% for those treated with definitive CCRT (P<.0001)., Conclusions: Patients with advanced stage SCC of the tonsil who underwent surgery followed by CCRT had the greatest OS. Patients undergoing upfront surgery may avoid chemotherapy without jeopardizing survival. Triple-modality therapy may provide a survival benefit for a subset of patients with advanced stage tonsil cancer. Cancer 2017;123:3269-76. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Despite improvement in preoperative imaging, surgical technique, and adjuvant therapy, the prognosis of patients with tongue squamous cell carcinoma (SCC) is still unsatisfactory. The mammalian target of rapamycin (mTOR) play a key role in the regulation of tumor cell proliferation and survival. However, the significance of mTOR on the prognosis of tongue SCC remains largely undefined. In the present study, immunohistochemistry was performed to evaluate the expression of phosphorylated mTOR (p-mTOR) in 160 surgically resected tongue SCC, and correlated with survival. Univariate analysis revealed that p-mTOR overexpression (P = 0.006) was associated with inferior overall survival. In multivariate comparison, p-mTOR overexpression (P = 0.002, hazard ratio = 2.082) remained independently associated with worse overall survival. In vitro study, tongue cancer cells treated with everolimus, the specific mTOR inhibitor, or transfected with mTOR-mediated siRNAs dramatically attenuated the abilities of cell proliferation by MTT and BrdU assays. In 4-NQO-induced tongue cancer murine model, mTOR inhibitors significantly decreased the incidence of tongue SCC. In conclusion, p-mTOR overexpression was independently associated with poor prognosis of patients with tongue SCC. In vitro and vivo, mTOR inhibition showed the promising activity in tongue SCC. Our results suggest that inhibition of mTOR signaling pathway may be a novel therapeutic target for tongue SCC.

Purpose: The white blood cell (WBC) indices have been reported to have a prognostic impact in cancer of multiple organs including head and neck cancer; however; site and stage stratification was not attempted, and compelling evidence has shown that early cancers have a different distribution and prognostic ability than late-stage cancers. We studied the prognostic importance of WBC indices in early oral tongue cancers., Patients and Methods: The retrospective data of primary pT1N0 to pT2N0 oral tongue cancers treated between 2009 and 2013 were charted. WBC indices such as the neutrophil count, lymphocyte count (LC), platelet count (PC), and monocyte count, along with derived indices such as the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR), were analyzed by multivariate analysis with other clinicopathologic prognostic factors., Results: A total of 133 patients fulfilled the inclusion criteria; the minimum follow-up period for living patients was 36 months. A total of 22 patients reported disease relapse, and 11 patients died of disease. Multivariate analysis showed LC (hazard ratio [HR], 0.206; 95% confidence interval [CI], 0.092 to 0.46; P < .001), PC (HR, 1.011; 95% CI, 1.001 to 1.021; P = .026), PLR (HR, 1.012; 95% CI, 1.008 to 1.016; P < .001), and LMR (HR, 0.721; 95% CI, 0.596 to 0.872; P = .001) are significant independent prognostic factors for disease-free survival. Distant metastasis (HR, 9.014; 95% CI, 2.303 to 38.914; P = .004), LC (HR, 0.091; 95% CI, 0.015 to 0.558; P = .01), PC (HR, 1.023; 95% CI, 1.006 to 1.041; P = .009), PLR (HR, 1.016; 95% CI, 1.004 to 1.027; P = .002), and LMR (HR, 0.58; 95% CI, 0.387 to 0.868; P = .008) are significant independent prognostic factors for overall survival., Conclusions: Low pretreatment LMR and high PLR indicate poor survival in patients with early tongue cancer. We suggest close follow-up for this subgroup despite radical resection with clear margins., (Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether the extent of expression of hyaluronan (HA) and epidermal growth factor receptor (EGFR) in squamous cell carcinoma of the mobile tongue can predict the risk of cervical metastasis and survival., Study Design: Retrospective histopathologic study., Methods: Surgical specimens from 64 patients who had undergone surgery for squamous cell carcinoma of the mobile tongue were assessed using immunohistochemistry to investigate the expression of HA and EGFR in the primary tumours, and the data were then correlated to cervical metastasis and survival., Results: There was a significant correlation between the intensity of HA staining and patient survival (p .024), and a weak correlation between the staining proportion of EGFR and the risk for regional recurrence (AUC 66)., Conclusions: This study indicates that immunoscoring using HA could be used to provide prognostic tools for tongue cancer, and that it might be of interest to study the prognostic properties of EGFR further concerning the risk for regional recurrence after the primary treatment.

Background: DNA repair systems play a critical role in protecting the human genome from damage caused by carcinogens. Modifications in DNA repair genes may be responsible for tumor development and resistance of malignant cells to chemotherapeutic agents. The major pathway for oxidative DNA damage repair is the base excision repair pathway. This study aimed to assess the immunoexpression of DNA repair proteins APE-1 and XRCC-1 and its association with clinical, histologic, and survival parameters in oral tongue squamous cell carcinoma, to investigate a possible role for those proteins in tumor behavior., Methods: The expression of APE-1 and XRCC-1 was evaluated by immunohistochemistry in 82 cases of oral tongue squamous cell carcinoma. Histopathological grading was performed for each case. Pearson's chi-square and Fisher's exact tests were used to determine the association between protein expressions and clinicopathological features of tumors, whereas Kaplan-Meier curves and Cox regression were used to analyze disease-specific and disease-free survival. Statistical significance was set at P ≤ 0.05., Results: APE-1 was highly expressed in the nucleus and cytoplasm in 64.6% of cases, and XRCC-1 showed overexpression only in the nucleus in 61% of cases. High expression of XRCC-1 was significantly associated with tumors at early clinical stages (I and II, P < 0.01) and nodal status (P = 0.03). Both proteins were not associated with other clinical parameters, histopathological grading, or survival., Conclusions: DNA base excision repair proteins APE-1 and XRCC-1 are upregulated in oral tongue squamous cell carcinoma, and XRCC-1 expression is associated with better clinical staging and nodal status., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Despite complete resection of the early stage of oral tongue cancer by partial glossectomy, late cervical lymph node metastasis is frequently observed. Gene amplification of ACTN4 (protein name: actinin-4) is closely associated with the metastatic potential of various cancers. This retrospective study was performed to demonstrate the potential usefulness of ACTN4 gene amplification as a prognostic biomarker in patients with stage I/II oral tongue cancer. Fifty-four patients with stage I/II oral tongue cancer were enrolled retrospectively, in accordance with the reporting recommendations for tumour marker prognostic studies (REMARK) guidelines. The copy number of ACTN4 and the protein expression of actinin-4 were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. The overall survival time of patients with gene amplification of ACTN4 was significantly shorter than that of patients without gene amplification (P=0.0010, log-rank test). Gene amplification of ACTN4 was a significant independent risk factor for death in patients with stage I/II oral tongue cancer (hazard ratio 6.08, 95% confidence interval 1.66-22.27). Gene amplification of ACTN4 is a potential prognostic biomarker for overall survival in oral tongue cancer., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives/hypothesis: To evaluate the long-term disease control, survival, and complications after definitive radiotherapy (RT) alone or combined with adjuvant chemotherapy with or without planned neck dissection for base of tongue squamous cell carcinoma (SCC)., Study Design: We retrospectively reviewed the medical records of 467 patients treated at the University of Florida with definitive RT alone or combined with adjuvant chemotherapy between 1964 and 2011 for base of tongue SCC., Methods: Median follow-up was 5.6 years. Median total dose to the primary site was 74.4 Gy. Eighty-seven patients (19%) were treated with once-daily fractionation, and 380 (81%) received altered fractionation schedules. Intensity-modulated RT was used in 128 patients (27%). Chemotherapy was administered to 173 (37%) patients. Planned neck dissection after RT was performed in 226 patients (48%). Data regarding p16 pathway activation were available for 25 patients., Results: At 5 years, the local, local-regional, and regional control rates were 85.5%, 80.0%, and 90.0%, respectively. The 5-year overall, cause-specific, and distant metastasis-free survival rates were 59.1%, 71.5%, and 84.1%, respectively. Sixty-four patients (14%) developed one or more severe late complications. Fifty patients (11%) required late gastrostomy tube placement., Conclusions: This study supports the continued use of RT alone or combined with adjuvant chemotherapy for patients with base of tongue SCC, as this treatment yields high rates of cause-specific survival and disease control, with a relatively low rate of late complications., Level of Evidence: 4. Laryngoscope, 127:1589-1594, 2017., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Incidence rates for oral tongue squamous cell carcinoma (SCC) are steadily rising worldwide., Methods: All patients diagnosed with primary oral tongue SCC at the 5 university hospitals in Finland from 2005 to 2009 were studied. The mean follow-up time was 43 months (median, 54 months; range, 0-111 months)., Results: Three hundred sixty patients with primary oral tongue SCC were identified. Treatment with curative intent was provided for 328 patients (91%). The 5-year disease-specific survival (DSS) rates were as follows: stage I 87%; stage II 73%; stage III 69%; and stage IV 51%. The 5-year recurrence-free survival in general has improved from 47% in our previous published series (1995-1999) to 65% in the current series (p < .001)., Conclusion: The outcome of oral tongue SCC has significantly improved in Finland. However, the relatively high number of disease recurrences in patients with stage I and II disease, when compared with patients with stage III and IV disease, calls for an investigation of new treatment approaches. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1306-1312, 2017., (© 2017 Wiley Periodicals, Inc.)