Impact of epidermal growth factor receptor,mesenchymal–epithelial transition factor,and insulin-like growth factor receptor 1 expression on survival of patients with oral and oropharyngeal cancer

The aim of this study was to evaluate the impact of expression of epidermal growth factor receptor (EGFR), mesenchymal–epithelial transition factor (c-Met), and insulin-like growth factor receptor 1 (IGF-1R) protein on response to treatment and survival in patients with oral and oropharyngeal squamous cell carcinoma (SCC). EGFR, c-Met, and IGF-1R immunohistochemical (IHC) scores were generated based on the incidence and intensity of expression of the biomarkers evaluated in paraffin-embedded sections of biopsy specimens taken before treatment from 113 patients given neoadjuvant chemoradiotherapy followed by resection for primary locally advanced oral and oropharyngeal SCC. Correlations were assessed between the IHC of the biomarkers and the patients’ clinicopathological variables using Spearman's rank test. Cox's regression models were used to evaluate the impact of EGFR, c-Met, and IGF-1R, expression on survival.     

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

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

Elevated expression of protease-activated receptor 1 via ΔNp63 down-regulation contributes to nodal metastasis in oral squamous cell carcinoma

Protease-activated receptor 1 (PAR1) is known as a thrombin receptor. Recent studies have reported PAR1 expression in various malignancies; however, its role in oral squamous cell carcinoma (OSCC) requires clarification. A previous study showed that down-regulation of ΔNp63, a homolog of p53, augments PAR1 expression in OSCC. In the present study, the association of PAR1 expression with clinicopathological findings in OSCC was examined retrospectively. Expression of PAR1, thrombin, and ΔNp63 was examined immunohistochemically in OSCC specimens. Patients were divided into three groups based on the expression pattern of PAR1 at the invasive front: group A, PAR1-negative in both cancer and stromal cells; group B, positive in stromal cells but negative in cancer cells; group C, positive in both cancer and stromal cells. Histologically high-grade tumours were significantly more common in group C. Patients in group C had the highest incidence rate of nodal metastasis (P < 0.001) and a lower survival rate (P = 0.085) than those in the other groups. At the invasive front, in group C, thrombin was expressed but ΔNp63 expression was weak. These results indicate that increased PAR1 expression in both cancer and stromal cells could be a useful predictive marker of nodal metastasis and that ΔNp63 is involved in regulating PAR1 expression.     

A population-based study of the epidemiology of oral squamous cell carcinoma in the Netherlands 1989–2018, with emphasis on young adults

There has been an increasing trend in oral squamous cell carcinoma (OSCC) in patients under 45 years of age. The aim of this study was to evaluate the burden of OSCC in the Netherlands between 1989 and 2018 among young adults (age 20–34 years) when compared to adults (age 35–44 years), and to describe the burden in older groups as well, utilizing cancer registry data to characterize incidence patterns by age, sex, and risk factors. A total of 18,963 cases of OSCC were reported. The overall incidence rate, as measured by annual percentage change (APC), increased significantly from 1989 to 2010 by 1.3% per year (95% confidence interval (CI) 0.9–1.7%) but decreased thereafter by ?0.9% (95% CI ?2.5% to 0.7%). Annual incidence increased significantly by 2.4% (95% CI 1.1–3.8%) for patients aged 20–34 years, while it decreased for those aged 35–44 years by ?0.9% (95% CI ?1.7% to 0.0%). In patients older than 60 years, incidence rates increased overall (60–74 years: APC 1.8%, 95% CI 1.5–2.1%; ≥75 years: APC 1.5%, 95% CI 1.2–1.9%). Overall, 66.5% of patients were smokers and 65.3% were alcohol consumers. The marked differences in incidence within the young age subgroups warrants further investigation to elucidate any likely disparity in biological process and clinical outcomes in these populations.     

IκB kinase α: an independent prognostic factor that promotes the migration and invasion of oral squamous cell carcinoma

IκB kinase α (IKKα) is associated with tumourigenesis, metastasis, and poor prognosis. However, its expression and function in oral squamous cell carcinoma (SCC) remain unknown. The aim of this study was to elucidate the clinicopathological associations and functions of IKKα in oral squamous cell carcinoma (SCC). We made an immunohistochemical analysis of IKKα in 94 tissue microarrays of specimens of oral SCC. We also examined IKKα expression in the patients’ samples by quantitative real-time polymerase chain reaction (qRT-PCR), as well as the migration, invasion, and matrix metalloproteinase (MMP) activity of the cells under IKKα knockdown treatment. In oral SCC, immunostaining for IKKα was found in 60 of the 94 patients, and it correlated with lymph node status and poor prognosis. Univariate and multivariate analysis using Cox’s proportional hazards model identified that IKKα expression was an independent predictor of distant- disease-free survival (p < 0.05) and overall survival in oral SCC (p < 0.05). Knocking down IKKα suppressed cell migration and invasion in oral SCC cells. Our results indicate that IKKα has an important role in promoting oral SCC, and it may be a useful biomarker and therapeutic target for diagnosis and treatment.     

[18F]FDG-PET/CT improves the detection of synchronous malignancies at primary staging of oral squamous cell carcinoma – A retrospective study

The purpose of this study was to show the non-inferiority of [¹⁸F]FDG-PET/CT compared with panendoscopy with regards to secondary malignancies of the UADT, and to evaluate the diagnostic performance of PET/CT for detecting synchronous malignancies.Patients with newly diagnosed OSCC and both panendoscopy and [¹⁸F]FDG-PET/CT at primary staging were enrolled in this retrospective study. The accuracy in detecting synchronous malignancies was assessed for both modalities, and their diagnostic measures for the detection of malignancies within the UADT were compared. Histopathological analysis and clinical follow-up served as reference standards.In total, 182 patients were enrolled in this study. Eighteen patients (9.9%) had in total 22 synchronous malignancies, of which eight were located within the UADT. [¹⁸F]FDG-PET/CT detected all malignancies within the whole body (sensitivity: 100%) and yielded false-positive results in four cases (specificity: 97.6%). Sensitivity ([¹⁸F]FDG-PET/CT: 100% vs panendoscopy: 87.5%), specificity (99.4% vs 100%), negative predictive value (100% vs 99.4%), and positive predictive value (88.9% vs 100%) for detecting secondary UADT malignancies did not differ between modalities (all p = 0.32).Within the limitations of the study it seems that [¹⁸F]FDG-PET/CT detects synchronous malignancies of the UADT with an accuracy comparable to panendoscopy, and enables highly sensitive whole-body tumor screening in patients with newly diagnosed OSCC. This could be a relevant factor for therapeutic decision making in clinical routine.     

Clinical significance of panendoscopy in initial staging of oral squamous cell carcinoma and detection of synchronous second malignancies of the upper aerodigestive tract — Insights from a retrospective population-based cohort study

The aim of this study was to examine the prevalence of synchronous upper aerodigestive tract (UAT) tumors within oral squamous cell carcinoma (OSCC) patients, and to specify distinct risk groups who benefit from panendoscopy.Definite clinical and pathohistological characteristics, as well as overall and recurrence-free survival (OAS and RFS, respectively) of OSCC patients with and without synchronous second UAT tumors, carcinomas in situ, or higher-grade dysplasia/metaplasia, were evaluated based on a retrospective population-based cohort study, including alignment with cancer registry data.Out of 727 included OSCC patients, 465 cases (64.0%) received panendoscopy. Among these, 18 UAT tumors were detected, all of which were linked to patients with a positive history of nicotine abuse. Every synchronous UAT tumor was revealed by panendoscopy, which, analyzed as an independent staging procedure, was accompanied by a low complication rate (1.7%). When illuminating the impact of a second UAT tumor in OSCC patients, survival analysis revealed reduced 5-year OAS (63.9% vs 43.5%, p = 0.010) and RFS (57.1% vs 32.4%, p = 0.016) for patients with a second oncology diagnosis of the UAT.Within the limitations of the study, it seems that panendoscopy should be performed in the majority of patients suffering from OSCC, because most of them have a history of smoking and drinking, which correlates with an increased risk of developing synchronous UAT tumors.     

Staging more important than grading? Evaluation of malignancy grading,depth of invasion,and resection margins in oral squamous cell carcinoma

Clinical Oral Investigations - The present study evaluated the predictive value of staging and grading parameters concerning the presence of lymph-node metastases, overall survival (OS), and...     

Mechanism of long-chain noncoding RNA PCGEM1 in the regulation of the invasion and metastasis of oral squamous carcinoma cells via transforming growth factor β2/Smad2 signaling pathway

目的 探讨长链非编码RNA（lncRNA）PCGEM1通过转化生长因子β2（TGF β2）/Smad2信号通路调控口腔鳞状细胞癌（OSCC）侵袭和转移的机制。方法 将60例OSCC患者癌组织及距离癌组织超过2 cm处的正常组织纳入研究,实时定量聚合酶链反应（qRT-PCR）检测miR-148a、lncRNA PCGEM1在OSCC组织及正常组织、人正常口腔黏膜上皮细胞（OMEC）及人源OSCC细胞株KB、BcaCD885、SCC-4、CAL27、SCC-15中的表达情况;分析lncRNA PCGEM1和miR-148a表达与患者临床病理信息之间的关系。构建lncRNA PCGEM1沉默细胞系KB-siPCGEM1及阴性对照（KB-NC）,并以KB作为空白对照组,采用MTT、Transwell和划痕实验检测lncRNA PCGEM1对KB细胞增殖、侵袭和迁移能力的影响;使用生物信息学网站starBase预测lncRNA PCGEM1可以互补结合的微小RNA（miRNA）,再根据www.microRNA.org网站预测相应miRNA可靶向结合的基因;免疫印迹（Western blotting）检测TGF β2/Smad2信号通路蛋白表达情况。结果 qRT-PCR结果显示,OSCC组织中lncRNA PCGEM1、miR-148a的表达水平高于正常组织（P<0.05）;lncRNA PCGEM1和miR-148a在不同TNM分期、淋巴结转移和组织分化程度的患者癌组织中表达差异均有统计学意义（P<0.05）;与空白对照组和KB-NC组相比,KB-siPCGEM1组细胞OD_{492 nm}值下降,细胞侵袭数量及迁移率降低,差异均具有统计学意义（P<0.05）;生物信息学预测结果显示,lncRNA PCGEM1可与miR-148a互补结合,miR-148a与TGFβ2存在靶向结合位点;qRT-PCR和Western blotting检测结果显示,KB-siPCGEM1组中miR148a、TGFβ2及p-Smad 2的表达明显低于空白对照组与KB-NC组（P<0.05）,空白对照组和KB-NC组的差异无统计学意义（P>0.05）。结论 lncRNA PCGEM1在OSCC中高表达,高表达lncRNA PCGEM1可能通过上调miR-148a水平,强化TGF β2/Smad2信号通路,从而促进OSCC的进展。     

Interaction between tumour necrosis factor-α gene polymorphisms and substance use on risk of betel quid-related oral and pharyngeal squamous cell carcinoma in Taiwan

Objective

Betel quid (BQ) components induce the secretion of tumour necrosis factor-alpha (TNF-α) in oral keratinocytes, which promotes oral mucosal inflammation and oral cancer. This study was carried out to evaluate the association of TNFA genetic variants (−308G>A and −238G>A) with the risk and prognosis of BQ-related oral and pharyngeal squamous cell carcinoma (OPSCC).

Design

A total of 403 subjects (205 cancer cases and 198 healthy controls) who habitually chewed BQ were recruited. The genotypes were determined by TaqMan real-time assays.

Results

G allele and G/G genotype at TNFA −308 were associated with a 1.95-fold (95%CI: 1.16–3.28, p_corrected = 0.024) and 2.28-fold (95%CI: 1.30–4.00, p_corrected = 0.008) increased risk of cancer as compared to those with A allele or A/A + A/G genotypes, respectively. In addition, G allele (p = 0.080) and G/G genotype (p = 0.076) at TNFA −238 were associated with a borderline but statistically significant increased risk of OPSCC. The combined G/G + G/G genotype at both loci had a 2.37-fold increased risk of OPSCC as compared to those with other combined genotypes (95%CI: 1.41–4.00, p = 0.001). Interactions between combined genotypes and smoking status were also found to contribute to risk of BQ-related OPSCC. There was no association of TNFA genotypes with clinicopathologic findings or the survival of OPSCC patients.

Conclusions

BQ-chewers who carry the G allele or G/G genotype in TNFA −308 may have an increased risk of OPSCC. The intensity of cigarette smoking modulates the effect of the combined TNFA genotypes on risk of BQ-related OPSCC.     

Tumor–stroma ratio is a crucial histological predictor of occult cervical lymph node metastasis and survival in early-stage (cT1/2N0) oral squamous cell carcinoma

Occult cervical lymph node metastasis is a significant prognostic factor in patients with early-stage (cT1/2N0) oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the potential value of the tumor–stroma ratio (TSR) as a histological predictor of occult cervical metastasis and survival in early-stage OSCC. This retrospective study included 151 patients who underwent excision of the primary lesion and elective neck dissection from 2013 to 2017. The clinicopathological features of the tumor, risk factors associated with occult neck metastasis, and prognostic factors for overall survival (OS) and disease-free survival (DFS) were studied. A significant correlation of TSR (P = 0.009) was found with occult neck metastasis in the multivariate logistic regression model. Multivariate Cox proportional hazards regression analysis showed that the TSR (P = 0.002) and perineural invasion (P = 0.011) were associated with OS. Occult neck metastasis (P = 0.032) was associated with DFS. These findings indicate that assessment of the TSR might be useful in prognostication for early-stage OSCC patients. Moreover, the TSR is effective in allowing an accurate evaluation of the risk of occult neck metastasis, and this may be easily applicable in the routine pathological diagnosis and clinical decision-making for elective neck dissection.     

Aberrant expression of β-catenin and its association with ΔNp63, Notch-1, and clinicopathological factors in oral squamous cell carcinoma

The present study focuses on the correlation between the expression pattern of β-catenin (component of Wnt signaling), ΔNp63 (proliferation marker), and Notch 1 (transmembrane receptor) in oral squamous cell carcinoma. The study also aims to investigate the interaction between β-catenin and ΔNp63 in oral cancer. Furthermore, we also analyzed the prognostic significance of β-catenin, ΔNp63, and Notch 1 in oral squamous cell carcinoma. Immunohistochemical analysis of β-catenin, ΔNp63, and Notch 1 were done in 62 cases of oral squamous cell carcinoma. Co-immunoprecipitation analysis was done to study the possible interaction between β-catenin and ΔNp63 in oral cancer. Kaplan-Meier method was used to estimate overall and disease-free survival, and the Log-rank test was used to compare the resulting curves. Statistically significant positive correlation was found between the localization of β-catenin and the expression of ΔNp63 (p = 0.001**, r (s) = 0.427), whereas, no significant association was found between the expression pattern of β-catenin and Notch 1. Interestingly, interaction between β-catenin and ΔNp63 was observed in oral carcinoma. Moreover, β-catenin and ΔNp63 may be related to worst survival in oral carcinoma. Statistically significant positive association between localization of β-catenin and expression of ΔNp63 suggests that they might have dependent roles in maintaining the proliferation of oral carcinoma cells. In addition, the downregulated expression of Notch 1 was related to invasion and differentiation status of oral carcinoma cells. Furthermore, β-catenin and ΔNp63 may be used as independent prognostic markers of oral carcinoma. On the other hand, interaction of β-catenin with ΔNp63 may be a key event in maintaining the proliferation of oral carcinoma cells. The present study indicates that β-catenin and ΔNp63 may be used as independent prognostic markers of oral carcinoma and the interaction of β-catenin with ΔNp63 may be a crucial event in regulating proliferation and differentiation of oral carcinoma cells, which may be used as a target for therapeutic implications.     

Hemimandibulectomy and therapeutic neck dissection with radiotherapy in the treatment of oral squamous cell carcinoma involving mandible: a critical review of treatment protocol in the years 1994–2004

This retrospective non-randomized 10-year follow-up study compared 147 patients with squamous cell carcinoma (SCC) of the oral cavity requiring hemimandibulectomy, treated by surgical resection, therapeutic neck dissection and radiotherapy. The 5-year survival rates were compared related to localization, size of the tumour, infiltration of locoregional lymph nodes, distant metastases, histopathological grading, radicality of surgery, and invasion of tumour into the mandible. Occurrence of tumour relapse and its localization was studied. The mean 5-year survival rate was 26%. Patients with SCC of the mandibular alveolar process had higher rates; the lowest rates occurred in SCC of the buccal mucosa. Survival rate was significantly lower with insufficient resection of the tumour (85% relapse). An important number of patients with radical resection died within 3 months of surgery. In almost 55% of the mandibles tumour was not present. In 5% of infiltrated mandibles, dissemination into inferior alveolar nerve was proven. Decreasing survival rate was seen with increasing size of tumour and higher histological grade. Therapeutic neck dissection significantly reduces survival rate and increases the percentage of lymph node relapse. Elective neck dissection should be performed in SCC requiring hemimandibulectomy. Primary reconstruction should reverse the high percentage of postoperative complication arising from increased radicality.