Alhadi Almangush

Depth of invasion, tumor budding, and worst pattern of invasion: Prognostic indicators in early-stage oral tongue cancer

Oral (mobile) tongue squamous cell carcinoma (SCC) is characterized by a highly variable prognosis in early‐stage disease (T1/T2 N0M0). The ability to classify early oral tongue SCCs into low‐risk and high‐risk categories would represent a major advancement in their management.

A simple novel prognostic model for early stage oral tongue cancer.

The prognostication of patient outcome is one of the greatest challenges in the management of early stage oral tongue squamous cell carcinoma (OTSCC). This study introduces a simple histopathological model for the prognostication of survival in patients with early OTSCC. A total of 311 cases (from Finland and Brazil) with clinically evaluated early stage OTSCC (cT1-T2cN0cM0) were included in this multicentre retrospective study. Tumour budding (B) and depth of invasion (D) were scored on haematoxylin-eosin-stained cancer slides. The cut-off point for tumour budding was set at 5 buds (low <5; high ≥5) and for depth of invasion at 4mm (low <4mm; high ≥4mm). The scores of B and D were combined into one model: the BD predictive model. On multivariate analysis, a high risk score (BD score 2) correlated significantly with loco-regional recurrence (P=0.033) and death due to OTSCC (P<0.001) in early stage OTSCC. The new BD model is a promising prognostic tool to identify those patients with aggressive cases of early stage OTSCC who might benefit from multimodality treatment.

Tumour budding in head and neck squamous cell carcinoma – a systematic review

Tumour budding is a specific type of invasive growth in carcinomas characterized by invading single tumour cells or small clusters of tumour cells (<5 cells) at the invasive front (IF). It has been documented in numerous publications during the past few decades, but its value as a prognostic marker in head and neck squamous cell carcinoma (HNSCC) has been analysed only recently. In this review we aimed to address the question of whether or not tumour budding has an impact upon the progression and prognosis of HNSCC. We systematically reviewed the databases of PubMed, Scopus and Web of Science for articles that studied tumour budding in squamous cell carcinoma of the head and neck region. The search was limited to articles published in the English literature before March 2014. A total of 122 hits were retrieved; however, only five reports met the inclusion criteria. The findings of these reports suggested a strong association between tumour budding and tumour progression, in addition to strong correlation with patient prognosis. Standardization of the scoring method and the risk stratification cut‐off point is necessary before the inclusion of tumour budding in pathological reports during daily practice.

Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis

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.

Prognostic value of tumour budding in oesophageal cancer: a meta‐analysis

Recently, tumour budding (TB) has been suggested as a strong prognostic marker in oesophageal cancer. The aim of this systematic review is to test the prognostic value of TB in oesophageal cancer by a meta‐analysis of previously published studies. We systematically reviewed the literature related to TB by using the bibliographic databases of Scopus, PubMed, and Web of Science. The search was limited to publications in the English language up to and including December 2014. There are 11 retrospective studies in which TB has been evaluated in oesophageal cancer. Two authors independently extracted the results from eligible studies. The meta‐analysis of eligible studies revealed that TB is a significant prognosticator for overall survival in oesophageal cancer, with a risk ratio (RR) of 2.97 [95% confidence interval (CI) 1.81–4.85; P = 0.0023] in univariate analysis, and with an RR of 2.07 (95% CI 1.22–3.52; P = 0.017) in multivariate analysis. We conclude that a high TB score is a promising prognostic marker of poor survival in oesophageal cancer. Because of its simplicity, reproducibility and high predictive power, TB is strongly recommended to be included in the routine pathology report of oesophageal cancer.

MicroRNA and protein profiles in invasive versus non-invasive oral tongue squamous cell carcinoma cells in vitro

Abstract Complex molecular pathways regulate cancer invasion. This study overviewed proteins and microRNAs (miRNAs) involved in oral tongue squamous cell carcinoma (OTSCC) invasion. The human highly aggressive OTSCC cell line HSC‐3 was examined in a 3D organotypic human leiomyoma model. Non‐invasive and invasive cells were laser‐captured and protein expression was analyzed using mass spectrometry‐based proteomics and miRNA expression by microarray. In functional studies the 3D invasion assay was replicated after silencing candidate miRNAs, miR‐498 and miR‐940, in invasive OTSCC cell lines (HSC‐3 and SCC‐15). Cell migration, proliferation and viability were also studied in the silenced cells. In HSC‐3 cells, 67 proteins and 53 miRNAs showed significant fold‐changes between non‐invasive vs. invasive cells. Pathway enrichment analyses allocated “Focal adhesion” and “ECM‐receptor interaction” as most important for invasion. Significantly, in HSC‐3 cells, miR‐498 silencing decreased the invasion area and miR‐940 silencing reduced invasion area and depth. Viability, proliferation and migration weren’t significantly affected. In SCC‐15 cells, down‐regulation of miR‐498 significantly reduced invasion and migration. This study shows HSC‐3 specific miRNA and protein expression in invasion, and suggests that miR‐498 and miR‐940 affect invasion in vitro, the process being more influenced by mir‐940 silencing in aggressive HSC‐3 cells than in the less invasive SCC‐15.

Toll-like receptor 9 expression in mucoepidermoid salivary gland carcinoma may associate with good prognosis.

BACKGROUND Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. Although several biomarkers have been evaluated, histological grade remains the most valuable prognostic marker. Toll-like receptor 9 (TLR9) is an immune receptor recognizing microbial DNA. Its expression associates with prognosis or cancer properties in several cancers. This study examined the role of TLR9 in MEC. METHODS Sixty patients with salivary gland MEC were collected from two Finnish university hospitals, and tumor samples were stained for TLR9. Salivary gland high-grade MEC cell line (UT-MUC-1) was cultured to assess TLR9 and MMP-13 expression. The function of TLR9 was studied in vitro using traditional Matrigel(®) invasion assay and novel human myoma organotypic model. RESULTS Cancer-specific survival was related with tumor grade (P = 0.01), and there were no deaths in patients with low-grade MEC. TLR9 was expressed in 56 of 60 (93%) tumors. High TLR9 expression indicated better survival in the patient series (P = 0.002) and showed a trend for association with lower disease stage (P = 0.06) and higher differentiation grade (P = 0.068). In multivariate analysis, TLR9 expression was prognostically insignificant due to heavy correlation to disease stage and higher gradus. Treating UT-MUC-1 cells with TLR9 ligand CpG in vitro induced MMP-13 expression and invasion in Matrigel(®) invasion assay, whereas decreased invasion was seen in myoma organotypic model. CONCLUSION Functional TLR9 is present in salivary MEC, and high level of expression may indicate good prognosis. However, more studies are needed to evaluate biological consequences of TLR9 interaction in tumor cells.

Improved outcomes with oral tongue squamous cell carcinoma in Finland

Incidence rates for oral tongue squamous cell carcinoma (SCC) are steadily rising worldwide.

Tumor-infiltrating lymphocytes associate with outcome in non-endemic nasopharyngeal carcinoma: a multicenter study

The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been studied recently in many cancers. For the first time in a nonendemic region, we have evaluated the prognostic value of TILs in a whole population-based nationwide cohort of nasopharyngeal carcinoma (NPC) in Finland. A total of 115 cases from Finnish hospitals were included. TILs were analyzed using hematoxylin and eosin-stained slides according to the criteria of the International Immuno-Oncology Biomarker Working Group. TILs were evaluated separately in stromal and tumor compartments. The log-rank test and univariable and multivariable analyses were used to compare survival in patients with tumors with low and high TILs. A significant positive correlation was observed between the occurrence of intratumoral and stromal TILs (P < .001). In multivariable analysis, NPC cases with low intratumoral TILs had poor overall survival with a hazard ratio (HR) of 2.55 and 95% confidence interval (95% CI) of 1.60 to 4.05 (P < .001). Cases with low intratumoral TILs also had poor disease-specific survival (HR, 2.02; 95% CI, 1.16-3.52; P = .015). Keratinized tumors with low intratumoral TILs were associated with an even poorer overall survival (HR, 3.94; 95% CI, 2.17-7.15; P < .001) and a poor disease-specific survival (HR, 2.97; 95% CI, 1.46-6.05; P = .009). Our study demonstrates that the evaluation of TILs is simple and can be assessed routinely in NPC.

Prognostic impact of tumour–stroma ratio in early‐stage oral tongue cancers

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.