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

Background: Survival rate for oral tongue squamous cell carcinoma (OTSCC) is still poor and, despite Tumor–Node–Metastasis staging system has been recently updated, patients included under the same stage still show difference in prognosis. Perineural invasion (PNI) emerged to be an indicator of tumor aggressive behavior and unfortunate events. In this study, we investigate the clinic and prognostic value of PNI in a cohort of OTSCC patients. Methods: About 200 patients with OTSCC were retrospectively evaluated the presence of PNI. PNI was furtherly descripted as uni‐/multifocal and as intra‐/peritumoral. Disease‐Specific and Relapse‐Free Survival (DSS; RFS) were estimated; moreover, we included PNI in the current AJCC 8th Staging System, improving the prognostication model. Results: Perineural invasion was found in 40.5% of patients. Intratumoral PNI predicted patients at high risk of being diagnosed with lymph–node metastasis. Tumors with positive PNI reported a worse DSS (Hazard Ratio=1.878, p‐value = 0.008). Moreover, patients exhibiting both multifocal intra‐ and peritumoral PNI reported poorest DSS (Hazard Ratio = 2.409, p‐value = 0.010). Patients were reclassified in a new staging system in case of multifocal PNI, providing better stratification capacity. Conclusions: Perineural invasion might serve as an additional prognostic factor in OTSCC, and by integrating PNI in the staging system, further improvements in prognostication might be reached. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) is an ascending and agressive disease. The search for new molecular markers is emerging to solve difficulties in diagnosis, risk management, prognosis and effectiveness of treatments. Proteins related to apoptotic machinery have been identified as potential biomarkers. Caspase 3 is the main effector caspase and has a key role in apoptosis. The objective of this systematic review and meta-analysis is to review studies that analyze changes in Caspase 3 and Cleaved Caspase 3 expression both in oral premalignant disorders (OPMD) as well as in head and neck cancer (HNC). This study also proposes to review the prognostic values associated with HNC according to the expression of Caspase 3. Medline (via PubMed), EMBASE, Scopus, Cochrane, Web of Science and Grey Literature Database were screened from inception to june of 2022 and 18 studies were selected and 8 were included in the prognostic meta-analysis. Results related to the comparison of Caspase 3 expression demonstrated similar expression of Caspase 3 in HNC, with an average of 51.9% (9.5–98.1) showing high/moderate expression compared to 45.7% (14.6–84.7) in OPMD. Of interest, Cleaved Caspase 3 resulted incresed in HNC when compared with OPMD, being 73.3% (38.6–88.3) versus 22.9% (7.1–38.7). Pooled Fixed effect of HR values (95% CI) for OS related to Caspase 3 IHC expression in HNC patients was 1.48 (95% CI 0.95–2.28); also, the rate of heterogeneity was low, as revealed by I2 = 31%. For DFS was 1.07 (95% CI 0.79–1.45) with I2 = 0% and DSS showed a HR of 0.88 (95% CI 0.69–1.12) with I2 = 37%. Caspase 3 and Cleaved Caspase 3 expression could be linked with malignancy progression, but the expression of Caspase 3 did not influence the prognosis of patients with HNC. [ABSTRACT FROM AUTHOR]

Simple Summary: The results of tumor budding are an independent prognostic factor of locoregional recurrences in many solid cancers, including colorectal, nasopharyngeal, esophageal, and lung cancer. Regarding oral squamous cell carcinoma, tumor budding predicts poor survival outcomes regardless of the tumor subsite and the pathological stage. Several detection methods for tumor budding have been proposed in the literature in order to reach an agreement on a standardized scoring system. However, the lack of a standardized assessment method prevents its evaluation in a multidisciplinary setting. In this context, this study aims to critically review the literature data regarding the prognostic role of tumor budding in oral squamous cell carcinoma. The validation of a tumor budding detection method based on tumor stage and site could be relevant to improving risk stratification and planning the clinical management of patients. Moreover, tumor budding could be included in daily pathological practice to better predict the patient's outcomes. Tumor Budding (TB) represents a single cancer cell or a small cluster of less than five cancer cells on the infiltrative tumor front. Accumulating evidence suggests TB is an independent prognostic factor in oral squamous cell carcinoma (OSCC). However, its exact role is not yet elucidated, and a standardized scoring system is still necessary. The study aims to extensively review the literature data regarding the prognostic role of TB in OSCC. The results of TB are an independent prognostic factor of poor survival outcomes in OSCC. To date, the manual detection of hematoxylin and eosin-staining or pancytokeratin-immunostaining sections are the most commonly used methods. Between the several cut-offs, the two-tier system with five buds/field cut-offs provides better risk stratification. The prognostic role of the BD model in predicting survival outcomes was extensively validated; however, the inclusion of DOI, which is already a staging parameter, encouraged other authors to propose other models, integrating TB count with other adverse risk factors, such as the tumor–stroma ratio and tumor-infiltrated lymphocytes. The prognostic relevance of TB in OSCC highlights its evaluation in daily pathological practice. Therefore, the TB detection method and the TB scoring system should be validated based on tumor stage and site. [ABSTRACT FROM AUTHOR]

Inflammation seems to play a critical role in the development and progression of different cancers. Neutrophil-to-lymphocyte ratio (NLR) is an easily measurable marker of systemic inflammation. The purpose of this systematic review and meta-analysis was to evaluate the prognostic role of the pre-treatment NLR, in terms of overall survival (OS) and disease-free survival (DFS), in patients with primary head and neck squamous cell carcinoma (HNSCC) treated by surgery alone or followed by chemo/radiotherapy. This systematic review was performed according to the guidelines reported in the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Meta-analysis of OS and DFS was performed using the inverse of variance test. Fixed-effect models were used on the basis of the presence of heterogeneity. Risk of bias assessment and trial sequential analysis (TSA) were also performed; the quality of the evidence was evaluated via the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The analysis revealed that a higher value of pre-treatment NLR correlates with a statistically significant decrease of OS (HR, 1.56; 95% CI: [1.35, 1.80]; p < 0.00001) and a lower DFS (HR, 1.64; 95% CI: [1.30, 2.07]; p < 0.0001) in HNSCC patients. [ABSTRACT FROM AUTHOR]

Background: In patients with squamous cell carcinoma of the oral tongue (OTSCC), current tumor node metastasis staging system fails to identify at‐risk patients associated with early relapse and poor prognosis despite complete surgical resection. Given the importance of tumor‐infiltrating lymphocytes (TILs) in the development of cancers, here we investigated the prognostic significance of the immune phenotype in OTSCC. Methods: Hematoxylin‐eosin stained sections of OTSCCs from 211 patients were evaluated. Cancers were classified as (a) immune‐inflamed when TILs were found next to tumor cell nests; (b) immune‐excluded when TILs were found in the stroma, outside the tumor; and (c) immune‐desert for tumors lacking lymphocyte infiltrate. The prognostic significance of these immune phenotypes classes was investigated. Data were further validated on an independent cohort from The Cancer Genome Atlas database. Results: Immune‐desert phenotype was the least represented group of OTSCCs in our cohort (11.8%) and served as an independent prognostic factor. Patients with immune‐desert tumors exhibited worse disease‐specific survival (HR = 2.673; [CI: 95% 1.497‐4.773]; P =.001), overall survival (HR = 2.591; [CI: 95% 1.468‐4.572]; P =.001), and disease‐free survival (HR = 2.313; [CI: 95% 1.118‐4.786]; P =.024) at multivariate analysis. Conclusions: We identified a specific subgroup of OTSCCs with poor prognosis. Tumor‐infiltrating lymphocytes density and localization could serve as an integrative parameter to the current staging system and inform the selection of most appropriate treatments. In particular, the tumor immune phenotype could improve the stratification of patients with more aggressive disease. [ABSTRACT FROM AUTHOR]

Mortality is linked to tumor budding (TB) in certain neoplasms. TB as a relevant histopathological feature is conditioned by tumor site, a specific study on head and neck squamous cell carcinoma (HNSCC) is needed. A comprehensive meta-analysis was undertaken to investigate the relationship between TB and HNSCC-related outcomes. Overall 42 studies were included. Patients harboring high TB reported an Overall Survival (OS) Hazard Ratio (HR) of 2.63 (95% confidential interval (CI) 2.04–3.39; p-value < 0.001), Disease-free Survival (DFS) HR of 1.88 (95%CI 1.57–2.24; p-value <0.001) and Disease-specific Survival (DSS) HR of 2.14 (95%CI 1.81–2.52; p-value <0.001). Lymph Node Metastasis (LNM) studies harbored null heterogeneity and marked association with TB (Odds Ratio (OR) = 4.48, 95%CI 2.97–6.76; p-value < 0.001). Trial Sequential Analysis (TSA) supported definitive results for DSS. The study has provided compelling evidence that there is a significant association between TB and a worse prognosis for HNSCC. [Display omitted] • Tumor budding (TB) is characterized by isolated cells or clusters of tumor cells in the stroma of the invasive front of cancer. • This condition is a relevant histopathological feature that is conditioned by the tumor site. • Mortality is linked to TB in certain neoplasms. • A meta-analysis investigated the relationship between TB and head and neck squamous cell carcinoma (HNSCC) related outcomes. • The results provided a compelling association between TB and a worse prognosis in HNSCC patients. [ABSTRACT FROM AUTHOR]

Objective: Tumor associated macrophages (TAMs) are among the most abundant cells of the tumor microenvironment. Several studies have been performed to investigate whether TAM markers, namely CD68 and CD163, could serve as prognostic factors in patients with squamous cell carcinoma of the head and neck (SCCHN). The aim of this systematic review and meta-analysis was to synthetize the available evidence of the literature about the role of CD68+ and CD163+ TAMs as prognostic factors in SCCHN.Materials and Methods: This systematic review was performed according to the guidelines reported in the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Meta-analysis of overall survival, disease-free survival and progression-free survival was performed using the inverse of variance test. A random- or a fixed- effect model was used on the basis of the presence of heterogeneity. Risk of bias assessment and subgroup analysis were also performed.Results: High stromal expression of CD163+ TAMs correlated with both poor overall survival (HR, 2.26; 95% CI: [1.47, 3.47]; P < 0.001) and progression-free survival (HR, 2.29; 95% CI: [1.11, 4.71]; P = 0.03). Conversely, abundance of CD68+ TAMs was not associated with overall survival (HR, 1.25; 95% CI: [0.86, 1.80]; P = 0.24) and disease-free survival (HR, 2.06; 95% CI: [0.84, 5.05]; P = 0.11).Conclusions: Findings from this study revealed that whilst IHC analysis of the generic macrophage marker CD68+ has no prognostic utility in patients with SCCHN, the M2-like marker CD163+ predicts poor prognosis. Our data suggest that assessment of CD163+ TAMs in SCCHN has potential for future clinical use. Further well-standardized studies should be performed to confirm these results. [ABSTRACT FROM AUTHOR]

Background: ADAR1 is an enzymatic protein, which catalyzes a RNA editing reaction by converting Adenosine to Inosine, and its expression has been found to be dysregulated in many cancer types. The aim of this study was to analyze the expression of ADAR1 in oral squamous cells carcinoma.Methods: In order to analyze the ADAR1 mRNA expression, data from The Cancer Genome Atlas (TCGA) database were downloaded and analyzed. In addition, immunohistochemistry analysis was performed on an institutional database including 46 samples of oral squamous cell carcinoma in a tissue microarray (TMA).Results: No statistically significant correlation linked the mRNA ADAR1 expression to any clinic-pathological variables in the TCGA database. Immunohistochemistry analysis of ADAR1 showed different expressions between normal mucosa and tumor tissue. Focusing on the subcellular localization, the nuclear expression of ADAR1 correlated with higher grading of differentiation (ρ = 0.442; P-value = 0.002); the general expression of ADAR1 either in cytoplasm or in nuclei, correlated with the Gender of patients (Cytoplasm expression: ρ = -0.295; P-value = 0.049; while for nuclear expression: ρ = +0.374; P = 0.011); cytosol expression resulted to be an independent protective prognostic factor (HR = 0.047; C.I. 95% 0.007-0.321; P-value = 0.002).Conclusion: Higher expression of ADAR1 into the cytoplasm resulted to be an independent prognostic factor. In order to understand ADAR1 role in cancer, further studies should be performed, in bigger cohort and under a bio-molecular point of view. [ABSTRACT FROM AUTHOR]

Management of oral potentially malignant disorders (OPMDs) is still challenging. Despite the diagnostic ascertainment by bioptic examination, this method is poorly informative of the prognosis and subsequent malignant transformation. Prognosis is based on histological findings by grading of dysplasia. Immunohistochemical expression of p16INK4a has been investigated in different studies, with controversial results. In this scenario, we systematically revised the current evidence about p16INK4a immunohistochemical expression and the risk of malignization of OPMDs. After a proper set of keywords combination, 5 databases were accessed and screened to select eligible studies. The protocol was previously registered on PROSPERO (Protocol ID: CRD42022355931). Data were obtained directly from the primary studies as a measure to determine the relationship between CDKN2A/P16INK4a expression and the malignant transformation of OPMDs. Heterogeneity and publication bias were investigated by different tools, such as Cochran's Q test, Galbraith plot and Egger and Begg Mazumdar's rank tests. Meta-analysis revealed a twofold increased risk to malignant development (RR = 2.01, 95% CI = 1.36–2.96 - I2 = 0%). Subgroup analysis did not highlight any relevant heterogeneity. Galbraith plot showed that no individual study could be considered as an important outlier. Pooled analysis showed that p16INK4a assessment may arise adjunct tool to dysplasia grading, leading to an optimized determination of the potential progression to cancer of OPMDs. The p16INK4a overexpression analysis by immunohistochemistry techniques has a multitude of virtues that may facilitate its incorporation in the day-to-day prognostic study of OPMDs. [ABSTRACT FROM AUTHOR]

Simple Summary: Prognostic models to choose the right treatment schedule are needed in order to translate into practice a personalized approach. None of these models have been still entered into the clinical practice for what concern oral squamous cell carcinoma (OSCC). In this manuscript we performed a systematic review and subsequent quality assessment of already development prognostic model for OSCC with the aim to take stock of the situation on their possible clinical use. (1) Background: An accurate prediction of cancer survival is very important for counseling, treatment planning, follow-up, and postoperative risk assessment in patients with Oral Squamous Cell Carcinoma (OSCC). There has been an increased interest in the development of clinical prognostic models and nomograms which are their graphic representation. The study aimed to revise the prognostic performance of clinical-pathological prognostic models with internal validation for OSCC. (2) Methods: This systematic review was performed according to the Cochrane Handbook for Diagnostic Test Accuracy Reviews chapter on searching, the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines, and the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). (3) Results: Six studies evaluating overall survival in patients with OSCC were identified. All studies performed internal validation, while only four models were externally validated. (4) Conclusions: Based on the results of this systematic review, it is possible to state that it is necessary to carry out internal validation and shrinkage to correct overfitting and provide an adequate performance for optimism. Moreover, calibration, discrimination and nonlinearity of continuous predictors should always be examined. To reduce the risk of bias the study design used should be prospective and imputation techniques should always be applied to handle missing data. In addition, the complete equation of the prognostic model must be reported to allow updating, external validation in a new context and the subsequent evaluation of the impact on health outcomes and on the cost-effectiveness of care. [ABSTRACT FROM AUTHOR]

Aim: Musashi 2 (MSI2), which is an RNA-binding protein, plays a fundamental role in the oncogenesis of several cancers. The aim of this study is to investigate the expression of MSI2 in Oral Squamous Cell Carcinoma (OSCC) and evaluate its correlation to clinic-pathological variables and prognosis. Materials and Methods: A bioinformatic analysis was performed on data downloaded from The Cancer Genome Atlas (TCGA) database. The MSI2 expression data were analysed for their correlation with clinic-pathological and prognostic features. In addition, an immmunohistochemical evaluation of MSI2 expression on 108 OSCC samples included in a tissue microarray and 13 healthy mucosae samples was performed. Results: 241 patients' data from TCGA were included in the final analysis. No DNA mutations were detected for the MSI2 gene, but a hyper methylated condition of the gene emerged. MSI2 mRNA expression correlated with Grading (p = 0.009) and overall survival (p = 0.045), but not with disease free survival (p = 0.549). Males presented a higher MSI2 mRNA expression than females. The immunohistochemical evaluation revealed a weak expression of MSI2 in both OSCC samples and in healthy oral mucosae. In addition, MSI2 expression directly correlated with Cyclin-D1 expression (p = 0.022). However, no correlation has been detected with prognostic outcomes (overall and disease free survival). Conclusions: The role of MSI2 expression in OSCC seems to be not so closely correlated with prognosis, as in other human neoplasms. The correlation with Cyclin-D1 expression suggests an indirect role that MSI2 might have in the proliferation of OSCC cells, but further studies are needed to confirm such results. [ABSTRACT FROM AUTHOR]

Exosomes are extracellular vesicles found in saliva and other body fluids. These vesicles range in size from 30 to 150 nm and play a crucial role in intercellular communication, transporting different biomolecules, actively targeting cells. These vesicles regulate both physiological and pathological processes within recipient cells. MicroRNAs (miRs) are transported within exosomes and are delivered to target cells where they influence signaling pathways, taking on a crucial regulatory role in oncogenesis; for example, they are implicated in progression and infiltration of various cancers, such as head and neck squamous cell carcinoma (HNSCC). A systematic literature search based on specific keywords, according to the PRISMA guidelines, was carried out on PubMed, Web of Science, Scopus, and Google Scholar. Only original articles were selected during this review. The risk of bias was assessed by QUADAS-2. At the end of the selection process 9 articles were included. In these studies, 41 miRs showed differential expression between healthy subjects and patient with HNSCC. The techniques varied among studies for the extraction and analysis of exosomal miRs. We presented also salivary exosomal miRs pathways, to give insights about pathogenetic mechanisms. Exosomal microRNA are promising biomarkers for HNSCC detection. MiR-10b-5p, miR-486–5p, miR-24–3p, miR-412–3p, and miR-512–3p are the most promising markers applicable to diagnostics, while miR-1307–5p and miR-519c–3p resulted overexpressed and correlated to worse survival outcomes. • Salivary exosomal miRNAs are significant clinical promise in early diagnosis of HNSCC. • Salivary exosomal miRNAs are significant clinical promise in prognosis of HNSCC. • Salivary exosomal miRNAs as indicators of the tumor's stage. • Salivary exosomal miRNAs pathways in HNSCC. [ABSTRACT FROM AUTHOR]