This study aimed to explore the relationship between the timing of radiotherapy (RT) initiation after surgery and long-term outcomes in patients with tongue squamous cell carcinoma (TSCC). We retrospectively analyzed TSCC Patients who underwent external beam radiotherapy (≥ 60 Gy) following surgical resection without evidence of distant metastasis. Patients were categorized according to tumor stage and the interval between surgery and start of RT. The primary outcomes assessed were loco-regional control (LRC), disease-free survival (DFS), and overall survival (OS). A total of 108 patients were included. Among early-stage TSCC patients, delaying RT beyond 47 days post-surgery showed no statistically significant difference in DFS. For patients with locally advanced-stage disease, a longer interval between surgery and RT was associated with a significant trend toward improved DFS. OS did not significantly differ based on RT timing across stages. Our findings suggest that modest delays in initiating postoperative RT may not adversely affect DFS or OS in early-stage TSCC, and longer intervals may not clearly determine poorer outcomes in advanced-stage disease. However, these observations are preliminary and should be interpreted with caution given the small sample size, limited number of events, and retrospective design. Larger prospective studies are required to test this hypothesis and clarify optimal timing of postoperative RT in TSCC.

The incidence of squamous cell carcinoma of the oral tongue (SCCOT) among young adults is increasing in several regions of the world. Age-dependent differences in the biology of SCCOT have been suspected. We used the Olink Explore 3072 high-throughput platform to comprehensively quantify plasma proteins in 24 young (≤ 40 years of age) and 50 old (> 50 years of age) individuals. Eight young and 20 old individuals were diagnosed with SCCOT, four young and nine old individuals with SCC at other oral subsites (SCCOO), and the remaining 12 young and 21 old individuals were healthy controls. Dimension reduction analysis, differential expression analysis, and functional enrichment analysis were performed to characterize young patient-specific biological signatures. Plasma levels of 2923 proteins were obtained. Principal component analysis indicated age-related expression patterns. Comparing young patients to young controls/old patients/old controls, differential abundance analysis showed that increases in protein levels of Peroxiredoxin 2 (PRDX2) and C-C motif chemokine ligand 26 (CCL26) and a decrease in Kallikrein related peptidase 4 (KLK4) were young patient-specific. Reactome pathway enrichment analysis identified "Cellular response to chemical stress," "Detoxification of reactive oxygen species" and "Cellular responses to stimuli" as the top altered pathways in young patients with SCCOT. Abnormal cellular stress and aberrant immune regulation could thus be linked to cancer development in young patients. The unique plasma proteomic signature observed in young patients with SCCOT suggests that they constitute a specific group with distinct underlying pathophysiological processes.

Squamous cell carcinoma of the oral tongue (SCCOT) represents an aggressive malignancy characterized by high metastatic potential and significant heterogeneity in its tumor microenvironment. The tumor-stroma ratio (TSR) has emerged as a prognostic biomarker, with higher stromal content frequently correlating with worse survival outcomes. Traditional approaches using the standard 50% TSR cutoff may not be optimal for SCCOT, and visual TSR estimation introduces variability during TSR region annotation. This study aimed to develop and validate a dedicated TSR estimation model for SCCOT by incorporating representative TSR regions from the invasive tumor front of whole slide images and to determine the optimal TSR threshold for prognostic stratification. Using hematoxylin and eosin-stained images from The Cancer Genome Atlas as a discovery cohort and whole slide images from Norrland's University Hospital Umea, Sweden (NUS) as a validation cohort, we developed a computational model to estimate TSR. The model demonstrated a high correlation with pathologist-based TSR estimation in both discovery (R = 0.848, p < 0.01) and validation (R = 0.783, p < 0.01) cohorts. The optimal 55% cutoff identified by the model improved prognostic accuracy over the traditional 50% threshold, with patients having high stroma within the tumor invasive front showing worse overall (log-rank p = 0.006) and disease-specific (log-rank p = 0.016) survival. Our computational TSR model for SCCOT demonstrates that automated TSR estimation enhances prognostic accuracy at an optimal cutoff of 55%, contributing to more precise risk stratification and potentially enabling personalized treatment strategies in SCCOT management.

The anatomy of the tongue is three-dimensionally complex and is thought to play a central role in the local growth of oral tongue squamous cell carcinoma (OTSCC). Understanding patterns of tumor extension could improve a multimodal therapeutic approach. Thus, the main aim of this study was to provide a histological and microanatomical analysis of surgical specimens after compartmental surgery for OTSCC. The present prospective observational study included primary cT3 OTSCC (according to the eighth edition of the TNM classification) treated in an academic tertiary referral center with curative compartmental surgery, from July 2016 to July 2019. Analysis of histologic macrosections allowed assessment of standard pathologic parameters as well as a detailed analysis of the position of OTSCC cells from microanatomic and topographic standpoints. Of the 28 patients included, 71.4% were males, with a mean age of 64.9 years. Nine (32.1%) patients presented satellitosis, which was always located within the T-N tract. OTSCCs displaying satellitosis had a significantly higher median pathologic depth of invasion (DOI). A radiologic and pathological DOI > 15 mm significantly predicted the presence of satellites. There was a significant relationship between the presence of satellites and both positive lymph nodes and distant metastases. Approximately one-third of cases of intermediate-to-advanced OTSCC are characterized by tumor satellites located in the T-N tract. DOI exceeding 15 mm and the presence of clinically appreciable nodal metastases best predict the presence of satellitosis. Satellite-bearing OTSCC behave more aggressively, with an increased risk of distant metastasis and reduced survival.

The field cancerization concept indicates the presence of pre-cancerous changes in clinically normal tissue surrounding the tumor. In squamous cell carcinoma of the oral tongue (SCCOT) which is infrequently linked to human papillomavirus infection, we have previously reported that clinically normal tongue contralateral to tumor (NTCT) is molecularly abnormal. Here, combining our transcriptomic and genomic data, we aimed to investigate the contribution of molecular changes in NTCT to cancer development. Microarray gene expression data of 14 healthy controls, 23 NTCT and 29 SCCOT samples were investigated to characterize transcriptional profiles in NTCT. Whole exome sequencing and RNA-sequencing data of paired NTCT and tumor samples from 15 SCCOT patients were used to study correlation between copy number variation and differential gene expression. Using supervised multivariate partial least squares discriminant analysis, a total of 61 mRNAs that distinguish NTCT from healthy tongue were selected. Functional enrichment analysis of the 22 upregulated genes showed increased "positive regulation of nitrogen compound metabolic process" in NTCT. All 12 genes involved in this process have roles in apoptosis (anti- and/or pro-apoptotic). Compared to healthy controls, Zinc Finger Protein 395 (ZNF395), a pro-apoptotic tumor suppressor located on chromosome 8p, was the only gene showing increased mRNA level in NTCT whereas decreased in SCCOT. Given the frequent loss of chromosome 8p in SCCOT, the impact of ZNF395 copy number variation on gene expression was further examined, revealing a positive correlation between copy number and mRNA level (correlation coefficient = 0.572, p < 0.001). NTCT is susceptible to malignant transformation, where tissue homeostasis is maintained at least partly through regulation of apoptosis. Loss of the pro-apoptotic gene ZNF395 could thus initiate cancer development.