Pain severity is related to molecular pathways underlying aggressive disease and poor survival in OSCC

Pain is one of the worst symptoms experienced by patients with oral squamous cell carcinoma (OSCC), which impairs patients' function and quality of life. Yet its clinical and molecular determinants remain poorly defined. The objective of this study was to investigate how pain, quality of life (QoL), and tumor biology intersect to improve prognostication and patient-centered care. This prospective multi-institutional study enrolled 196 OSCC patients from Loma Linda University (LLU) and the University of Alabama at Birmingham (UAB). Pain was assessed using the UCSF Oral Cancer Pain Questionnaire and, Brief Pain Inventory (BPI). Functional and symptom disturbance (QoL) were characterized using EORTC QLQ-C30/H&N35. Flash frozen tumors were collected at surgery for RNA-Seq. Data were analyzed using Spearman correlation, Wilcoxon, Kruskal-Wallis tests, ANCOVA, Kaplan-Meier log-rank test, and Cox hazard regression. Our results revealed that patients reporting high pain demonstrated significantly lower overall QoL, including reduced functional scores (physical, role, emotional, cognitive, and social functioning) and higher symptom burden (p<0.05), entirely independent of their cancer stage at diagnosis. Additionally, morphine milligram equivalents (MME/day) were strongly correlated with pain severity and worse QoL metrics (p<0.05). Kaplan-Meier analysis showed that high pain (UCSF and BPI), higher symptom score, and higher H&N35 score, lower global health status score and functional score, and opioid use were associated with worse survival (p<0.05). After adjustment for confounders (age, sex, race, pathologic stage, PNI, LVI, smoking status), Cox hazard regression analysis revealed functional score (HR = 0.5, CI 95% [0.287-0.873]), symptom score (HR = 2.144, CI 95% [1.169-3.934]), HN35 scores (HR = 2.192, CI 95% [1.195-4.023]) and opioid use (HR = 2.665, CI 95% [1.510-4.706]) as independent predictors of survival. RNAseq analysis of 128 patients comparing high- and low-pain tumors identified significant enrichment in GO pathways related to axonogenesis, neuron to neuron synapse, and in KEGG involved pathways of neurodegeneration-multiple disease, Alzheimer's, and Huntington's disease pathways. In addition, the top dysregulated GO pathways in patients with low function (low functional score) were cytoplasmic translation, ribosome biogenesis, and regulator of signal transduction by p53 class mediator. In conclusion, these findings demonstrated that pain severity, opioid requirement, and diminished quality of life are tightly linked to aggressive tumor features and poorer survival in OSCC. Molecular analyses highlight the potential of neural-associated dysregulation in OSCC pain.