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PubMed2026

Effect of Smoking in Oropharyngeal Cancer Treated With TORS: Systematic Review and Meta-Analysis.

OBJECTIVE: While smoking has been implicated as a risk factor for recurrence in HPV-associated oropharyngeal squamous cell cancer (OPSCC) treated with definitive chemoradiation, its prognostic impact on surgically treated OPSCC is less clear. DATA SOURCES: MEDLINE, Embase, CENTRAL, and Scopus. REVIEW METHODS: Articles describing patients with HPV-associated OPSCC treated with transoral robotic surgery (TORS), which reported oncologic outcomes by smoking history, were included. RESULTS: 2079 patients were included across 12 studies. Median age was 58.5 years, and 1808 (87.0%) were male. HPV-associated disease was reported in 1681 (80.9%) patients. T stage was most commonly T2 in 831 (40.0%) and T1 in 764 (36.7%). N stage was N2 in 854 (41.1%), N1 in 544 (26.2%), and N0 in 307 (14.8%). 931 (44.8%) were considered individuals with a smoking history, while 1045 (50.3%) were considered without a smoking history. Median follow up was 33.7 months. Meta-analysis using a fixed effects model demonstrated an overall hazard ratio of 1.4 (95% confidence interval 1.0-2.0) for disease recurrence, 2.7 (95% confidence interval 1.5-4.8) for overall survival, and 1.4 (95% confidence interval 0.4-4.6) for disease specific survival. CONCLUSIONS: In this population of predominantly HPV-associated OPSCC treated with TORS, meta-analysis demonstrated no significant difference in recurrence-free survival or disease-specific survival between individuals with and without a smoking history. Individuals with a smoking history appeared to have worse overall survival, although only five studies reported on this outcome. Further research is required to clarify the prognostic influence of smoking on OPSCC treated with TORS.

Humans↗

PubMed2025

Analytical and clinical performance validation of HPV-SEQ, a novel NGS-based liquid biopsy platform for detection and quantification of human papilloma virus circulating tumor DNA.

BACKGROUND: Human papillomavirus (HPV) is the primary causative driver of oropharyngeal squamous cell carcinoma (OPSCC). Accurate detection of HPV-DNA is critical for risk stratification and management of OPSCC. However, assays designed to detect HPV in primary tumors do not allow monitoring of HPV-DNA over time, whereas commercially available droplet digital PCR-based methods for assessment of circulating cell free (cf)HPV-DNA in plasma remain suboptimal, hindering adaptation into clinical practice. We have developed HPV-SEQ, a novel next-generation-sequencing (NGS) based method for detection and quantification of HPV16/18 DNA in plasma of patients with OPSCC. METHODS: The assay uses primers targeting the L1 gene of HPV16 and HPV18 viral genomes and strain specific calibrators at a defined concentration to determine the ratio of native HPV to a known standard, enabling accurate reporting of patient-derived HPV16/18 viral load in a sample. This study was conducted using two different patient populations in addition to healthy donors and contrived material. All experiments were performed to fulfill several applicable analytical, performance and validation guidelines. RESULTS: A thorough analytical characterization and clinical validation of this platform demonstrates that HPV-SEQ detects cfHPV-DNA with exceptional limit of quantification and high precision, providing a foundation for integrating this platform into clinical settings. CONCLUSIONS: This ultra-sensitive HPV profiling method with optimal analytical performance may represent a significant advancement in risk stratification, treatment management, and post-treatment surveillance for patients with OPSCC.

Humans↗

PubMed2026

Incidence of retropharyngeal lymph node involvement in oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: Retropharyngeal lymph node (RPN) involvement in oropharyngeal squamous cell carcinoma (OPSCC) may influence prognosis, staging, radiotherapy target volumes, and treatment strategy. However, its true prevalence and association with clinicopathological factors remain incompletely defined. METHODS: A systematic review and meta-analysis was performed in accordance with the PRISMA 2020 statement. MEDLINE, EMBASE, EMCARE, PubMed, Web of Science, Scopus, and the Cochrane Library were searched from database inception to 15 June 2026. Studies reporting radiological or pathological assessment of retropharyngeal lymph node (RPN) involvement in oropharyngeal squamous cell carcinoma (OPSCC) were included. Pooled prevalence estimates were calculated using a random-effects model, with subgroup analyses according to tumour stage, nodal status, HPV status, and primary tumour subsite. RESULTS: Fourteen studies comprising 8,887 patients were included. The pooled prevalence of RPN involvement was (95% CI 11-16%; 95% PI 6-24%), with substantial heterogeneity. HPV-negative tumours demonstrated higher prevalence than HPV-positive tumours (21% vs 11%). Prevalence increased with advancing T stage, from 2% in T1 to 18% in T4 disease, and was higher in node-positive than node-negative disease (16% vs 1%). Tonsillar primaries showed higher prevalence than base of tongue tumours (14% vs 8%). Among patients with RPN involvement, the pooled distant metastasis rate was 16%. CONCLUSION: RPN metastases were identified in approximately one in eight patients with OPSCC and were more frequent in HPV-negative disease, advanced stage, and tonsillar primaries. These findings support careful evaluation of the retropharyngeal space during staging and may assist risk stratification in selected higher-risk patients.

Humans↗

PubMed2026

Refining the Multivariable Predictive-Prognostic PREDICTR-OPC Model for Survival in Surgical Escalation for Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVES: The PREDICTR-OPC model is the only prognostic classifier for oropharyngeal squamous cell carcinoma (OPSCC) also predictive of surgical outcomes. Of the four biomarkers included, survivin contributes minimally and presents practical limitations. This study aimed to refine and simplify the model by removing survivin, then re-assess its prognostic predictive performance compared to the original. METHODS: This retrospective cohort study analyzed a multi-center training cohort (n = 600) and an external validation cohort (n = 385) of OPSCC patients. Tumor biopsies were stained for p16, high-risk human papillomavirus (HR-HPV) DNA, tumor-infiltrating lymphocytes (TILs), and survivin and independently scored by at least three certified pathologists. Cox proportional hazards models assessed overall survival (OS), comparing three-biomarker (p16, HR-HPV, TILs) and four-biomarker models. Hazard ratios (HRs) for OS were estimated in the validation cohort, adjusting for covariates. Discrimination, calibration, and decision curve analysis (DCA) evaluated performance and clinical utility. RESULTS: Among 985 patients (median age: 57 years), median OS = 8.8 years (95% CI: 6.9-10.5). The three-biomarker model yielded HR = 4.10 (95% CI: 2.41-6.98, p < 0.001) for high- vs. low-risk groups in the validation cohort, comparable to the four-biomarker model (HR = 4.24, p < 0.001). Surgery was associated with improved OS in high-risk (HR = 0.45, p = 0.001) but not low-risk (HR = 0.83, p = 0.72) patients, consistent with the original model. The models performed similarly across all metrics (e.g., Concordance Index: 0.71 vs. 0.72; Brier Score: 0.22 for both) as was model fit (Likelihood Ratio Test: p = 0.066). DCA revealed comparable clinical benefit. CONCLUSION: Removing survivin preserves PREDICTR-OPC's predictive performance, offering a more cost-effective, easier-to-implement tool for OPSCC treatment recommendations.

Humans↗

PubMed2026

HPV circulating tumor DNA as a potential prognostic and predictive biomarker in head and neck squamous cell carcinoma: a systematic review.

PURPOSE: Human papillomavirus circulating tumor DNA (HPVctDNA) has emerged as a promising prognostic biomarker in HPV-related head and neck squamous cell carcinoma (HNSCC). This systematic review aimed to synthesize current evidence on the diagnostic accuracy and prognostic value of HPVctDNA in HNSCC management. MATERIAL/METHODS: We systematically reviewed a PubMed-indexed database of studies published between January 2012 and September 2025. Eligible studies were assessed for design, primary tumor site and stage, treatment modality, HPVctDNA detection method, diagnostic accuracy (sensitivity and specificity), and reported clinical endpoints. Descriptive syntheses were performed; sensitivity and specificity were standardized to proportions and summarized as median values per group. RESULTS: A total of 60 studies, including 8,234 patients were analyzed, of which 41 (68.3%) focused exclusively on oropharyngeal squamous cell carcinoma (OPSCC) and 17 (28.3%) included mixed HPV-related HNSCC subsites and HPV-positive cancers of unknown primary. The median follow-up across the included studies was 23 months. Among the included studies, 19 were retrospective (31.7%) and 33 were prospective (55.0%), with a small proportion of cross-sectional and randomized clinical trials. Overall, 40 (66.7%) evaluated the role of HPVctDNA in a curative setting. Plasma was the most common sample type, analyzed in 55 studies (91.7%), while 5 studies also included saliva. Detection methods varied: 40 employed droplet digital PCR (ddPCR), 16 used quantitative PCR (qPCR) and 4 applied NGS-based assays. Most of these studies (38, 63.3%) evaluated the prognostic utility of HPVctDNA, while only 4 (6.7%) assessed HPVctDNA in a screening or diagnostic setting. Regarding diagnostic accuracy, the median sensitivity across evaluable studies was 91.1%, while the median specificity was 99.4%. In OPSCC-only cohorts, the median sensitivity and specificity were 89.4% and 99.4%, respectively. Dynamic changes in HPVctDNA levels during or after treatment were consistently associated with outcomes: clearance or sustained negativity correlated with higher response rates, improved progression-free survival and overall survival, while persistent positivity or increasing levels predicted disease progression and recurrence. CONCLUSIONS: HPVctDNA demonstrates high diagnostic and prognostic accuracy in HPV-related HNSCC, especially OPSCC, supporting its use for prognosis, treatment monitoring and early detection of recurrence. However, prospective interventional studies are still required to demonstrate that HPVctDNA-guided treatment decisions improve clinical outcomes before routine implementation.

Humans↗

PubMed2026

Discovery and validation of a prognostic SPP1/PLAU signature in HPV-negative oropharyngeal squamous cell carcinoma.

BACKGROUND: This study aimed to identify and validate robust prognostic biomarkers for oropharyngeal squamous cell carcinoma (OPSCC), with a specific focus on the high-risk HPV-negative subtype. METHODS: Integrated bioinformatics analysis was performed on transcriptomic data from four GEO datasets (n = 418 samples). Differentially expressed genes (DEGs) were identified, and a protein-protein interaction (PPI) network was constructed for the most dysregulated genes. Key modules were analyzed via survival analysis and multivariate Cox regression. The top candidate genes were validated at the protein level using immunohistochemistry (IHC) in an independent cohort of 304 OPSCC patients. RESULTS: A 33-gene module related to extracellular matrix organization showed significant prognostic association. It stratified patients into high- and low-risk groups with markedly different overall survival (HR = 2.71, p < 0.001). From this module, SPP1 and PLAU were identified as independent prognostic factors through multi-step screening. Both genes were significantly overexpressed in tumors (approximately 20-fold and 10-fold, respectively, p < 0.001), with high expression strongly correlated with advanced tumor stage (p < 0.01) and, notably, the HPV-negative subtype (p < 0.001). In survival analysis, high expression of either SPP1 or PLAU was associated with poorer overall survival (SPP1: p < 0.001; PLAU: p < 0.001) and progression-free survival (p < 0.001). IHC validation confirmed high protein expression in 69.7% (SPP1) and 54.8% (PLAU) of cancer tissues. A prognostic nomogram integrating the SPP1/PLAU signature with clinical variables was constructed with strong predictive accuracy (C-index = 0.75). CONCLUSION: The SPP1/PLAU dual-gene signature is a robust and independent prognostic biomarker for OPSCC, with particular clinical utility for stratifying high-risk HPV-negative patients.

Humans↗