Search Results (306)

Background: Convolutional neural networks (CNNs) perform well in histopathological classification of oral squamous cell carcinoma (OSCC), but their robustness across distinct tissue domains remains insufficiently studied. This study assessed whether a CNN trained only on primary oral and oropharyngeal squamous cell carcinoma images remained transferable to an independent metastatic lymph node histopathology dataset. Methods: Three public datasets containing 14,760 OSCC/OPSCC and 8530 normal oral mucosa images were combined for model development. An ImageNet-pretrained EfficientNetB0 backbone was used as a fixed feature extractor with a task-specific binary classification head. Performance was first assessed on an independent internal testing subset and subsequently evaluated on 20,000 H&E-stained normal and metastatic lymph node patches from a separate public dataset. Results: The model achieved an internal testing accuracy of 91.48%, with 92.95% sensitivity, 88.92% specificity, 93.56% precision, a 93.25% F1-score, and a Youden’s J index of 0.819. External validation resulted in a substantial decrease in overall classification performance, with an accuracy of 56.91%, specificity of 33.32%, precision of 48.71%, F1-score of 63.37%, balanced accuracy of 61.99%, MCC of 0.279, and a Youden’s J index of 0.240. Nevertheless, sensitivity for metastatic tissue remained high at 90.66%, indicating a markedly asymmetric external error profile characterized predominantly by false-positive classifications. Conclusions: The marked performance decrease during external validation demonstrates the limitations of direct cross-domain transfer between substantially different histopathological environments. However, the preserved sensitivity suggests that some discriminative information remained transferable beyond the development domain. These findings support partial rather than universal cross-domain generalization and emphasize the importance of independent out-of-distribution evaluation when assessing deep learning robustness in computational pathology. Full article

Liquid biopsy, the analysis of tumor-derived material in blood, saliva, and other body fluids, is increasingly explored for the diagnosis, surveillance, and molecular characterization of head and neck squamous cell carcinoma (HNSCC). Its performance, however, is not uniform across the disease, and the reason is fundamentally molecular. human papillomavirus (HPV)-positive oropharyngeal cancers carry viral oncogenes that are absent from the host genome and therefore provide a near ideal, tumor specific circulating marker, whereas HPV-negative tumors are driven by a heterogeneous somatic landscape that offers no single universal target. In this narrative review, we adopt a molecular perspective. We first examine the biological origin of circulating tumor DNA and of the other analytes that liquid biopsy can interrogate including circulating tumor HPV DNA, viral transcripts, microRNAs, extracellular vesicles, and methylation signatures. We then consider how analytical platforms, from droplet digital PCR to next generation and ultrasensitive whole-genome sequencing, translate these molecules into measurements. Only afterward do we discuss the clinical questions, organized by clinical objective rather than by individual study: diagnosis and early detection, prognosis and risk stratification, treatment response monitoring, minimal residual disease and surveillance, and biomarker guided de-escalation in HPV-positive disease. Twelve registered clinical trials, involving approximately 1183 patients, are presented as illustrations of these questions. We close on the biological and technical gaps that still separate promising signals from clinical practice, and on the multi analyte and dynamic strategies most likely to bridge them. At present, liquid biopsy should be regarded as a complementary tool rather than as a replacement for established clinicopathological assessment. Full article

Background and Clinical Significance: Oropharyngeal squamous cell carcinoma (OPSCC) and small-cell neuroendocrine carcinoma (SCNEC) are biologically distinct entities with markedly different prognostic and therapeutic implications. While HPV-negative OPSCC carries worse outcomes than HPV-positive disease, SCNEC is exceedingly rare, highly aggressive, and prone to early systemic dissemination. Their synchronous occurrence in the head and neck (HN) is exceptional and poses major diagnostic and therapeutic challenges. Case Presentation: A 54-year-old male, smoker and alcohol consumer, presented with a left tonsillar lesion and cervical lymphadenopathy. Biopsy confirmed p16-negative OPSCC. He underwent transoral robotic surgery with modified radical neck dissection. Histopathology unexpectedly revealed two distinct malignancies: keratinizing OPSCC in the tonsil and high-grade SCNEC in a cervical lymph node, confirmed by immunohistochemistry (synaptophysin, CD56, Ki-67 80%). Postoperative FDG-PET/CT performed within two months showed rapid systemic spread, including paravertebral, pulmonary, and pelvic nodal metastases. Despite recommendation for systemic therapy, the patient deteriorated quickly and died shortly thereafter. Conclusions: This study reports coexistence of p16-negative OPSCC and high-grade SCNEC in the HN. It highlights the diagnostic complexity, staging limitations, and therapeutic dilemmas of discordant histologies, while illustrating the fulminant clinical course typical of SCNEC of unknown origin. Early recognition, comprehensive pathology, and multidisciplinary management are essential, although prognosis remains dominated by the aggressive neuroendocrine component. Full article

Background/Objectives: Human papillomavirus (HPV) is now responsible for the majority of oropharyngeal squamous cell carcinomas (OPSCCs), an HPV-related cancer of direct relevance to the dental profession; oral-health providers may be well-positioned to perform routine oral examination, recognize suspicious signs, refer appropriately, and educate patients about HPV-related oropharyngeal cancer and HPV vaccination. This study assessed knowledge, attitudes and practices regarding sexually transmitted infections (STIs), HPV, HIV/AIDS and HPV-related oral and oropharyngeal cancer among secondary-school students in Apulia, Italy, with particular attention to the dental setting. Methods: A cross-sectional study was conducted by the University of Foggia among 1224 students from three secondary schools at the end of the 2025/2026 school year) using a self-administered 108-item questionnaire. A 63-item composite knowledge score was computed; “don’t know” answers were scored as incorrect and adequate knowledge defined a priori as ≥60% (Bloom’s cut-off). The minimum required sample (737) was derived using Cochran’s formula adjusted for a cluster-sampling design effect. Results: Overall knowledge was low (mean 28.5%, SD 18.2); only 5% reached the ≥60% threshold (Bloom’s cut-off). Only 14.8% of students were aware that HPV can cause oropharyngeal cancer, the lowest figure among all oncogenic outcomes assessed and significantly lower in boys (11.2%) than girls (17.3%; p = 0.003), despite boys carrying the higher OPSCC risk. Knowledge was independently associated with female sex, age and sexual experience. Despite poor knowledge, 61.2% of students would like to receive the HPV vaccine. Conclusions: The dental visit may represent an under-used opportunity to address this oral-cancer-prevention knowledge gap; the integration of oral-health professionals into school-based and clinical HPV-prevention strategies is a plausible public-health implication. Full article

Head and neck cancer (HNC) comprises a heterogeneous group of tumours, most often of squamous cell origin, characterized by both high morbidity and mortality rates. It is the seventh most common form of cancer diagnosed in humans, accounting for approximately 4.7% of all cancers. Among HNCs, neck squamous cell carcinoma (HNSCC) is predicted to become the most common form of human cancer. Some sources include oesophagus (ESCC) in this group due to their similar histology, being described as upper aerodigestive tract cancers (UADT). Unfortunately, 60–70% of cases are diagnosed late, i.e., at clinical stages III-IV. As a result, despite modern surgical techniques and oncological treatments, the survival rate remains below 40–60% due to frequent lymph node metastases and local tumour recurrence. There is a growing concern that diet and inflammatory dietary components may influence the initiation and development of HNSCC. The inflammatory potential of diets can be quantified by the Dietary Inflammatory Index (DII). The DII was derived from an analysis of 45 dietary constituents that either increase or decrease inflammation. Several recent clinical studies have noted a significant relationship between DII score and many inflammation-associated chronic diseases, such as obesity, cardiovascular and neurodegenerative disorders, and diabetes, and the incidence of various human cancers, i.e., prostate, ovarian, breast, colorectal cancer, and HNC. However, few studies have investigated the relationship between DII and HNSCC, with most being limited to observational, case-control, and cross-sectional studies. Therefore, the aim of this narrative review is to present the substantial oncological aspects of DII, discuss the use of DII and its modification, the Energy-Adjusted Dietary Inflammatory Index (E-DII), as indicators of HNSCC risk. It also introduces key diet-induced pro- and anti-inflammatory mechanisms and the cellular molecular signalling pathways determining the carcinogenesis of HNSCC. It provides a comprehensive overview of the current literature, including key opinion-forming systematic reviews, as well as molecular, observational, cross-sectional and case-control studies, all of which are accessible via scholarly databases such as PubMed/EMBASE/Web of Science. Thus, the work serves as a compendium of up-to-date knowledge on the relationship between DII/ED-II score and HNSCC etiopathogenesis and the influence of a diet-induced persistent inflammatory microenvironment. Full article

Background: Head and neck squamous cell carcinoma (HNSCC) remains a major global health challenge due to the lack of effective and non-invasive diagnostic tools, often resulting in late-stage detection of cancer. Small extracellular vesicles (sEVs) have emerged as promising biomarkers for early cancer detection and disease monitoring due to their omnipresence and stability in bodily fluids, such as blood plasma. In addition, cancer-derived sEVs specifically carry cargo reflective of oncogene-derived molecular alterations. In summary, these characteristics position sEVs as a potential platform for non-invasive testing of HNSCC. Methods: Plasma-derived sEVs from HNSCC patients (n = 71) and benign subjects (n = 25) were isolated using size exclusion chromatography. Proteomic profiling via liquid chromatography-tandem mass spectrometry identified potential candidate biomarkers, followed by ELISA validation. Results: Proteomic analyses revealed a significant enrichment of multiple proteins in HNSCC-derived sEVs compared to sEVs derived from non-cancer individuals. The von Willebrand factor (vWF) was significantly higher in HNSCC patient-derived sEVs compared to those derived from benign individuals. A validation cohort confirmed that sEV-associated vWF (sEV-vWF) effectively distinguished HNSCC patients from benign subjects, demonstrating strong diagnostic performance, specifically in laryngeal HNSCC (AUC = 0.82) and oropharyngeal HNSCC (AUC = 0.96) patient cohorts. Moreover, postoperative reductions and recurrence-associated increases in sEV-vWF levels corresponded with clinical outcomes, indicating its potential as a dynamic disease indicator. Conclusions: These findings highlight sEV-vWF as a novel and non-invasive biomarker with potential applications in early detection and real-time monitoring of HNSCC, supporting advancement toward precision liquid biopsy strategies in head and neck oncology. Full article

Background and Objectives: Oropharyngeal squamous cell carcinoma (OPSCC) is a biologically heterogeneous disease. p16 immunohistochemistry is widely used as a surrogate marker for human papillomavirus (HPV)–associated OPSCC and plays a key role in prognostication and staging. However, p16 overexpression does not invariably reflect transcriptionally active HPV infection, and the clinical significance of p16–HPV discordance remains incompletely defined, particularly in populations with high exposure to traditional carcinogens. Materials and Methods: We conducted a retrospective cohort study of patients diagnosed with OPSCC between 2016 and 2020 at a tertiary referral center in Taiwan. p16 immunohistochemistry was performed in all cases, and transcriptionally active high-risk HPV was assessed by RNA in situ hybridization in p16-positive tumors. Clinicopathologic characteristics, carcinogen exposure profiles, and survival outcomes, including overall survival (OS) and disease-free survival (DFS), were analyzed according to p16 and HPV status. Results: Among 140 patients with OPSCC, 49 (35%) were p16-positive, of whom 44 (90%) demonstrated transcriptionally active HPV. Compared with p16-negative tumors, p16-positive OPSCC was significantly associated with lymphoepithelial organ involvement, non-keratinizing morphology, lower clinical stage, and less exposure to alcohol, betel nut, and tobacco. In Kaplan–Meier and univariable analyses, p16 positivity was associated with significantly improved OS and DFS. In contrast, p16-positive/HPV RNA-negative tumors exhibited clinicopathologic features more closely resembling p16-negative OPSCC, including greater keratinization and higher carcinogen exposure. Conclusions: p16-positive/HPV RNA-negative tumors showed clinicopathologic features suggestive of biological heterogeneity; however, the small number of discordant cases precludes definitive conclusions regarding survival differences. These findings support selective HPV RNA testing in p16-positive OPSCC with atypical clinicopathologic features, particularly in carcinogen-endemic populations. Full article

Background: Human papillomavirus (HPV)-unrelated oropharyngeal squamous cell carcinoma (OPSCC) is a clinically aggressive disease characterized by poor outcomes and limited prognostic biomarkers. The Hippo–YAP pathway has emerged as a key regulator of tumorigenesis in epithelial cancers, although its role in OPSCC remains incompletely defined. Methods: We conducted a retrospective study including 215 patients with HPV-negative OPSCC treated surgically with curative intent. Tissue microarrays were constructed, and immunohistochemical analysis of YAP1 and TAZ expression was performed. Associations with clinicopathological variables, disease-free survival (DFS) and disease-specific survival (DSS) were assessed using univariable and multivariable analyses. Results: Nuclear and cytoplasmic YAP1 expression were detected in 53% and 85.6% of tumors, respectively. Both nuclear and cytoplasmic YAP1 expression were significantly associated with reduced DFS (p = 0.019 and p = 0.004, respectively) and DSS (p = 0.01 and p = 0.006, respectively). Multivariable analysis identified nodal involvement (HR = 1.64, p = 0.023) and nuclear YAP1 expression (HR = 1.65, p = 0.004) as independent predictors of DFS, and advanced tumor stage (HR = 1.57, p = 0.038), nodal involvement (HR = 2.34, p < 0.001), and nuclear YAP1 expression (HR = 1.78, p = 0.002) as independent predictors of DSS. In contrast, nuclear TAZ expression was observed at a lower frequency (14.5%) and showed no significant association with clinical parameters or survival outcomes. Conclusions: YAP1 expression, particularly its nuclear activated form, emerges as an independent poor prognostic factor in HPV-negative OPSCC, whereas nuclear TAZ expression was rather infrequent and showed no clinical relevance. These findings highlight the importance of Hippo pathway dysregulation in this tumor subtype and suggest the potential of YAP1 as both a prognostic biomarker and a therapeutic target. Full article

Background and Objectives: p16 immunohistochemistry (IHC) is widely used as a surrogate marker for high-risk human papillomavirus (HPV)-driven carcinogenesis in oropharyngeal squamous cell carcinoma. Diagnostic reliability in laryngeal squamous cell carcinoma (LSCC) is still up for debate, particularly because HPV DNA detection, p16 overexpression, and transcriptionally active HPV infection may be discordant at this anatomical site. This systematic review aimed to assess the diagnostic performance of p16 IHC as a surrogate marker for high-risk HPV status in primary invasive LSCC. Materials and Methods: A systematic review was conducted in accordance with PRISMA principles and prospectively registered in PROSPERO. PubMed, Scopus, and Web of Science, and citation searches were used to identify studies reporting paired p16 IHC and tumour-based molecular HPV testing in invasive LSCC. Eligible HPV reference standards included HPV DNA PCR/genotyping, DNA in situ hybridization, RNA in situ hybridization, and E6/E7 mRNA detection. Data were synthesized narratively because of substantial heterogeneity in p16 thresholds, HPV assays, and study populations. Results: Fourteen studies were included. p16 positivity thresholds varied widely, ranging from ≥30% moderate/strong staining to ≥70–75% diffuse nuclear and cytoplasmic staining. HPV reference standards also differed substantially across studies. Overall, p16 IHC showed inconsistent concordance with molecular HPV testing. Studies using RNA-based reference standards showed that transcriptionally active HPV was uncommon in LSCC and that p16-positive tumours often lacked evidence of active HPV transcription. Conclusions: p16 IHC should not be used as a standalone surrogate marker for high-risk HPV-driven carcinogenesis in invasive LSCC. When HPV attribution is clinically or analytically important, p16-positive cases should be confirmed using HPV-specific molecular testing, preferably RNA-based assays. Future prospective studies using standardized p16 protocols and transcriptionally active HPV reference standards are needed. Full article

The potential impact of propofol on head and neck cancer (HNC) progression and clinical outcomes, in relation to both direct effects on tumor biology and indirect effects mediated by perioperative immune and inflammatory responses, remains controversial. Most mechanistic evidence currently available for HNC originates from studies of oral squamous cell carcinoma. Accordingly, mechanistic findings are interpreted primarily as OSCC-derived evidence and should not be generalized to all HNC subsites without further validation. To address this, we critically examined propofol’s potential role as a perioperative anesthetic modulator of tumor biology and host responses. Preclinical studies have demonstrated that propofol suppresses proliferation, induces apoptosis, inhibits angiogenesis, and enhances 5-fluorouracil chemosensitivity. Conversely, other studies report enhanced epithelial–mesenchymal transition, migration, and invasion through SNAI1 upregulation, highlighting the context-dependent nature of propofol-mediated effects. The generalizability of these molecular observations to other HNC subsites, including laryngeal, hypopharyngeal, and oropharyngeal cancers, remains unclear. Clinically, propofol-based total intravenous anesthesia has been associated with reduced postoperative pulmonary complications and improved perioperative recovery. However, currently available HNC-specific studies have not demonstrated a consistent improvement in overall or recurrence-free survival. These discrepancies likely reflect tumor heterogeneity, variations in experimental design, perioperative confounding factors, and differences in host immune and inflammatory responses. This narrative review was based on literature identified through PubMed, Scopus, and Google Scholar, and integrates current mechanistic, immunological, and clinical evidence regarding propofol exposure during cancer surgery. Current evidence supports the perioperative benefits of propofol-based anesthesia; however, its long-term oncologic significance in HNC remains inconclusive and warrants further prospective, mechanism-driven, and biomarker-guided investigations. Full article

The global incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing, mainly due to a rise in human papillomavirus-positive (HPV+) cases. In Denmark, this group now constitutes more than 70% of newly diagnosed patients with OPSCC, making HPV+ OPSCC an increasing health issue. Approximately 10–15% of patients experience recurrence after treatment, and 30% die within five years of diagnosis. Detecting recurrence can be challenging, as it relies on either visible findings during clinical examination or symptoms reported by the patient. However, recent studies have shown that circulating tumor HPV-DNA (ctHPV-DNA) is a promising biomarker for detecting recurrence. The aim of the study presented in this protocol is to investigate whether prospective and systematic ctHPV-DNA testing can improve the standard follow-up program by detecting recurrence earlier than, or simultaneously with, clinical or radiological examination. This study is a prospective diagnostic accuracy study aiming to include 200 newly diagnosed patients with HPV+ OPSCC. Patients will be followed systematically with blood samples at baseline before treatment initiation and at every standard follow-up visit after treatment completion for up to three years. If a sample after treatment completion is positive for ctHPV-DNA, the patient will be referred for clinical ENT examination and a PET/CT scan to assess if the patient has detectable recurrence. This study will provide novel knowledge of the sensitivity and specificity of ctHPV-DNA testing for detecting recurrence in patients with HPV+ OPSCC, based on a large, prospectively and systematically followed cohort in which positive ctHPV-DNA findings will be acted upon clinically. Full article

Background: Circulating tumor HPV DNA (ctHPV DNA) has shown clinical value in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), but its relationship with tumor burden and its role in prognosis, especially when combined with clinicoradiological factors, remain to be further defined. Methods: We analyzed 103 patients with HPV-positive OPSCC enrolled in an observational biomarker study, most of whom received induction chemotherapy or chemoimmunotherapy followed by definitive radiotherapy. Blood samples were collected at pretreatment, post-radiotherapy, and follow-up time points, and ctHPV DNA levels were quantified using droplet digital PCR. Baseline clinicoradiological parameters from contrast-enhanced MR or CT and ¹⁸F-FDG PET/CT were analyzed for their association with ctHPV DNA levels and clinical outcomes. Results: Baseline ctHPV DNA correlated with primary tumor volume (V_T), nodal volume (V_N), total tumor volume (V_T+N), and the number of involved primary tumor sites and lymph node regions, particularly LN-related features. V_T and maximum LN diameter were independent predictors of baseline ctHPV DNA. Detectable follow-up ctHPV DNA was associated with inferior progression-free survival but showed low sensitivity and positive predictive value for relapse detection. Integrative stratification using baseline ctHPV DNA and V_T+N identified a potential high-risk subgroup with high tumor volume but paradoxically low ctHPV DNA (VOL^highDNA^low). Exploratory RNA-seq analysis was performed to investigate potential biological features underlying this discordance, and a seven-gene signature associated with PFS was identified. Conclusions: These findings suggest that baseline ctHPV DNA reflects tumor burden and may provide additional information for upfront risk stratification in HPV-positive OPSCC, warranting further validation in larger prospective cohorts. Full article

Background/Objectives: Human papillomavirus (HPV) is a well-established risk factor for oropharyngeal squamous cell carcinoma (OPSCC), with p16 expression serving as a reliable surrogate marker for HPV involvement and an important prognostic indicator. While data exist on the demographic and clinical features of p16-positive OPSCCs on a national scale, limited data exist for Nevada. Methods: This retrospective study evaluated the relationship between p16 positivity and OPSCC presentation in Northern Nevada, with specific attention to associations between p16 status, sex, socioeconomic factors, smoking history, and presenting symptoms. We reviewed medical records of 296 patients diagnosed with OPSCC with concomitant HPV testing at the Renown Regional Medical Center from 2014–2024. Variables of interest included sex, age at diagnosis, smoking pack-years, Nevada census-based income quintile, county of residence, and initial symptoms such as dysphagia and sore throat. Multivariate logistic regression was performed to assess associations between these variables and p16 status. Conclusions: We found that sex was the only variable significantly associated with p16 positivity: females had significantly lower odds of being p16-positive compared to males (OR: 0.36, 95% CI: 0.20–0.65, p = 0.001). This finding of sex-based disparity in HPV-related OPSCC is consistent with national trends. This study is limited by its regional focus and lack of data on other social determinants of health. Nonetheless, the results underscore the importance of gender-informed prevention strategies and highlight the need for further research into the biological and behavioral contributors to this disparity. Full article

Background/Objectives: Oral cavity squamous cell carcinoma (OSCC) remains a major global health burden, with outcomes strongly dependent on stage at diagnosis. Although the oral cavity is directly accessible to clinical examination, many cases are still detected at advanced stages. This narrative review aimed to summarize current trends in OSCC diagnosis and early monitoring, with emphasis on non-invasive and minimally invasive techniques and biomarkers. Methods: A semi-systematic narrative literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science using predefined combinations of OSCC-, early-detection-, imaging-, cytology-, liquid-biopsy-, salivaomics-, artificial-intelligence-, and biosensor-related terms. English-language systematic reviews, meta-analyses, reviews of reviews, translational studies, and clinically relevant original articles were prioritized, with explicit attention to oral cavity-specific evidence and clearly identified extrapolation from broader head-and-neck or oropharyngeal cancer settings. Results: Conventional oral examination and histopathological assessment of biopsy specimens remain the diagnostic foundation. Adjunctive methods may support lesion triage, biopsy-site selection, risk stratification, and early monitoring, but cannot replace tissue diagnosis. Narrow-band imaging, optical coherence tomography, and molecular brush cytology appear particularly promising for specialist assessment and surveillance. Liquid biopsy and saliva-based biomarker platforms offer translational potential, particularly for repeatable monitoring, but clinical implementation is limited by methodological heterogeneity, pre-analytical variability, inconsistent thresholds, and insufficient external validation. Artificial intelligence and biosensor platforms remain promising but largely developmental. Conclusions: Progress in early OSCC diagnosis and monitoring will most likely depend on integrated diagnostic models combining clinical examination, adjunctive imaging, minimally invasive sampling, molecular biomarkers, and computational decision-support tools, validated in prospective multicenter studies. Full article

Background/Objectives: Human papillomavirus (HPV) is a well-established prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC); however, the short-term treatment response remains heterogeneous, particularly among HPV-positive patients. Given the high prevalence of malnutrition in head and neck cancer, this study examined whether baseline nutritional status, body composition and functional status were associated with early treatment response in OPSCC according to HPV status. Methods: A prospective observational multicenter cohort study of newly diagnosed OPSCC patients eligible for curative-intent treatment was conducted at three tertiary hospitals in Barcelona, Spain. Baseline assessments comprised anthropometry, computed tomography (CT)-based body composition at L3, functional performance tests, systemic inflammatory biomarkers and nutritional diagnosis by the Patient-Generated Subjective Global Assessment (PG-SGA). Early treatment response, assessed around 12 weeks post-therapy, was classified as complete remission (CR) or non-complete remission (NCR). Classification tree analyses were performed separately by HPV status. Results: Of 101 enrolled patients, 97 completed post-treatment assessment, of whom 51% were HPV-positive. Among HPV-positive patients, PG-SGA score was the main discriminating variable for early response within the classification tree model, with CR achieved in 74% of patients scoring <6 versus 33% of those scoring ≥6 (AUC 0.68, 95% CI 0.55–0.82). Conversely, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and age were the primary discriminating variables in HPV-negative patients (AUC 0.81, 95% CI 0.70–0.93). In both HPV subgroups, body composition and inflammatory markers were not retained in the analysis once nutritional and functional status were considered. Conclusions: PG-SGA-defined nutritional status was associated with early treatment response in HPV-positive patients, while functional status was the main variable retained in HPV-negative patients. These findings support the potential clinical value of standardized nutritional assessment in OPSCC and suggest that early identification of poor nutritional status or functional impairment may help refine supportive care planning at treatment initiation. Full article