The incidence of oropharyngeal squamous cell carcinoma (OPSCC) associated with infection by the human papillomavirus (HPV) continues to increase and 71% of OPSCC cases in the United States are HPV+. We have previously performed microRNA profiling of HPV+ vs HPV- OPSCC and identified miR-106b as significantly elevated in HPV+ cases (Miller et al., 2015; Am J Path 185:679-92 [1]). MicroRNA target prediction identified the gene PDCD1LG2 as a highly ranked target of miR-106b. This gene corresponds to the protein programmed cell death ligand 2 (PD-L2), a high affinity ligand for the programmed cell death protein 1 (PD-1) receptor on T-cells. The objective of this study was to evaluate PD-L2 expression in a panel of HPV+ and HPV- OPSCC tumors. Using tissues from two distinct patient cohorts, results show significantly lower PD-L2 protein expression levels in HPV+ tumors. These data suggest that future research on regulation of PD-L2 expression in HPV+ OPSCC is warranted.
Background Cases of oral squamous cell carcinoma (OSCC) with mandibular invasion have traditionally been considered indications for surgical resection because definitive radiotherapy has been associated with suboptimal tumor control and a substantial risk of osteoradionecrosis (ORN). Structural bone recovery after high-dose irradiation has generally been considered unlikely. Case presentation We report three cases of advanced OSCC with mandibular invasion treated with definitive chemoradiotherapy (CRT) incorporating a proton beam boost and super-selective intra-arterial chemotherapy (IAC). All three patients achieved a complete response and local control; however, one died of distant metastatic disease. Serial imaging demonstrated progressive mandibular bone repair, including cortical restoration and trabecular bone recovery, without clinical or radiographic evidence of ORN during long-term follow-up. Discussion These findings suggest that tumor-induced mandibular destruction may undergo structural recovery following successful definitive CRT, even when the mandible is included within the high-dose treatment volume. Durable tumor control, preservation of regional vascularity, infection control, and residual osteogenic capacity may have contributed to re-ossification. In addition, the conformal dose distribution achieved with proton beam therapy and optimized super-selective intra-arterial chemotherapy may have supported local tumor control and bone repair. However, because this report is a small retrospective case series without quantitative imaging assessment or histopathological confirmation, these findings should be interpreted cautiously and require validation in larger studies. Conclusion Radiologic mandibular re-ossification may occur in selected patients with mandibular-invasive OSCC after definitive CRT incorporating a proton beam boost and super-selective IAC.
Oral mucositis (OM) is a common, severe, and dose-limiting toxicity of radiotherapy and chemotherapy, particularly in patients with head and neck malignancies or those undergoing hematopoietic stem cell transplantation. Affecting up to 80–100% of irradiated patients and approximately 40% of those receiving conventional chemotherapy, OM is characterized by painful inflammation and ulceration of the oral mucosa, leading to impaired nutrition, increased infection risk, prolonged hospitalization, life-long dental disease, treatment interruptions, and substantial healthcare costs. Despite its high prevalence and clinical burden, effective preventive and therapeutic options for OM remain limited.At the molecular level, OM pathogenesis is initiated by excessive generation of reactive oxygen species (ROS) resulting from radiolysis of water during radiation exposure and metabolic stress induced by cytotoxic chemotherapy. These ROS drive oxidative stress, DNA damage, lipid peroxidation, activation of proinflammatory transcription factors within epithelial and immune cells (macrophages, neutrophils) such as NF-κB, and amplification of cytokine signaling, culminating in epithelial barrier breakdown and ulceration. Emerging evidence suggests that the angiotensin II (Ang II)/angiotensin type 1 receptor (AT1R) axis may further exacerbate mucosal injury by stimulating NADPH oxidase (NOX)–dependent ROS production, thereby amplifying redox imbalance and inflammatory signaling.This review synthesizes current understanding of oxidative stress and the Ang II/AT1R–NOX pathway in mucositis pathobiology and evaluates therapeutic strategies targeting these mechanisms. We highlight preclinical evidence supporting the antioxidant Tempol, a superoxide dismutase mimetic that scavenges ROS, and angiotensin receptor blockers (ARBs), which attenuate upstream NOX activation. We propose a dual-targeting model in which concurrent suppression of ROS generation and neutralization of accumulated oxidants may more effectively mitigate oral mucosal injury than single-pathway interventions.Collectively, targeting oxidative stress and its upstream amplifiers represents a promising, mechanism-based approach for preventing and treating oral mucositis. Further mechanistic studies and well-designed clinical trials are warranted to validate this strategy and translate these insights into improved supportive care for patients undergoing mucosal toxic cancer therapies.
Purpose Bucco-facial nodes are at risk of harboring metastases from mucosal cancers of the skin, nose, maxillary sinus, and buccal mucosa. The incidence of level IX involvement is not well established but likely below 10%. This multicenter study aims to evaluate the incidence of metastases to level IX and its subgroups and assess its impact on target volume delineation. Materials and methods A search for eligible patients was conducted using the Aria, Mosaiq, and Redcap databases. We included patients with cancer of buccal mucosa, retromolar trigone, oral gum, nasal cavity, nasal vestibule, and paranasal sinuses. Clinical history, imaging (CT, MRI, [18F]-FDG PET), and pathology reports were reviewed. Facial nodes were classified according to Rouvière's anatomical subgroups. Results Among 102 patients (66 men, 36 women; median age 74), level IX metastases were identified in 7 cases (6.8%). Two cases were diagnosed histopathologically in patients without preoperative imaging evidence: one retromolar trigone and one buccal mucosa tumor. Five cases were identified clinically: one nasal vestibule tumor, three retromolar trigone tumor, and one buccal mucosa tumor. No cases originating from the nasal cavity or paranasal sinuses were found. The level IX subgroups involved were: supramandibular alone (n = 2), supramandibular + buccinator (n = 3), buccinator alone (n = 1), and infraorbital alone (n = 1). Conclusion Although rare, facial node metastases are clinically relevant in advanced or recurrent retromolar trigone, buccal mucosa and nasal vestibule cancers. Based on our data, a subclassification of level IX into IXa (supramandibular and buccinator) and IXb (infraorbital) is proposed.
Background Parotid gland adenocarcinomas are rare malignant tumors within the broader group of salivary gland carcinomas, accounting for 3% to 6% of head and neck cancers. BRAF mutations are exceptionally rare in this histology, and evidence supporting BRAF-targeted therapy remains limited to isolated case reports. Case presentation We report a 60-year-old man with de novo metastatic parotid adenocarcinoma harboring a BRAF V600E mutation (FoundationOne CDx; no NTRK, ALK, ETV6, KRAS, or NRAS alterations), diagnosed and managed at Nord Franche-Comté Hospital, France. Following sequential failure of paclitaxel-carboplatin-denosumab, androgen deprivation therapy, and epirubicin-cyclophosphamide, and after the onset of leptomeningeal carcinomatosis, fourth-line combined BRAF/MEK inhibition with dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) achieved a complete metabolic response on paired 18F-FDG PET/CT at 3 months, with disease control maintained for 8 months. The patient died 19 months after diagnosis, providing a complete clinical course with a defined final endpoint. Conclusions To our knowledge, this is the first reported parotid adenocarcinoma achieving a PET-confirmed complete metabolic response to dabrafenib-trametinib, notably in the fourth line setting after leptomeningeal progression. This observation supports systematic BRAF V600E testing in advanced salivary gland carcinomas and reinforces the rationale for tumor-agnostic BRAF/MEK inhibition in this rare molecular subset.
Objectives To assess the relationship between radiographically identified sarcopenia and posttreatment swallowing function in patients undergoing primary resection and free flap reconstruction for squamous cell carcinoma of the oral cavity. Materials and methods Skeletal muscle area was measured at the C3 level using computed-tomography scans of the head and neck in 54 patients with squamous cell carcinoma of the oral cavity. Sarcopenia was assessed using sex-specific cutoffs for skeletal muscle index. Posttreatment swallowing outcomes were assessed using the Functional Oral Intake Score. Results Skeletal muscle index was negatively correlated with age-at-surgery (p = 0.0231). Preoperative sarcopenia was present in 44.4% (24/54) of patients. Patients with normal swallowing function had significantly higher skeletal muscle indices before surgery, compared to patients with swallowing impairment (p = 0.0245). In patients younger than 65 years old, skeletal muscle indices were significantly less in those that required tube feeds at their 6-month postoperative swallowing evaluation, compared to those who did not (p = 0.0241). Sarcopenia status was not associated with functional differences in gastrostomy tube requirement, tracheostomy requirement, time before oral intake, or survival with mean follow-up of 31.7 months. Conclusion Skeletal muscle status may have a prognostic and functional impact on patients with oral cavity squamous cell carcinoma. Pretreatment skeletal muscle index is associated with swallowing function at the time of evaluation and with feeding tube reliance after surgery on univariate analysis. Future assessments of sarcopenia should incorporate functional assessments in addition to radiographic assessments for better prognostic utility.
Background Accurate staging of the clinically node-negative neck remains a major challenge in clinically early-stage (cT1–T2N0) oral tongue squamous cell carcinoma (OTSCC). Sentinel lymph node biopsy (SLNB) has emerged as a less invasive alternative to elective neck dissection (END), the feasibility and diagnostic accuracy of methylene blue dye as a single tracer remain inadequately defined. Methods This prospective study included 51 patients with cT1–T2N0 OTSCC. All patients underwent SLNB using methylene blue dye as a single tracer, followed by ispilateral selective neck dissection of levels I–III. Sentinel lymph nodes (SLNs) were assessed intraoperatively by frozen section and definitive histopathology. Histopathological findings from the neck dissection specimen served as the reference standard. Diagnostic performance parameters of SLNB were calculated. Results SLNs were successfully identified in all patients, resulting in a 100% identification rate. The mean number of SLNs harvested per patient was 2.18 ± 1.46, most commonly located at level IIA. Occult cervical metastasis was detected in 9 patients (17.6%). SLNB correctly identified 8 of 9 patients with nodal metastasis and 42 of 42 node-negative patients. One false-negative case was observed, while no false-positive results occurred. Accordingly, SLNB demonstrated a sensitivity of 88.9%, specificity of 100%, positive predictive value of 100%, negative predictive value of 97.7%, and overall diagnostic accuracy of 98.0%. Increasing depth of invasion was significantly associated with cervical nodal metastasis (p = 0.019). Conclusions Methylene blue-guided SLNB was feasible and showed a high negative predictive value in this cohort of clinically early-stage (cT1–2N0) oral tongue squamous cell carcinoma. Depth of invasion was significantly associated with cervical nodal metastasis. Larger multicenter studies with standardized pathology protocols and long-term follow-up are needed before this approach can be recommended more broadly.
Neutrophil to lymphocyte ratio (NLR) is an inflammatory index with prognostic value in a variety of solid tumors. It is easily derived from routine blood tests, and elevated ratios have shown association with poor outcomes in several settings. However, the association of NLR with response to neoadjuvant PD-1 inhibitors in head and neck squamous cell carcinoma remains unclear. We performed a hypothesis-generating receiver operating characteristic (ROC) analysis of 42 patients to explore associations between pathologic response to neoadjuvant nivolumab and: (1) baseline pre-treatment NLR, (2) on-treatment NLR, and (3) percent change in NLR between these two time points. Percent change in NLR demonstrated the highest area under the curve (AUC) for major pathologic response (0.67, 95% CI: 0.47–0.87) and partial response (0.65, 95% CI: 0.48–0.82), though these findings were not statistically significant. A >22.1% increase in NLR from baseline was associated with failure to achieve major or partial pathologic response, with specificity of 0.82 (95% CI: 0.67–0.92) and sensitivity of 0.58 (95% CI: 0.25–0.84), though again findings were not statistically significant. These exploratory results warrant validation in larger cohorts.
The critical function of the lymphatic system is to support tissue homeostasis through clearance of interstitial fluid. Lymphatic drainage from the head and neck tissues converges at the cervical lymphatic system, the central gateway through which lymph enters the peripheral blood. Surgical resection of neck lymph nodes and destruction of lymphatics by radiotherapy impedes lymph clearance, and the accumulation of metabolic waste and inflammatory cells affects the physiological function of various tissues dependent on neck lymphatics for drainage. Unlike breast cancer, lymphedema in head and neck cancer patients is under-reported due to the complexity of its presentation and limited standardized diagnostic instruments. For this review, the PubMed, Embase, and Cochrane Library databases were searched from inception to December 2025 using the combination of terms “head and neck lymphedema” and “cancer”, and the results were curated based on evidence and clinical relevance. This review integrates our current understanding of head and neck lymphedema (HNL), including pathophysiology, disease staging, assessment tools, current management and promising treatment advances, and emerging evidence of potential adverse effects on distant tissues of the head and neck. The impact of lymphedema on cutaneous and mucosal structures as well as other head and neck tissues increases the burden on the patient's quality of life. Head and neck oncologists are uniquely positioned to detect early lymphedema changes and direct care for timely multidisciplinary interventions to mitigate pathological progression to irreversible tissue changes.
Objectives To assess the synergistic impact of radiotherapy-induced xerostomia and dysphagia on malnutrition in Greek Head and Neck Cancer (HNC) survivors compared with matched controls, and to psychometrically validate the Greek version of the MD Anderson Dysphagia Inventory (MDADI). Materials and methods A cross-sectional, case-control study was conducted with 66 HNC patients (3 months post-RT) and 67 age- and sex-matched healthy controls (Oct 2024–Apr 2025). The study adhered to STROBE guidelines (Ethics No. 37871). Participants completed the MDADI, Xerostomia Inventory (XI), and PG-SGA Short Form. Statistical analyses included Cronbach's alpha for validation, Mann–Whitney U tests, Spearman's ρ, multivariable logistic regression, and Receiver Operating Characteristic (ROC) curve analysis to determine diagnostic accuracy. Results The Greek MDADI demonstrated excellent internal consistency (α = 0.92) and discriminant validity (Patients: 61.0 vs. Controls: 83.0, p < 0.001). Xerostomia and dysphagia were highly prevalent and strongly correlated (ρ = −0.69, p < 0.001). In the multivariable model, dysphagia emerged as the sole independent predictor of malnutrition (OR = 0.86, 95% CI: 0.77–0.95, p = 0.004), indicating a 14% risk reduction for every 1-point improvement in MDADI. ROC analysis identified an MDADI score of <53 as the optimal cutoff for detecting malnutrition risk (AUC = 0.78, Sensitivity 55%, Specificity 93%). Conclusions Dysphagia is the primary driver of malnutrition in the early post-RT period. The Greek MDADI is a valid clinical tool, and a score below 53 should serve as a "red flag" triggering immediate nutritional and speech-pathology intervention. Integrated management of the xerostomia-dysphagia-malnutrition cluster is essential for survivorship care.
Rationale and objective The worst pattern of invasion (WPOI) has been in the last few years a highly studied pathological parameter. There is a clear trend of non-cohesive WPOI (4-5) to be highly aggressive and to affect outcomes negatively. The aim of this study was to investigate the link between WPOI and other clinicopathological parameters which are the lymph node metastasis (LNM), depth of invasion (DOI) and tumor size (TS). Methods This was a retrospective cohort study. The patients enrolled in the study were diagnosed with oral squamous cell carcinoma (OSCC) and underwent treatment at the Department of Stomatology, Oral and Maxillofacial Surgery at University Hospital Ibn Rochd (CHU 20th August). The exposure variable was the Worst Pattern of Invasion (WPOI) The outcome variables were LNM, DOI and TS. All statistical analysis was conducted using JASP version 0.19.3.0. Results A total of 33 patients were included in the study. The mean age was 65.1 years and the sample showed a clear male predominance. The relationship between WPOI and LNM was examined using a chi-squared test. Among patients with non-cohesive WPOI, 6 out of 13 (46.2%) had LNM, compared to 4 out of 20 (20%) in the cohesive WPOI group. Although the percentage of LNM was higher in the non-cohesive group, this difference was not statistically significant (X2(1) = 2.552,p = 0.110). An independent samples t-test was performed to assess the relationship between WPOI and DOI. The mean DOI was greater in the non-cohesive group (12.54 mm, SD = 8.09 mm) compared to the cohesive group (8.80 mm, SD = 5.69 mm). This difference, however, was not statistically significant (t(31) = −1.562,p = 0.129). The relationship between WPOI and TS was analyzed using an independent samples t-test. Interestingly, the mean TS was larger in the cohesive group (42.60 mm, SD = 26.39 mm) than in the non-cohesive group (32.08 mm, SD = 10.63 mm). This difference was also not statistically significant (t(31) = 1.361,p = 0.183). Conclusion Although the results weren't statistically significant, they should be put into the broader context of the study sample size of (n = 33). The higher incidence of LNM and higher DOI in the non-cohesive group (types 4-5) is in line with the strong correlation found in the literature. Our results, while not statistically significant, corroborate the established link between non-cohesive WPOI and more aggressive disease.
Background Minichromosome maintenance (MCM) proteins play a vital role in cell cycle progression. The MCM 5 protein is one of the key proteins that binds to Chromatin in a cell cycle dependent manner and restricts the replication of the chromosome to only one round per cell cycle. Objectives To evaluate the role of MCM5 in the biological behavior of Oral Cavity Squamous cell carcinomas of patients from a tertiary care centre. Method This study evaluated the immunohistochemical expression of MCM-5 protein in primary oral squamous cell carcinomas(n = 90). Formalin Fixed Paraffin Embedded tissue (FFPE) sections of the tumors were immunhistochemically stained with the monoclonal antibody MCM-5 (EP-84, Pathnsitu, Livermore, CA, USA). The correlation between the expression of MCM5 and clinico-pathological features of the dysplastic lesions and oral squamous cell carcinoma tumors was analysed. The association between the expression of MCM5 and patient outcomes was also evaluated. Results The mean nuclear MCM5 LI for the 90 cases of OSCC ranged from 0 to 90 (mean 52.88 +- 2.084). A higher mean nuclear MCM5 LI was associated with the higher histological tumor grade (p = 0.002). Tumors of an advanced clinical stage had a higher mean nuclear MCM5 LI compared to tumors of an early clinical stage (p = 0.039) Conclusions The MCM-5 protein is a key molecule that is altered during the carcinogenic process of squamous cell carcinomas of the oral cavity. A higher expression of MCM5 is indicative of aggressive tumor behaviour of oral cavity squamous cell carcinomas.
Clinically significant oral mucositis (OM) is a frequently reported toxicity of TROP-2 directed ADCs containing a topoisomerase inhibitor payload, such as datapotamab deruxtecan (Dato-DXd). It seems likely that the mechanism underlying this important toxicity is consistent with the established biological cascade associated with other cytotoxic regimens and a consequence of the expression of TROP-2 on normal oral mucosa. Since it is probable that the biological processes underlying TROP-2 ADC induced OM are distinct from the inflammatory pathogenesis of stomatitis caused by mTOR inhibitors (mIAS), a rational interventional strategy which recognizes these different biological targets is critical for developing effective prevention and treatment.
Background Adenomatoid odontogenic tumor (AOT) is a rare benign epithelial odontogenic tumor that typically occurs in young females and is most often associated with an impacted maxillary canine. Although usually managed via transoral enucleation, endoscopic endonasal surgery has emerged as a potential alternative for selected lesions. Case Presentation A 25-year-old woman presented with progressive right-sided nasal obstruction and clear rhinorrhea. Nasal endoscopy revealed a smooth submucosal bulge arising from the right inferior meatus that filled the right nasal cavity. Computed tomography demonstrated a well-defined expansile lesion occupying the right maxillary sinus, containing internal calcifications and an impacted canine tooth. The tumor was completely removed using an endoscopic endonasal approach. Histopathology confirmed the diagnosis of AOT. At the 18-month follow-up, endoscopic examination showed complete healing without recurrence. Discussion Endoscopic endonasal surgery offers advantages over transoral approaches in selected cases, including improved visualization, avoidance of oroantral complications, absence of external incisions, and suitability for large maxillary sinus lesions. Conclusion This case demonstrates the feasibility of complete AOT removal using an endoscopic endonasal approach. Further reports with long-term follow-up are required to clarify indications and outcomes for this technique.
Background Receptor tyrosine-protein kinase erbB-3 (HER3) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and is typically associated with chemotherapy resistance and poor prognosis. However, the dynamics of HER3 expression following induction chemotherapy (ICT) remain poorly understood, and its impact on the tumor immune microenvironment (TIME) is largely unknown. Methods We analyzed 98 patients with locally advanced HNSCC who received ICT between 2012 and 2020. HER3 immunohistochemistry (IHC) was performed using the D22C5 clone on formalin-fixed paraffin-embedded specimens collected pre- and/or post-ICT. HPV status was determined for all samples. Compositional changes in immune cell subsets within the tumor and peritumoral areas were evaluated via multiplex IHC. Results The cohort (mean age: 62.9 years; 83.3% male) predominantly presented with stage III or IV disease (97.2%). The oropharynx was the most common primary site (66.7%), with 52.8% of patients being HPV-positive. High HER3 expression (H-score >100) strongly correlated with HPV positivity (p=0.005), particularly within oropharyngeal tumors (p=0.003). The objective response rate (ORR) to ICT was higher in the HER3-high group compared to the HER3-low group (87% vs. 69%; p=0.090), a trend consistent with HPV status (p=0.090). In 16 paired samples, HER3 expression increased post-ICT, most notably among smokers. Patients with high HER3 expression tended to have longer relapse-free survival and improved overall survival (76.3 vs. 42.4 months; p = 0.168) compared to those with low HER3 expression. At baseline, the tumor immune microenvironment (TIME) of HER3-high tumors was significantly enriched with CD4+FoxP3+ regulatory T cells (Tregs), compared to HER3-low tumors (p=0.032). Post-ICT, HER3-high tumors exhibited a marked depletion of Tregs (p=0.019), while CD8+ cytotoxic T cells increased significantly across all groups (p<0.01). Finally, external validation using TCGA-HNSCC database confirmed that HER3 mRNA expression is positively associated with Tregs enrichment, independent of HPV status. Conclusion High HER3 expression in HNSCC is significantly associated with HPV positivity and predicts favorable clinical outcomes following ICT. Our findings suggest that ICT modulates the TIME by depleting immunosuppressive CD4+FoxP3+ Tregs specifically in HER3-high tumors while simultaneously recruiting immunostimulatory CD8+ T cells regardless of HER3 expression. This shift potentially converts an immunosuppressive environment into an immunostimulatory one.
Background Artificial intelligence (AI) is increasingly integrated into pathology, but its accuracy in immunohistochemical (IHC) marker selection remains underexplored. This study evaluated LeChat's ability to recommend IHC markers for benign and malignant salivary gland tumors, focusing on accuracy, completeness, relevance, consistency, and marker-level errors across tumor types and subtypes. Methods A total of 21 tumor types were selected and classified by behavior (benign vs. malignant) and histologic subtype. Expert-derived reference panels served as the gold standard. For each tumor, LeChat was queried three times using standardized prompts. Recommendations were scored across three domains: accuracy (inclusion of essential markers), completeness (inclusion of secondary markers), and relevance (absence of irrelevant markers). Composite scores (range: 3–9) and intra-tumor variability were calculated. Mann–Whitney U and Kruskal–Wallis tests assessed differences by tumor category and subtype. Marker-level analysis evaluated over- and under-recommendations. Results Across 63 total prompts, LeChat achieved a mean accuracy of 1.56, completeness of 1.59, and relevance of 2.35. Only 3.2 % of prompts included all essential markers, and 17.5 % achieved composite scores ≥7. No responses included both primary and secondary markers. Performance did not differ significantly between benign and malignant tumors (p = 0.405), nor across histologic subtypes (p = 0.988). Tumor-level variability was highest for basaloid squamous cell carcinoma and lowest for pleomorphic adenoma. Marker-level analysis identified 14 false positives (e.g., CD20, IgG4) and 9 false negatives (e.g., SOX10, β-catenin). A moderate correlation was observed between marker frequency and accuracy (r = 0.48, p < 0.01). Conclusion LeChat's IHC recommendations were generally relevant but frequently incomplete and inconsistent, particularly for malignant and histologically complex tumors. Despite its potential for assisting in straightforward cases, current performance remains inferior to expert standards. These findings highlight the limitations of general-purpose LLMs in pathology workflows and emphasize the need for domain-specific refinement before clinical integration.
