BackgroundCurrent treatment options for nonmetastatic laryngeal squamous cell carcinoma include radiotherapy, chemoradiotherapy, and surgery, which can result in significant morbidity. This study reports the 20‐year outcomes of a single‐modality chemotherapy as a larynx preservation strategy in patients with stage II–IVa laryngeal squamous cell carcinoma (LSCC).MethodsIn this single‐institution, single‐arm, prospective clinical trial, 31 patients with stage II–IVa LSCC received three or four cycles of paclitaxel, ifosfamide, and a platinum agent (TIP). Patients with a pathologic complete response (pCR) by biopsy assessment received three additional cycles without local therapy. Patients with a partial response underwent conservation laryngeal surgery (CLS). The primary end point was 2‐year larynx preservation rate (LPR). Secondary end points included recurrence‐free survival (RFS), overall survival (OS), and long‐term complications.ResultsWith a median follow‐up time of 21 years, 11 patients (35%) achieved a pCR and were managed with chemotherapy alone. None required laryngectomy, and only one experienced recurrence, which was successfully salvaged with radiotherapy. Among 19 patients who underwent CLS or radiotherapy, seven experienced recurrence and six required laryngectomy. The 20‐year LPR was 72%; median OS was 13.5 years, and median RFS was 10.3 years. Patients with a pCR had significantly fewer long‐term complications, including lower rates of feeding tube and tracheostomy dependence (p < .01).ConclusionsThis long‐term follow‐up reinforces that TIP alone is an effective larynx preservation strategy in patients with LSCC who achieve a pCR. Further investigations of systemic therapy for laryngeal cancer treatment, including less toxic combinations and immunotherapy as well as incorporating tissue‐ and blood‐based biomarkers, are warranted.

Smoking-associated laryngeal squamous cell carcinoma (LSCC) is characterized by high metastatic potential and poor prognosis. However, the underlying molecular mechanisms remain insufficiently understood. This study utilized single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to explore the heterogeneity of the tumor microenvironment in smoking-associated LSCC. Thirteen distinct cellular subpopulations within the tumor microenvironment are identified, with STC2 and ITGA5 emerging as smoking-associated prognostic markers. STC2 exhibited bifurcated differentiation within tumor epithelial cells, categorized as Tumor_C1 and Tumor_C2. The two subtypes are linked to vascular permeability and DNA replication pathways, respectively. Mechanistically, nicotine activated the JAK2/STAT3 signaling pathway through CHRNA5, resulting in direct STAT3 binding to the STC2 promoter and modulation of its transcription. STC2 subsequently upregulated TGFBI, which interacted with ITGA5 on endothelial cells, regulating vascular permeability and facilitating hematogenous dissemination of LSCC cells. Furthermore, STC2 knockdown altered F-actin cytoskeletal dynamics by modulating small GTPase signaling, impairing filopodia formation and epithelial polarity restoration. This study elucidates the tumor-endothelial interactions mediated by STC2 and ITGA5 in smoking-associated LSCC, emphasizing their roles in tumor progression and vascular permeability. These findings suggest potential prognostic biomarkers and therapeutic targets to improve the clinical management of smoking-associated LSCC.

Laryngeal squamous cell carcinoma (LSCC) is a significant subtype of head and neck cancers, with tobacco and alcohol being primary risk factors. Many studies have shown that human endogenous retroviruses (HERVs), specifically HERV-K and HERV-H, have been implicated in the development and progression of various cancers, including head and neck cancers; nevertheless, there is a lack of research on the expression levels of HERV-K and HERV‐H in LSCC. In this research, the differential expression of HERV-K Rec, Env, Np9, and HERV-H pol transcripts was assessed in 144 laryngeal biopsy specimens (72 polyps and 72 LSCC samples) utilizing quantitative Real‐time PCR. The results showed a significant upregulation of HERV-K Env and HERV-H pol in the LSCC group compared to the polyp group (p < 0.001), suggesting their potential role in LSCC progression. The ROC curve analysis further supported the diagnostic significance of HERV-H pol and HERV-K Env transcripts in distinguishing LSCC from noncancerous polyps (HERV-H pol: AUC = 0.86; HERV-K Env: AUC = 0.76). Moreover, being over 50 years old and having an opium addiction were linked to increased expression levels of HERV-H Pol and HERV-K Env, suggesting a potential connection between these elements and laryngeal cancer (p < 0.001). These results highlight the possible utility of HERV-H pol and HERV-K Env as biomarkers for the diagnosis and prognosis of LSCC. Undoubtedly, additional research is imperative to establish the clinical efficacy of these biomarkers.

Despite evidence linking histone lactylation to tumorigenesis, its specific regulatory role in laryngeal squamous cell carcinoma (LSCC) is still not well defined. Histone H3K18 lactylation (H3K18la) levels in LSCC tissues were analyzed by immunohistochemistry (IHC) and western blot, showing significantly higher levels than non-tumor tissues. Treatment with the sodium oxamate (SO) effectively reduced H3K18la level, thereby suppressing LSCC cell proliferation and migration while inducing apoptosis. Mechanistically, H3K18la upregulated Runt-related transcription factor 2 (RUNX2) expression, which in turn activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway to promote aggressive LSCC phenotypes. Our findings demonstrate that H3K18la facilitates LSCC progression by enhancing malignant cellular behaviors, thereby offering potential therapeutic targets for LSCC intervention.

Association of duffy antigen receptor for chemokines with clinical conditions: A scoping review

SERPINH1 promotes malignant progression of laryngeal squamous cell carcinoma via COL7A1-mediated Wnt/β-catenin signaling.

Prognostic impact and risk factors of level IV/V lymph nodes metastasis in laryngeal squamous cell carcinoma.

Abstract Background Histopathological markers may facilitate disease prognosis and patient-specific treatment. The aim of this study is to evaluate tumor budding and other histopathological markers in laryngeal squamous cell carcinoma. This is a retrospective descriptive analysis of the histopathology of 116 patients with primary squamous cell cancer of the larynx. We reviewed the tumor budding score, degree of differentiation, lymphovascular and perineural invasion, stromal and host lymphocyte response, and depth and pattern of invasion. The outcomes were lymph node metastasis and disease-specific survival. Results The average age of the patients was 64.95 ± 9.92 years, 94.0% were male, and 71.55% had advanced disease (T3 and T4). Most patients (84.5%) had a negative clinical nodal stage, 58.6% underwent neck dissection, 24.1% had a positive histopathological nodal stage, and 22 patients (18.1%) had regional recurrence, bringing the total of regional metastasis to 36.2% ( n = 42). Immunohistochemistry increased the observed budding activity. High budding activity &gt;5/high-powered field was associated with advanced T stages, lymph node metastasis, and depth of invasion &gt;5 mm. Conclusion Tumor budding and depth and pattern of invasion may be prognostic factors in laryngeal squamous cell cancer. Further research is needed to determine whether they may be evaluated in biopsy material.

Over activation of c-MYC oncogene (gene locus: 8q24.21) - predominantly due to the amplification of the gene - is a critical genetic imbalance involved in malignant transformation of normal epithelia. Our aim was to explore the differences in c-MYC protein expression in a series of laryngeal (LSCC) and hypopharyngeal squamous cell carcinomas (HPSCCs). We retrospectively analyzed a set of sixty (n=60) paraffin embedded laryngeal-hypopharyngeal squamous cell carcinomas (L-PHSCC) tissue sections by immunocytochemistry (IHC) for the detection of c-MYC protein expression. A digital image analysis (DIA) algorithm was also performed for measuring objectively the corresponding immunostaining intensity levels of the examined protein. The correlation of c-MYC protein expression levels with various clinicopathological characteristics was assessed. High and moderate staining intensity levels of c-MYC protein expression were identified in 46/60 (76.6%) of the examined cases (21/60 and 25/60, respectively), whereas the rest of them demonstrated low expression values (14/60, 23.4%). c-MYC expression was significantly correlated with the anatomic location of the malignancies (p=0.03), with the stage of the disease (p=0.004), as well as with the grade of differentiation (p=0.049). Interestingly, c-MYC diffuse nuclear/cytoplasmic expression was observed mainly in advanced-stage carcinomas. c-MYC overexpression is a common feature in L-HPSCCs, mainly due to c-MYC oncogene overactivation. Increased levels of nuclear and diffuse cytoplasmic c-MYC protein are associated with aggressive phenotypes in patients with L-HPSCCs. Given the emerging interest in oncogene-targeted therapies in modern oncology, identifying patients with distinct c-MYC genetic, epigenetic, and proteomic signatures represents a promising strategy for personalized treatment approaches.

ObjectiveNeddylation is a crucial posttranscriptional modification involved in tumor progression. This study aimed to explore neddylation-associated biomarkers and the underlying mechanism in laryngeal squamous cell carcinoma (LSCC).MethodsThis study evaluated the expression of neddylation-related genes (NRGs) retrieved from the Reactome and TCGA databases to conduct a series of analyses and constructed an LSCC prognostic risk model followed by functional enrichment and mechanism prediction. Moreover, the key genes involved in this signature were also confirmed in an in vitro cell model.ResultsA total of 79 NRGs were differentially expressed in LSCC (P.adj <0.05). A prognostic gene signature was constructed, and COMMD2, WSB2 and CUL9 were determined to be prognostic genes. The nomogram indicated that this gene signature performed well in forecasting the 1-, 3-, and 5-year overall survival of LSCC patients. The CUL9 and WSB2 genes were enriched in RIBOSOME, and silencing WSB2 significantly inhibited the malignant behaviors of LSCC cells. In this gene signature, patients could be markedly distinguished into high- and low-risk groups characterized by different immune infiltration and drug sensitivity between them. WSB2 and COMMD2 jointly predicted that hsa-miR-185-5p, hsa-miR-4644 and hsa-miR-4306 were the common microRNAs (miRNAs) and regulatory networks.ConclusionThis study successfully established a neddylation-associated prognostic risk model for LSCC and revealed that COMMD2, WSB2, and CUL9 could act as new therapeutic targets, which might provide valuable information for the research and treatment of LSCC.

Disclosure: I.E. Hernandez Castro: None. E.J. Sola Sanchez: None. M.M. Mangual Garcia: None.Head and neck squamous cell carcinoma (SCC) have predilection for cervical lymph node metastasis, with the lungs, mediastinum, bone, and central nervous system being the most common metastatic sites. Thyroid metastases from laryngeal SCC are rare. Differentiating primary thyroid malignancies from metastases is crucial for treatment and prognosis. We present a case of SCC metastases to the thyroid, which could have been mistaken for a poorly differentiated thyroid carcinoma. A 75-year-old male, former smoker, with a 55 pack-years history that quit 20 years ago, and laryngeal carcinoma (diagnosed in 2022) was treated with radiotherapy and chemotherapy, followed by total salvage laryngectomy and subtotal thyroidectomy in 2024. The patient was referred to our endocrinology clinic at San Juan City Hospital for uncontrolled hypothyroidism (TSH 43mIU/L), for which levothyroxine therapy was initiated. Preoperative imaging did not reveal any thyroid lesions. A post-surgical thyroid ultrasound (2024) revealed a solid, hypoechoic left thyroid nodule of 1.8 x 1.3 x 1.7 cm measurements without calcifications or other suspicious features. Fine-needle aspiration cytology (FNA) reported Bethesda VI: malignant and poorly differentiated carcinoma, with findings highly suggestive of SCC. Immunohistochemistry (IP25-17) was negative for TTF-1, favoring a non-thyroidal origin. A PET CT scan is pending to evaluate for additional metastatic disease and guide therapeutic management. Thyroid metastases from SCC are rare, with laryngeal cancer as an unusual primary source. Most secondary thyroid malignancies arise from renal, lung, or breast cancer, making this case a unique diagnostic challenge. The absence of TTF-1 positivity supported metastatic SCC rather than primary thyroid malignancy. Given the patient’s history and pathological findings, the diagnosis of SC metastasis to the thyroid was established. Management options include surgical resection, systemic therapy, and palliative care, depending on metastatic burden. This case highlights the importance of distinguishing metastatic SCC from primary thyroid malignancies, as treatment strategies differ significantly. Endocrinologists should maintain a high index of suspicion for thyroid metastases in patients with a history of head and neck malignancies, particularly laryngeal SCC. No specific sonographic features have been described for metastatic SCC to the thyroid, and this pathology could also be mistaken for benign thyroid adenomas, further complicating the diagnosis. Further studies are needed to establish optimal management strategies for these rare cases.Presentation: Sunday, July 13, 2025

Disclosure: W. Lewis: None. N. Chan: None. A.R. Gosmanov: None.Background: Therapy of hyponatremia due to syndrome of inappropriate antidiuresis (SIAD) in ambulatory setting can be challenging due to difficulties in persistent adherence to fluid restriction and lack of standardized pharmacological approaches aiming to restore sodium homeostasis. In complicated cases when conventional strategies are exhausted, correction of hyponatremia in such patients may require additional measures. In this regard, there is early evidence that off-label use of SGLT-2 inhibitors added to maximal fluid restriction measures can modestly improve serum sodium (SNa) in SIAD patients. Clinical presentation: A 67-yo Caucasian male with history of laryngeal and esophageal squamous cell carcinoma in remission, hypothyroidism, and a 40-year smoking history was referred to endocrinology clinic for evaluation of chronic hyponatremia. Patient was known to have chronically mildly reduced SNa levels in 130-134 (135-145 mEq/L) range; however recent assessments in primary office showed unexplained SNa decrease to 122 mEq/L. In endocrinology clinic, weight was 69.5 kg, blood pressure was 152/78 mmHg, he was euvolemic on examination and not on medications that could affect SNa. Extensive laboratory evaluation revealed serum osmolarity of 279 (275-295 mOsm/kg), uric acid of 4.0 (3.5-7.8 mg/dL), serum cortisol at 8am of 16.4 (5-25 mcg/dL) and normal renal function, fasting glucose, lipid profile, liver tests and TSH along with spot urine Na of 46mEq/L and osmolarity 390 (350-900 mOsm/kg) suggesting that patient`s hyponatremia was due to SIAD. As prior recommendations to restrict fluid intake were not successful, we initiated oral NaCl 1g twice daily and furosemide 20mg daily and re-enforced the importance of fluid restriction. During follow up in 10 weeks, his SNa had not changed. In the setting of no meaningful improvements in SNa and emergence of new data showing modest therapeutic effects of SGLT-2 inhibitors in mild-to-moderate hyponatremia SIAD cases, we initiated empagliflozin 25 mg daily. Within one-week SNa increased from 125 to 127 mEq/L and to 137 mEq/L over 6 months period. This allowed us to initiate graded taper of NaCl and furosemide resulting in complete discontinuation of both medications over next 9 months while maintaining SNa in 134-136 mEq/L range with corresponding measured serum osmolarity in 279-294 mOsm/kg range. He remains eunatremic on empagliflozin monotherapy. SGLT-2 inhibitor adherence was confirmed by pharmacy records and periodic monitoring of urinalysis that showed marked glucosuria. Empagliflozin use did not lead to any adverse effects. Conclusion: SGLT-2 inhibitors can improve SNa level in SIAD by promoting electrolyte-free water excretion while preserving solute balance. This case highlights potential utility of empagliflozin and SGLT-2 inhibitors in general as an adjunct therapy in patients with refractory hyponatremia due to SIAD.Presentation: Sunday, July 13, 2025

Contemporary initial management trends for locally advanced laryngeal carcinoma remain unclear. This study evaluated whether initial treatment for clinical tumor stage 4a (cT4a) laryngeal cancer has changed over time and associated survival. Retrospective cohort study using the National Cancer Database (NCDB) from 2004 to 2022 of patients with cT4a laryngeal squamous cell carcinoma. Survival outcomes were analyzed with the Mann-Kendall test, Kaplan-Meier method, logistic regression, Cox-proportional hazards, and log-rank tests. Among 12 142 cT4a laryngeal cancer patients (81.3% male, mean age 60.9 years), initial surgical management increased from 41.0% in 2004 to 65.3% in 2022. Two-year overall survival increased from 58.2% (2004) to 70.3% (2021). Upfront surgery was independently associated with higher 2-year overall survival on multivariable analysis, Kaplan-Meier, and log-rank testing (p < 0.001). For patients with cT4a laryngeal cancer, management with initial surgery has become more popular and may offer improved overall survival compared to initial nonsurgical management.

ABSTRACTObjectiveTo investigate adjuvant therapy considerations, utilization, and associated overall survival (OS) following upfront laryngectomy for laryngeal squamous cell carcinoma (LSCC).MethodsThe 2010 to 2017 National Cancer Database was retrospectively reviewed for patients undergoing upfront laryngectomy (N = 3360). Kaplan–Meier, multivariable binary logistic, and Cox proportional hazards regression models were implemented.ResultsAmong 2997 patients with consideration(s) for adjuvant radiotherapy (aRT) (i.e., pT3‐4, pN2‐3 classification, lymphovascular invasion, pathologic extranodal extension (pENE), and/or positive surgical margins [PSM]), 1176 (39.2%) did not undergo adjuvant therapy and were considered to have missed aRT. Among 992 patients with consideration(s) for adjuvant chemoradiotherapy (aCRT) (i.e., pENE and/or PSM), 169 (17.0%) underwent aRT alone and were considered to have missed aCRT. Older age and increased distance to the reporting facility were associated with higher adjusted odds of both missed aRT (p < 0.001) and missed aCRT (p < 0.025). Patients with pENE only (N = 343, 57.6%) and pENE and PSM (N = 96, 56.8%) underwent aCRT more frequently than those with PSM only (N = 97, 42.5%) (p < 0.001). Missed aRT was associated with worse OS among 2005 patients with consideration(s) for aRT alone (i.e., pT3‐4, pN2‐3 classification, and/or LVI without pENE or PSM) (aHR 1.23, 95% CI 1.05–1.44, p = 0.011) and among 992 patients with consideration(s) for aCRT (aHR 1.85, 95% CI 1.52–2.24, p < 0.001).ConclusionMissed aRT following upfront laryngectomy for LSCC occurs frequently and portends worse OS. Identifying patients at risk of off‐guideline management may create opportunities for quality improvement in the multidisciplinary care of patients undergoing upfront laryngectomy for LSCC.Level of Evidence4.

Laryngeal cancer is a common malignant tumor of the head and neck worldwide. This study aimed to identify potential risk genes, with a particular focus on GPR65, and to investigate its functional mechanism in pathogenesis of laryngeal cancer. Comprehensive analyses, including scRNA-seq analysis, genome-wide association study (GWAS), eQTL, and TCGA data, were conducted to identify risk genes for laryngeal cancer and characterize the function of these risk genes. Next, qRT-PCR, immunohistochemistry, cell proliferation, cell migration, and invasion assays were employed to verify the expression of GPR65 and its function in laryngeal squamous cell carcinoma (LSCC) in vitro. Single-cell analysis screened 416 highly expressed genes in CD8+ central memory T cells (CD8_CM). Mendelian randomization (MR) analysis identified GPR65 as a crucial gene in the development of laryngeal cancer. GPR65 expression was significantly elevated in the tumor tissues compared to normal tissues, with particularly high levels observed in stage IV HNSCC. In vitro, LSCC cell lines (TU686 and Hep-2) exhibited marked upregulation of GPR65 relative to normal epithelial cells, and siRNA-mediated silencing of GPR65 suppressed the proliferation, migration, and invasion of LSCC cells. Furthermore, GPR65 expression showed a positive correlation with immune cell infiltration, particularly CD8+ T cells and M1 macrophages. This study identified GPR65 as a potential risk gene for laryngeal cancer through single-cell transcriptomics and MR analyses and provided novel evidence of its involvement in the development of the cancer. The present findings showed that highly expressed GPR65 was a tumor-promoting gene in laryngeal cancer, showing its clinical value as a potential therapeutic target.

The optimal surgical management in advanced laryngeal squamous cell carcinoma (ALSCC) is still under debate. The extent of neck dissection as well as the nodal involvement affect survival metrics in head and neck cancer (HNSCC) patients. Despite pN status, other parameters like nodal yield (NY) or lymph node ratio (LNR) have been investigated before. There are data showing that log odds of positive lymph nodes (LODDS) are a good survival prognosticator in HNSCC in general but specific data on ALSCC is missing. This study aims to assess the prognostic value of lymph node count features on survival in ALSCC. We conducted a retrospective patient chart review on curative intent laryngectomy and bilateral neck dissection for ALSCC between 2009 and 2024 at a tertiary care center. Investigated lymph node count features besides NY included lymph node burden (LNB = number of positive lymph nodes), LNR (= LNB/NY) and the LODDS = log ((LNB + 0.5) / (NY-LNB + 0.5)). Univariate survival analysis was performed using the log-rank testing and Kaplan-Meier curves. The R maxstat package was utilized for an optimized cut-off point determination for cohort risk stratification. We included 56 patients who underwent laryngectomy and bilateral neck dissection in our department. Survival analysis revealed a 5-year OS of 51% and median OS of 60.7months. The LODDS ranged from -2.48 to 0.37 with a mean value of -1.68 ± 0.50. The cut-off at -1.94 for LODDS showed a 5-year DSF of 33% vs. 61% with a HR of 0.27 (p = 0.005) and the optimized cut-off of -1.55 showed significant differences in 5-year OS (69 vs. 17%, HR: 0.29, p = 0.003). LODDS indicated the highest concordance indices for both DFS and OS compared to LNB and LNR. We propose LODDS to serve as a superior prognosticator compared to LNB and LNR concerning DFS and OS in TL for ALSCC. LODDS values of -1.94 for DFS and -1.55 for OS appear as suitable thresholds for risk stratification.

Objective Characterize T-cell profiles in laryngeal squamous cell carcinoma (LSCC) using single-cell RNA sequencing and develop a prognostic model. Methods ScRNA-seq of LSCC tissues identified T-cell subtypes and marker genes. A prognostic model was constructed using COX and LASSO regressions with TCGA data, validated through bootstrap resampling and GEO dataset. Results Seven T-cell subtypes were detected. The model (HNRNPM, HSPH1, JMJD6, KDM5C, LCK) effectively predicted prognosis and correlated with immune infiltration, tumor mutational burden, and drug sensitivity. Conclusion This study provides insights into T-cell heterogeneity in LSCC and establishes a validated prognostic risk model for predicting survival and therapeutic outcomes.

To analyze the correlation between vocal tract dimensions and patient tolerance to office-based laryngeal surgery (OBLS) using the transnasal approach. The medical records and video-recordings of all patients who underwent OBLS between September 2024 and May 2025 were reviewed. Only patients who had a pre-operative computed tomography (CT) scan of the neck and had filled out the IOWA tolerance questionnaire were included in this study. A total of 11 anatomical measurements of the upper airway were evaluated. These included: Velum Length, vertical position of the larynx, distance from nostril to the vocal folds, distance from nostril to hard/Soft palate junction, distance from nostril to posterior nasopharyngeal mucosa, nasopharyngeal width, length of the oral component of the vocal tract, velopharyngeal width, oropharyngeal width, opening of the Hypopharynx, hypopharyngeal width. Patient tolerance to the procedure was assessed using the IOWA Satisfaction with Anesthesia Scale, which ranges between -3 and +3 (completely satisfied). Twenty patients, with a mean age of 62.55 ± 14.93 years, were included. The most common voice diagnosis was unilateral vocal fold paralysis (60%), followed by laryngeal squamous cell carcinoma (25%). The most commonly performed procedures were injection laryngoplasty (65%) and laryngeal biopsy (15%). There was a moderate negative correlation between velum length and IOWA scores (r = -0.568, p = 0.009). There was no statistically significant correlation between any other vocal tract measurements and IOWA scores. This investigation showed that the longer the velum, the lower the tolerance score for office-based laryngeal surgery.

Ceritinib (LDK378) inhibits laryngeal squamous cell carcinoma progression via regulating ROS-induced mitochondrial apoptosis and inducing oxidative stress.

Laryngeal squamous cell carcinoma (LSCC) is one of the major malignant cancers worldwide. Emerging evidence has demonstrated that N6-methyladenosine (m6A) modification affects gene expression by regulating RNA metabolic processes, dynamically and reversibly regulated by its "writers", "erasers" and "readers". m6A modification plays an important role in the occurrence and development of various tumors. Recent studies have shown that m6A modifications are abnormally expressed in LSCC cells and tissues and participate in the malignant phenotypes of LSCC including cell proliferation, invasion, metastasis and chemotherapy resistance by mediating m6A regulators. This fundings may provide new directions for the molecular classification and targeted treatment of LSCC. In this review, we will focus on the molecular mechanism and potential clinical function of m6A modification in LSCC and emphasize its potential as a biomarker for the clinical diagnosis, prognosis, and treatment of LSCC.