Assessment of the risk of malignancy in Bethesda III thyroid nodules: a comprehensive review.

The increasing prevalence of thyroid cancer emphasizes the need for a thorough assessment of risk of malignancy in Bethesda III nodules. Various methods ranging commercial platforms of molecular genetic testing (including Afirma® GEC, Afirma® GSC, ThyroSeq® V3, RosettaGX®, ThyGeNEXT®/ThyraMIR®, ThyroidPRINT®) to radionuclide scans and ultrasonography have been investigated to provide a more nuanced comprehension of risk estimation. The integration of molecular studies and imaging techniques into clinical practice may provide clinicians with improved and personalized risk assessment. This integrated approach we feel may enable clinicians to carefully tailor interventions, thereby minimizing the likelihood of unnecessary thyroid surgeries and overall crafting the optimal treatment. By aligning with the evolving landscape of personalized healthcare, this comprehensive strategy ensures a patient-centric approach to thyroid nodule and thyroid cancer management.

Pharyngeal Reconstruction Methods to Reduce the Risk of Pharyngocutaneous Fistula After Primary Total Laryngectomy: A Scoping Review.

INTRODUCTION: The most common early postoperative complication after total laryngectomy (TL) is pharyngocutaneous fistula (PCF). Rates of PCF are higher in patients who undergo salvage TL compared with primary TL. Published meta-analyses include heterogeneous studies making the conclusions difficult to interpret. The objectives of this scoping review were to explore the reconstructive techniques potentially available for primary TL and to clarify which could be the best technique for each clinical scenario. METHODS: A list of available reconstructive techniques for primary TL was built and the potential comparisons between techniques were identified. A PubMed literature search was performed from inception to August 2022. Only case-control, comparative cohort, or randomized controlled trial (RCT) studies were included. RESULTS: A meta-analysis of seven original studies showed a PCF risk difference (RD) of 14% (95% CI 8-20%) favoring stapler closure over manual suture. In a meta-analysis of 12 studies, we could not find statistically significant differences in PCF risk between primary vertical suture and T-shaped suture. Evidence for other pharyngeal closure alternatives is scarce. CONCLUSION: We could not identify differences in the rate of PCF between continuous and T-shape suture configuration. Stapler closure seems to be followed by a lower rate of PCF than manual suture in those patients that are good candidates for this technique.

Recurrent Differentiated Thyroid Cancer: The Current Treatment Options.

Differentiated thyroid carcinomas (DTC) have an excellent prognosis, but this is sometimes overshadowed by tumor recurrences following initial treatment (approximately 15% of cases during follow-up), due to unrecognized disease extent at initial diagnosis or a more aggressive tumor biology, which are the usual risk factors. The possible sites of recurrence are local, regional, or distant. Local and regional recurrences can usually be successfully managed with surgery and radioiodine therapy, as are some isolated distant recurrences, such as bone metastases. If these treatments are not possible, other therapeutic options such as external beam radiation therapy or systemic treatments should be considered. Major advances in systemic treatments have led to improved progression-free survival in patients previously considered for palliative treatments; among these treatments, the most promising results have been achieved with tyrosine kinase inhibitors (TKI). This review attempts to give a comprehensive overview of the current treatment options suited for recurrences and the new treatments that are available in cases where salvage surgery is not possible or in cases resistant to radioiodine.

Locoregional strategies to decrease postoperative pain and neck discomfort after open thyroidectomy: A scoping review.

Adequate pain control enhances patients' quality of life and allows a quick return to normal activities. Current pain management practices may contribute to the crisis of opioid addiction. We summarize the evidence that evaluates locoregional interventions to decrease pain and neck discomfort after thyroidectomy. We designed a scoping review. The search strategy was made in the Pubmed/MEDLINE and EMBASE database. We included only systematic reviews and RCTs that compared two or more strategies. Forty-nine publications including 5045 patients fulfilled criteria. Sore throat frequency is higher for endotracheal intubation and topical administration of anesthetic before intubation decreases this. Pre-incisional infiltration of the surgical wound decreases postoperative pain. Bilateral superficial plexus nerve block decreases analgesic requirements during and after thyroidectomy. Wound massage and neck exercises decrease postoperative discomfort. Locoregional interventions significantly impact postoperative pain and may reduce opioid use and improve patient outcomes.

Driving role of head and neck cancer cell secretome on the invasion of stromal fibroblasts: Mechanistic insights by phosphoproteomics.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are major players in tumor-stroma communication, and participate in several cancer hallmarks to drive tumor progression and metastatic dissemination. This study investigates the driving effects of tumor-secreted factors on CAF biology, with the ultimate goal of identifying effective therapeutic targets/strategies for head and neck squamous cell carcinomas (HNSCC). METHODS: Functionally, conditioned media (CM) from different HNSCC-derived cell lines and normal keratinocytes (Kc) were tested on the growth and invasion of populations of primary CAFs and normal fibroblasts (NFs) using 3D invasion assays in collagen matrices. The changes in MMPs expression were evaluated by RT-qPCR and kinase enrichment was analyzed using mass spectrometry phosphoproteomics. RESULTS: Our results consistently demonstrate that HNSCC-secreted factors (but not Kc CM) specifically and robustly promoted pro-invasive properties in both CAFs and NFs, thereby reflecting the plasticity of fibroblast subtypes. Concomitantly, HNSCC-secreted factors massively increased metalloproteinases levels in CAFs and NFs. By contrast, HNSCC CM and Kc CM exhibited comparable growth-promoting effects on stromal fibroblasts. Mechanistically, phosphoproteomic analysis predominantly revealed phosphorylation changes in fibroblasts upon treatment with HNSCC CM, and various promising kinases were identified: MKK7, MKK4, ASK1, RAF1, BRAF, ARAF, COT, PDK1, RSK2 and AKT1. Interestingly, pharmacologic inhibition of RAF1/BRAF using sorafenib emerged as the most effective drug to block tumor-promoted fibroblast invasion without affecting fibroblast viability CONCLUSIONS: Our findings demonstrate that HNSCC-secreted factors specifically fine tune the invasive potential of stromal fibroblasts, thereby generating tumor-driven pro-invasive niches, which in turn to ultimately facilitate cancer cell dissemination. Furthermore, the RAF/BRAF inhibitor sorafenib was identified as a promising candidate to effectively target the onset of pro-invasive clusters of stromal fibroblasts in the HNSCC microenvironment.

Neck Surgery for Non-Well Differentiated Thyroid Malignancies: Variations in Strategy According to Histopathology.

Lymph node metastases in non-well differentiated thyroid cancer (non-WDTC) are common, both in the central compartment (levels VI and VII) and in the lateral neck (Levels II to V). Nodal metastases negatively affect prognosis and should be treated to maximize locoregional control while minimizing morbidity. In non-WDTC, the rate of nodal involvement is variable and depends on the histology of the tumor. For medullary thyroid carcinomas, poorly differentiated thyroid carcinomas, and anaplastic thyroid carcinomas, the high frequency of lymph node metastases makes central compartment dissection generally necessary. In mucoepidermoid carcinomas, malignant peripheral nerve sheath tumors, sarcomas, and malignant thyroid teratomas or thyroblastomas, central compartment dissection is less often necessary, as clinical lymphnode involvement is less common. We aim to summarize the medical literature and the opinions of several experts from different parts of the world on the current philosophy for managing the neck in less common types of thyroid cancer.

The Role of Vitamin D in Autoimmune Thyroid Diseases: A Narrative Review.

Vitamin D (VitD) deficiency has garnered significant attention in contemporary medical research. Although the canonical biological activity of VitD manifests itself mainly in the regulation of calcium-phosphorus metabolism, recent studies show that, thanks to the presence of numerous receptors, VitD may also play an important role in regulating the immune system. VitD deficiency has been demonstrated to impact autoimmune disease, coeliac disease, infections (including respiratory/COVID-19), and patients with cancer. Recent studies also show that VitD plays a significant role in autoimmune thyroid diseases (AITDs). Many studies have shown a correlation between low VitD levels and chronic autoimmune thyroiditis - Hashimoto thyroiditis (HT), Graves' disease (GD), and postpartum thyroiditis (PPT). This review article, therefore, describes the current state of knowledge on the role of VitD in AITDs, including HT, GD, and PTT.

Oncological and functional outcomes of transoral laser surgery for hypopharyngeal carcinoma.

BACKGROUND: Surgical resection or radiotherapy (RT) are standard approaches for early-staged hypopharyngeal squamous cell carcinoma (HPSCC). Transoral laser microsurgery (TOLMS) seems to provide good oncological and functional results with few local complications. The aim of our study was to analyze the outcomes of TOLMS, with or without neck dissection or RT, in the treatment of HPSCC in a tertiary referral center. METHODS: A retrospective study was conducted in patients with early T-category (T1-T2) HPSCC treated by TOLMS. RESULTS: A total of 34 patients were included in the study. The series includes 17 (50%) T1 and 17 (50%) T2 classified tumors. The 5-year overall survival and disease-specific survival rates were 51% and 66%, respectively, with a 5-year local control rate of 92%. All patients reassumed oral diet and none of them had a tracheostomy at the end of the follow-up. CONCLUSIONS: TOLMS offers an effective treatment option in terms of oncologic control and function preservation in locally circumscribed HPSCC.

Epstein-Barr virus directed screening for nasopharyngeal carcinoma in individuals with positive family history: A systematic review.

OBJECTIVES: Evidence to support Epstein-Barr virus (EBV)-directed population nasopharyngeal carcinoma (NPC) screening has been growing. Familial aggregation is a well-recognized phenomenon in endemic regions. This systematic review summarizes the role of EBV-directed screening in individuals with a positive family history (FH+) of NPC. METHODS: We searched four electronic databases from their inception to October 2021. We included studies on individuals with FH+ of NPC who had undergone EBV-directed investigations, with no restriction in the testing methods or analytic techniques. The primary and secondary outcomes were EBV positivity rates and NPC incidence rates, respectively. Meta-analyses were performed using the random-effect model. RESULTS: Ten cross-sectional studies (n = 7436) and three cohort studies (n = 4306) were included. The pooled relative risk (RR) of EBV positivity between individuals with and without FH+ of NPC were 2.79 (95 % CI 1.37-5.68, p = 0.005) for viral capsid antigen (VCA) IgA, 3.09 (95 % CI 0.65-14.83, p = 0.16) for Epstein-Barr nuclear antigen (EBNA1) IgA, and 1.76 (95 % CI 1.04-2.96, p = 0.03) for combined EBNA1/VCA IgA. In the three cohort studies, the NPC incidence rates ranged from 90.2 to 266 per 100 000 person-years with high proportions of early-stage diseases. FH+ individuals who were EBV-positive had a 2.5 to 30.7-fold risk of NPC development compared to their EBV-negative counterparts. CONCLUSION: Family members of NPC patients had significantly higher EBV positivity rates than the general population. FH+ individuals who are EBV-positive had high risks of developing NPC. Familial screening using EBV serology may facilitate early NPC detection in endemic areas.

Voice outcomes in patients with advanced laryngeal and hypopharyngeal cancer treated with chemo-radiotherapy.

Objective: Patients with locally advanced laryngeal and hypopharyngeal cancer (LHC) are often treated with chemo-radiotherapy to avoid total laryngectomy, although voice problems may occur even if not markedly manifest. We sought to evaluate the impact of chemoradiation on voice and quality of life. Methods: We studied 21 patients with locally advanced LHC with tumour control at least two years after chemo-radiotherapy. None manifested clinical symptoms related to the treatment and maintained an activity considered as within normal limits. All patients had a voice handicap index (VHI) of less than 15. Voice function was evaluated by perceptual vocal analysis (CAPE-V) and aerodynamic and acoustic study. Quality of life was assessed with the EORTC-H&N35 (voice items 46, 53 and 54). Results: Voice changes were frequent, with alterations in all CAPE-V attributes, and predominantly type II and III spectrograms in acoustic analysis (78%). The EORTC-H&N35 scale showed a reduction in scores in 10-40% of items related to voice. Conclusions: Subclinical voice disorders are common after chemo-radiotherapy. Although patients consider vocal impairment to be very minor and to not interfere with their daily life, it may contribute to a reduced quality of life.

Voice Outcome After Carbon Dioxide Transoral Laser Microsurgery for Glottic Cancer According to the European Laryngological Society Classification of Cordectomy Types - A Systematic Review.

BACKGROUND: Voice outcome after carbon dioxide transoral laser microsurgery (CO2TOLMS) for glottic cancer is of prime importance. However, a comprehensive overview according to the European Laryngological Society (ELS) classification of cordectomies is still lacking. The aim of this systematic review is to summarize data on voice outcome associated with individual types of ELS glottic cordectomy after CO2TOLMS. MATERIALS AND METHODS: A systematic review of the literature was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. The initial search identified 936 records of which 25 publications were then included. Voice outcome data (Voice Handicap Index [VHI] version 30, grade of dysphonia [G] and maximum phonation time [MPT]) were extracted per resection type. Weighted averages were calculated. RESULTS: Data show a gradual increase in the VHI scores although they were still similar for all cordectomy types (range 14.2 to 21.5). The grade of dysphonia showed a gradual increase with increasing resection depth (range 1.0 to 1.9). There was a gradual decrease in the MPT (range 15.2 to 7.2). CONCLUSION: Voice outcome is related to cordectomy type with mild dysphonia characterizing ELS type I, II and III cordectomies, while more extended cordectomies (ELS type IV, V and VI) result in moderate dysphonia and shortness of breath during phonation. The voice handicap experienced by patients is limited even in the more extended cordectomies.

Asymptomatic swallowing disorders may be present in individuals with laryngeal and hypopharyngeal cancer treated with chemo-radiotherapy.

PURPOSE: Patients with advanced laryngeal and hypopharyngeal cancer are often treated with chemo-radiotherapy to avoid total laryngectomy. Subclinical swallowing disorders could be present in these patients even though patients do not complain of any symptoms. We sought to evaluate the impact of chemoradiation on swallowing and quality of life. METHODS: We studied 21 patients undergoing chemo-radiotherapy for advanced laryngeal and hypopharyngeal cancer. All patients were tumor-free and none reported symptoms related to dysphagia during follow-up or showed altered routine screening tests (EAT-10) to detect it. Swallowing functions were assessed using volume-viscosity swallow test (V-VST) and fiberoptic endoscopic evaluation of swallowing (FEES). Quality of life was assessed with the EORT-H&N35, and SWAL-QOL scales. RESULTS: Frequent alterations in swallowing efficacy (100%) and safety (85.5%) were detected with V-VST and FEES. Quality-of-life scales showed a reduction in their scores between 12 and 17%, mainly in the areas of symptoms. CONCLUSION: Swallowing disorders are common after chemo-radiotherapy, even in patients who do not clinically manifest these disorders, contributing to a decrease in patients' quality of life. FEES and V-VST are useful procedures to detect asymptomatic swallowing disorders.

SDCBP Modulates Stemness and Chemoresistance in Head and Neck Squamous Cell Carcinoma through Src Activation.

To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. SDCBP depletion sensitized biopsy-derived and established HNSCC cell lines to cisplatin (CDDP) and reduced CSC markers, Src activation being the main SDCBP downstream target. In mice, SDCBP-depleted cells formed tumors with decreased mitosis, Ki-67 positivity, and metastasis over controls. Moreover, the fusocellular pattern of CCL-138-R cell-derived tumors reverted to a more epithelial morphology upon SDCBP silencing. Importantly, SDCBP expression was associated with Src activation, poor differentiated tumor grade, advanced tumor stage, and shorter survival rates in a series of 382 HNSCC patients. Our results reveal that SDCBP might be a promising therapeutic target for effectively eliminating CSCs and CDDP resistance.

Prognostic Relevance of CD4+, CD8+ and FOXP3+ TILs in Oral Squamous Cell Carcinoma and Correlations with PD-L1 and Cancer Stem Cell Markers.

This study investigates the relevance of tumor-infiltrating lymphocytes (TILs) in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis of stromal/tumoral CD4+, CD8+ and FOXP3+ TILs is performed in 125 OSCC patients. Potential relationships with the expression of tumoral PD-L1 and cancer stem cell (CSC) markers (NANOG, SOX2, OCT4, Nestin and Podoplanin (PDPN)) are assessed. CD4+ and CD8+ TILs are significantly associated with smoking and alcohol habits. CD4+ and CD8+ TILs show an inverse relationship with NANOG and SOX2 expression, and FOXP3+ TILs is significantly correlated with Nestin and PDPN expression. High infiltration of CD4+ and CD8+ TILs and a high tumoral CD8+/FOXP3+ ratio are significantly associated with tumors harboring positive PD-L1 expression. Infiltration of stromal/tumoral FOXP3+ TILs and a low stromal CD8+/FOXP3+ ratio are significantly associated with better disease-specific survival. Multivariate analysis reveals that the stromal CD8+/FOXP3+ TILs ratio is a significant independent prognostic factor. Regarding OSCC patient survival, the CD8+/FOXP3+ TILs ratio is an independent prognostic factor. TILs may act as biomarkers and potential therapeutic targets for OSCC.

Tumor-Infiltrating CD20+ B Lymphocytes: Significance and Prognostic Implications in Oral Cancer Microenvironment.

Immunohistochemical analysis of stromal/tumoral CD20+ B lymphocytes was performed in 125 OSCC patients. Correlations with immune profiles CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocytes (TILs), tumoral PD-L1, and stem-related factors NANOG and SOX2 were assessed, and also associations with clinical data and patient survival. There was a strong positive correlation between the infiltration of CD20+ B lymphocytes and other immune profiles (i.e., CD4+, CD8+, and FOXP3+ TILs, and CD68+ and CD163+ macrophages) both in stroma and tumor nests. Strikingly, CD20+ TILs were inversely correlated with NANOG/SOX2 expression. Stromal CD20+ TILs were significantly associated with T classification and second primary tumors. A stratified survival analysis showed that tumoral CD20+ TILs were significantly associated with prognosis in male and younger patients, with tobacco or alcohol consumption, high tumoral CD8+ TILs, low tumoral infiltration by CD68+ macrophages, positive PD-L1 expression, and negative NANOG/SOX2. Multivariate Cox analysis further revealed clinical stage and tumoral CD20+ TILs independently associated with disease-specific survival (HR = 2.42, p = 0.003; and HR = 0.57, p = 0.04, respectively). In conclusion, high CD20+ TIL density emerges as an independent good prognostic factor in OSCC, suggesting a role in antitumor immunity. This study also uncovered an inverse correlation between CD20+ TILs and CSC marker expression.

Endonasal endoscopic surgery for sinonasal squamous cell carcinoma from an oncological perspective.

Endonasal endoscopic surgery (EES) has been applied to the management of sinonasal (SN) tumors based on recent advances in endoscopic surgical techniques and technologies over the past three decades. EES has been mainly indicated for benign tumors and less aggressive malignant tumors. Notwithstanding this, EES has been gradually adopted for squamous cell carcinoma (SCC), which is the most common histology among SN malignancies. However, an analysis of the outcomes of EES for patients with SCC is difficult because most articles included SCC a wide range of different tumor histologies. Therefore, we herein review and clarify the current status of EES focusing on SCC from an oncological perspective. The oncologic outcomes and the ability to achieve a histologically complete resection are similar between endoscopic and open approaches in highly selected patients with SN-SCC. Surgical complications associated with EES are likely similar for SN-SCC compared to other sinonasal malignancies. The indications for a minimally invasive approach such as EES in the management of patients with SN-SCC should be stricter than those for less aggressive malignant tumors because of the aggressive nature of SCC. Also, it is important to achieve negative surgical margins with EES in patients with SCC. We believe that the indications for EES for SN-SCC are widening due to advances in diagnostic imaging, and endoscopic surgical techniques and technologies. However, while expanding the indications for EES for SN-SCC we must carefully confirm that the outcomes support this strategy.

Prognostic role of intraparotid lymph node metastasis in primary parotid cancer: Systematic review.

BACKGROUND: The prognostic importance of intraparotid lymph node metastasis (P+) in patients with primary parotid gland carcinoma is unclear. METHODS: Nineteen retrospective and noncomparative cohort studies, published between 1992 and 2020, met the inclusion criteria and included 2202 patients for this systematic review. RESULTS: The pooled prevalence of the P in adult patients in the unselected studies was 24.10% (95% confidence interval = 17.95-30.25). The number of P+ lymph nodes per patient was counted in only three studies and ranged from 1 to 11. The 5-year recurrence-free survival rate based on Kaplan-Meier analysis varied from 83% to 88% in P- patients compared to 36% to 54% in P+ patients. The average hazard ratio for tumor recurrence in patients with P+ compared to P- was 2.67 ± 0.58. CONCLUSIONS: P+ is an independent negative prognostic factor in primary parotid gland cancer and should be included into the treatment planning.

Expresión de E-cadherina y beta-catenina en carcinomas de células escamosas de laringe e hipofaringe / Expression of E-cadherin and Beta-catenin in Laryngeal and Hypopharyngeal Squamous Cell Carcinomas

INTRODUCCIÓN Y OBJETIVOS: La disfunción del complejo E-cadherina/catenina está relacionada directamente con la carcinogénesis y el desarrollo de metástasis. El objetivo de este trabajo es investigar el significado pronóstico de la expresión de E-cadherina y beta-catenina en carcinomas de células escamosas de laringe e hipofaringe tratados quirúrgicamente. MATERIAL Y MÉTODOS: Se obtuvieron muestras de tejido tumoral de 133 pacientes consecutivos con carcinomas escamosos de cabeza y cuello (68 de laringe y 65 carcinomas de hipofaringe), que fueron sometidos a tratamiento quirúrgico en nuestro hospital entre 2000 y 2005. La expresión de E-cadherina y beta-catenina se analizó mediante inmunohistoquímica, cuantificando el porcentaje de células teñidas y la intensidad de la tinción. RESULTADOS: La expresión de E-cadherina y beta-catenina fue evaluable en 59 muestras de carcinomas de laringe y en 58 de hipofaringe. En tumores de laringe se observó una asociación significativa entre la baja expresión de beta-catenina de membrana y tumores avanzados T4 y la recidiva tumoral. A nivel de hipofaringe se encontró una asociación significativa de la expresión positiva de Beta-catenina nuclear con pobre diferenciación histológica (p = 0,02). En el análisis multivariante solo la presencia de metástasis ganglionares era factor predictor independiente de disminución de la supervivencia específica para enfermedad en carcinoma de células escamosas de laringe. CONCLUSIONES: La expresión de E-cadherina y beta-catenina no parece tener utilidad pronóstica superior al TNM en los carcinomas epidermoides de laringe e hipofaringe

INTRODUCTION AND OBJECTIVES: Dysfunction of the E-cadherin/catenin complex is directly related to carcinogenesis and metastases development. The aim of this paper is to investigate the prognostic significance of E-cadherin and Beta-catenin expression in surgically treated laryngeal and hypopharyngeal squamous cell carcinomas. MATERIAL AND METHODS: Tumour tissue samples were obtained from 133 consecutive patients with squamous cell carcinomas of the head and neck: 68 of the larynx and 65 hypopharyngeal carcinomas, who underwent surgical treatment in our hospital between 2000 and 2005. E-cadherin and beta-catenin expression was analysed by immunohistochemistry, quantifying the percentage of stained cells and the intensity of staining. RESULTS: E-cadherin and beta-catenin expression was evaluable in 59 laryngeal carcinomas and in 58 cases of hypopharyngeal carcinomas. In the laryngeal tumours, a significant association was found between the low expression of membrane Beta-catenin with T4 tumours and tumour recurrence. In the hypopharynx there was a significant association between positive expression of nuclear beta-catenin and poor histological differentiation (P = .02). In the multivariate analysis, only the presence of lymph node metastases was an independent predictive factor of decreased disease-specific survival in laryngeal squamous cell carcinomas. CONCLUSIONS: The expression of E-cadherin and beta-catenin does not show prognostic significance in laryngeal and hypopharyngeal squamous cell carcinomas over the TNM classification

Prognostic Significance of the Pluripotency Factors NANOG, SOX2, and OCT4 in Head and Neck Squamous Cell Carcinomas.

Cancer stem cells (CSCs) play major roles in tumor initiation, progression, and resistance to cancer therapy. Several CSC markers have been studied in head and neck squamous cell carcinomas (HNSCC), including the pluripotency factors NANOG, SOX2, and OCT4; however, their clinical significance is still unclear. NANOG, SOX2, and OCT4 expression was evaluated by immunochemistry in 348 surgically-treated HNSCC, and correlated with clinicopathological parameters and patient outcomes. mRNA expression was further analyzed in 530 The Cancer Genome Atlas (TCGA) HNSCC. NANOG protein expression was detected in 250 (72%) cases, more frequently in patients with lymph node metastasis (p = 0.003), and was an independent predictor of better survival in multivariate analysis. While OCT4 expression was undetectable, SOX2 expression was observed in 105 (30%) cases, and strongly correlated with NANOG expression. Combined expression of both proteins showed the highest survival rates, and double-negative cases the worst survival. Strikingly, the impact of NANOG and SOX2 on outcome varied depending on tumor site and lymph node infiltration, specifically showing prognostic significance in pharyngeal tumors. Correlation between NANOG and SOX2 at mRNA and protein was specifically observed in node positive (N+) patients, and consistently correlated with better survival rates. According to our findings, NANOG protein expression is frequent in HNSCC, thereby emerging as an independent predictor of better prognosis in pharyngeal tumors. Moreover, this study uncovers a differential impact of NANOG and SOX2 expression on HNSCC prognosis, depending on tumor site and lymph node infiltration, which could facilitate high-risk patient stratification.