Head and neck neoplasms have a poor prognosis because of their late diagnosis. Finding a biomarker to detect these tumors in an early phase could improve the prognosis and survival rate. This literature review provides an overview of biomarkers, covering the different -omics fields to diagnose head and neck neoplasms in the early phase. To date, not a single biomarker, nor a panel of biomarkers for the detection of head and neck tumors has been detected with clinical applicability. Limitations for the clinical implementation of the investigated biomarkers are mainly the heterogeneity of the study groups (e.g., small population in which the biomarker was tested, and/or only including high-risk populations) and a low sensitivity and/or specificity of the biomarkers under study. Further research on biomarkers to diagnose head and neck neoplasms in an early stage, is therefore needed.

Esophageal squamous cell neoplasms (ESCNs) are the most common second primary neoplasm in patients with head and neck squamous cell carcinoma (HNSCC), and few studies have focused on metachronous ESCNs. We aimed to evaluate the incidence of and risk factors for metachronous ESCNs and to provide a reasonable endoscopic follow-up plan for HNSCC patients. We extended our prospective cohort since October 2008 by recruiting incident HNSCC patients. All enrolled patients were interviewed to collect information on substance use (smoking, alcohol, and betel nut) and esophagogastroduodenoscopy (EGD) with Lugol chromoendoscopy results for synchronous ESCNs soon after HNSCC diagnosis. Endoscopic screenings for metachronous ESCNs were performed 6 to 12 months after the previous examinations. A total of 1042 incident HNSCC patients were enrolled, but only 175 patients met all the criteria and were analyzed. A total of 20 patients had metachronous ESCNs (20/175, 11.4%). Only the initial Lugol-voiding lesion (LVL) classification significantly predicted the development of metachronous ESCNs. Patients with an LVL classification of C/D had a higher risk of developing metachronous ESCNs than those with an LVL classification of A/B (adjusted odds ratio: 5.03, 95% confidence interval: 1.52-16.67). The mean interval for developing metachronous ESCNs was 33 months, but the shortest interval for developing metachronous esophageal squamous cell carcinoma was 12 months. Lugol chromoendoscopy screening among incident HNSCC patients predicts the risk of developing metachronous ESCNs. A closer follow-up with an endoscopy every 6 months is recommended for those with LVL classifications of C and D.

The incidence of second primary neoplasms arising in the skin reconstructive flap (SNAF) is increasing because of the increase in head and neck flap reconstruction and cancer survival. Prognosis, optimal treatment, and their clinicopathological-genetic features are under debate and are difficult to diagnose. We retrospectively reviewed SNAFs based on a single center's experience over 20 years. Medical records and specimens of 21 patients with SNAF who underwent biopsies between April 2000 and April 2020 at our institute were retrospectively analyzed. Definite squamous cell carcinoma and the remaining neoplastic lesions were subclassified as flap cancer (FC) and precancerous lesions (PLs), respectively. Immunohistochemical studies focused on p53 and p16. TP53 sequencing was conducted using next-generation sequencing. Seven and 14 patients had definite FC and PL, respectively. The mean number of biopsies/latency intervals was 2.0 times/114 months and 2.5 times/108 months for FC and PL, respectively. All lesions were grossly exophytic and accompanied by inflamed stroma. In FC and PL, the incidences of altered p53 types were 43% and 29%, respectively, and those of positive p16 stains were 57% and 64%, respectively. Mutation of TP53 in FC and PL were 17% and 29%, respectively. All except one patient with FC under long-term immunosuppressive therapy survived in this study. SNAFs are grossly exophytic tumors with an inflammatory background and show a relatively low altered p53 and TP53 rate and a high p16 positivity rate. They are slow-growing neoplasms with good prognoses. Diagnosis is often difficult; therefore, repeated or excisional biopsy of the lesion may be desirable.

This novel meta-analysis was conducted to systematically and comprehensively evaluate the prognostic role of the pretreatment PNI in patients with head and neck neoplasms (HNNs) undergoing radiotherapy.

Thyroid storm is a rare but life-threatening emergency that prompts urgent intervention to halt its potentially disastrous outcomes. There is not much literature available on thyroid storm in head neck trauma and non-thyroid/parathyroid head neck surgery. Due to rarity of thyroid storm in head and neck trauma/surgery patients, its diagnosis becomes challenging, is often misdiagnosed and causes delay in the diagnosis and management. Therefore, the aim of this work was to compile, analyze and present details to develop a consensus and augment available literature on thyroid storm in this group of patients.

Head and neck paragangliomas (HNPGLs) are rare neoplasms with a high degree of heritability. Paragangliomas present as polygenic diseases caused by combined alterations in multiple genes; however, many driver changes remain unknown.

Interventions for head/neck cancer (HNC) survivors may not address their cancer-related and general health needs.

Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. While numerous potent dietary insults were considered as oncogenic players for HNSCC development, the impact of metabolic imbalance was less emphasized during HNSCC carcinogenesis. Previous preclinical and epidemiological investigations showed that DM could possibly be correlated with greater incidence and poorer prognosis in HNSCC patients; however, the outcomes from different groups are contradictive and underlying mechanisms remains elusive. In the present study, the changes of cellular malignancy in response to prolonged glucose incubation in HNSCC cells were examined. The results demonstrated that hyperglycemia enhanced HNSCC cell malignancy over time through suppression of cell differentiation, promotion of cell motility, increased resistance to cisplatin, and up-regulation of the nutrient-sensing Akt/AMPK-mTORC1 pathway. Further analysis showed that a more aggressive tongue neoplastic progression was found under DM conditions compared to non-DM state whereas DM pathology led to a higher percentage of cervical lymph node metastasis and poorer prognosis in HNSCC patients. Taken together, the present study confirms that hyperglycemia and DM could enhance HNSCC malignancy and the outcomes are of great benefit in providing better anti-cancer treatment strategy for DM patients with HNSCC.

Development of head and neck squamous cell carcinoma (HNSCC) is characterized by accumulation of mutations in several oncogenes and tumor suppressor genes. We have formerly described the mutation pattern of HNSCC and described NOTCH signaling pathway alterations. Given the complexity of the HNSCC, here we extend the previous study to understand the overall HNSCC mutation context and to discover additional genetic alterations. We performed high depth targeted exon sequencing of 51 highly actionable cancer-related genes with a high frequency of mutation across many cancer types, including head and neck. DNA from primary tumor tissues and matched normal tissues was analyzed for 37 HNSCC patients. We identified 26 non-synonymous or stop-gained mutations targeting 11 of 51 selected genes. These genes were mutated in 17 out of 37 (46%) studied HNSCC patients. Smokers harbored 3.2-fold more mutations than non-smokers. Importantly, TP53 was mutated in 30%, NOTCH1 in 8% and FGFR3 in 5% of HNSCC. HPV negative patients harbored 4-fold more TP53 mutations than HPV positive patients. These data confirm prior reports of the HNSCC mutational profile. Additionally, we detected mutations in two new genes, CEBPA and FES, which have not been previously reported in HNSCC. These data extend the spectrum of HNSCC mutations and define novel mutation targets in HNSCC carcinogenesis, especially for smokers and HNSCC without HPV infection.

Neuroendocrine carcinoma (NEC) of the head and neck is a rare type of malignancy, accounting for only 0.3% of all head and neck cancers, and its clinicopathological and genomic features have not been fully characterized. We conducted a retrospective analysis of 27 patients with poorly differentiated NEC of the head and neck seen at our institution over a period of 15 years. Patient characteristics, adopted therapies, and clinical outcomes were reviewed based on the medical records. Pathological analysis and targeted sequencing of 523 cancer-related genes were performed using evaluable biopsied/resected specimens based on the clinical data. The most common tumor locations were the paranasal sinus (33%) and the oropharynx (19%). Eighty-one percent of the patients had locally advanced disease. The 3-year overall survival rates in all patients and in the 17 patients with locally advanced disease who received multimodal curative treatments were 39% and 53%, respectively. Histologically, large cell neuroendocrine carcinoma was the predominant subtype (58% of evaluable cases), and the Ki-67 labeling index ranged from 59 to 99% (median: 85%). Next-generation sequencing in 14 patients identified pathogenic/likely pathogenic variants in TP53, RB1, PIK3CA-related genes (PREX2, PIK3CA, and PTEN), NOTCH1, and SMARCA4 in six (43%), three (21%), two (14%), two (14%), and one (7%) patients, respectively. Sequencing also detected the FGFR3-TACC3 fusion gene in one patient. The median value of the total mutational burden (TMB) was 7.1/Mb, and three patients had TMB ≥ 10. Regardless of the aggressive pathological features, our data revealed favorable clinical characteristics in the patients with locally advanced disease who received curative treatment. The lower TP53 and RB1 mutation prevalence rates compared to those described for small cell lung cancer suggests the biological heterogeneity of NEC in different parts of the body. Furthermore, the FGFR3-TACC3 fusion gene and mutations in genes encoding the components of the NOTCH and PI3K/AKT/mTOR pathways found in our study may be promising targets for NEC of the head and neck.

Oropharyngeal dysphagia (OD) is a high impact morbidity in head-and-neck cancer (HNC) patients. A wide variety of instruments are developed to screen for affective symptoms and OD. The current paper aims to systematically review and appraise the literature to obtain insight into the prevalence, strength, and causal direction of the relationship between affective symptoms and OD in HNC patients. This review was conducted in accordance with the PRISMA statement. A systematic search of the literature was performed using PubMed, PsycINFO, Cochrane, and Embase. All available publications reporting on the relationship between affective conditions and swallowing function in HNC patients were included. Conference papers, tutorials, reviews, and studies with less than 5 patients were excluded. Fifteen studies met the inclusion criteria. The level of evidence and methodological quality were assessed using the ABC-rating scale and QualSyst critical appraisal tool. Eleven studies reported a positive relationship between affective symptoms and OD. The findings of this paper highlight the importance of affective symptom screening in dysphagic HNC patients as clinically relevant affective symptoms and OD seems to be prevalent and coincident in this population. Considering the impact of affective symptoms and OD on patients' daily life, early detection and an integrated interdisciplinary approach are recommended. However, due to the heterogeneity of study designs, outcomes, and outcome measures, the generalization of study results is limited.

Recurrent/metastatic (R/M) head and neck cancers bear a poor prognosis. In this analysis, we examined the efficacy and the outcome of targeted therapy recommendations based on the patients' molecular tumor portrait after failure of all standard therapy options. In this single-center, real-world retrospective analysis of our platform for precision medicine, we analyzed the molecular profile of 50 patients diagnosed with R/M head and neck cancer. Tumor samples of the patients were examined using next-generation sequencing panels of mutation hotspots, microsatellite instability (MSI) testing, and immunohistochemistry (IHC). In 31 cases (62.0% of all patients), a molecular-driven targeted therapy approach was recommended. Eventually, 14 patients (28%) received the suggested targeted therapy. Six of fourteen patients (43%) achieved stable disease conditions and four patients (29%) experienced a progressive disease. The median time to treatment failure was 2.8 months. Therapy recommendations were significantly more often issued for men (p = 0.037) than for women. This analysis demonstrated that precision medicine provided the basis for molecular-driven therapy recommendations in over half of the patients with advanced therapy refractory head and neck cancers, with significantly more therapy recommendations for men. Our analysis showed that although precision medicine approaches are implementable and feasible for the management of recurrent/metastatic head and neck cancers in daily clinical routine, there are major limitations and challenges that have to be overcome.

Angiosarcomas are rare malignant tumors of the endothelium, arising commonly from the head and neck region (AS-HN) and recently associated with ultraviolet (UV) exposure and human herpesvirus-7 infection. We examined 81 cases of angiosarcomas, including 47 cases of AS-HN, integrating information from whole genome sequencing, gene expression profiling and spatial transcriptomics (10X Visium). In the AS-HN cohort, we observed recurrent somatic mutations in CSMD3 (18%), LRP1B (18%), MUC16 (18%), POT1 (16%) and TP53 (16%). UV-positive AS-HN harbored significantly higher tumor mutation burden than UV-negative cases (p = 0.0294). NanoString profiling identified three clusters with distinct tumor inflammation signature scores (p < 0.001). Spatial transcriptomics revealed topological profiles of the tumor microenvironment, identifying dominant but tumor-excluded inflammatory signals in immune-hot cases and immune foci even in otherwise immune-cold cases. In conclusion, spatial transcriptomics reveal the tumor immune landscape of angiosarcoma, and in combination with multi-omic information, may improve implementation of treatment strategies.

Aim: To assess the longitudinal pattern of pro-inflammatory cytokines and growth factors in serum up to 1 year following treatment for head and neck cancer. Materials and Methods: Patients with newly diagnosed, curable head and neck cancer were included (n = 30). The most common subsite was oropharynx (n = 13) followed by oral cavity (n = 9). Blood was drawn from all patients at regular intervals (before treatment, 7 weeks after the start of the treatment, and at 3 months and 1 year after termination of treatment) and analyzed for cytokines (Il-1β, Il-2, Il-4, Il-5, Il-6, Il-8, Il-10, GM-CSF, TNF-α, and IFN-γ) and growth factors (G-CSF, FGF-2, EGF, and VEGF). Results: The time point of the peak level of pro-inflammatory cytokines was 7 weeks after start of treatment which corresponded for the majority of patients with termination of radiotherapy or chemoradiotherapy. Patients undergoing chemoradiotherapy exhibited a significant increase of IL-1β, IL-6, and IL-10 at 7 weeks as compared to pre-treatment levels. At 1 year after termination of treatment four patients experienced recurrence of disease while 26 patients were considered disease-free. The patients with recurrence had significantly higher levels of IL-1β, IL-6, IL-8, and IL-10 at 7 weeks after the start of treatment than patients without recurrence. Correlated with T stadium patients with T3-T4 had higher levels of IL-1β and IL-8 than patients with T1-T2 7 weeks after the start of treatment. Conclusions: The observed immune response in this explorative study demonstrates that chemoradiotherapy may induce not only a local treatment effect on the immune system but also effects far outside the irradiated field. The result of the study indicates that analysis of a pro-inflammatory panel of cytokines in serum at 7 weeks after the start of treatment could be of prognostic value in patients with head and neck cancer. Further study of a larger cohort could help identify patients at larger risk for recurrent disease with measurements of pro-inflammatory cytokines under and after treatment.

No abstract available

Whether "periodontal disease" can be considered as an independent risk factor for head and neck cancer (HNC) remains controversial. The aim of the current meta-analysis was to quantitatively assess this relationship in order to determine whether this represents a true risk factor, with implications for cancer prevention and management. PubMed, Scopus, and Embase databases were systematically searched. Selective studies were reviewed, and meta-analysis was performed to estimate the pooled odds ratio (OR) with 95% confidence intervals (CIs) on eligible studies using a random effects model. In total, 21 eligible observational studies (4 cohorts and 17 case-controls) were identified for qualitative synthesis after a review of 1051 articles. Significant heterogeneity could be identified in measures utilized for reporting of periodontal disease. Meta-analysis performed on nine studies that employed objective measures for reporting periodontal disease demonstrated a significant association between periodontal disease and HNC [OR 3.17, 95% CI, 1.78-5.64]. A diseased periodontium represents an independent risk marker, and a putative risk factor, for HNC. Prospective studies with standardized measures of periodontal disease severity and extent, integrated with microbiological and host susceptibility facets, are needed to elucidate the mechanisms of this positive association and whether treatment of the former influences the incidence and outcomes for HNC.

Despite the relative effectiveness of standard cancer treatment strategies, head and neck cancer (HNC) is still considered one of the leading causes of mortality and morbidity. While selected bioactive compounds of plant origin reveal a pro-apoptotic effect, kaempferol and fisetin flavonols have been reported as potential anti-cancer agents against malignant neoplasms. To date, their exact role in signaling pathways of head and neck cancer cells is largely unknown. Based on the various methods of cytotoxicity testing, we elucidated that kaempferol and fisetin inhibit proliferation, reduce the capacity of cell migration, and induce apoptosis in SCC-9, SCC-25, and A-253 HNC cells in a dose-dependent manner in vitro (p < 0.05, fisetin IC50 values of 38.85 µM, 62.34 µM, and 49.21 µM, and 45.03 µM, 49.90 µM, and 47.49 µM for kaempferol-SCC-9, SCC-25, and A-253, respectively). The obtained results showed that exposure to kaempferol and fisetin reduces Bcl-2 protein expression, simultaneously leading to the arrest in the G2/M and S phases of the cell cycle. Kaempferol and fisetin inhibit cell proliferation by interfering with the cell cycle, which is strongly associated with the induction of G2/M arrest, and induce apoptosis by activating caspase-3 and releasing cytochrome c in human HNC cells. In addition, investigating flavonols, by inhibiting anti-apoptotic proteins from the Bcl-2 family and damaging the mitochondrial transmembrane potential, increased the level of cytochrome c. While flavonols selectively induce apoptosis of head and neck cancer cells, they may support oncological therapy as promising agents. The discovery of new derivatives may be a breakthrough in the search for effective chemotherapeutic agents with less toxicity and thus fewer side effects.

The Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common human cancer, causing 350,000 individuals die worldwide each year. The overall prognosis in HNSCC patients has not significantly changed for the last decade. Complete understanding of the molecular mechanisms in HNSCC carcinogenesis could allow an earlier diagnosis and the use of more specific and effective therapies. In the present study we used deep sequencing to characterize small non-coding RNAs (sncRNAs) in serum from HNSCC patients and healthy donors. We identified, for the first time, a multi-marker signature of 3 major classes of circulating sncRNAs in HNSCC, revealing the presence of circulating novel and known miRNAs, and tRNA- and YRNA-derived small RNAs that were significantly deregulated in the sera of HNSCC patients compared to healthy controls. By implementing a triple-filtering approach we identified a subset of highly biologically relevant miRNA-mRNA interactions and we demonstrated that the same genes/pathways affected by somatic mutations in cancer are affected by changes in the abundance of miRNAs. Therefore, one important conclusion from our work is that during cancer development, there seems to be a convergence of oncogenic processes driven by somatic mutations and/or miRNA regulation affecting key cellular pathways.

Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent and aggressive neoplasms of this anatomical region. Many studies evaluated the neoplastic cells, but few works focused on the tumor microenvironment. In the present study, we investigated the distribution and mast cell density (MCD) in malignant and premalignant lesions of the oral cavity, tongue, pharynx, and larynx. There were analyzed 52 specimens of HNSCC, and 15 biopsies taken from patients with dysplasia. Results were compared with those found in a control group of 10 biopsies of oral mucosa from patients with inflammatory diseases. Slides stained with Hematoxylin-Eosin were used for the histopathological diagnosis and grade, and mast cells (MCs) were identified by immunohistochemistry, using anti-MC tryptase. MCs were counted using a method similar to that proposed for microvessel density. We found a significant increase in the number of MCs from the normal oral mucosa until overt carcinoma. Unlike normal tissues, in HNSCC, many MCs were found between tumor cells. We found no relationship between MCs and blood vessels in the tumor area. A significant statistical correlation was found between dysplastic and malignant tumors, but not between tumors with a different grade. Also, it was not found relationship between MCD and the anatomical location of the tumor. Based on these results, we believe that MCD evaluated by anti-MC tryptase is an independent factor of prognosis and reflects an unfavorable outcome.

Immune checkpoint molecules are important targets in cancer immunotherapy, but their association with prognosis in patients with head and neck cancer is controversial. In this meta-analysis, we searched for 12 immune checkpoint molecules in the PubMed, Embase and Cochrane Library databases and retrieved 52 studies with 7127 participants. Among the molecules included in the search, indoleamine 2, 3-dioxygenase (IDO), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) met the inclusion criteria for further analysis. Higher expression of IDO was associated with poorer overall survival in head and neck cancer patients (P = 0.011), but higher expression of PD-L1 correlated with better overall survival specifically in nasopharyngeal carcinoma patients (P = 0.01). In a sensitivity analysis, higher PD-L1 expression correlated with better progression-free survival (P = 0.043), and was associated with better overall survival in Caucasian subjects (P = 0.02), nasopharyngeal carcinoma patients (P = 0.015), and studies with small sample sizes (P = 0.001). PD-1 had no prognostic significance. There was no publication bias affecting the results. Thus, among the immune checkpoint molecules, IDO and PD-L1 are potential prognostic predictors in head and neck cancer.