Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications.

Strongly associated with tobacco use, heavy alcohol consumption, and with high-risk human papillomavirus (HPV) infection, head and neck squamous cell carcinoma (HNSCC) is a frequently lethal, heterogeneous disease whose pathogenesis is a multistep and multifactorial process involving genetic and epigenetic events. The majority of HNSCC patients present with locoregional advanced stage disease and are treated with combined modality strategies that can markedly impair quality of life and elicit unpredictable results. A large fraction of those who undergo locoregional treatment and achieve a complete response later develop locoregional recurrences or second field tumors. Biomarkers that are thus able to stratify risk and enable clinicians to tailor treatment plans and to personalize post-therapeutic surveillance strategies are highly desirable. To date, only HPV status is considered a reliable independent predictor of treatment response and survival in patients with HNSCC arising from the oropharyngeal site. Recent studies suggest that telomere attrition, which may be an early event in human carcinogenesis, and telomerase activation, which is detected in up to 90 % of malignancies, could be potential markers of cancer risk and disease outcome. This review examines the current state of knowledge on and discusses the implications linked to telomere dysfunction and telomerase activation in the development and clinical outcome of HNSCC.

Non-endemic locoregionally advanced nasopharyngeal carcinoma: long-term outcome after induction plus concurrent chemoradiotherapy in everyday clinical practice.

The aim of this study was to evaluate the long-term outcome in Caucasian population of a non-endemic area treated for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) with multidrug platinum-based induction plus concurrent chemoradiotherapy (IC/CCRT) in everyday clinical practice setting. Between May 1990 and July 2007, 75 patients with newly diagnosed histologically confirmed LA-NPC were given IC/CCRT. All patients were judged suitable to receive conventional fractionated course of radiotherapy to a dose of 70 Gy in 35 fractions (2 Gy per fraction). The intended chemotherapy regimen consisted in one cycle of induction chemotherapy followed by radiotherapy concomitantly with two cycles of chemotherapy. Each cycle of chemotherapy included cis-platinum, 100 mg/m(2), and continuous infusion of 5-fluorouracil, 1,000 mg/m(2)/d for 5 days. The median follow-up in survivors was 122 months. The complete response rate after CCRT was 90.7%. The main limiting toxicity was grade 3 and 4 pharyngeal mucositis (46.7%). Five-year cumulative rate of locoregional control (LRC), distant control (DC), overall survival (OS), and event-free survival (EFS) was 80.1, 82.2, 72.0, and 66.7%, respectively. Ten-year cumulative rate of LRC, DC, OS, and EFS was 73.4, 73.8, 57.1, and 55.2%, respectively. At multivariate analysis advanced N category and low hemoglobin levels at baseline were found to be independent predictors for both worse OS and EFS. In everyday clinical practice, treating LA-NPC with cisplatin-based IC/CCRT was relatively safe and long-term effective.

Deep neck infections: a study of 365 cases highlighting recommendations for management and treatment.

The aims of this investigation were to review the clinical behavior of deep neck infections (DNIs) treated in our institution in order to identify the predisposing factors of life-threatening complications and propose valuable recommendations for management and treatment. A total of 365 adult patients with DNIs were retrospectively identified. One-hundred and thirty-nine patients (38.1%) underwent surgical drainage. Overall, 226 patients (61.9%) responded effectively to intravenous antimicrobial therapy only. There were 67 patients (18.4%) developing life-threatening complications. Diabetes mellitus (odd ratio 5.43; P < 0.001) and multiple deep neck spaces involvement (odd ratio 4.92; P < 0.001) were the strongest independent predictors of complications. The mortality rate was 0.3%. Airway obstruction and descending mediastinitis are the most troublesome complications of DNIs. In selected patients, a trial of intravenous antibiotic therapy associated with an intensive computed tomography-based wait-and-watch policy may avoid an unnecessary surgical procedure. However, about one-fourth of patients present significant comorbidities, which may negatively affect the course of the infection. In these cases and in patients with large or multiple spaces infections, a more aggressive surgical strategy is mandatory.

The importance of early detection of ENT symptoms in mild-to-moderate COVID-19.

OBJECTIVES: Patients with coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may present with a wide range of symptoms. In this paper, a detailed characterisation of mild-to-moderate ear, nose nd throat (ENT) symptoms is presented with the aim of recognising the disease early to help reduce further spread and progression. METHODS: A total of 230 cases testing positive for SARS-CoV-2 and 134 negative controls were recruited for a case-control analysis. Symptoms were analysed using the Acute Respiratory Tract Infections Questionnaire, while other symptoms were investigated by ad hoc questions. RESULTS: Among the study samples (n = 364), 149 were males and 215 were females with age ranging from 20 to 89 years (mean 52.3). Four main groups of symptoms were obtained: influenza-like symptoms, ENT-symptoms, breathing issues and asthenia-related symptoms, representing 72%, 69%, 64% and 53% of overall referred clinical manifestations, respectively. ENT symptoms, breathing issues and influenza-like symptoms were associated with positivity to SARS-CoV-2, whereas asthenia-related symptoms did not show a significant association with SARS-CoV-2 infection after controlling for other symptoms, comorbidities and demographic characteristics. CONCLUSIONS: ENT symptoms are equally represented with influenza-like ones as presenting symptoms of COVID-19. Patients with ENT symptoms should be investigated for early identification and prevention of SARS-CoV-2 spread.

Detection of HPV16/18 E6 Oncoproteins in Head and Neck Squamous Cell Carcinoma Using a Protein Immunochromatographic Assay.

OBJECTIVES/HYPOTHESIS: The accurate diagnostic assessment of clinically relevant human papillomavirus (HPV) infections in patients with head and neck squamous cell carcinoma represents an urgent unmet medical need. The aim of this study was to determine feasibility, accuracy, and clinical significance of HPV16/18 E6 oncoprotein detection on cytological specimens from oropharyngeal squamous cell carcinoma (OPSCC) and neck lymph node metastasis of SCC from unknown primary tumor (CUP) via a protein immunochromatographic assay. STUDY DESIGN: Cross-sectional study. METHODS: Cytological specimens from primary tumor and neck metastases were collected from 34 patients with OPSCC or CUP and applied to a lateral flow format test that detects HPV16 and HPV18 E6 oncoproteins. E6 oncoprotein positivity or negativity in these specimens was compared to the specimens' "HPV-driven" reference status, defined by presence of HPV-DNA in combination with p16INK4a overexpression and/or HPV E6 seropositivity. RESULTS: Eighteen of 29 OPSCC (62%) and three of five CUP (60%) were HPV-driven according to our reference method. The E6 oncoprotein lateral flow test had a sensitivity of 94% (95% CI: 70%-100%) and a specificity of 100% (95% CI: 66%-100%) on primary tumor, and a sensitivity of 88% (95% CI: 64%-99%) and a specificity of 100% (95% CI: 74%-100%) on neck metastases. Test agreement between the E6 lateral flow test and the clinical reference method, HPV-DNA plus p16INK4a was excellent, both for primary lesion and neck metastases. CONCLUSIONS: We found the detection of HPV16/18 E6 oncoproteins to be a feasible, highly reliable, and low-invasive method to assess "HPV-driven" status in OPSCC and CUP. LEVEL OF EVIDENCE: II Laryngoscope, 131:1042-1048, 2021.

TERT Promoter Mutations and rs2853669 Polymorphism: Useful Markers for Clinical Outcome Stratification of Patients With Oral Cavity Squamous Cell Carcinoma.

OBJECTIVE: To date, no useful prognostic biomarker exists for patients with oral squamous cell carcinoma (OCSCC), a tumour with uncertain biological behaviour and subsequent unpredictable clinical course. We aim to investigate the prognostic significance of two recurrent somatic mutations (-124 C>T and -146 C>T) within the promoter of telomerase reverse transcriptase (TERT) gene and the impact of TERT single nucleotide polymorphism (SNP) rs2853669 in patients surgically treated for OCSCC. METHODS: The genetic frequencies of rs2853669, -124 C>T and -146 C>T as well as the telomere length were investigated in 144 tumours and 57 normal adjacent mucosal (AM) specimens from OCSCC patients. RESULTS: Forty-five tumours harboured TERT promoter mutations (31.3%), with -124 C>T and -146 C>T accounting for 64.4% and 35.6% of the alterations respectively. Patients with -124 C>T TERT promoter mutated tumours had the shortest telomeres in the AM (p=0.016) and showed higher risk of local recurrence (hazard ratio [HR]:2.75, p=0.0143), death (HR:2.71, p=0.0079) and disease progression (HR:2.71, p=0.0024) with the effect being potentiated by the co-occurrence of T/T genotype of rs2853669. CONCLUSION: -124 C>T TERT promoter mutation as well as the T/T genotype of the rs2853669 SNP are attractive independent prognostic biomarkers in patients surgically treated for OCSCC, with the coexistence of these genetic variants showing a synergistic impact on the aggressiveness of the disease.

TERT promoter hotspot mutations and their relationship with TERT levels and telomere erosion in patients with head and neck squamous cell carcinoma.

PURPOSE: To evaluate the prevalence of two recurrent somatic mutations (-124 C>T and -146 C>T) within the promoter of the gene encoding telomerase reverse transcriptase (TERT) as well as their relationship with TERT level, telomeres length, and outcome in patients with head and neck squamous cell carcinomas (HNSCCs). METHODS: We evaluate the prevalence of TERT promoter mutations, TERT levels, and telomere length in paired cancer tissue and adjacent mucosa (AM) in a series of HNSCCs. RESULTS: Cancer tissue and AM specimens from 105 patients were analyzed. Telomere length and TERT mRNA levels were estimated using real-time polymerase chain reaction. TERT promoter mutations were assessed using Sanger sequencing. Out of 105 cases, 101 were considered suitable for the analysis. TERT promoter harbored mutations in 12 tumors (11.9%), with -124 C>T and -146 C>T accounting for 83.3% and 16.7% of the alterations, respectively. No mutations were detected in AM samples. The prevalence of TERT promoter mutations was significantly higher in oral cavity SCCs (10 out of 27 tumors; 37%), and telomere length in AM was shorter in patients with tumors carrying TERT promoter mutations than in patients with unmutated TERT promoter cancers (p = 0.023). TERT levels in tumor did not significantly differ according to the mutational status of TERT promoter. No significant association was found between TERT promoter status and overall survival. CONCLUSION: TERT promoter mutations are most likely a late event in tumor development, occurring in a context of critically short telomeres, mostly in patients with oral cavity SCC. TERT levels, but not TERT promoter mutational status impact clinical outcome.

Predictive and prognostic significance of telomerase levels/telomere length in tissues and peripheral blood in head and neck squamous cell carcinoma.

A growing body of evidence indicates that the expression of TERT, the catalytic subunit of telomerase, is a biological marker of progression in several cancers. We investigated the predictive and prognostic role of TERT levels and telomere length in tissues and peripheral blood in patients with head and neck squamous cell carcinoma (HNSCC). High TERT levels in cancer tissues were independently associated with worse response to therapy (odds ratio [OR]:6.26), regional failure (hazard ratio [HR]:5.75), progression (HR:2.12), and death (HR:3.53). Longer telomeres in the mucosa surrounding the tumor (SM) were independently associated with a lower risk of mucosal failure (HR:0.39). While telomere length in peripheral blood mononuclear cells (PBMC) significantly decreased with age, no correlation was found between age and telomere length in SM. No associations were found between TERT levels in plasma and telomere length in PBMC and the prognostic variables. High levels of TERT transcripts in cancer cells represent a reliable prognostic marker for identifying HNSCC patients with risk of progression. The altered relationship of telomere length to age in SM compared with PBMC suggests that in a subset of cases the phenotypically normal SM constitutes an acquired telomere-shortened epithelial field prone to genetic instability.

Absence of disruptive TP53 mutations in high-risk human papillomavirus-driven neck squamous cell carcinoma of unknown primary.

BACKGROUND: To enforce the evidence for causality between high-risk human papillomavirus (hrHPV) infections and neck squamous cell carcinoma from unknown primary (NSCCUP) and provide biological basis for treatment de-intensification, we searched for TP53 mutations in association with HPV status. METHODS: TP53 mutations were searched for by amplification of exons 4 to 10. RESULTS: Of the 70 NSCCUP, 27 (39%) harbored HPV infection. TP53 sequencing resulted in the identification of 19 patients harboring single mutations including 16 disruptive alterations (84%). The association of TP53 mutations and HPV could be evaluated in 48 NSCCUP including those with disruptive mutation in any exon (n = 16) and those without mutations but with complete sequence of exons 4 to 9 (n = 32): no disruptive mutations were found in the 17 HPV-driven NSCCUP but in 16 of the 31 non-HPV-driven NSCCUP (P = .0002). CONCLUSION: In a fraction of cases, NSCCUP is an HPV-driven entity harboring wild-type TP53 gene or nondisruptive TP53 mutations. HPV-driven NSCCUP might benefit from treatment de-intensification.

Head and Neck Extranodal Interdigitating Dendritic Cell Sarcoma: Case Report and Review of the Literature.

Interdigitating dendritic cell sarcoma (IDCS) is an exceedingly rare neoplasm originating from professional antigen presenting cells normally located in the T zone of the lymph node. The purpose of this report was to describe the first case of the IDCS of the submandibular gland and perform a review of the literature of head and neck IDCS. We present a case of an 81-year-old man with a 5 months history of slowly enlarging painless mass in right submandibular region. Fine needle aspiration cytology was suggestive of squamous cell carcinoma. The patient underwent surgical resection of the right submandibular gland and neck dissection. A malignant spindle cell proliferation involving the submandibular gland and colonizing one laterocervical lymph node was found. Morphology and immunophenotype prompted a differential diagnosis of a metastatic spindle cell melanoma versus an IDCS. Transmission electron microscopy was performed and supported a diagnosis of IDCS. The diagnosis of IDCS is a challenging task and may require a large array of techniques.