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Objectives/hypothesis: Early-stage laryngeal squamous cell carcinoma (LSCC) has yielded local control rates of 75% after radiotherapy. DNA methylation, in which DNA methyltransferases play an important role, has influence on tumorigenesis. In this study, we investigated the association between the expression of DNA methyltransferase 1 (DNMT1) and local control in early-stage LSCC treated with radiotherapy., Study Design: Retrospective cohort study., Methods: We analyzed a well-defined homogeneous series of 125 LSCC patients treated with radiotherapy with curative intent. The association of immunohistochemical expression of DNMT1 with local control was evaluated using Cox proportional hazard regression models., Results: With a median follow-up of 58 months, 29 local recurrences (23%) were observed. On univariate analysis, worse local control was associated with high DNMT1 expression (hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.10-6.01). Also, higher T-stage (HR 2.48, 95% CI 1.06-5.80) and positive N-status (HR 2.62, 95% CI 1.06-6.47) were associated with worse local control. Multivariate Cox regression demonstrated that high DNMT1 (HR 2.81; 95% CI 1.20-6.58) was independently associated with worse local control., Conclusions: We found an association between high DNMT1 expression and worse local control in a homogeneous well-defined cohort of early-stage LSCC patients treated with definitive radiotherapy. The association between DNA methylation status as determined by DNMT1 expression and local control suggests that DNMT1 acts as a potential prognostic tumor marker in treatment decision-making in early-stage laryngeal carcinoma., Level of Evidence: NA Laryngoscope, 132:801-805, 2022., (© 2021 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objective/hypothesis: Comparing detection and extension of malignant tumors by flexible laryngoscopy in the outpatient setting with laryngoscopy under general anesthesia using both White Light Imaging (WLI) and Narrow Band Imaging (NBI)., Study Design: Prospective study., Methods: Two hundred and thirty-three patients with laryngeal and pharyngeal lesions underwent flexible and rigid laryngoscopy, with both WLI and NBI. Extension of malignant lesions (n = 132) was compared between both techniques in detail., Results: Sensitivity of NBI during flexible endoscopy (92%), was comparable with that of WLI during rigid endoscopy (91%). The correlation of tumor extension between flexible and rigid laryngoscopy was high (r s  = 0.852-0.893). The observed tumor extension was significantly larger when using NBI in both settings. The use of NBI during flexible laryngoscopy leads to upstaging (12%) and downstaging (2%) of the T classification., Conclusions: NBI during flexible laryngoscopy could be an alternative to WLI rigid endoscopy. NBI improves visualization of tumor extension and accuracy of T staging., Level of Evidence: 3 Laryngoscope, 131:E2222-E2231, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: In early stage laryngeal squamous cell carcinoma (LSCC) radiotherapy with curative intent is a major treatment modality. TNM classification is used to define patients eligible for radiotherapy. Studies in early stage glottic LSCC identified several predictive biomarkers associated with local control. However, we recently reported that this predictive value could not be confirmed in supraglottic LSCC., Objective: To examine whether clinical behavior and protein expression patterns of these biomarkers differ between glottic and supraglottic LSCC., Study Design: Retrospective cohort study., Methods: Tumor tissue sections of 196 glottic and 80 supraglottic T1-T2 LSCC treated primarily with RT were assessed immunohistochemically for expression of pAKT, Ki-67 and β-Catenin. Expression data of HIF-1α, CA-IX, OPN, FADD, pFADD, Cyclin D1, Cortactin and EGFR in the same cohort of glottic and supraglottic LSCC, were retrieved from previously reported data. The relationship between glottic and supraglottic sublocalization and clinicopathological, follow-up, and immunohistochemical staining characteristics were evaluated using logistic regression and Cox regression analyses., Results: Glottic LSCC were correlated with male gender (P = .001), hoarseness as a primary symptom (P < .001), T1 tumor stage (P < .001), negative lymph node status (P < .001), and an older age at presentation (P = .004). Supraglottic LSCC patients developed more post-treatment distant metastasis when adjusted for gender, age, and T-status. While supraglottic LSCC was associated with higher expression of HIF-1α (P = .001), Cortactin (P < .001), EGFR (P < .001), and Ki-67 (P = .027), glottic LSCC demonstrated higher expression of CA-IX (P = .005) and Cyclin D1 (P = .001)., Conclusion: Differences in clinicopathological and immunohistochemical staining characteristics suggest that T1-T2 glottic and supraglottic LSCC should be considered as different entities., Level of Evidence: N/A. Laryngoscope, 2020., (© 2020 The Authors. The Laryngoscope published by Wiley Periodicals, Inc. on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: Most early stage laryngeal squamous cell carcinomas (LSCC) are treated with radiotherapy. Discovery of new biomarkers are needed to improve prediction of outcome after radiotherapy and to identify potential targets for systemic targeted therapy. The ataxia telangiectasia mutated (ATM) gene plays a critical role in DNA damage response induced by ionizing radiation., Methods: The prognostic value of immunohistochemical expression of pATM, pChk2, and p53 were investigated in 141 patients with T1-T2 LSCC curatively treated with external beam radiotherapy. Uni- and multivariable Cox regression analyses were performed to examine the relation between expression levels of markers and local control., Results: Local control was significantly worse in cases with high levels of pATM (HR 2.14; 95% CI, 1.08-4.24; P = .03). No significant associations with local control were found for pChk2 and p53 expression. The association of high pATM expression with poor local control was only found for supraglottic LSCC (HR 10.9; 95% CI, 1.40-84.4; P = .02)., Conclusion: Our findings suggest a potential role for ATM in response to radiotherapy in early stage supraglottic LSCC and imply ATM inhibition as a possibility to improve response to radiotherapy., Level of Evidence: NA Laryngoscope, 130: 1954-1960, 2020., (© 2020 The Authors. The Laryngoscope published by Wiley Periodicals, Inc. on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: The Fas-Associated Death Domain (FADD) gene is located in the chromosome 11q13-region and frequently is amplified in head and neck squamous cell carcinoma. Expression of FADD and its phosphorylated isoform (pFADD) have been associated with aggressive tumor growth, lymph node metastasis, and overall survival. Previously, we demonstrated that pFADD expression was related to a significantly improved local control in early stage (tumor [T]1 to T2) glottic laryngeal squamous cell carcinoma (LSCC). The aim of this study was to examine the prognostic value of pFADD and FADD in T1 to T2 supraglottic LSCC treated with primarily radiotherapy., Methods: Tumor tissue sections of 60 patients with T1 to T2 supraglottic LSCC treated with primarily radiotherapy were assessed immunohistochemically for expression of pFADD and FADD. Expression percentages and clinical parameters and their associations with clinical outcome were studied using Cox regression and Kaplan-Meier survival analyses. Expression percentages in supraglottic and glottic LSCC were compared using the Mann-Whitney U test., Results: Expression of pFADD and FADD in supraglottic and glottic LSCC did not significantly differ. In supraglottic LSCC, both pFADD and FADD did not show prognostic value for local control (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.98-1.03; HR 1.03, 95% CI 0.60-1.78, respectively) and overall survival (HR 0.99, 95% CI 0.98-1.01; HR 1.19, 95% CI 0.83-1.71 respectively). In this cohort, lymph node status was the best predictor for local control (HR 3.73, 95% CI 1.30-10.67)., Conclusion: In this homogeneous cohort of T1 to T2 supraglottic LSCC primarily treated with radiotherapy, lymph node status was associated with local recurrence, whereas the expression of pFADD was not., Level of Evidence: NA. Laryngoscope, 127:E301-E307, 2017., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: Recurrent respiratory papillomatosis (RRP) is a disease with a high disease burden. Few studies have assessed quality of life (QoL) of RRP patients. This study compares QoL of these patients with controls. Associations between QoL and sociodemographic and illness-related factors are examined, as is uptake of psychosocial care and speech therapy., Study Design: Prospective cross-sectional questionnaire research., Methods: Ninety-one RRP patients (response = 67%) from two university hospitals in the Netherlands and Finland completed the following patient reported outcome measures: (HADS), 15-dimensional health-related quality-of-life scale (15D), Voice Handicap Index (VHI) and the RAND 36-item health-related quality-of-life survey instrument (RAND-36) assessing health-related QoL and voice handicap, and they provided sociodemographic, illness-related, and allied healthcare use. Descriptive analyses, χ 2 tests, t tests, analysis of variance tests, and Pearson correlations were computed to describe the study population and to examine differences between groups., Results: RRP patients had significantly higher mean scores on depression, health-related QoL (15D) and on voice problems (VHI), and significantly lower mean scores on anxiety than controls. Dutch patients had more pain and a decreased general health perception (RAND-36) than controls. Dutch patients and older patients were more depressed, women were more anxious, older patients had lower health-related QoL, and smoking was significantly associated with voice handicap. Patients who had received psychosocial care had significantly higher HADS-depression mean scores than patients who did not receive psychosocial care., Conclusions: Having RRP has significant effect on voice-related QoL and depression, but has no negative effect on anxiety and health-related QoL. Risk factors for decreased functioning are different than previously hypothesized by many authors. Prevention should be aimed at these risk factors., Level of Evidence: 4. Laryngoscope, 127:1826-1831, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)