Glendon Gardner

Human papillomavirus outcomes in an access-to-care laryngeal cancer cohort.

Objective. Human papillomavirus (HPV), particularly HPV16, is a causative agent for 25% of head and neck squamous cell cancer, including laryngeal squamous cell cancer (LSCC). HPV-positive (HPV+ve) patients, particularly those with oropharyngeal SCC, have improved prognosis. For LSCC patients, this remains to be established. The goal was to determine stage and survival outcomes in LSCC in the context of HPV infection. Study Design. Historical cohort study. Setting. Primary care academic health system. Subjects and Methods. In 79 patients with primary LSCC, HPV was determined using real-time quantitative polymerase chain reaction. χ2 or Fisher exact test was used to test the association of HPV+ve with 21 risk factors including race, stage, gender, age, smoking, alcohol, treatment, and health insurance. Kaplan-Meier and log-rank tests were used to study the association of HPV and LSCC survival outcome. Results. HPV16 was detected in 27% of LSCC patients. Caucasian American (CA) patients had higher HPV prevalence (33%) than did African American (AA) LSCC patients (16%; P = .058). HPV was significantly associated with gender (P = .016) and insurance type (P = .001). There were no differences in survival between HPV+ve and HPV-negative (HPV-ve) patients. There was no association with HPV and other risk factors including stage (early vs late). Conclusion. We found a high prevalence of HPV in men and a lower prevalence of HPV infection in AA compared with CA. Despite the strikingly better survival of patients with HPV+ve oropharyngeal tumors, even when adjusted for smoking, this correlation does not seem to hold true in the larynx. Larger multiethnic LSCC cohorts are needed to more clearly delineate HPV-related survival across ethnicities.

The cost of vocal fold paralysis after thyroidectomy.

To determine the added cost of care and analyze risk factors in patients who suffered vocal fold paralysis (VFP) after thyroid surgery.

Epigenetic events underlie the pathogenesis of sinonasal papillomas

Benign inverted papillomas have been reported as monoclonal but lacking common genetic alterations identified in squamous cell carcinoma of the head and neck. Epigenetic changes alter the heritable state of gene expression and chromatin organization without change in DNA sequence. We investigated whether epigenetic events of aberrant promoter hypermethylation in genes known to be involved in squamous head and neck cancer underlie the pathogenesis of sinonasal papillomas. Ten formalin-fixed paraffin DNA samples from three inverted papilloma cases, two exophytic (everted) papilloma cases, and two cases with inverted and exophytic components were studied. DNA was obtained from microdissected areas of normal and papilloma areas and examined using a panel of 41 gene probes, designed to interrogate 35 unique genes for aberrant methylation status (22 genes) using the methylation-specific multiplex-ligation-specific polymerase assay. Methylation-specific PCR was employed to confirm aberrant methylation detected by the methylation-specific multiplex-ligation-specific polymerase assay. All seven cases indicated at least one epigenetic event of aberrant promoter hypermethylation. The CDKN2B gene was a consistent target of aberrant methylation in six of seven cases. Methylation-specific PCR confirmed hypermethylation of CDKN2B. Recurrent biopsies from two inverted papilloma cases had common epigenetic events. Promoter hypermethylation of CDKN2B was a consistent epigenetic event. Common epigenetic alterations in recurrent biopsies underscore a monoclonal origin for these lesions. Epigenetic events contribute to the underlying pathogenesis of benign inverted and exophytic papillomas. As a consistent target of aberrant promoter hypermethylation, CDKN2B may serve as an important epigenetic biomarker for gene reactivation studies.

Delineating an epigenetic continuum in head and neck cancer

A tissue field of somatic genetic alterations precedes the histopathological phenotypic changes of carcinoma. Genomic changes could be of potential use in the diagnosis and prognosis of pre-invasive squamous head and neck carcinoma (HNSCC) lesions and as markers for cancer risk assessment. Studies of sequential molecular alterations and genetic progression of pre-invasive HNSCC have not been clearly defined. Studies have shown recurring alterations at chromosome 9p21 (location of the CDKN2A) and TP53 mutations in the early stages of HNSCC. However, gene silencing via hypermethylation is still a relatively new idea in the development of HNSCC and little is known about the contribution of epigenetics to the development of neoplasia, its transformation, progression, and recurrence in HNSCC. This review examines the role of promoter hypermethylation of tumor suppressor genes in the progression continuum from benign papillomas to malignancy in HNSCC.

Vocal Fold Vibration After Photofrin-Mediated Photodynamic Therapy for Treatment of Early-Stage Laryngeal Malignancies

OBJECTIVE/HYPOTHESIS To analyze vocal fold vibration after photofrin-mediated photodynamic therapy (PDT) for the treatment of Tis and T1N0M0 squamous cell carcinoma (SqCCa) tumors of the larynx. It was hypothesized that key attributes of vocal fold vibration would return to baseline within 1-6 months of treatment. STUDY DESIGN Retrospective. METHODS Laryngovideostroboscopic data were retrospectively analyzed for eight patients with Tis-T1N0M0 SqCCa tumors of the larynx treated with photofrin-mediated PDT. Baseline and posttreatment videostroboscopy images of select vibratory characteristics of the vocal folds were randomized and analyzed by a speech-language pathologist and fellowship-trained laryngologist specializing in voice disorders. RESULTS Significant improvement in mucosal wave (P=0.003) and amplitude of vibration (P=0.004) occurred at greater than or equal to 20 weeks post-PDT compared with baseline. Comparing results within 5 weeks postprocedure to 10-19-weeks postprocedure revealed significant improvement in amplitude of vibration (P=0.013) and nonvibrating portion of the vocal fold (P=0.020). Comparing results within 5-weeks postprocedure to 20 or more weeks postprocedure revealed significant improvement in amplitude of vibration (P=0.001), mucosal wave (P=0.001), and nonvibrating portion of the effected fold (P=0.001). CONCLUSION Photofrin-mediated PDT allows for preservation of function and structure of the larynx without systemic toxicity; however, it may take 4-5 months or more for key vibratory characteristics of the vocal folds to recover posttreatment.

Abstract 650: IGSF4 methylation is an independent marker of HPV positive OPSCC.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Human papilloma virus (HPV) is a known causative agent for oropharyngeal squamous cell cancer (OPSCC). The goal of our study was to determine the relationship of HPV type 16 (HPV16) infection and methylation status in an OPSCC cohort. HPV16 was detected using real-time quantitative PCR (qPCR) in a retrospective cohort of 111 primary OPSCC. A 24 tumor suppressor gene candidate panel was assessed for methylation using the methylation specific-multiplex ligation-dependent probe amplification (MS-MLPA) assay. Univariate associations with HPV and gene methylation, age, gender, race and smoking were analyzed using Fishers exact tests and logistic regression. A final multiple logistic regression model, to include patient characteristics and genes significant on univariate analysis, was built using backwards selection of genes. Statistical significance was set at p<0.05 and all analyses were done using SAS 9.2. In univariate analyses, Caucasian American (CA) OPSCC were more likely to be HPV positive as compared to African American (AA) OPSCC (OR=3.01, 95% CI 1.28, 7.07, p=0.011). Also, smoking (never vs current) [OR=3.60 (1.06, 12.24), p=0.04], and TIMP3, DAPK1, ESR1, and IGSF4 were associated with HPV positive status (OR=5.03, p=0.021; OR=3.71, p=0.04; OR=5.03, p=0.021; OR=7.68, p=0.012, respectively). The final model, after controlling for patient characteristics and after backward elimination of genes, indicated IGSF4 methylation is an independent predictor of HPV positive status [OR=7.07 (1.22, 40.79), p=0.029]. HPV infection status is independently associated with methylation of IGSF4, indicating interplay of DNA methylation and HPV in OPSCC pathogenesis. Citation Format: Kang Mei Chen, Josena K. Stephen, Meredith Mahan, Shaleta Havard, George Divine, Glendon Gardner, Vanessa P. Schweitzer, Maria J. Worsham. IGSF4 methylation is an independent marker of HPV positive OPSCC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 650. doi:10.1158/1538-7445.AM2013-650