Malignant salivary gland tumors of the tongue: A multicenter REFCOR study.

Salivary carcinomas of minor salivary glands are very infrequent tumors. When located in the tongue, the therapeutic strategy may comprise upfront surgery, which may be debilitating, and/or (chemo-)radiotherapy. The aim of this study was to identify the prognostic factors of salivary carcinomas of the tongue in a population-based cohort. This retrospective multicentric study, based on the "Réseau d'Expertise Français sur les Cancers ORL Rares" (REFCOR), included all the patients with a salivary carcinoma of the tongue, diagnosed between January 2009 and December 2018. Dubious slides were reviewed by REFCOR expert pathologists to ensure diagnostic accuracy. Treatment was performed in accordance with national REFCOR recommendations. From 28 centers, 103 patients were included in this study. Median age at diagnosis was 63 years, and 60.2% were female. Tumors were adenoid cystic carcinomas (41.7%), mucoepidermoid carcinomas (30.1%), and other adenocarcinomas (28.2%). Primary treatment was surgical for 61.2% of them. Five-year overall survival (OS) and event-free survival (EFS) rates were 84.7% and 38.6%, respectively. In multivariable analysis, EFS was significantly worse in case of nonsurgical treatment, alcohol consumption, and glossotonsillar sulcus involvement. N-positive status was the only significant prognostic factor for OS in multivariable analysis. Salivary carcinomas of the tongue represent a heterogeneous group of rare tumors, with a high risk of recurrence. In this national cohort, surgery was associated with better EFS and N-status was the main independent prognostic factor for OS.

Association between sexual behaviour and head and neck cancer in the French West Indies: a case-control study based on an Afro-Caribbean population.

BACKGROUND: Worldwide, a significant proportion of head and neck cancers is attributed to the Human papillomavirus (HPV). It is imperative that we acquire a solid understanding of the natural history of this virus in head and neck squamous cell carcinoma (HNSCC) development. Our objective was to investigate the role of sexual behaviour in the occurrence of HNSCC in the French West Indies. Additionally, we evaluated the association of high risk of HPV (Hr-HPV) with sexual behaviour in risk of cancer. METHODS: We conducted a population-based case-control study (145 cases and 405 controls). We used logistic regression models to estimate adjusted odds-ratios (OR), and their 95% confidence intervals (CI). RESULTS: Compared to persons who never practiced oral sex, those who practiced at least occasionally had a lower HNSCC risk. First sexual intercourse after the age of 18 year was associated with a 50% reduction of HNSCC risk, compared to those who began before 15 years. HNSCC risk was significantly reduced by 60% among persons who used condoms at least occasionally. The associations for ever condom use and oral sex were accentuated following the adjustment for high-risk HPV (Hr-HPV). Oral Hr-HPV was associated with several sexual behaviour variables among HNSCC cases. However, none of these variables were significantly associated with oral HPV infections in the population controls. CONCLUSION: First intercourse after 18 years, short time interval since last intercourse and ever condom use were inversely associated with HNSCC independently of oral Hr-HPV infection. Sources of transmission other than sexual contact and the interaction between HPV and HIV could also play a role in HNSCC etiology.

Head and neck cancer risk factors in the French West Indies.

OBJECTIVES: The incidence of head and neck squamous cell carcinoma (HNSCC) in the French West Indies (FWI) is relatively high, despite a low prevalence of tobacco smoking and alcohol drinking. Little is known about other risk factors in the FWI. We assessed associations between several factors and HNSCC risk, their population attributable fractions (PAF) in the FWI, and compared these PAFs by subsite, sex and age. MATERIALS AND METHODS: We conducted a population-based case-control study (145 cases and 405 controls). We used logistic regression models to estimate adjusted odds-ratios (OR), PAFs and their 95% confidence intervals (CI). RESULTS: Tobacco smoking, alcohol drinking, high-risk HPV, family history of HNC, low BMI and several occupations and industries were significantly associated to the occurrence of HNSCC. The majority of HNSCC cases were attributable to tobacco smoking (65.7%) and alcohol (44.3%). The PAF for the combined consumption of tobacco and/or alcohol was 78.2% and was considerably larger in men (85%) than in women (33%). The PAFs for the remaining risk factors were 9% for family history of HNSCC, 9% for low BMI, 15% for high-risk HPV, and 25% for occupations. The overall PAF for all risk factors combined was 89.0% (95% CI = 82.0-93.2). The combined PAFs by sex were significantly greater in men (93.4%, 95% CI = 87.5-96.5) than in women (56.4%, 95% CI = 18.7-76.6). CONCLUSION: Tobacco and alcohol appeared to have the greatest impact on HNSCC incidence among the studied risk factors, especially among men. Prevention programs for HNSCC in the FWI should target tobacco and alcohol cessation, particularly in men. Future research should emphasise on the role of occupational factors to better understand this disease.

Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase ß and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma.

BACKGROUND: African Americans with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than whites. This study investigated the functional importance of ancestry-informative single-nucleotide polymorphisms (SNPs) in HNSCC and also examined the effect of functionally important genetic elements on racial disparities in HNSCC survival. METHODS: Ancestry-informative SNPs, RNA sequencing, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of expression quantitative trait locus (eQTL) analyses were also replicated with a Gene Expression Omnibus (GEO) data set. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated. RESULTS: Five ancestry-related SNPs were identified as cis-eQTLs in the DNA polymerase ß (POLB) gene (false discovery rate [FDR] < 0.01). The homozygous/heterozygous genotypes containing the African allele showed higher POLB expression than the homozygous white allele genotype (P < .001). A replication study using a GEO data set validated all 5 eQTLs and also showed a statistically significant difference in POLB expression based on genetic ancestry (P = .002). An association was observed between these eQTLs and OS (P < .037; FDR < 0.0363) as well as DFS (P = .018 to .0629; FDR < 0.079) for oral cavity and laryngeal cancer patients treated with platinum-based chemotherapy and/or radiotherapy. Genotypes containing the African allele were associated with poor OS/DFS in comparison with homozygous genotypes harboring the white allele. CONCLUSIONS: Analyses show that ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparities in patients diagnosed with oral cavity and laryngeal cancer. Cancer 2017;123:849-60. © 2016 American Cancer Society.

Prevalence of oral HPV infection among healthy individuals and head and neck cancer cases in the French West Indies.

PURPOSE: Human papillomavirus (HPV) is known to play a role in the development of head and neck squamous cell carcinomas (HNSCC) and to date, no study has reported on the association between oral HPV infection and HNSCC in the Caribbean. The objective was to determine the prevalence of oral HPV infection in the French West Indies (FWI), overall and by HPV genotype, among HNSCC cases and healthy population controls. METHOD: We used data from a population-based case-control study conducted in the FWI. The prevalence of oral HPV was estimated separately among 100 HNSCC cases (mean age 59 years) and 308 population controls (mean age 57 years). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using a logistic regression adjusting for age, sex, tobacco, and alcohol consumption, to assess the association between oral HPV infection and HNSCC. RESULTS: Prevalence of oral HPV infections was 26% in controls (30% in men and 14% in women) and 36% in HNSCC cases (36% in men, 33% in women). HPV52 was the most commonly detected genotype, in cases and in controls. The prevalence of HPV16, HPV33, and HPV51 was significantly higher in cases than in controls (p = 0.0340, p = 0.0472, and 0.0144, respectively). Oral infection with high-risk HPV was associated with an increase in risk of HNSCC (OR 1.99, 95% CI 0.95-4.15). HPV16 was only associated with oropharyngeal cancer (OR 16.01, 95% CI 1.67-153.64). CONCLUSION: This study revealed a high prevalence of oral HPV infection in this middle-aged Afro-Caribbean population, and a specific distribution of HPV genotypes. These findings may provide insight into HNSCC etiology specific to the FWI.

[Mammary analog secretory carcinoma of the parotid gland]. / Carcinome salivaire sécrétoire, analogue des carcinomes sécrétoires mammaires.

Mammary analog secretory carcinoma (MASC) of the parotid gland is a rare and recently described lesion. We report the case of a 46-year-old man with a tumor of the parotid gland which was carried to the diagnosis of MASC. Diagnostic was confirmed by highlighting the ETV6-NTRK3 gene translocation. However, some morphologic and immunohistochemical features are suggestive of this entity. This carcinoma should be distinguished from its main differential diagnoses: acinic cell carcinoma and low grade cribriform cystadenocarcinoma.

Inhibitory effects of hepatocyte growth factor and interleukin-6 on transforming growth factor-beta1 mediated vocal fold fibroblast-myofibroblast differentiation.

OBJECTIVES: The role of myofibroblasts in vocal fold scarring has not been extensively studied, partly because of the lack of a robust in vitro model. The objective of this investigation was to develop and characterize a myofibroblast in vitro model that could be utilized to investigate the molecular mechanism of myofibroblast differentiation and function in injured vocal fold tissue. METHODS: Differentiation of human primary vocal fold fibroblasts (hVFFs) to myofibroblasts was stimulated with 5, 10, or 20 ng/mL of recombinant transforming growth factor-beta1 (TGF-beta1). Cultures were analyzed by immunofluorescence and Western blotting, with an alpha-smooth muscle actin (alpha-SMA) antibody used as a myofibroblast marker. Normal rabbit vocal folds were treated with 10 ng/mL of TGF-beta1 for 7 days for in vivo corroboration. The effects of interleukin-6 (IL-6) and hepatocyte growth factor (HGF) on myofibroblast differentiation were studied with Western blots. RESULTS: The hVFFs demonstrated positive alpha-SMA labeling in cells stimulated by 10 and 20 ng/mL TGF-beta1, indicating that hVFFs were capable of differentiation to myofibroblasts. Transforming growth factor-beta1 induced the largest increase in alpha-SMA at 10 ng/mL on day 5 of treatment. Both HGF and IL-6 suppressed the expression of TGF-beta1-induced alpha-SMA. CONCLUSIONS: Our work characterizes a useful in vitro model of TGF-beta1-mediated vocal fold fibroblast-myofibroblast differentiation. The extent of differentiation appears to be attenuated by HGF, suggesting a potential mechanism to support prior work indicating that HGF plays a protective role in reducing scar formation in vocal fold injuries. Paradoxically, IL-6, which has been shown to play a profibrotic role in dermal studies, also attenuated the TGF-beta1 response.

Joint effect of tobacco, alcohol, and oral HPV infection on head and neck cancer risk in the French West Indies.

We investigated the role of tobacco and alcohol consumption on the occurrence of head and neck squamous cell carcinomas (HNSCC), and the joint effects of these factors with oral human papillomavirus (HPV) infection in the French West Indies, in the Caribbean. We conducted a population-based case-control study (145 cases and 405 controls). We used logistic regression models to estimate adjusted odds ratios (OR) and their 95% confidence intervals (CI). Two-way interactions were assessed on both multiplicative and additive scales. Current smoking (OR = 11.6, 95% CI = 6.7-20.1), drinking more than five glasses of alcohol per day (OR = 2.7, 95% CI = 1.2-4.7), and oral infection with High-risk HPV (OR = 2.4, 95% CI = 1.1-5.0) were significantly associated with HNSCC. The combined exposure to tobacco and alcohol produced a significant synergistic effect on the incidence of HNSCC. Oral infection with High-risk HPV increased the risk of HNSCC in never smokers and nondrinkers. The effects of tobacco, alcohol, and of the combined exposure of tobacco and alcohol were substantially lower in HPV-positive than in HPV-negative HNSCC. This is the first case-control study to investigate the role of tobacco smoking, alcohol drinking and oral HPV infection in an Afro-Caribbean population. Although each of these risk factors has a significant effect, our findings indicate that tobacco and alcohol play a less important role in Hr-HPV-positive HNSCC. Further investigations are warranted notably on the interaction of these three risk factors by cancer site.

Prevalence and characteristics of HPV-driven oropharyngeal cancer in France.

BACKGROUND: France has one of the highest incidence of head and neck cancers in Europe. Despite this, the epidemiological impact of high-risk human papilloma virus (HR-HPV) remains poorly investigated. METHODS: We prospective assessed the proportion of oropharyngeal cancers due to HR-HPV in 15 hospitals throughout France. HPV-status was determined by p16-immunohistochemistry, and by detection of HPV-DNA using in situ hybridization. Cancers were classified as HPV-driven if both p16-immunohistochemistry and HPV-DNA assays were positive. Demographical and clinical features were recorded. RESULTS: 291 patients with palatine-tonsil or tongue-base cancers were recruited from March-2011 to July-2012. Of these, 43.1% of samples were p16-positive and 37.7% were positive for both p16 and HPV-DNA. Prognosis was significantly better in patients with HPV-driven cancers, with smoking negatively impacting patients' oncological outcomes. CONCLUSION: In France, more than a third of tonsillar and tongue base cancers are HPV-driven. More research concerning the evolution of HPV-driven cancers over time is needed.

Inflammatory cytokine responses to synthetic extracellular matrix injection to the vocal fold lamina propria.

OBJECTIVES: We determined cytokine profiles for tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, IL-1alpha, and IL-1beta after injection of a synthetic extracellular matrix into the vocal fold lamina propria. METHODS: Transcript expression of inflammatory cytokines was measured with real-time polymerase chain reaction on postoperative days 1, 3, 5, 10, and 21 in 25 rabbits that underwent bilateral vocal fold biopsy with Extracel-LG (Carbylan-GSX 5%) immediately injected into the wound in the left vocal fold and saline solution injected into the wound in the right vocal fold. Two unwounded normal rabbit larynges were also harvested for controls. RESULTS: Significantly elevated levels of TNF-alpha, IL-1beta, and IL-6 were measured on day 3 in a comparison between Extracel-LG-injected vocal folds and saline solution-injected control vocal folds and between Extracel-LG-injected vocal folds and normal vocal folds. All cytokine levels returned to baseline by day 21. CONCLUSIONS: A mild short-term inflammatory response was measured early after injection of a synthetic extracellular matrix into the vocal fold lamina propria.

Effect of a synthetic extracellular matrix on vocal fold lamina propria gene expression in early wound healing.

An improved understanding of molecular response in the vocal folds to a synthetic extracellular matrix (sECM) during early wound repair is essential for understanding functional improvement of the tissue and implementation of future tissue-engineering strategies. The present study used real-time reverse transcriptase polymerase chain reaction to measure transcript expression of selected markers (procollagen alpha 2 type I, fibronectin, fibromodulin, hyaluronan synthase 2, and hyaluronidase 2) in 20 rabbits that underwent vocal fold biopsy bilaterally. After the biopsy, Carbylan-GSX 5% was injected immediately into the left vocal fold, and saline was injected into the right vocal fold. Two unwounded normal rabbit larynges were also harvested. Animals were sacrificed at days 1, 3, 5, and 10 post-surgery. At days 1, 3, and 10, no significant differences were found between the Carbylan-GSX-treated and saline-treated groups. At day 5, significant differences in procollagen (p = 0.02), fibronectin (p = 0.02), and transforming growth factor beta1 (p = 0.02) between the Carbylan-GSX-treated and saline-treated groups were measured. The presence of a sECM in the wound bed during the early stages of repair amplified the normal rabbit vocal fold wound-healing response over a short period of time. This amplification provided an optimal environment for tissue regeneration and may lead to the recovery of the functional biomechanical properties of the vocal folds necessary for voice production.

Vocal fold tissue repair in vivo using a synthetic extracellular matrix.

Chemically modified hyaluronic acid (HA)-gelatin hydrogels have been documented to support attachment, growth, and proliferation of fibroblasts in vitro and to facilitate repair and engineering of tissues in vivo. The objective of this study was to determine the optimal composition of a synthetic extracellular matrix (sECM) that would promote wound repair and induce tissue regeneration in a rabbit vocal fold wound healing model. The sECM was formed using a thiol-modified semisynthetic glycosaminoglycan (GAG) derived of HA (Carbylan-SX) mixed with a thiolated gelatin derivative, co-cross-linked with poly(ethylene glycol) diacrylate to form Carbylan-GSX. Forty rabbits underwent vocal fold biopsy bilaterally. Rabbits were treated with Carbylan-SX, which lacks gelatin, or with Carbylan-GSX with different gelatin concentrations (2.5%, 5%, 10%, and 20%) via unilateral injection of the vocal fold at the time of biopsy. Saline was injected in the contralateral vocal fold as a control. Three weeks after biopsy and injection, animals were euthanized and mRNA levels of procollagen type 1, fibronectin, transforming growth factor beta 1 (TGF-beta1), fibromodulin, HA synthase 2, hyaluronidase 2, and tissue biomechanics were evaluated. Hyaluronidase mRNA levels were found to be significantly elevated in for Carbylan-GSX 20% w/w gelatin compared to controls. Both Carbylan-SX and Carbylan-GSX significantly improved tissue elasticity and viscosity. Carbylan-GSX containing 5% w/w gelatin showed the most promise as a scaffold material for vocal fold tissue regeneration.

Fine needle aspiration of the vocal fold lamina propria in an animal model.

OBJECTIVES: The development of a minimally invasive fine needle aspiration (FNA) technique for vocal fold (VF) biopsy would have far-reaching implications and applicability in laryngology. The objective of this study was to determine whether FNA of the VF lamina propria is feasible and whether it causes injury to the VF. METHODS: Unilateral VF FNA was performed with a 26-gauge needle on 20 rabbits. The FNA cell collection of the lamina propria was confirmed by cytology. Four weeks after the FNA, the rabbits were painlessly sacrificed and the larynges were harvested. Histologic analysis of the VF lamina propria included Masson's trichrome and elastin-van Gieson stains. The linear viscoelastic shear properties, elastic modulus, and viscous modulus of the tissue were measured. RESULTS: Compared to the contralateral normal VFs, those VFs that underwent FNA demonstrated no significant differences in levels of collagen (p = .17) and elastin (p = .94). Rheologically, the elastic shear modulus and viscous modulus did not significantly differ between the normal and FNA VFs (p = .9380 and p = .9359, respectively). CONCLUSIONS: Fine needle aspiration of the VF lamina propria is feasible without injury and offers a potentially promising, less invasive alternative to be developed for future diagnostic and therapeutic management of VF lesions.

Differential gene expression profiling of vocal fold polyps and Reinke's edema by complementary DNA microarray.

OBJECTIVES: Our purpose was to determine whether complementary DNA (cDNA) microarray analysis (MA) can establish distinct gene expression profiles for 2 phenotypically similar vocal fold lesions: Reinke's edema (RE) and polyps. Established transcript profiles can provide insight into the molecular and cellular processes involved in these diseases. METHODS: Eleven RE specimens and 17 polyps were analyzed with MA for 8,745 genes. Further MA profiling was attempted within each lesion group to identify molecular markers for reflux exposure and smoking. Prediction analysis was used to predict lesion classification for 2 unclassified samples. A real-time polymerase chain reaction was performed to corroborate MA transcript levels for selected significant genes. RESULTS: Sixty-five genes were found to differentiate RE and polyps (p = .0088). For RE, 19 genes were differentiated for reflux exposure (p = .016). No genes were found to differentiate smokers from nonsmokers. For polyps, no genes were found to differentiate for reflux (p = .16) and smoking (p = .565). Categorization of unclassified lesions was possible with a minimum of 13 genes. CONCLUSIONS: We demonstrate the feasibility of benign lesion classification based on MA. Microarray analysis is useful not only for improving diagnosis and classification of such lesions, but also for potentially generating prognostic indicators and targets for therapy.

Epidemiology and Characteristics of Kikuchi-Fujimoto Disease in the African-Descent Population of Martinique, French West Indies.

OBJECTIVE: To provide an epidemiologic description of Kikuchi-Fujimoto disease (KFD), and to describe its relationship with systemic lupus erythematosus (SLE) in a population of sub-Saharan origin. METHODS: Patients were retrospectively included on the basis of lymph node histology compatible with KFD reported in Martinique from 1991 until 2013. In order to describe the characteristics of the disease in a larger cohort, we subsequently included more patients of Afro-Caribbean origin from Guadeloupe and French Guiana. RESULTS: In Martinique, mean annual incidence between 1991 and 2013 was 2.78 cases for 1 million inhabitants (95% confidence interval 1.73-3.93). A total of 36 Afro-Caribbean patients from the 3 French American regions were included. Mean age was 30.5 years (range 5-59 years) and the female:male ratio was 3:1. The main characteristics were cervical adenopathies (88.8%), fever (83.3%), asthenia (73.0%), weight loss (64.4%), and recurrence in 33.3%. KFD was associated with lupus (n = 9 for SLE, n = 2 for cutaneous lupus) in 36.6% (11 of 30). CONCLUSION: We report the first epidemiologic description of KFD in a population of sub-Saharan origin. According to our data, this disease is present in the black African diaspora and is strongly associated with autoimmune diseases, particularly lupus.

[Kinetic values of lymphoscintigraphy of sentinel ganglion in cutaneous cervicofacial melanomas]. / Valeurs cinetiques de la lymphoscintigraphie du ganglion sentinelle dans les melanomes malins cutanes cervico-faciaux.

OBJECTIVE: The aim of this study was to evaluate the lymphoscintigraphy appearance time (LAT) of the sentinel lymph node (SLN) in head and neck cutaneous melanoma and to determine whether a correlation exists between LAT and SLN status (negativity or positivity). DESIGN/SETTING: In vivo study. MATERIALS AND METHODS: A retrospective cohort of 33 patients with Breslow index >or= 1.5 mm, Clark index >or= 4 mm, and ulceration > 1 mm underwent a lymphoscintigraphy and SLN biopsy for a cutaneous head and neck melanoma. MAIN OUTCOME MEASURES: LAT was noted and correlated to SLN status, Breslow and Clark indices, ulceration, and recurrence. RESULTS: Sixty SLNs were identified; 58 were removed, and 17 were positive. In 31% (n = 18), the LAT was < 10 minutes; in 59% (n = 34), the LAT was > 10 minutes and < 30 minutes; and in 10% (n = 6), the LAT was > 30 minutes. SLN was significantly positive (p = .02) when the LAT was less than 10 minutes and the negative predictive value was 100% for LAT > 30 minutes. A recurrence was significantly observed (p = .02) for LAT < 10 minutes. CONCLUSION: LAT > 30 minutes is associated with negative SLN in head and neck melanoma; however, a prospective study on a more important cohort is needed for a better evaluation of this new variable.