How long do tympanostomy ventilation tubes last in pediatric patients with otitis media with effusion or adhesion? A study using Kaplan-Meier survival analysis.

OBJECTIVE: The purpose of this study was to evaluate the functional duration and survival rate of tympanostomy ventilation tubes and the complications associated with their use in pediatric patients who underwent tube insertion for otitis media with effusion (OME). Complications were analyzed including recurrence and tympanic membrane perforation after the tube removal or extrusion. METHODS: Altogether, 447 ears from 234 pediatric patients younger than 15 years of age were studied retrospectively. All patients had undergone long-term tympanostomy ventilation tube: the Goode T-tube insertion for OME at the Osaka Women's and Children's Hospital, which is the pediatrics specialty hospital between April 2014 and March 2016. They were typically followed up every 3-4 months or more frequently if necessary due to otorrhea or tube infection. Subsequently, the tube duration, survival rates of the tube especially at 22 months after insertion defined as "full-term placement", and the rates of recurrence and perforation were calculated and statistically evaluated. RESULTS: Of 447 ears, 335 ears from 184 patients underwent their first tube insertion, and 112 ears from 64 patients underwent their second or subsequent tube insertion within the targeted period. Two hundred ears from 106 patients were associated with a cleft palate. The survival rate at full-term placement was 51.7%. The recurrence rate was 56.3%, and the rate of the tympanic perforation was 8.5%. CONCLUSIONS: Approximately half of the tubes survived for 22 months. The perforation rate was relatively low; however, recurrence of OME was seen in more than half the ears.

Behavioral Therapy for Muscular Objective Tinnitus in Forceful Eyelid Closure Syndrome (FECS): A Case Report.

This report presents the case of a patient with forceful eyelid closure syndrome (FECS) who did not have an otologic history of facial paresis. The patient was an 11-year-old girl. She complained of a click noise in the left ear simultaneous with eyelid closure and was referred to our department. A microphone in the external auditory canal captured a click noise simultaneously with eye blinking. Impedance audiometry of the left ear showed a slight compliance reduction simultaneously with eye blinking, whereas a pure-tone audiogram, tympanogram, computed tomography (CT), magnetic resonance imaging (MRI), and movement of the palate and pharynx were normal. Her previous otologic history was unremarkable and did not include facial paresis. She was diagnosed with FECS due to contraction of the tensor tympanic muscle. Treatment with an anticonvulsant for 2 months showed no effects on her tinnitus and she was bothered by her drowsiness and dizziness. Behavioral therapy (BT) was started, and the tinnitus was remarkably reduced in 7 months. BT for patients with muscular tinnitus, including FECS, may be a preferred choice rather than surgical procedure and medication including an anticonvulsant and muscle relaxant.

Radiation Therapy Alone for Human Papillomavirus-Related Squamous Cell Carcinoma of the Oropharynx: A Single-Arm, Phase 2 Study.

PURPOSE: Human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx (OPSCC) is extremely radiosensitive. Radiation therapy plus high-dose cisplatin remains the standard of care but causes long-term toxicity. Treatment deintensification approaches that reduce toxicity while maintaining survival are desirable for HPV-related OPSCC. METHODS AND MATERIALS: We conducted a single-arm, multicenter, phase 2 trial. Patients with newly diagnosed, biopsy-proven, American Joint Committee on Cancer (seventh edition) stage III or IV OPSCC positive for both p16 and HPV DNA were eligible. Patients with T4, N3, or T1N1 disease were excluded. Smoking history was not included in eligibility criteria. Patients received intensity modulated radiation therapy (IMRT) of 70 Gy in 35 fractions or 70.4 Gy in 32 fractions without chemotherapy. The primary endpoint was complete response or complete metabolic response 10 weeks after IMRT completion. RESULTS: Between September 13, 2013, and November 15, 2016, 39 patients were enrolled according to a 2-stage Simon design. Twenty-three patients (59%) had smoked for more than10 pack-years. Thirty-six patients (92%) had tumors genotyped as HPV16. Thirty-seven patients (95%) received full-dose radiation therapy and 35 (90%) had complete response or complete metabolic response. Median follow-up was 51 months (interquartile range, 41-63 months). One patient (3%) had regional recurrence and 3 (8%) had distant metastasis. One patient died of disease. The 2-year progression-free survival rate was 94% (95% CI, 81%-99%), and the 2-year overall survival rate was 100%. Common grade 3 adverse events during IMRT included mucositis in 10 patients (26%) and dysphagia in 7 patients (18%). No patients were dependent on a feeding tube at 1 month after IMRT completion. No grade 3 or 4 late adverse events were observed. CONCLUSIONS: IMRT alone is associated with excellent response as well as reduced toxicity and could be a treatment option for carefully selected patients with locally advanced "true" HPV-related OPSCC. Further studies are warranted.

Radiotherapy alone as a possible de-intensified treatment for human papillomavirus-related locally advanced oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is defined by p16 positivity and/or HPV DNA positivity. Because survival of patients with HPV-related OPSCC after chemoradiotherapy is favorable, a de-intensified treatment is expected to lead to less morbidity while maintaining low mortality. The association of tumor p16 and HPV DNA status with survival after radiotherapy alone remains unknown. METHODS: We retrospectively examined survival of 107 patients with locally advanced OPSCC after radiotherapy alone (n = 43) or chemoradiotherapy (n = 64) with respect to tumor p16 and HPV DNA status, using Cox's proportional hazard model. RESULTS: Survival after radiotherapy alone was significantly worse in p16-positive/HPV DNA-negative locally advanced OPSCC than in p16-positive/HPV DNA-positive locally advanced OPSCC. In bivariable analyses that included T category, N category, TNM stage, and smoking history, the survival disadvantage of p16-positive/HPV DNA-negative locally advanced OPSCC remained significant. There was no significant difference in survival after chemoradiotherapy between p16-positive/HPV DNA-positive locally advanced OPSCC and p16-positive/HPV DNA-negative locally advanced OPSCC. Survival in p16-positive/HPV DNA-positive locally advanced OPSCC after radiotherapy alone was similar to that after chemoradiotherapy, which stayed unchanged in bivariable analyses after adjustment of every other covariable. Survival of p16-negative/HPV DNA-negative locally advanced OPSCC was poor irrespective of treatment modality. CONCLUSIONS: Survival in p16-positive locally advanced OPSCC differs depending on HPV DNA status. Radiotherapy alone can serve as a de-intensified treatment for p16-positive/HPV DNA-positive locally advanced OPSCC, but not for p16-positive/HPV DNA-negative locally advanced OPSCC.

Transaminase Activity Predicts Survival in Patients with Head and Neck Cancer.

Various serum biomarkers have been developed for predicting head and neck squamous cell carcinoma (HNSCC) prognosis. However, none of them have been proven to be clinically significant. A recent study reported that the ratio of aspartate aminotransaminase (AST) to alanine aminotransaminase (ALT) had a prognostic effect on non-metastatic cancers. This study aimed to examine the effect of the AST/ALT ratio on the survival of patients with HNSCC. Clinical data of 356 patients with locoregionally advanced HNSCC were collected. The effect of the AST/ALT ratio on overall survival was analyzed using a Cox proportional hazard model. Moreover, recursive partitioning analysis (RPA) was used to divide the patients into groups on the basis of the clinical stage and AST/ALT ratio. The prognostic ability of this grouping was validated using an independent data set (N = 167). The AST/ALT ratio ranged from 0.42 to 4.30 (median, 1.42) and was a prognostic factor for overall survival that was independent of age, primary sites, and tumor stage (hazard ratio: 1.36, confidence interval: 1.08-1.68, P = 0.010). RPA divided patients with stage IVA into the following two subgroups: high AST/ALT (≥2.3) and low AST/ALT (<2.3) subgroups. The 5-year survival rate for patients with stage III, stage IVA with a low AST/ALT ratio, stage IVA with a high AST/ALT ratio, and stage IVB were 64.8%, 49.2%, 28.6%, and 33.3%, respectively (p < 0.001). Compared with the low AST/ALT group, the adjusted hazard ratio for death was 2.17 for high AST/ALT group (confidence interval: 1.02-.22 P = 0.045). The AST/ALT ratio was demonstrated to be a prognostic factor of HNSCC. The ratio subdivided patients with stage IVA into low- and high-risk groups. Moreover, intensified treatment for the high-risk group may be considered.

Health insurance status and survival among patients with head and neck cancer in Japan.

BACKGROUND: Healthcare systems vary among countries, and in many countries, insurance and economic statuses significantly impact the mortality associated with head and neck squamous cell carcinoma (HNSCC). Japan prides itself on its unique healthcare and health insurance system, which provides equal coverage and healthcare access with low individual payments to most citizens. Additionally, citizens in poverty are covered by insurance for the poor (public assistance) and receive medical and other types of assistance. Hence, they have no barriers to healthcare services. This study aimed to determine the impact of health insurance status on mortality in Japanese patients with HNSCC. METHODS: We reviewed 409 patients with HNSCC, using the Kaplan-Meier method to estimate overall survival. The association between insurance status and disease stage at diagnosis was analyzed via logistic regression. Cox and Fine-Gray proportional hazard models were employed to investigate the impact of insurance status on survival. RESULTS: The public assistance and other insurances groups did not significantly differ in clinical stage distribution. The 5-year overall survival, cumulative incidence of HNSCC death, and cumulative incidence of other death rates were 63.3 and 59.1 %, 27.0 and 31.8 %, and 10.3 and 9.7 % for the public assistance and other insurances groups, respectively. The adjusted subdistribution hazard ratio for the association between public assistance and HNSCC death was 0.73 (95 % confidence interval 0.44-1.21). CONCLUSIONS: The demonstrated non-inferiority of public assistance regarding HNSCC-specific mortality indicates the equality of healthcare in Japan, irrespective of the insurance status, and the superiority of the Japanese healthcare system.

Risk factors associated with competing mortality among patients with head and neck cancer in Japan.

Conclusions This study demonstrated a high incidence of competing mortality in patients with head and neck cancer (HNC). It identified age to be an independent prognostic factor for non-cancer mortality. These findings contribute to the appropriate treatment selection in clinical settings and study design in clinical trials. Objectives To investigate the incidences of second primary cancer (SPC) and non-cancer mortalities among patients with HNC and reveal the determinant factors for these mortalities. Methods This study reviewed the records of 334 patients with HNC between 2006-2012. The cumulative incidences of HNC, non-cancer, and SPC mortalities were estimated. A Fine and Gray regression model was used to investigate factors associated with cancer and non-cancer mortalities. Results The 5-year cumulative incidences of HNC, SPC, and non-cancer mortalities were 28.0%, 2.5%, and 6.5%, respectively. In univariate analysis, the factors associated with SPC mortality were tumor site and comorbidity, whereas those associated with non-cancer mortality were age, gender, and comorbidity. In multivariate analysis, age (sub-distribution hazard ratio = 2.59) was the independent risk factor for non-cancer mortality.

[A Case of Nasopharyngeal Cancer with Febrile Neutropenia Followed by Death during Adjuvant Chemotherapy].

Chemotherapy-related death can occur, but is rarely experienced in the case of head and neck cancer. In this report, we present the case of a 55-year-old male who died of a severe febrile neutropenia during adjuvant chemotherapy. He was initially diagnosed as having nasopharyngeal carcinoma (cT2N0M0), and concurrent chemoradiotherapy was used as a primary treatment. He did not show any critical side effects during that therapy. After residual disease was proven by biopsy, docetaxel, cisplatin and 5-fluorouracil (TPF) therapy was introduced as adjuvant chemotherapy. The patient developed a high fever with a decreased neutrophil count on day 8, and went into a state of shock on day 9. He underwent immediate systemic management, but methicillin-resistant Staphylococcus aureus (MRSA) pneumonia and enteritis were uncontrolled, resulting in death on day 43. The autopsy findings suggested that the main cause of death was acute respiratory distress syndrome (ARDS), but cytomegalovirus (CMV) infection was also noted in multiple organs. . Since it is assumed from literature that the mortality rate in TPF therapy is about 2-4%, it was considered that prior sufficient explanations and informed consent should be required before this therapy.

Factors predicting severe infections during chemotherapy in head and neck cancer patients.

CONCLUSIONS: The head and neck cancer patients with more co-morbidities and those dependent on tube feeding are at a high risk of severe infections during chemotherapy. Therefore, prophylaxis with colony-stimulating factors and/or antibiotics should be considered for those patients. OBJECTIVES: To investigate the risk factors for severe infection during chemotherapy in head and neck cancer patients. METHODS: A retrospective study was conducted of 129 patients with head and neck cancer who received taxane-based and platinum-based chemotherapy between 2008-2013. Logistic regression models were used to evaluate risk factors. RESULTS: Febrile neutropenia occurred in 50 patients out of the 129 (39%), severe infections occurred in 24 patients (19%), and bacteremia in two patients (2%). In univariate analysis, low serum albumin levels and tube feeding were significantly associated with severe infections (p = 0.015 and < 0.001, respectively). In multivariate analysis, the odds ratios for a higher modified Charlson co-morbidity index and tube feeding were 2.80 and 9.74, respectively. These two were independent predictive factors for severe infections (p = 0.020 and 0.001, respectively).

Docetaxel, cisplatin, and fluorouracil for patients with inoperable recurrent or metastatic head and neck squamous cell carcinoma.

OBJECTIVE: The first-line treatment for inoperable recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) has long been the combination of cisplatin and fluorouracil (PF). Recently, cetuximab has been shown to provide an additional survival benefit to PF. It remains unknown whether docetaxel adds additional benefits to PF. Therefore, we sought to evaluate the efficacy and toxicity of docetaxel, cisplatin, and fluorouracil (TPF) for inoperable recurrent or metastatic HNSCC. METHODS: A retrospective chart review from January 2005 to March 2013 identified patients who were treated with docetaxel 60 mg/m(2) on day 1, followed by cisplatin 60 mg/m(2) on day 1, and fluorouracil 600 mg/m(2)/day on days 1-5 (modified TPF) every 4 weeks for inoperable recurrent or metastatic HNSCC. RESULTS: Twenty-four patients were identified; seven and five patients had locoregional disease only and distant metastasis only, respectively, while 12 patients had locoregional disease and distant metastasis simultaneously. Of the 17 patients with distant metastasis, multiple organs were affected in 9 patients, with the most frequently affected organ being the lung (n=11). Three patients had no prior treatment, whereas 21 patients underwent intensive prior treatment. In 17 of 21 patients who had received prior treatment, the treatment included chemoradiotherapy and/or chemotherapy. The median number of cycles of modified TPF was two (range, 1-5). One patient showed complete response, four patients showed partial response, two patients had stable disease, and 17 patients had progressive disease. Overall, the rate of objective response was 21%, with a 95% confidence interval (CI) of 9-40%. Median overall survival was 8.0 months (95%CI, 4.4-10.6 months). The treatment efficacy differed significantly according to extent of disease. Objective response in patients with distant metastasis alone was better than in patients with locoregional disease with or without distant metastasis (60% vs. 11%, respectively; P=0.02). Median overall survival in the former patients was longer than in the latter patients (not reached vs. 7.0 months, respectively; P=0.02). Fifteen patients (63%) had Grades 3-4 neutropenia, and seven patients (29%) developed Grade 3 febrile neutropenia. There were no toxic deaths. CONCLUSION: The efficacy of modified TPF in the setting of first-line treatment for recurrent or metastatic HNSCC is not very high, while the toxicity is acceptable with extensive care. The development of more efficacious chemotherapeutic regimen is required.

Prognostic significance of serum squamous cell carcinoma antigen in patients with head and neck cancer.

CONCLUSIONS: Serum squamous cell carcinoma antigen (SCC-Ag) level was an independent prognostic factor for survival in patients with head and neck squamous cell carcinoma (HNSCC), and the prognostic value depended on the carcinoma site. OBJECTIVES: To assess the value of SCC-Ag as a prognostic indicator in patients with HNSCC and to determine the effect of primary tumor site on prognosis. METHODS: We reviewed 493 patients with HNSCC between 2004 and 2012. The chi-squared test was used to assess associations between SCC-Ag levels and TNM classification. A Cox proportional hazard model was used to assess the hazard ratio of SCC-Ag at different sites for death, and it was analyzed as a continuous variable. RESULTS: The median serum level of SCC-Ag was 1.1 ng/ml (range 0-20). SCC-Ag was significantly higher in patients with advanced T and N classification tumors. Primary sites in the oral cavity, in the hypopharynx, advanced T and N classification, distant metastasis, and SCC-Ag were negatively associated with survival in univariate analysis. Multivariate analysis revealed that SCC-Ag was a significant risk factor for overall survival in cancers of the oral cavity, hypopharynx, and larynx, but not in oropharyngeal cancer.

Prognostic significance of body mass index before treatment for head and neck cancer.

BACKGROUND: Patients with head and neck cancer frequently experience malnutrition. The purpose of this study was to examine the impact of nutritional status on prognosis and its association with treatment modalities. METHODS: This retrospective study included 706 patients with head and neck cancer diagnosed between 2004 and 2012. The effects of pretreatment body mass index (BMI) on overall survival were analyzed using the Kaplan-Meier method and Cox regression model. RESULTS: BMI ranged from 11.6 to 38.0 kg/m2 (median, 21.5) and was a prognostic factor for survival, independent of primary site, and tumor stage. The 5-year survival rates for underweight, normal, and overweight groups were 32.2%, 62.7%, and 73.5%, respectively. The hazard ratios of BMI in the surgery, chemoradiation, and radiation groups were 0.95, 0.91, and 0.79, respectively, and the latter two were statistically significant. CONCLUSION: The impact of BMI is determined by the types of cancer treatment. Pretreatment BMI should be considered while deciding treatment.

Chemoradiation therapy for squamous cell carcinoma of the external auditory canal: A meta-analysis.

BACKGROUND: The standard treatment for advanced external auditory canal squamous cell carcinoma (SCC) is subtotal temporal bone resection and postoperative radiation therapy (RT), whereas chemoradiation therapy (CRT) is used in some institutions to improve patient prognosis. The purpose of this study was to evaluate the efficacy of CRT in external auditory canal SCC treatment. METHODS: Meta-analyses of external auditory canal SCC studies were performed. We extracted 5-year overall survival rates and number of patients for aggregate patient data, and types of treatment and outcomes for individual patient data. RESULTS: The 5-year overall survival rate of 752 patients was 57%. In the individual patient data meta-analysis, the 5-year overall survival rates of patients who received surgery ± RT, preoperative CRT, definitive CRT, and postoperative CRT were 53.5%, 85.7%, 43.6%, and 0%, respectively. CONCLUSION: Our data suggest that preoperative CRT may improve the survival of surgically treated patients with external auditory canal SCC and that definitive CRT may be equivalent to surgical resection.

Factors associated with malnutrition in patients with head and neck cancer.

CONCLUSIONS: Comorbidities as well as T classification were the primary determinants for the nutritional status of patients with head and neck cancer. OBJECTIVES: We aimed to elucidate the underlying conditions of malnutrition in patients with head and neck cancer. METHODS: We retrospectively reviewed 726 patients diagnosed with head and neck cancer between 2004 and 2013. Associations between malnutrition and clinical parameters were assessed using univariate and multivariate analyses. RESULTS: Median body mass index was 21.5 (range 11.6-38.0). According to World Health Organization criteria, the nutritional status of these patients was classified into four groups: underweight (18%), normal (63%), overweight (17%), and obese (1%). Comorbidities were detected in 40% of patients. Multivariate analysis revealed the following factors to be independent factors associated with malnutrition: advanced T stage, metachronous cancer, collagen disease, gastrointestinal disease, and pulmonary disease.

Volumetric PET/CT parameters predict local response of head and neck squamous cell carcinoma to chemoradiotherapy.

It is not well established whether pretreatment (18) F-FDG PET/CT can predict local response of head and neck squamous cell carcinoma (HNSCC) to chemoradiotherapy (CRT). We examined 118 patients: 11 with nasopharyngeal cancer (NPC), 30 with oropharyngeal cancer (OPC), and 77 with laryngohypopharyngeal cancer (LHC) who had completed CRT. PET/CT parameters of primary tumor, including metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and mean standardized uptake value (SUVmax and SUVmean ), were correlated with local response, according to primary site and human papillomavirus (HPV) status. Receiver-operating characteristic analyses were made to access predictive values of the PET/CT parameters, while logistic regression analyses were used to identify independent predictors. Area under the curve (AUC) of the PET/CT parameters ranged from 0.53 to 0.63 in NPC and from 0.50 to 0.54 in OPC. HPV-negative OPC showed AUC ranging from 0.51 to 0.58, while all of HPV-positive OPCs showed complete response. In contrast, AUC ranged from 0.71 to 0.90 in LHC. Moreover, AUCs of MTV and TLG were significantly higher than those of SUVmax and SUVmean (P < 0.01). After multivariate analysis, high MTV >25.0 mL and high TLG >144.8 g remained as independent, significant predictors of incomplete response compared with low MTV (odds ratio [OR], 13.4; 95% confidence interval [CI], 2.5-72.9; P = 0.003) and low TLG (OR, 12.8; 95% CI, 2.4-67.9; P = 0.003), respectively. In conclusion, predictive efficacy of pretreatment (18) F-FDG PET/CT varies with different primary sites and chosen parameters. Local response of LHC is highly predictable by volume-based PET/CT parameters.

[Treatment outcome and failure pattern of olfactory neuroblastoma: a clinical analysis of 14 cases and meta-analysis of Japanese cases].

The olfactory neuroblastoma, first described in 1924, is a rare tumor arising from the olfactory epithelium. Because of its rarity, it is difficult to accrue a large individual series. To elucidate the characteristics of olfactory neuroblastomas in Japan, we report herein on our institutional experience of 14 cases and reviewed 104 cases reported from Japan. In our cases, one out of nine surgically treated patients died during treatment and the remaining 8 patients are alive without disease. Among the five non-surgically treated patients, four patients experienced local treatment failure and the other one patient died of metastasis. In the 104 Japanese cases, 54 patients were treated with multimodality treatment including surgery and radiation. The 3-year overall survival rates for surgically treated patients and non-surgically treated patients were 85% and 73%, respectively. The prognostic factors for survival were modified Kadish stage, Hyams' grade and surgical treatment. Further investigation is required for the validation of endoscopic resection.

Human papillomavirus and cystic node metastasis in oropharyngeal cancer and cancer of unknown primary origin.

The clinical significance of human papillomavirus (HPV) in neck node metastasis from cancer of unknown primary (CUP) is not well established. We aimed to address the relationship of HPV status between node metastasis and the primary tumor, and also the relevance of HPV status regarding radiographically detected cystic node metastasis in head and neck squamous cell carcinoma (HNSCC) and CUP. HPV DNA was examined in 68 matched pairs of node metastasis and primary tumor, and in node metastasis from 27 CUPs. In surgically treated CUPs, p16 was examined immunohistochemically. When tonsillectomy proved occult tonsillar cancer in CUP, HPV DNA and p16 were also examined in the occult primary. Cystic node metastasis on contrast-enhanced computed tomography scans was correlated with the primary site and HPV status in another series of 255 HNSCCs and CUPs with known HPV status. Node metastasis was HPV-positive in 19/37 (51%) oropharyngeal SCCs (OPSCCs) and 10/27 (37%) CUPs, but not in non-OPSCCs. Fluid was collected from cystic node metastasis using fine needle aspiration in two OPSCCs and one CUP, and all fluid collections were HPV-positive. HPV status, including the presence of HPV DNA, genotype, and physical status, as well as the expression pattern of p16 were consistent between node metastasis and primary or occult primary tumor. Occult tonsillar cancer was found more frequently in p16-positive CUP than in p16-negative CUP (odds ratio (OR), 39.0; 95% confidence interval (CI), 1.4-377.8; P = 0.02). Radiographically, cystic node metastasis was specific to OPSCC and CUP, and was associated with HPV positivity relative to necrotic or solid node metastasis (OR, 6.2; 95% CI, 1.2-45.7; P = 0.03). In conclusion, HPV status remains unchanged after metastasis. The occult primary of HPV-positive CUP is most probably localized in the oropharynx. HPV status determined from fine needle aspirates facilitates the diagnosis of cystic node metastasis.

Human papillomavirus and p53 mutations in head and neck squamous cell carcinoma among Japanese population.

We aimed to reveal the prevalence and pattern of human papillomavirus (HPV) infection and p53 mutations among Japanese head and neck squamous cell carcinoma (HNSCC) patients in relation to clinicopathological parameters. Human papillomavirus DNA and p53 mutations were examined in 493 HNSCCs and its subset of 283 HNSCCs. Oropharyngeal carcinoma was more frequently HPV-positive than non-oropharyngeal carcinoma (34.4% vs 3.6%, P < 0.001), and HPV16 accounted for 91.1% of HPV-positive tumors. In oropharyngeal carcinoma, which showed an increasing trend of HPV prevalence over time (P < 0.001), HPV infection was inversely correlated with tobacco smoking, alcohol drinking, p53 mutations, and a disruptive mutation (P = 0.003, <0.001, <0.001, and <0.001, respectively). The prevalence of p53 mutations differed significantly between virus-unrelated HNSCC and virus-related HNSCC consisting of nasopharyngeal and HPV-positive oropharyngeal carcinomas (48.3% vs 7.1%, P < 0.001). Although p53 mutations were associated with tobacco smoking and alcohol drinking, this association disappeared in virus-unrelated HNSCC. A disruptive mutation was never found in virus-related HNSCC, whereas it was independently associated with primary site, such as the oropharynx and hypopharynx (P = 0.01 and 0.03, respectively), in virus-unrelated HNSCC. Moreover, in virus-unrelated HNSCC, G:C to T:A transversions were more frequent in ever-smokers than in never-smokers (P = 0.04), whereas G:C to A:T transitions at CpG sites were less frequent in ever-smokers than in never-smokers (P = 0.04). In conclusion, HNSCC is etiologically classified into virus-related and virus-unrelated subgroups. In virus-related HNSCC, p53 mutations are uncommon with the absence of a disruptive mutation, whereas in virus-unrelated HNSCC, p53 mutations are common, and disruptive mutagenesis of p53 is related with oropharyngeal and hypopharyngeal carcinoma.

Synchronous bilateral tonsillar carcinomas associated with human papillomavirus.

Although the incidence of human papillomavirus (HPV)-positive oropharyngeal carcinoma is increasing, only a limited number of synchronous bilateral HPV-positive tonsillar carcinomas have been reported to date. Here, we describe an additional case of 61-year-old female. Pathological analysis proved squamous cell carcinoma in biopsy specimens from bilateral tonsillar lesions and a fine needle aspirate from an enlarged cervical node. Polymerase chain reaction (PCR) and direct sequencing showed HPV-16 DNA in all of the biopsy specimens and fine needle aspirate with completely concordant sequences. Bilateral tonsillar lesions were immunohistochemically positive for p16. Taken together with radiological findings, she was diagnosed to have bilateral tonsillar carcinomas (cT1N2bM0 on the right side and cT2N0M0 on the left side). We administered concurrent chemoradiotherapy to treat these synchronous lesions, and the restaging workup resulted in overall complete response. No recurrent and/or metastatic disease has been evident 20 months after the restaging. It seems reasonable to include bilateral tonsils as a therapeutic target in the treatment of HPV-positive unknown primary carcinoma.