The impact of COVID-19 pandemic on head and neck cancer diagnosis and treatment.

Background/purpose: Following the COVID-19 pandemic, there were reports of diagnostic delays and a surge in the prevalence of advanced head and neck cancer (HNC). We conducted a retrospective study on the impact of COVID-19 on the number of newly diagnosed HNC among patients who underwent screening at our center to understand the temporal changes. Materials and methods: We investigated the Union for International Cancer Control guidelines-TNM classification, presence of subjective symptoms at the time of consultation, and initial treatment from the medical records of first-time patients with HNC who visited our head and neck surgery department during 2019-2021 and compared them with those before (2019) and after (2020-2021) the pandemic. Results: A total of 1245 patients were included in the study. The number of patients were 437, 417, and 391 in 2019, 2020, and 2021, respectively, indicating a downward trend following the pandemic. When the incidence of early (stage 0-II) and advanced (stage III-IV) HNC cancers was compared, the proportion of patients with early-stage cancer declined. Among them, significant primary tumor progression was observed in T classification. The number of patients with no subjective symptoms at initial diagnosis was decreasing significantly. Conclusion: A decrease in the proportion of HNC patients with early-stage cancer and primary tumor progression was observed after the pandemic in 2020 and 2021. The number of early-stage malignancies may have dropped due to patients' unwillingness to visit a doctor.

A new combined index of SUVmax of lymph node in PET / CT by a weighting coefficient plus its maximum minor axis in CECT to evaluate occult lymph node metastasis in clinical N0 patients with tongue cancer.

To predict occult nodal metastasis in clinical N0 patients with tongue cancer, we developed combined index (CI) : SUVmax of the largest lymph node in PET / CT by weighting coefficient plus its maximum minor axis (< 10 mm) in contrast-enhanced CT (CECT). In this retrospective study, 57 clinical N0 patients with tongue cancer, who underwent elective supraomohyoid neck dissection at cervical levels of I-III were enrolled. The cutoff value of SUVmax of 2.0 obtained using receiver operating characteristic (ROC) analysis predicted the postoperative positive cervical levels containing metastatic lymph nodes from clinical N0 cervical levels in tongue cancer patients with a sensitivity of 54.5% and a specificity of 78.2%. The cutoff value of CI with weighting coefficient of 1.5 obtained using ROC analysis was 9.8 at the maximum area under the curve of 0.750. The cutoff value of 9.8 predicted the postoperative positive cervical levels containing metastatic lymph nodes from clinical N0 cervical levels in tongue cancer patients with a sensitivity of 68.2% and a specificity of 81.5%. These findings suggest that CI of functional PET / CT and morphological CECT components might improve the diagnostic performance of occult nodal metastasis to select clinical N0 patients with tongue cancer preferable for elective neck dissection. J. Med. Invest. 68 : 154-158, February, 2021.

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.

Death unrelated to cancer and death from aspiration pneumonia after definitive radiotherapy for head and neck cancer.

BACKGROUND AND PURPOSE: The incidence of hypopharyngeal and supraglottic cancer (HSC) is high in Japan. This study aimed to retrospectively identify risk factors for death unrelated to cancer and death from aspiration pneumonia after definitive radiotherapy (RT) for HSC. MATERIALS AND METHODS: Overall, 391 patients who began definitive RT for HSC between 2006 and 2014 were identified from the Osaka International Cancer Institute electronic database. Among 391 patients, 33 had a history of surgery for esophageal cancer (EC) and 19 received simultaneous RT for synchronous EC. The cause of death was divided into 3 main categories: "cancer under study," "other malignancy," and "unrelated to cancer." Cox proportional hazard model was used to estimate the hazard ratio (HR). RESULTS: The median follow-up for survivors was 8 (range 3.6-14.1) years. At the last follow-up, 202 patients died. Death from "cancer under study," "other malignancy," and "unrelated to cancer" occurred in 92 (45.5%), 55 (27.2%), and 55 (27.2%) patients, respectively. Twelve patients died from aspiration pneumonia. In multivariate analysis for death unrelated to cancer and death from aspiration pneumonia, history of surgery for EC (HR: 3.87, p < 0.001; HR: 6.84, p = 0.007, respectively) and simultaneous RT for synchronous EC (HR: 3.74, p = 0.006; HR: 16.37, p < 0.001, respectively) were significant risk factors. CONCLUSION: The laryngeal preservation approach by RT for HSC patients with a history of surgery for EC and simultaneous RT for synchronous EC should be used with caution.

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.

Chemoradiotherapy with weekly low-dose docetaxel and cisplatin concurrent with radiation for patients with locally advanced nasopharyngeal carcinoma, followed by adjuvant chemotherapy for selected patients.

OBJECTIVE: We investigated the efficacy and safety of concurrent chemoradiotherapy using weekly low-dose docetaxel and cisplatin in patients with locally advanced nasopharyngeal carcinoma. METHODS: This was a retrospective analysis of 31 patients who were treated with this regimen from 2001 to 2014. Concurrent chemoradiotherapy consisted of radiotherapy with a total dose of 59.4-70.2 Gy plus weekly administration of docetaxel (5-10 mg/m2) and cisplatin (20 mg/m2), up to six cycles. At least two cycles of platinum-based adjuvant chemotherapy were prescribed for Stage IV and Stage III patients with partial response or stable disease after concurrent chemoradiotherapy. RESULTS: Of the 31 patients, 28 (90%) completed concurrent chemoradiotherapy as planned. The overall complete response and partial response rates were 42% and 52%, respectively. Seventeen of the 21 patients who were prescribed adjuvant chemotherapy underwent it. After a median follow-up of 39.1 months for the 23 surviving patients, 9 (29%) developed locoregional recurrence or progression and 6 patients (19%) developed distant metastasis. The 3-year overall survival and progression-free survival rates were 76% and 56%, respectively. Univariate analyses revealed that clinical stage was a significant predictor of complete response, overall survival and progression-free survival. The most serious adverse events were mucositis during concurrent chemoradiotherapy and neutropenia during adjuvant chemotherapy. CONCLUSIONS: This concurrent chemoradiotherapy protocol showed practical efficacy with high feasibility and acceptable toxicity. To improve the progression-free survival of patients with Stage IV disease who are treated by this protocol, changes to their treatment strategy should be considered.

Phase II study of docetaxel, cisplatin, and concurrent radiation followed by platinum-based adjuvant chemotherapy for technically unresectable, locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Phase I study of weekly administration of low-dose docetaxel/cisplatin concurrent with conventionally fractionated radiotherapy for locally advanced head and neck squamous cell carcinoma suggested the recommended dose of docetaxel at 10 mg/m2 and cisplatin at 20 mg/m2. Phase II study of the concurrent chemoradiotherapy for technically resectable disease showed satisfactory results. METHODS: This phase II study was designed to address efficacy and safety when patients with technically unresectable disease were treated with concurrent chemoradiotherapy, followed by two cycles of moderate-dose platinum-based adjuvant chemotherapy: docetaxel, cisplatin, and fluorouracil (modified TPF). Modified TPF was replaced with docetaxel/carboplatin when renal impairment became evident. Surgical salvage was considered when residual or recurrent locoregional disease was technically resectable and free of distant metastasis. RESULTS: Of 33 enrolled patients, 31 were analyzable: 24 (78 %) and 18 (58 %) patients completed chemoradiotherapy and adjuvant chemotherapy, respectively; 15 (48 %) patients completed study treatment per protocol, and overall complete response rate was 45 %. Seven patients underwent surgical salvage, which was successful in 4 patients. At a median follow-up of 60.8 months for surviving patients, median progression-free survival and median overall survival were 16.2 and 39.9 months, respectively. Grade 3 or 4 toxicity included mucositis (77 %) and dysphagia (45 %) during the chemoradiotherapy period and neutropenia (100 %) and febrile neutropenia (35 %) during the adjuvant period. No patient died of toxicity. CONCLUSION: The tested regimen seems effective, although there is room for improvement in adjuvant chemotherapy because of the high toxicity and low compliance of modified TPF.

Selective neck irradiation for supraglottic cancer: focus on Sublevel IIb omission.

OBJECTIVE: To estimate selective neck irradiation omitting surgical Sublevel IIb. METHODS: Bilateral necks of 47 patients (94 necks) were subjected to definitive radiotherapy for supraglottic cancer. Sixty-nine and 25 necks were clinically node negative (cN-) and clinically node positive (cN+), respectively. We subdivided Sublevel IIb by the international consensus guideline for radiotherapy into Sublevel IIb/a, directly posterior to the internal jugular vein, and Sublevel IIb/b, which was behind Sublevel IIb/a and coincided with surgical Sublevel IIb. Bilateral (Sub)levels IIa, III, IV and IIb/a were routinely irradiated, whereas Sublevel IIb/b was omitted from the elective clinical target volume in 73/94 treated necks (78%). RESULTS: Two patients presented with ipsilateral Sublevel IIb/a metastases. No Sublevel IIb/b metastasis was observed. Five patients experienced cervical lymph node recurrence; Sublevel IIb/a recurrence developed in two patients, whereas no Sublevel IIb/b recurrence occurred even in the cN- necks of cN+ patients or cN0 patients. The 5-year regional control rates were 91.5% for Sublevel IIb/b-omitted patients and 77.8% for Sublevel IIb/b treated patients. CONCLUSIONS: Selective neck irradiation omitting Sublevel IIb/b did not compromise regional control and could be indicated for cN- neck of supraglottic cancer.

Trends in the Detail of the Stage and Survival Rate in Hypopharyngeal Cancer over 20 Years.

Background: Hypopharyngeal cancer frequently presents at an advanced stage and has one of the worst prognosis among the head and neck cancers. Recently, superficial hypopharyngeal cancers with a good prognosis have been detected with a novel endoscopic technique, such as narrow band imaging. Objectives: To evaluate trends in the detail of the stage and survival rate in hypopharyngeal cancer over 20 years. Patients and methods: Between 1993 and 2012, 722 patients with hypopharyngeal cancer treated at the Osaka Medical Center for Cancer and Cardiovascular Disease were studied retrospectively. The 20-year period was subdivided into 5-year periods; Period A (1993-1997, n=101), Period B (1998-2002, n=123), Period C (2003-2007, n=196) and Period D (2008-2012, n=302). The patients at Stage I-II were divided into superficial cancer as Stage I-IIs and invasive cancer as Stage I-IIi. In every period, a transition of the staging and overall survival rate were compared. Results: The 5-year overall survival in Period A, B, C and D were 34%, 39%, 54% and 60%, respectively. The patients at Stage III-IV in Period A, B, C and D comprised 32%, 36%, 47% and 54%, respectively. Both survival rates improved significantly from Period B to C. The ratio of Stage 0 and Stage I-IIs increased significantly from Period C to D. Whereas the 5-year overall survival rates of Stage 0 and Stage I-IIs were similar (80% vs 88%), the 5-year overall survival of Stage I-IIi was significantly poor. Excluding Stage 0 and Stage I-IIs, the 5-year overall survival had little change from Period C to D. Conclusion: The reason for the improvement in hypopharyngeal cancer prognosis was the prognostic improvement of advanced cancer from Period B to C, and an increase in superficial cancer from Period C to D.

[Videofluoroscopic Examination of Swallowing Using the AsR Score for Postoperative Swallowing Function in Oral Cancer Patients].

To evaluate the postoperative swallowing function in head and neck cancer patients, videofluoroscopic examination of swallowing (VF) proved useful as a qualitative evaluation, but was complex as a quantitative evaluation. We made use of the AsR score which consisted of a 10-point scale as a quantitative evaluation of VF. To identify the usefulness of the AsR score, 146 patients who had undergone extensive resection and reconstruction with free flaps or pedicle grafts were reviewed. The AsR score of VF for the first time after surgery was defined as "first score", and at the last time in the hospital was defined as "last score". The correlations between the first score and continuity of direct therapy, and between the last score and way of nutrition at the time of discharge were examined. Using the ROC (receiver operator characteristic) analysis and the AUC (area under the curve) the cut-off values of the AsR score were estimated. One hundred and thirty one patients could continue direct therapy after the first time of VF. The first score detected continuity of direct therapy with high accuracy (AUC = 0.946), furthermore using a cut-off of 5, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were about 96.2%, 86.6%, 98.4%, and 72.2%, respectively. At the time of discharge, 138 patients had no limitation of oral intake and 8 patients had a limitation e.g. PEG (n = 7) and a total laryngectomy for preventing aspiration (n = 1). The last score detected oral intake ability with no limitation with high accuracy (AUC = 0.925). Using a cut-off of 6, the sensitivity, specificity, PPV and NPV were about 82.6%, 87.5%, 99.1% and 22.6%, respectively. The AsR score is useful as a quantitative evaluation of postoperative swallowing function in oral cancer patients.

Endoscopic submucosal dissection as minimally invasive treatment for superficial pharyngeal cancer: a phase II study (with video).

BACKGROUND AND AIMS: Although endoscopic submucosal dissection (ESD) has been applied for superficial pharyngeal cancer, no prospective trials have been reported. To investigate the efficacy and safety of ESD for superficial pharyngeal cancer, we conducted a prospective phase II trial. METHODS: Fifty-four patients with 73 lesions were enrolled from September 2010 to August 2014, and ESD was performed. The primary endpoint was the complete resection rate. Secondary endpoints were safety, recurrence-free survival, overall survival, and incidence of metachronous pharyngeal cancer. RESULTS: Fifty-four patients had stage 0-III cancer: stage 0, n = 22; stage I, n = 14; stage II, n = 17; and stage III, n = 1. The en bloc resection rate was 100%, and the complete resection rate was 79.5% (58/73 lesions; 95% confidence interval, 68%-88%). No serious adverse events related to ESD were encountered. Four patients required nasogastric intubation and feeding. No patients required percutaneous endoscopic gastrostomy and tracheotomy. Swallowing, speech, and airway functions were preserved in all patients. One of the 54 patients died of an unrelated illness. Median follow-up was 27 months (range 6-55 months). Local cervical lymph node metastasis was observed in 1 patient, and the case was salvaged successfully with lymph node dissection. The 3-year overall and recurrence-free survival rates were 97.7% and 98.1%, respectively. Cumulative development of multiple cancers of the pharynx at 3 years was 18.4%. CONCLUSIONS: ESD appears to be a safe and effective minimally invasive treatment in patients with superficial pharyngeal cancer. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000003623.).

Phase 2 study of docetaxel, cisplatin, and concurrent radiation for technically resectable stage III-IV squamous cell carcinoma of the head and neck.

PURPOSE: We investigated the efficacy and safety of weekly low-dose docetaxel and cisplatin therapy concurrent with conventionally fractionated radiation in patients with technically resectable stage III-IV squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Between March 2004 and October 2011, we enrolled 117 patients, of whom 116 were analyzable (43 had oropharyngeal cancer, 54 had hypopharyngeal cancer, and 19 had laryngeal cancer), and 85 (73%) had stage IV disease. Radiation consisted of 66 Gy in 33 fractions. Docetaxel, 10 mg/m(2), followed by cisplatin, 20 mg/m(2), administered on the same day were given once a week for 6 cycles. The primary endpoint was overall complete response (CR) rate after chemoradiation therapy. Human papillomavirus (HPV) DNA in oropharyngeal cancer was examined by PCR. RESULTS: Of 116 patients, 82 (71%) completed treatment per protocol; 102 (88%) received the full radiation therapy dose; and 90 (78%) and 12 (10%) patients received 6 and 5 chemotherapy cycles, respectively. Overall CR rate was 71%. After median follow-up of 50.9 months (range: 15.6-113.9 months for surviving patients), 2-year and 4-year overall survival rates were 82% and 68%, respectively. Cumulative 2-year and 4-year local failure rates were 27% and 28%, respectively, whereas distant metastasis rates were 15% and 22%, respectively. HPV status in oropharyngeal cancer was not associated with treatment efficacy. Acute toxicity included grade 3 and 4 in-field mucositis in 73% and 5% of patients, respectively, whereas myelosuppression and renal injury were minimal. No patients died of toxicity. Feeding tube dependence in 8% and tracheostomy in 1% of patients were evident at 2 years postchemoradiation therapy in patients who survived without local treatment failure. CONCLUSIONS: Local control and survival with this regimen were satisfactory. Although acute toxicity, such as mucositis, was common, late toxicity, such as laryngoesophageal dysfunction, was minimal. Therapy using weekly low-dose docetaxel and cisplatin concurrent with radiation warrants further evaluation.

Treatment outcomes of external-beam radiotherapy for squamous cell carcinoma of the base of the tongue.

PURPOSE: To evaluate definitive external-beam radiotherapy (EBRT) for patients with base of the tongue (BOT) cancers. METHODS: We reviewed results for 26 patients with BOT cancers who were treated with EBRT. Clinical stages T1, T2, T3, and T4a were observed for 10, 7, 4, and 5 patients, respectively, and stages N0, N1, N2a, N2b, N2c, and N3 were observed for 4, 2, 5, 6, 8, and 1 patients, respectively. More than half of the patients (n = 19) were stage IVA. Standard total delivered doses were 70 Gy to primary tumors and cervical lymph node (CLN) metastases and 40-46 Gy to elective nodal regions. Eleven patients with advanced loco-regional disease received concurrent or neoadjuvant chemotherapy. Four T3 patients and one T2 patient received 2 or 3 cycles of concurrent intra-arterial cisplatin with EBRT (RADPLAT). RESULTS: Three-year overall survival was 69 % (95 % CI 47-83 %), with a median follow-up period of 33 months. Three-year local control was 100, 86, 100, and 20 % for T1, T2, T3, and T4 patients, respectively. Three-year regional control was 100 % for N0, N1, and N2a, 83 % for N2b, 75 % for N2c, and 0 % for N3 patients. Treatment failed for 7 patients. All 5 patients undergoing RADPLAT achieved complete responses and did not develop local recurrence. CONCLUSIONS: We achieved favorable outcomes for patients with T1-T3 BOT cancers by use of definitive EBRT with or without chemotherapy.

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.

Immediate effectiveness of humming on the supraglottic compression in subjects with muscle tension dysphonia.

AIMS: To verify whether humming corrects supraglottic compression in muscle tension dysphonia (MTD) patients. METHODS: We enrolled 23 MTD participants (13 male, 10 female) showing supraglottic compression. Each individual was instructed to perform 3 types of phonation under transnasal laryngofiberscopy: natural phonation, humming phonation without pitch change and subsequent um-hum phonation, i.e. humming with pitch glide up as if agreeing with someone. The degree of supraglottic compression was estimated with 2 parameters. The false vocal fold and anterior-posterior indices (the FVF and AP indices) were calculated by normalizing the lateral width and AP length of the visible vocal cords at phonation normalized to the mean vocal cord length at inspiration, respectively. These indices were compared among the tasks. RESULTS: All the MTD participants but 5 females accomplished decreases in the vocal roughness scores upon the phonatory tasks. The whole MTD group showed significant increases in the FVF and AP indices even after humming without pitch change with a dominance of the AP index. The humming-responsive MTD subgroup showed greater increases in both indices than the humming-resistant subgroup. CONCLUSION: These data demonstrate that humming corrects both the lateral and AP components of supraglottic compression in most MTD patients.

[A case of laryngeal necrosis following concurrent chemoradiotherapy for advanced hypopharyngeal cancer after insertion of a nasogastric tube].

A 62-year-old male with cT4bN2cM0 hypopharyngeal carcinoma with ipsilateral vocal cord fixation was initially treated with concurrent chemoradiotherapy. Since the patient complained of dysphagia caused by mucositis, a nasogastric tube was placed on the day of irradiation with a dose of 20 Gy. Bilateral vocal cord fixation and laryngeal necrosis became evident 3 weeks after the concurrent chemoradiotherapy. He underwent a total pharyngolaryngectomy (neck dissection, and reconstruction with a free jejunal graft) followed by adjuvant chemotherapy. It is highly suspected that the nasogastric tube compressed the mucosa of the post cricoid region, resulting in laryngeal necrosis.

Limitation of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography (FDG-PET) to detect early synchronous primary cancers in patients with untreated head and neck squamous cell cancer.

OBJECTIVE: Patients with head and neck squamous cell carcinoma (HNSCC) often develop synchronous multiple primary cancers. It is important to detect second primary cancer in HNSCC patients, because it influences treatment selection of primary cancer. The aim of this study was to evaluate the utility of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) for detecting synchronous primary cancers at the initial staging of patients with HNSCC. METHODS: Three hundred and forty-seven patients with untreated HNSCC underwent FDG-PET with or without computed tomography fusion and other routine workups, including upper gastrointestinal Lugol chromoendoscopy, for the initial staging. We examined the prevalence of second primary cancer in these patients and the utility of PET. RESULTS: We identified 57 synchronous primary cancers in 53 patients, of which only 33 % were detected with PET. The most common site for the second primary cancer was the esophagus (49 %), followed by stomach (14 %) and head and neck (11 %). Most early-stage esophageal cancers and stomach cancers were detected using Lugol chromoendoscopy but not PET. CONCLUSION: Although PET is useful for detecting synchronous primary cancers, it is not a sensitive technique for detecting early esophageal cancers and gastric cancers. Therefore, Lugol chromoendoscopy is indispensable for detecting synchronous upper gastrointestinal cancers in HNSCC patients.