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Metastatic cutaneous squamous cell carcinoma (SCC) of the head and neck poses a significant therapeutic challenge due to its aggressive biologic behavior. We conducted a retrospective study of 71 patients-58 men and 13 women, aged 28 to 88 years (mean: 71)-who had been treated at our university-affiliated tertiary care medical center for metastatic cutaneous SCC over a 15-year period. In addition to demographic data, we compiled and analyzed information on tumor characteristics, the site and extent of metastasis, treatment, follow-up, and outcome. Among the tumor factors, poorly differentiated carcinoma was an independent predictor of poorer disease-free survival, and older age was found to be an independent predictor of poorer overall survival. We found no significant difference in disease-free or disease-specific survival among patients with parotid involvement, neck involvement, or both. In our series, the site of nodal involvement appeared to have no prognostic significance in patients with metastatic cutaneous SCC of the head and neck.

Objectives/hypothesis: Despite advances in radiotherapy and chemotherapy treatments for head and neck cancers, the local failure rate is high. In most radiotherapy-resistant cases, surgery is performed; however, some cases are considered unresectable. No standard treatment for these situations has been established. In this study, we review our experience with brachytherapy (BT), which has a different biological mechanism than standard radiotherapy., Methods: All patients received prior radiation to the recurrence area. Median high-dose radiation BT dose was 50 Gy, administered in 5 to 10 Gy fractions twice daily for 5 days. High-dose radiation was given via four to 10 catheters inserted under local anesthesia (3 patients) or general anesthesia with preventive tracheostomy (10 patients)., Results: Thirteen patients received BT from 2010 to 2014. Male:female ratio was 1.6:1, and median age was 66 years (range 23-89). Of those 13 patients, 10 patients were diagnosed with squamous cell carcinoma (SCC) of the oral cavity, two patients with SCC of the nasal mucosa, and one patient with eccrine duct carcinoma. Prior radiation dose ranged from 60 to 70 Gy. Local control was achieved in 11 of 13 patients; only 15.3% (2 of 13) had in-field recurrence. Five patients developed local out-of-field recurrence, and two developed distant metastases. Five patients are alive with no evidence of disease. No major toxicities were encountered. Two patients had severe mucositis and recovered within several weeks., Conclusion: Brachytherapy for radiotherapy-resistant head and neck cancers is feasible with minor adverse events, which enables good local control. However, many advanced head and neck cancers develop regional or distant metastases; therefore, additional treatment should be suggested., Level of Evidence: 4. Laryngoscope, 126:2246-2251, 2016., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Systemic inflammatory events and localized disease, mediated by the microbiome, may be measured in saliva as head and neck squamous cell carcinoma (HNSCC) diagnostic and prognostic biomonitors. We used a 16S rRNA V3-V5 marker gene approach to compare the saliva microbiome in DNA isolated from Oropharyngeal (OPSCC), Oral Cavity Squamous Cell Carcinoma (OCSCC) patients and normal epithelium controls, to characterize the HNSCC saliva microbiota and examine their abundance before and after surgical resection.The analyses identified a predominance of Firmicutes, Proteobacteria and Bacteroidetes, with less frequent presence of Actinobacteria and Fusobacteria before surgery. At lower taxonomic levels, the most abundant genera were Streptococcus, Prevotella, Haemophilus, Lactobacillus and Veillonella, with lower numbers of Citrobacter and Neisseraceae genus Kingella. HNSCC patients had a significant loss in richness and diversity of microbiota species (p<0.05) compared to the controls. Overall, the Operational Taxonomic Units network shows that the relative abundance of OTU's within genus Streptococcus, Dialister, and Veillonella can be used to discriminate tumor from control samples (p<0.05). Tumor samples lost Neisseria, Aggregatibacter (Proteobacteria), Haemophillus (Firmicutes) and Leptotrichia (Fusobacteria). Paired taxa within family Enterobacteriaceae, together with genus Oribacterium, distinguish OCSCC samples from OPSCC and normal samples (p<0.05). Similarly, only HPV positive samples have an abundance of genus Gemellaceae and Leuconostoc (p<0.05). Longitudinal analyses of samples taken before and after surgery, revealed a reduction in the alpha diversity measure after surgery, together with an increase of this measure in patients that recurred (p<0.05). These results suggest that microbiota may be used as HNSCC diagnostic and prognostic biomonitors., Competing Interests: The authors have no conflicts of interest with the subject matter or materials discussed in this manuscript.

Tumor suppressor genes (TSGs) are commonly inactivated by somatic mutation and/or promoter methylation; yet, recent high-throughput genomic studies have not identified key TSGs inactivated by both mechanisms. We pursued an integrated molecular analysis based on methylation binding domain sequencing (MBD-seq), 450K Methylation arrays, whole exome sequencing, and whole genome gene expression arrays in primary head and neck squamous cell carcinoma (HNSCC) tumors and matched uvulopalatopharyngoplasty tissue samples (UPPPs). We uncovered 186 downregulated genes harboring cancer specific promoter methylation including PAX1 and PAX5 and we identified 10 key tumor suppressor genes (GABRB3, HOXC12, PARP15, SLCO4C1, CDKN2A, PAX1, PIK3AP1, HOXC6, PLCB1, and ZIC4) inactivated by both promoter methylation and/or somatic mutation. Among the novel tumor suppressor genes discovered with dual mechanisms of inactivation, we found a high frequency of genomic and epigenomic alterations in the PAX gene family of transcription factors, which selectively impact canonical NOTCH and TP53 pathways to determine cell fate, cell survival, and genome maintenance. Our results highlight the importance of assessing TSGs at the genomic and epigenomic level to identify key pathways in HNSCC, deregulated by simultaneous promoter methylation and somatic mutations.

Background: Solid organ recipients are at an increased risk of developing various malignancies. We investigated the incidence, clinical features, and outcome of patients diagnosed with head and neck cancer after organ transplantation., Methods: A retrospective analysis was undertaken of patients who underwent solid organ transplantation (kidney, liver, lung, heart) treated at our institution from 1992 to 2010., Results: Of 2817 organ recipients, 175 patients (6.1%) developed 391 head and neck malignancies. Cutaneous malignancies were the most common (93%): squamous cell carcinoma (SCC; 51%) and basal cell carcinoma (BCC; 42%). The average interval from transplantation to diagnosis of head and neck malignancy was 7.3 years, with liver recipients diagnosed earlier. Eighteen percent of patients presented with an aggressive pattern of head and neck cancer, including 24% of patients with cutaneous SCC., Conclusion: Organ transplantation recipients are at a higher risk to develop head and neck cancer with an aggressive behavior characterized by multiple recurrences and decreased survival., (Copyright © 2013 Wiley Periodicals, Inc.)

The TNM classification is not specific for head and neck skin cancer and makes no allowance for disease extent. Studies have shown that the relative number of metastatic-to-examined lymph nodes, termed the Nodal ratio, is a reliable independent prognosticator in several types of cancer. The study was designed as a retrospective analysis in a university affiliated tertiary care center setting. The files of all patients (n = 71) with cutaneous head and neck squamous cell carcinoma and regional lymph node metastasis who attended a tertiary medical center between 1990 and 2008 were reviewed for clinical variables and outcome, and Nodal ratio was calculated. Data were analyzed for impact on survival. On multivariate analysis Nodal ratio and age were found to be significant predictors of overall survival. The N-ratio was the only significant predictor of disease-specific survival. Age, type of treatment (selective/modified neck dissection), pathologic N stage, and radiotherapy had no effect. The Nodal ratio is a potentially valuable prognostic index in cutaneous squamous cell carcinoma. The minimal number of nodes that need to be excised has to be determined.

Background: Failure rate of surgery for early tongue carcinoma remains high. We sought to identify patterns of failure and recurrence risk factors., Methods: Data review was carried out on 50 patients treated for early tongue carcinoma (T1/2N0M0); surgery was unsuccessful in 11 of these patients. All patients underwent transoral resection of the tongue tumor and prophylactic neck dissection (supraomohyoid)., Results: Tumor recurred within 3 to 18 months. Nine died of disease. Four had failure in neck level 4, 6 in level 1, and 1 simultaneously in level 1 and locally. Most tumors were moderately differentiated. Average depth was 6.64 mm., Conclusions: We report 11 patients with early tongue carcinoma who failed local excision with neck dissection. Failures occurred in level 4 (4 patients) and level 1 (7 patients). This group may benefit from extended neck surgery. Sex, age, stage, and depth of tumor were not significantly different in the group with treatment failure. Tumors in the group with treatment failure were more poorly differentiated., (Copyright © 2011 Wiley Periodicals, Inc.)

Background and Aims: Squamous cell carcinoma (SCC) of the oral tongue is one of the most frequent head and neck cancers. The over-70-year age group is the fastest growing segment of the population. Age, however, is not considered a prognostic factor in oral tongue SCC. This study investigated the clinical and histopathological characteristics, disease course, and outcome of SCC of the oral tongue in patients over 75 years old compared with younger patients., Methods: We reviewed the files of 85 patients with histologically proven SCC of the oral tongue who were treated in our department in 1992-2007 and followed for a minimum of 2 years. Findings were compared between those aged 75 years or more and younger patients., Results: Twenty-eight patients (33%) were aged 75 to 94 years (average 80.5±4.5 yrs), including 14 who were over 80 years old, and 57 patients were aged 15-74 years (average 51.1±18.2 yrs). No statistically significant differences were found between the groups in clinical or histopathological characteristics or patient outcome. The 5-year disease-free survival rate was 65% for patients over 75 and 58% for younger patients. Corresponding rates for 5-year disease-specific survival were 69% and 70%. These differences were not statistically significant., Conclusions: Patients over 75 with oral tongue SCC should be managed like younger patients in terms of clinical staging and co-morbidities. They should be given a chance for treatment, as their prognosis is no different from that of younger patients.

Background: Tobacco smoking and high alcohol consumption are considered major risk factors of oral tongue squamous cell carcinoma. This study compared disease outcome between patients with and without known risk factors., Methods: Patients with oral tongue squamous cell carcinoma treated at two major medical centers from 1994 to 2008 were identified by cancer registry search. The medical files were reviewed for background-and-disease-related data, risk factors, and outcome., Results: The study sample consisted of 291 patients: 175 had a history of heavy tobacco smoking and alcohol abuse and 116 did not. Comparison of the patients without risk factors between the two centers yielded no differences in background features. Men accounted for 74% of the total patients with risk factors and comprised 77% of the risk-factor group. The risk-factor group was characterized by a significantly higher mean tumor grade (p=0.0001) and greater tumor depth of invasion (p=0.022) than the non-risk-factor group. The 5-year local and regional control rates were 85.3% and 74%, respectively, with no significant difference between the groups. The 5-year overall survival rate was 68% in the risk-factor group and 64% in the non-risk-factor group (p=NS). Separate analysis of patients aged <40 years at diagnosis revealed a worse overall (p=0.015) and disease-free survival (p=0.038) in those without risk factors., Conclusions: The outcome of oral tongue carcinoma is similar in patients with and without risk factors. The worse prognosis in younger patients (<40 years) without risk factors suggests that the pathogenesis in these cases involves factors other than smoking and alcohol., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: To assess the possible effect of young age on clinical behaviour and survival outcome of squamous cell carcinoma of the oral tongue., Design: Retrospective, case control study., Setting: A major tertiary referral centre., Participants: Eighty-five patients with oral tongue squamous cell carcinoma with at least 2 years of follow-up., Main Outcome Measurements: Clinical and histopathological staging, disease-free survival, disease-specific survival and overall survival., Results: Eleven patients (13%) were younger than 30 years. Compared to the older patients, they had a significantly worse N stage (P = 0.041), more perineural invasion (P = 0.012), and higher rates, though not significant, of treatment failure (46%, including 60% with distant metastases, versus 35%, nearly all locoregional) and mortality (100% of treatment failures versus 73%). There were no significant between-group differences in 5-year disease-free, disease-specific, and overall survival., Conclusion: In this study, patients younger than 30 years of age presented with advanced tumour stages and with a different failure pattern compared to the older age group. This may be attributable to age-related biologic behaviour or delayed cancer diagnosis. Differences in disease free survival and overall survival could not be established.

Objectives/hypothesis: The posterior commissure is an uncommon site of glottic carcinoma. The aim of the study was to compare the clinical and prognostic characteristics of glottic carcinoma of the posterior commissure and the vocal cords., Study Design: Retrospective case control study., Methods: The study group consisted of 40 patients aged 32 to 84 years (mean, 62.7 +/- 10.7) diagnosed with T1 glottic carcinoma involving the posterior commissure from 1960 to 2008. Data on clinical features and outcome were collected from the medical files and compared with the data for 42 patients aged 30 to 87 years (mean, 64.4 +/- 11.8) with T1 vocal cord carcinoma., Results: : There were no significant differences in clinical characteristics between the groups except for the higher rate of smokers among the patients with vocal cord carcinoma (95% vs. 65%, P = .01). All patients were treated primarily with radiotherapy. Disease-free survival in the posterior commissure carcinoma group was 76.1% after 5 years and 72.3% after 10 years, and in the vocal cord carcinoma group, 95% after 5 and 10 years (P = .012). The risk of recurrence was higher when the tumor involved the posterior commissure (hazard ratio, 8.78; 95% CI, 1.12-68.5, P = .038)., Conclusions: T1 glottic carcinoma involving the posterior commissure has a more aggressive biological behavior and a worse prognosis than T1 glottic carcinoma of the vocal cords. Smoking, which is an important pathogenetic factor in vocal cord carcinoma, plays a lesser role in posterior commissure carcinoma. Laryngoscope, 2009.

Purpose: The standard treatment for patients with early glottic carcinoma in Israel has been radiotherapy. In recent years, encouraging results with laryngo-microscopic carbon dioxide laser surgery as a treatment for early glottic carcinoma has changed our treatment strategy. We conducted a retrospective study to investigate the results of carbon dioxide laser excisional technique for early glottic carcinoma (T1, T2)., Materials and Methods: Twenty-six had squamous cell carcinoma (SCC), (21 patients with T1 and 5 patients with T2 lesions), 3 had carcinoma in situ, (CIS) and 3 had verrucous carcinoma (VC)., Results: All patients were free of disease after salvage treatment at the most recent follow-up., Conclusions: Careful patient selection with endoscopic staging and strict follow-up are essential to secure good results in the treatment of carbon dioxide laser for early laryngeal carcinoma., (Copyright 2003, Elsevier Science (USA). All rights reserved.))

This study reviews the records of 56 patients with early glottic carcinoma involving the anterior commissure (T1N0M0) who were treated between 1958 and 1988 at Beilinson Medical Center. Five- and 10-year survival rates were 82% and 60%, respectively. Most failures were local (15 patients). In addition, three patients who were treatment failures had neck lesions (regional failure) and one had lung lesions (distant metastases). All 56 patients received irradiation as the only mode of initial treatment. The effectiveness of irradiation for anterior commissure lesions is therefore evaluated. The study supports previous reports suggesting that glottic carcinoma involving the anterior commissure is associated with a high rate of treatment failure.

Between 1958 and 1990 67 patients with an early glottic carcinoma involving the anterior commissure were treated by radiotherapy. Excluding three with carcinoma in situ, 64 had a T1N0M0 squamous cell carcinoma; in eight of these (12.5%) the tumour was only located in the anterior commissure, in 45 (70.3%) it also involved one vocal cord and in 11 (17.2%) both vocal cords. The overall 5-year survival rate was 85%. For those with only anterior commissure involvement it was 60%, with involvement of one vocal cord and the anterior commissure it was 89% and with involvement of both vocal cords 82%. The 3-year recurrence rate was 58% for patients with involvement of only the anterior commissure, 24% with involvement also of one vocal cord, and 45% for those with involvement of both vocal cords. It was found that in cases of early glottic carcinoma, involving the anterior commissure and treated by radiotherapy, the prognosis for recurrence and survival was poorest when the carcinoma was only located in the anterior commissure, and it was concluded that this group of patients deserves special consideration.

Between 1958 and 1983 at Beilinson Medical Center, Petah Tiqva, Israel, 75 patients were diagnosed as having squamous cell carcinoma of the body of the tongue. Of these, 42 were male and 33 female and the average age at the time of diagnosis was 61.6 years. 29.33% were in clinical stage I, 36% in stage II, 26.67% in stage III and 8% in stage IV. Fifteen patients underwent only surgery, nine received only irradiation and 51 received combined treatment. The 5-year survival rate was 68.3% with a significant difference between that for stage I (90%) and stage II (83.7%) and that for stages III and IV (43.07% and 0%, respectively) (P less than 0.001). Among the 24 with recurrence of the malignancy, 20 died despite treatment and four patients died of causes unrelated to the malignancy. From this experience it was concluded that local excision of the tumor should be performed only in stage I patients and that in stage II patients prophylactic treatment of the neck (neck dissection and irradiation) should be undertaken because of the high incidence of occult metastases.

Between 1950 and 1985, 570 patients with squamous cell carcinoma of the larynx were diagnosed and treated in the Otolaryngology Department of the Beilinson Medical Center. Of these, 20 patients (2.8%) were aged 40 years or younger. Twelve patients (60%) had glottic carcinoma in Stage I (T1N0M0) when initially diagnosed, one patient had supraglottic carcinoma in Stage I (T1N0M0) and seven patients (35%) had laryngeal carcinoma in Stage II (T2N0M0) and III (T3N0M0). Patients with T1N0M0 received only radiotherapy. Three patients with T2N0M0 underwent total laryngectomy and also received postoperative radiotherapy. Four patients with the tumor in T3N0M0 received pre-operative and postoperative radiotherapy in addition to total laryngectomy. The 5-year survival rate for T1N0M0 and T2N0M0 was 100% and for T3N0M0 66%. Although a high percentage of the young patients presented for treatment with advanced disease, the survival rate compared the same or favorably with rates in older patients. This supports the concept of aggressive treatment when there is a recurrence or second primary, particularly because it is well tolerated in the young age group who do not exhibit many of the conventional risk factors and therefore, have a better prognosis.