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Background: This study aims to assess the clinical efficacy of elective neck irradiation (ENI) in patients with esthesineuroblastoma (ENB), a rare malignant neoplasm, who are clinically node-negative., Methods: We conducted a retrospective analysis of 178 patients newly diagnosed with ENB at our institution between 2009 and 2021. Propensity score matching (PSM) was employed to compare node-negative patients treated with and without ENI. We extensively examined survival outcomes and treatment failure., Results: Of the 178 participants, 149 (83.7%) were lymph node-negative and staged in Modified Kadish A-C. 96 patients underwent ENI treatment, while 53 did not. At baseline, patients who received ENI differed from those who did not in terms of radiotherapy technique, staging, orbital invasion, surgical mode, and chemotherapy. After PSM, 43 pairs were available for analysis. ENI was observed to extend overall survival (OS, 5-year 73.9% vs. 84.0%; 3-year 76.9% vs. 97.1%, p = 0.022), progression-free survival (PFS, 5-year 38.5% vs. 84.6%; 3-year 50.5% vs. 94.5%, p < 0.001) and locoregional relapse-free survival (LRFS, 5-year 42.7% vs. 84.6%, p = 0.023; 3-year 57.3% vs. 94.5%, p < 0.001) in node-negative ENI patients. Failure pattern analyses revealed that ENI, which included level Ib, II, VIIa, significantly reduced the treatment failure rate. Furthermore, ENI did not significantly impact the prognosis of T1-2 patients, indicating potential clinical value of ENI in T3-4 patients., Conclusions: Our findings suggested that ENI decreased regional failure and significantly enhanced LRFS and PFS. ENI may be considered as an integral part of the initial treatment strategy for locally advanced node-negative ENB patients., (© 2024. The Author(s).)

Background: With modern treatment paradigms, olfactory neuroblastoma (ONB) has favorable overall survival (OS); however, the incidence of recurrence remains high. The primary aims of this study were to delineate the prognosis of recurrence of ONB and explore how recurrence subsites are associated with OS, disease-specific survival (DSS), and further recurrence., Methods: A retrospective chart review of ONB cases from nine academic centers between 2005 and 2021 was completed. Tumor characteristics, recurrence subsites, timelines to recurrence, additional recurrences, and survival estimates were determined using descriptive and time-to-event analyses., Results: A final cohort of 233 patients was identified, with 70 (30.0%) patients recurring within 50.4 (standard deviation ±40.9) months of diagnosis on average, consisting of local (50%), neck (36%), intracranial (9%), and distant (6%) recurrence. Compared with subjects without recurrence, patients with recurrence had significantly different primary American Joint Committee on Cancer T stage (p < 0.001), overall stage (p < 0.001), and modified Kadish scores (p < 0.001). Histopathology identified that dural involvement and positive margins were significantly greater in recurrent cases. First recurrence was significantly associated with worse 5-year DSS (hazard ratio = 5.62; p = 0.003), and subjects with neck or local recurrence had a significantly better DSS compared to intracranial or distant recurrence., Conclusions: Recurrent cases of ONB have significantly different stages and preoperative imaging factors. Patients with local or neck recurrence, however, have better DSS than those with intracranial or distant recurrence, independent of initial tumor stage or Hyams grade. Identifying specific factors that confer an increased risk of recurrence and DSS is important for patient counseling in addition to surveillance planning., (© 2024 ARS‐AAOA, LLC.)

Objective: Olfactory neuroblastoma (ONB) is a rare, malignant tumor of the sinonasal tract that arises from olfactory epithelium. Although surgery is the preferred first-line treatment, tumor involvement of adjacent structures may preclude the ability to achieve negative margins during initial resection. Herein, the authors examine the oncological outcomes of patients with positive margins after primary resection of ONB, with the aim of determining predictors of disease progression and patterns of recurrence., Methods: The authors performed an institutional review of 25 patients with positive-margin ONB after resection. Cox survival analyses were used to determine any statistically significant predictors of worse progression-free survival (PFS) and overall survival (OS)., Results: A total of 93 patients who were diagnosed with ONB were identified, of whom 25 patients had positive margins following their primary resection. Eleven (44%) had a delayed finding of positive margins that were initially negative in the operating room but returned as positive on final pathology. Four patients had subtotal resection (STR), whereas the remaining patients underwent gross-total resection. Twenty-four patients received adjuvant radiotherapy (96%), and 15 additionally received adjuvant chemotherapy (60%). Fourteen patients (56%) experienced recurrence/progression at a median time of 35 months following resection (IQR 19-70 months). Local recurrence occurred in 10 patients (40%), regional in 9 (36%), and distant metastasis in 2 (8%). In Cox survival analyses, the 5-year PFS and OS were 55.1% and 79.2%, respectively. Kadish stage D was predictive of worse PFS in univariate (hazard ratio [HR] 15.67, 95% CI 3.38-72.61, p < 0.001) and multivariate (HR 15.46, 95% CI 1.45-164.91, p = 0.023) analyses. Hyams grade, adjuvant chemotherapy, and primary radiotherapy were not associated with PFS. Furthermore, Kadish stage D and STR were predictive of worse OS in univariate analysis (HR 12.64, 95% CI 2.03-78.86, p = 0.007; HR 7.31, 95% CI 1.45-36.84, p = 0.016; respectively). However, local and regional recurrence was not associated with worse OS., Conclusions: Approximately half of patients with positive-margin ONB may experience disease recurrence. Patients with an advanced disease stage (Kadish D) may have a higher likelihood of developing recurrence/progression. Furthermore, patients with tumor burden following resection (STR and Kadish D) may have worse OS. However, in positive-margin ONB with no gross disease following initial resection, the presence of disease recurrence does not significantly alter survival when receiving salvage therapy.

Objectives: To explore the prognostic factors in patients with advanced olfactory neuroblastoma (ONB) underwent endoscopic surgery., Materials and Methods: Retrospective medical records were reviewed of patients with pathologically proven ONB who underwent endoscopic surgical resection. Clinicopathological characteristics including patient demographics, treatment, complications, follow-up, and outcomes were analyzed. Kaplan-Meier overall survival (OS) and disease-free survival (DFS) curves were plotted. Univariate and multivariate Cox regression models were used to determine prognostic factors., Results: Eighty-five patients with Kadish stage C ONB were examined. According to the various staging systems used, most patients harbored modified Kadish stage C (78.8%). Twenty-six patients (30.6%) underwent bony skull base resection, 11 (12.9%) underwent dura resection, and 24 (28.2%) underwent additional intracranial resection that included the olfactory bulb and duct. Median follow-up was 39 months. Five-year OS and DFS rates were 83.7% and 74.9%, respectively. Five-year OS was 100% in patients treated with bony skull base resection and 77.5% in those who were not ( P  = .052). Dura resection did not improve OS. Multivariate Cox regression analysis identified perioperative complications ( P  = .009), gross total resection ( P  = .004), orbital invasion ( P  = .014), postoperative radiotherapy ( P  = .030), and bony skull base resection ( P  = .019) as independent prognostic predictors., Conclusion: For patients with advanced ONB, endoscopic surgery in conjunction with radiotherapy and chemotherapy is effective and safe. Dura resection should be performed with caution in selected patients to balance survival and complications. Postoperative radiotherapy is important to improve OS and DFS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: Current olfactory neuroblastoma (ONB) staging systems inadequately delineate locally advanced tumors, do not incorporate tumor grade, and poorly estimate survival and recurrence., Objective: The primary aims of this study were to (1) examine the clinical covariates associated with survival and recurrence of ONB in a modern-era multicenter cohort and (2) incorporate Hyams tumor grade into existing staging systems to assess its ability to estimate survival and recurrence., Design, Setting, and Participants: This retrospective, multicenter, case-control study included patients with ONB who underwent treatment between January 1, 2005, and December 31, 2021, at 9 North American academic medical centers., Intervention: Standard-of-care ONB treatment., Main Outcome and Measures: The main outcomes were overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) as C statistics for model prediction., Results: A total of 256 patients with ONB (mean [SD] age, 52.0 [15.6] years; 115 female [44.9%]; 141 male [55.1%]) were included. The 5-year rate for OS was 83.5% (95% CI, 78.3%-89.1%); for DFS, 70.8% (95% CI, 64.3%-78.0%); and for DSS, 94.1% (95% CI, 90.5%-97.8%). On multivariable analysis, age, American Joint Committee on Cancer (AJCC) stage, involvement of bilateral maxillary sinuses, and positive margins were associated with OS. Only AJCC stage was associated with DFS. Only N stage was associated with DSS. When assessing the ability of staging systems to estimate OS, the best-performing model was the novel modification of the Dulguerov system (C statistic, 0.66; 95% CI, 0.59-0.76), and the Kadish system performed most poorly (C statistic, 0.57; 95% CI, 0.50-0.63). Regarding estimation of DFS, the modified Kadish system performed most poorly (C statistic, 0.55; 95% CI, 0.51-0.66), while the novel modification of the AJCC system performed the best (C statistic, 0.70; 95% CI, 0.66-0.80). Regarding estimation of DSS, the modified Kadish system was the best-performing model (C statistic, 0.79; 95% CI, 0.70-0.94), and the unmodified Kadish performed the worst (C statistic, 0.56; 95% CI, 0.51-0.68). The ability for novel ONB staging systems to estimate disease progression across stages was also assessed. In the novel Kadish staging system, patients with stage VI disease were approximately 7 times as likely to experience disease progression as patients with stage I disease (hazard ratio [HR], 6.84; 95% CI, 1.60-29.20). Results were similar for the novel modified Kadish system (HR, 8.99; 95% CI, 1.62-49.85) and the novel Dulguerov system (HR, 6.86; 95% CI, 2.74-17.18)., Conclusions and Relevance: The study findings indicate that 5-year OS for ONB is favorable and that incorporation of Hyams grade into traditional ONB staging systems is associated with improved estimation of disease progression.

Objectives/hypothesis: Olfactory neuroblastoma (ONB) is a rare sinonasal malignant neoplasm that is known to develop late recurrence. The aim of this study is to evaluate the long-term outcomes of patients with ONB and to determine the factors associated with prognosis., Study Design: Retrospective study., Methods: A retrospective review of the medical records of 139 patients diagnosed with ONB at MD Anderson Cancer Center was performed between 1991 and 2016. Descriptive statistics were calculated, and Kaplan-Meier curves were utilized to assess survival., Results: Median follow-up time was 75 months. Overall, 129 patients (92.8%) had surgery as part of their treatment and 82 (58.9%) patients received postoperative radiation therapy (PORT) or concurrent chemoradiotherapy. Endoscopic approaches were utilized for 72 patients, 69.4% of whom had pure endoscopic endonasal approaches. Five-year overall survival and disease-specific survival were 85.6% and 93.4%, respectively. Recurrence rate was 39.6% with a median time to recurrence of 42 months. Among the 31 patients who received elective nodal irradiation (ENI), two patients developed neck recurrence (6.4%) compared with 20 who developed neck recurrence when ENI was omitted (34.4%) (P = .003). Advanced Kadish stage, orbital invasion, intracranial invasion, and presence of cervical lymphadenopathy at the time of presentation were significantly associated with poor survival., Conclusion: ONB has an excellent survival. Surgical resection with PORT when indicated is the mainstay of treatment. Endoscopic approaches can be used as a good tool. Elective neck irradiation reduces the risk of nodal recurrence among patients with clinically N0 neck. Despite the excellent survival, recurrence rate remains high and delayed, highlighting the need for long-term surveillance., Level of Evidence: Level 4 Laryngoscope, 132:290-297, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Esthesioneuroblastoma (ENB) is a rare malignancy of the sinonasal tract and its infrequency has confounded efforts at clearly describing the survival trends associated with this neoplasm over the years. In this study, we reviewed survival trends in ENB and investigated the impact of treatment extent and modality on patient outcomes., Methods: We accessed the Surveillance, Epidemiology, and End Result (SEER) program to identify ENB cases from 1998 to 2016. A χ 2 test was used to compare the categorical covariates and a t test or Mann-Whitney U test was utilized for continuous variables. The impact of prognostic factors on survival was computed using a Kaplan-Meier analysis and multivariate Cox proportional hazards model. We divided ENB patients into 4 periods including 1998-2002, 2003-2007, 2008-2012, and 2013-2016, and investigated survival trends using the Kaplan-Meier curve and log-rank test., Results: ENB patients who underwent biopsy alone were associated with older age, larger tumor diameter, increased rates of tumor extension, nodal/distant metastases, and advanced stages as compared with patients undergoing tumor resection. Our results also demonstrated that surgical resection and adjuvant radiotherapy could confer survival advantages, whereas chemotherapy was associated with reduced survival in patients with ENB. Over the past 2 decades, surprisingly, there has been no change in survival rates for patient with ENB (P = 0.793)., Conclusions: Despite advanced diagnostic studies and modernized treatment approaches, ENB survival has remained unchanged over the years, calling for improved efforts to develop appropriate individualized interventions for this rare tumor entity. Our results also confirmed that surgery and adjuvant radiotherapy is associated with improved patient survival whereas the use of chemotherapy should be considered carefully., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Esthesioneuroblastoma (ENB) is a rare sinonasal malignancy with little known regarding how regional and socioeconomic differences in the United States alter disease survival. The aim of this study is to explore the geographic difference in clinical features, socioeconomic factors, and survival outcomes of ENB patients., Methods: ENB cases were extracted from the Surveillance, Epidemiology, and End Results registry from 1975-2016. Patient data were stratified based on geographical location and comparative analyses of socioeconomic features, disease characteristics, and survival patterns were performed. Kaplan-Meier regression analyses were used to estimate disease-specific survival (DSS)., Results: A total of 987 patients were identified: 56.4% West, 14.0% South, 12.7% Midwest, and 16.6% East. The West had the highest proportion of patients with Medicaid coverage (P < .001), stage A malignancy (P < .001), and treated with surgery and adjuvant radiotherapy (P < .001). The South had the highest proportion of patients who were Black (P < .001), uninsured (P < .001), and resided in rural areas (P < .001). Five-year DSS patterns were 81.0% (West), 79.8% (East), 67.4% (Midwest), and 72.7% (South) [P = .018]. Ten-year DSS outcomes were 74.0% (West), 73.7% (East), 60.9% (Midwest), and 63.6% (South) [P = .017]., Conclusion: In ENB patients, survival disparity exists in the United States based on geographical region. Patients from the West and East exhibit higher survival than those from the South and Midwest., Level of Evidence: 4 Laryngoscope, 131:E2162-E2168, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Purpose: The main objective of this study was to evaluate the cumulative incidence of cause-specific mortality and other causes of mortality for patients with olfactory neuroblastoma (ONB). The secondary aim was to model the probability of cause-specific death and build a competing risk nomogram to predict cause-specific mortality for this disease., Methods: Patients with ONB from 1975 to 2016 were identified from the Surveillance, Epidemiology, and End Results database. We estimated the cumulative incidence function (CIF) for cause-specific mortality and other causes of mortality, and constructed the Fine and Gray's proportional subdistribution hazard model, as well as a competing-risk nomogram based on Fine and Gray's model, to predict the probability of cause-specific mortality for patients with ONB., Results: After data selection, 826 cases were included for analysis. Five-year cumulative incidence of cause-specific mortality was 19.5% and cumulative incidence of other causes of mortality was 11.3%. Predictors of cause-specific mortality for ONB included tumor stage, surgery and chemotherapy. Age was most strongly predictive of other causes of mortality: patients aged > 60 years exhibited subdistribution hazard ratios of 1.063 (95 % confidence interval [CI] 1.05-1.08; p = 0.001). The competing risk nomogram for cause-specific mortality was well-calibrated, and had good discriminative ability (concordance index = 0.79)., Conclusions: We calculated the CIF of cause-specific mortality and other causes of mortality in patients with the rare malignancy ONB. We also built the first competing risk nomogram to provide useful individualized predictive information for patients with ONB.

Background: Olfactory neuroblastoma, or esthesioneuroblastoma (ENB), is an uncommon sinonasal malignancy arising from olfactory neuroepithelium that is optimally treated with surgical resection. The objective of this study is to determine preoperative predictors of undergoing open versus endoscopic approach for ENB and to investigate significant postoperative survival outcomes between the two surgical approaches., Methods: The National Cancer Database (NCDB) was queried for cases of ENB histology that were treated surgically from 2010 to 2015. Groups were stratified into open or endoscopic approach cohorts. Patient demographics, tumor characteristics, treatment modality, and 5-year overall survival were compared between the two groups using Chi-Square analysis and Kaplan-Meier survival analysis. Cases were classified as Kadish stage A, B, C, or D based on the "Collaborative Stage-Extension" codes in NCDB., Results: Of 533 patients meeting inclusion criteria, 276 (51.8%) patients underwent open, and 257 (48.2%) patients underwent endoscopic surgical approaches. Patients undergoing endoscopic surgery were more likely to be Kadish stages A and B and less likely to be stages C and D ( P  = .020). Those undergoing endoscopic approach overall had a shorter mean hospital stay postoperatively (3.8 vs. 7.0 days, P  < .001). Endoscopic cases had a greater 5-year overall survival (81.9% vs. 75.6%, P  = .030); after multivariate regression, there was a trend toward survival benefit to endoscopic surgery that did not reach clinical significance (HR 0.644, [0.392-1.058], P  = .083)., Conclusion: Although not statistically significant, there is a trend toward increased overall survival with an endoscopic approach in patients undergoing surgery for ENB as compared to an open approach, regardless of Kadish stage. An endoscopic approach is an adequate alternative to an open approach for the surgical treatment of ENB.

Background: Increasing evidence indicates that the pathology and the modified Kadish system have some influence on the prognosis of esthesioneuroblastoma (ENB). However, an accurate system to combine pathology with a modified Kadish system has not been established., Methods: This study aimed to set up and evaluate a model to predict overall survival (OS) accurately in ENB, including clinical characteristics, treatment and pathological variables. We screened the information of patients with ENB between January 1, 1976, and December 30, 2016 from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program as a training cohort. The validation cohort consisted of patients with ENB at Sun Yat-sen University Cancer Center and The First Affiliated Hospital of Sun Yat-sen University in the same period, and 87 patients were included. The Pearson's chi-squared test was used to assess significance of clinicopathological and demographic characteristics. We used the Cox proportional hazards model to examine univariate and multivariate analyses. The model coefficients were used to calculate the Hazard ratios (HR) with 95% confidence intervals (CI). Prognostic factors with a p-value < 0.05 in multivariate analysis were included in the nomogram. The concordance index (c-index) and calibration curve were used to evaluate the predictive power of the nomogram., Results: The c-index of training cohort and validation cohort are 0.737 (95% CI, 0.709 to 0.765) and 0.791 (95% CI, 0.767 to 0.815) respectively. The calibration curves revealed a good agreement between the nomogram prediction and actual observation regarding the probability of 3-year and 5-year survival. We used a nomogram to calculate the 3-year and 5-year growth probability and stratified patients into three risk groups., Conclusions: The nomogram provided the risk group information and identified mortality risk and can serve as a reference for designing a reasonable follow-up plan.

Background: The aim of this study is to evaluate the efficacy of different treatment strategies and the potential prognostic factors of esthesioneuroblastoma (ENB)., Materials and Methods: Between April 1984 and December 2018, 138 patients with non-metastatic ENB were retrospectively analyzed. The treatment modalities mainly included surgery alone (n = 7), radiotherapy alone (n = 33), concurrent chemoradiotherapy (n = 17), surgery combined with current chemoradiotherapy (n = 32), and surgery plus radiotherapy (n = 49)., Results: The median follow-up time for the entire cohort was 61 months (range, 4-231 months). The 5-year overall survival (OS), locoregional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS) rate were 69.6, 78.0 and 73.9%, respectively. Surgery combined with radiotherapy elicited superior survival results, and the combination of surgery and current chemoradiotherapy achieved the best prognoses for all patients, patients with advanced Kadish disease, patients receiving intensity modulated radiation therapy and those with positive surgical margin. Univariate analysis identified orbital invasion and treatment modalities were predictors for OS, LRFFS and DMFS. Lymph node metastasis was associated with OS and DMFS, but not LRFFS. Intracranial invasion, advanced Kadish stage and not receiving concurrent chemotherapy were also predictive of lower OS. Multivariate analyses indicated that lymph node metastasis was an independent prognostic factor affecting DMFS, whereas treatment modalities was independent prognostic factors for OS and LRFFS., Conclusion: Orbital invasion, intracranial invasion, lymph node metastasis and advanced Kadish disease at initial diagnosis were significantly associated with inferior prognosis. Regarding the treatment modality, the optimal strategy remined surgery with radiotherapy-based multimodality treatment. The concurrent chemoradiotherapy may play a more beneficial role.

Objective: To compare the Kadish and the modified Dulguerov staging of individual participants to determine the impact of stage and other prognostic factors on disease-free (DFS) and overall survival (OS)., Data Sources: Systematic review of EMBASE, MEDLINE, Cochrane Library, and CINAHL databases., Review Methods: The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) was followed for this study. Articles including patients with olfactory neuroblastoma (ONB) staged with both Kadish and Dulguerov staging systems were reviewed. The raw data from eligible studies were requested to perform an individual participant data (IPD) meta-analysis., Results: Pooled data from 21 studies representing 399 patients with ONB undergoing treatment with curative intent showed that increasing age, treatment with chemotherapy, and positive or unreported margin status portended worse DFS ( P < .05). Increasing stage for both Kadish and Dulguerov staging systems was prognostic for worse DFS and OS ( P < .05), with Kadish C representing a heterogeneous group with regard to outcome and corresponding Dulguerov T stage. Using the Akaike information criterion, the Dulguerov staging system had superior performance to the Kadish system for DFS (1088.72 vs 1092.54) and OS (632.71 vs 644.23)., Conclusion: This study represents the first IPD meta-analysis of ONB directly comparing the outcomes of Kadish and Dulguerov staging systems in patients treated with primary surgery. Both systems correlated with DFS and OS, with superior performance in the Dulguerov system. Furthermore, the Kadish C group represented a heterogeneous group with regard to outcomes after stratification by the Dulguerov system. Dulguerov T4 patients had the worst outcome, with most being approached with open resection.

Objective: The clinical data on olfactory neuroblastomas (ONBs) are scarce owing to their rarity. This study aimed to assess the potential prognostic factors, outcomes, and optimal treatment strategies in patients with ONB., Methods and Materials: The data of 217 patients with ONB between 1991 and 2019 were retrospectively reviewed. Long-term survival, potential prognostic factors, and outcomes with combined treatment strategies were analyzed., Results: All patients received radiotherapy (RT); 185 patients underwent surgery, and 139 patients received chemotherapy. The 5-year overall survival (OS), progression-free survival (PFS), locoregional failure-free survival (LRFS), and distant metastasis-free survival (DMFS) of the entire cohort were 80.0%, 79.0%, 79.3%, and 80%, respectively. On univariate analyses, R0/R1 resection, early Kadish stage, negative lymph nodes, absence of orbital invasion, and administration of surgery with RT were found to be favorable factors. Conversely, combined sequential treatment with surgery, RT, and chemotherapy was not associated with survival. Multivariate analysis demonstrated lymph node status, orbital invasion, and the combination of surgery and RT to be independent prognostic factors., Conclusions: Patients with ONB, who had lymph node metastases, orbital invasion diseases, advanced Kadish stages, R2 resection margins, and received RT alone, had poor outcomes. Combined administration of surgery and RT may be a potentially useful strategy in patients with advanced Kadish stages; the role of chemotherapy in these stages requires further evaluation., Competing Interests: Declaration of Competing Interest The authors have no personal or institutional conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Chemotherapy has been proposed as an adjunct to primary local therapy in esthesioneuroblastoma (ENB)/olfactory neuroblastoma (ON), but its role has not been precisely defined. Here, we evaluated its role in ENB treatment., Materials and Methods: The Surveillance Epidemiology and End Results (SEER) database was queried for ENB/ON (International Classification of Diseases-3 9522). Cases met criteria for inclusion if they were unique, had a primary location in the nasal cavity, and had adequate information for Kadish staging derivation. Univariable and multivariable Cox analyses assessed chemotherapy treatment effect on disease-specific survival (DSS) and overall survival (OS). Multiple imputation addressed missing data. A P<0.05 was designated for statistical significance., Results: In adjusted multivariable analyses, chemotherapy treatment was associated with inferior DSS (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.21-2.51; P=0.003) and OS (HR, 1.71; 95% CI, 1.26-2.32; P=0.001). Among the subset with local or regional disease treated with surgery and/or radiation therapy, chemotherapy remained associated with inferior outcomes DSS (HR, 2.78; 95% CI, 1.63-4.74; P<0.001) and OS (HR, 2.18; 95% CI, 1.45-3.27; P<0.001). Chemotherapy treatment misclassification did not explain these findings., Conclusions: This analysis does not support chemotherapy to improve either DSS or OS in primary ENB/ON treatment, after controlling for known ENB prognostic factors available from SEER. Other prognostic and treatment selection factors could exist which were not controlled in these analyses. Chemotherapy could beneficially affect outcomes other than DSS or OS. Although the concerns have been expressed regarding chemotherapy treatment misclassification in SEER, their analyses did not identify such misclassification as an explanation for our findings.

Objective: Optimal neck management in patients with olfactory neuroblastoma (ONB), a rare malignancy, remains uncertain. This study aimed to analyse patterns of cervical lymph node metastases and corresponding clinical outcomes and to investigate the value of elective neck irradiation (ENI) in this population., Methods and Materials: This study retrospectively reviewed clinical records, imaging findings, nodal metastasis features and treatment data of 217 patients with ONB treated at our hospital during 1991-2019. Univariate and multivariate analyses were used to assess the influence of cervical lymph node involvement on treatment outcomes. Survival and regional failure rates were compared between patients with or without ENI., Results: Thirty-two patients (14.7%) presented initially with cervical lymph node metastases, most frequently at levels II (10.6%, 23/217) and VIIa (5.5%, 12/217). Patients with and without cervical node metastasis differed significantly in overall (OS) (41.9% vs. 86.1%, p < 0.001), progression-free (PFS) (41.9% vs. 84.8%, p < 0.001), regional failure-free (45.9% vs. 89%, p < 0.001) and distant metastasis-free survival (41.5% vs. 86.1%, p < 0.001). Cervical lymph involvement was an independent factor affecting poor OS (hazard ratio, 0.184, 95% confidence interval, 0.078-0.436, p < 0.001) and PFS (hazard ratio, 0.198, 95% confidence interval, 0.088-0.445, p < 0.001). Moreover, 43.8% patients (95/217) underwent ENI, which significantly reduced the incidence of regional recurrence from 10.7% to 3.2% (χ 2  = 4.396, p = 0.036) but did not significantly affect other survival outcomes. Regional failures could be resolved using salvage treatment., Conclusions: Our findings indicate the importance of systematic therapy for patients with initial cervical lymph node metastases. ENI is not recommended for N0 disease., Competing Interests: Declaration of Competing Interest None declared, (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Olfactory neuroblastoma (ONB) is a malignant neoplasm that arises from the upper nasal vault., Objective: We present a retrospective case series and clinical analysis of 12 ONB cases., Materials and Methods: Patients with ONB treated at Mexico´s National Cancer Institute between 2011 and 2018., Results: The Kadish proportion of B, C, and D stage was 16%, 58%, or 25%, respectively. Hyams Grade 1, 2, or 3 was 25%, 50%, and 25%, respectively. The most common surgical approach was the craniofacial in 5 cases (42%), followed by the transfacial in 4 cases (33%), and the endonasal endoscopic approach in 3 cases (25%). Gross total resection was achieved in 8 patients (67%). Five patients (42%) underwent a second operation due to recurrent/progressive disease. The surgical complication rate was 8.3%. Progression-free survival was 41 months and the mean overall survival was 63.6 months., Conclusions: Surgical resection followed by radiotherapy, and chemotherapy for metastatic and recurrent disease provides the best outcome in terms of survival and recurrence. To the best of our knowledge, this is the first series of cases reported in Mexico., (Copyright: © 2020 Permanyer.)

Objectives/hypothesis: Sinonasal cancers are rare but have a poor prognosis. Most previous studies of these cancers have focused on 5-year disease-free survival, but recurrences are also known to occur after this period. We examined the post-5-year recurrence patterns in sinonasal cancer patients by histologic type to determine the indicators for extended and close follow-up requirements., Study Design: Retrospective chart review., Methods: A cohort of 241 sinonasal cancer patients was included. Demographic data, cancer site and stage, pathology and treatment results, and follow-up and survival data were collected., Results: Of the 241 patients, a complete remission occurred in 163 (72.4%) patients, but 83 (50.9%) of these cases developed recurrence, which occurred beyond the 5-year follow-up period in 19 cases (11.7%). The most common post-5-year recurrences were adenoid cystic carcinoma (six patients, 33.3%), followed by melanoma (three patients, 21.4%), poorly differentiated carcinoma (two patients, 18.2%), squamous cell carcinoma (six patients, 6.7%), and olfactory neuroblastoma (no patients, 0%). Post-5-year local recurrence was highest in adenoid cystic carcinoma (six patients, 33.3%), followed by melanoma (three patients, 21.4%), poorly differentiated carcinoma (two patients, 18.2%), and squamous cell carcinoma (five patients, 5.5%). Post-5-year regional recurrence occurred in one squamous carcinoma patient (1.1%), and distant metastasis was seen in one adenoid cystic carcinoma patient (5.5%)., Conclusions: Sinonasal cancer shows an 11.7% recurrence rate after a 5-year disease-free period. As this recurrence pattern varies by tumor pathology, a specific follow-up plan is needed for each cancer type., Level of Evidence: 3 Laryngoscope, 129:2451-2457, 2019., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, represents up to 3% of all sinonasal neoplasms. Hyams histologic grading is a promising tool in predicting metastases and establishing prognoses for this complex tumor., Methods: A systematic literature search was performed in the PubMed, Ovid MEDLINE, and Cochrane databases. ENB patients with Hyams I-II or III-IV were categorized as low-grade Hyams (LGH) or high-grade Hyams (HGH), respectively. Binary and continuous random-effects models were applied to calculate odds ratios (ORs) for the incidences of neck and distal metastases as well as for 5- and 10-year overall survival rates., Results: Of the 57 screened articles published from 1993 to 2018, 16 (525 patients) and 21 (563 patients) provided data for tumor metastases and overall survival rates, respectively. Neck metastasis was observed in 18.2% of HGH vs 7.9% of LGH patients. Distant metastasis was noted in 20.7% of HGH vs 8.9% of LGH patients. LGH patients had 5- and 10-year overall survival rates of 81.2% and 64.0%, respectively, as compared with 60.9% and 40.6%, respectively, for HGH patients. In comparing HGHs vs LGHs, the collective ORs for neck and distant metastases were 2.08 (95% confidence interval [CI], 1.09-3.99; p = 0.03) and 2.37 (95% CI, 1.07-5.26; p = 0.03), respectively. Moreover, in comparing LGHs vs HGHs, collective ORs for 5- and 10-year overall survival rates were 3.39 (95% CI, 2.09-5.49; p < 0.001) and 3.03 (95% CI, 1.82-5.06; p < 0.001), respectively., Conclusion: HGH ENBs, compared with LGH ENBs, are more likely to metastasize to neck or distal targets and to have lower overall survival rates., (© 2019 ARS-AAOA, LLC.)

Background: Past research established that surgery plus adjuvant radiotherapy (S + AR) improves overall survival (OS) in esthesioneuroblastoma (ENB). However, it is unknown if the addition of adjuvant chemotherapy (AC) further improves survival. The primary objective of this study was to compare survival among patients treated with S + AR alone to patients who underwent S + AR + AC., Methods: Retrospective review of patient records., Results: Thirty-eight patients met inclusion criteria for either S + AR or S + AR + AC treatment groups. The S + AR + AC group contained more patients with Kadish stage D disease, dural invasion, and positive histologic margins postsurgery. All S + AR + AC patients received platinum-based regimens, combined with etoposide in 67%. OS and recurrence-free survival did not differ between the two groups, even when restricting the analysis to patients with Kadish stages B and C disease., Conclusion: Patients who received platinum-based AC did not exhibit improved survival compared to S + AR alone. Further investigation, preferably prospective, into the optimal use of systemic therapy in ENB is warranted., (© 2018 Wiley Periodicals, Inc.)

Background: The available literature to guide treatment decision making in esthesioneuroblastoma (ENB) is limited., Objective: To define treatment patterns and outcomes in ENB according to treatment modality using a large national cancer registry., Methods: This study is a retrospective cohort analysis of 931 patients with a diagnosis of ENB who were treated with surgery, radiation therapy, and/or chemotherapy in the United States between the years of 2004 and 2012. Log-rank statistics were used to compare overall survival by primary treatment modality. Logistic regression modeling was used to identify predictors of receipt of postoperative radiotherapy (PORT). Cox proportional hazards modeling was used to determine the survival benefit of PORT. Subgroup analyses identified subgroups that derived the greatest benefit of PORT., Results: Primary surgery was the most common treatment modality (90%) and resulted in superior survival compared to radiation (P < .01) or chemotherapy (P < .01). On multivariate analysis, PORT was associated with decreased risk of death (hazard ratio [HR] 0.53, P < .01). PORT showed a survival benefit in Kadish stage C (HR 0.42, P < .01) and D (HR 0.09, P = .01), but not Kadish A (HR 1.17, P = .74) and B (HR 1.37, P = .80). Patients who received chemotherapy derived greater benefit from PORT (HR 0.22, P < .01) compared with those who did not (HR 0.68, P = .13). Predictors of PORT included stage, grade, extent of resection, and chemotherapy use., Conclusion: Best outcomes were obtained in patients undergoing primary surgery. The benefit of PORT was driven by patients with stages C and D disease, and by those also receiving chemotherapy.

Purpose: To evaluate the safety and efficacy of carbon-ion radiation therapy (C-ion RT) for locally advanced sinonasal malignant tumors in a multicenter retrospective study (J-CROS 1402 HN)., Methods and Materials: Clinical data were collected for patients who had sinonasal malignant tumors of stage N0-1M0 and received C-ion RT at 4 institutions in Japan between November 2003 and December 2014. Of the 458 patients, 393 had naïve tumors and 65 had recurrent tumors. The tumors were located in the nasal cavity (n = 263), maxillary sinus (n = 109), ethmoid sinus (n = 71), and other locations (n = 15). The histologic types were mucosal melanoma (n = 221, 48%), adenoid cystic carcinoma (n = 122, 27%), squamous cell carcinoma (n = 31, 7%), olfactory neuroblastoma (n = 30, 7%), adenocarcinoma (n = 21, 5%), and other types (n = 33, 7%). Of the 458 patients, 300 (66%) had T4 tumors. All patients received definitive C-ion RT., Results: The median follow-up period was 25.2 months for all patients (range, 1.4-132.3 months). The 2-year overall survival and local control rates were 79.6% and 84.1%, respectively. As analyzed according to histology, the 2-year overall survival rate was 68.0% for mucosal melanoma, 96.8% for adenoid cystic carcinoma, 70.0% for squamous cell carcinoma, 96.7% for olfactory neuroblastoma, and 89.7% for adenocarcinoma. Regarding late toxicities, 17% of patients developed grade 3 and 4 toxicities, of which visual impairment was the most common., Conclusion: The results of our multicenter study have demonstrated that C-ion RT can provide excellent clinical outcomes with acceptable late toxicities in patients who have locally advanced sinonasal malignant tumors., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to determine the clinical outcomes and review the management strategies for metastatic esthesioneuroblastoma., Methods: We conducted a systematic review and meta-analysis., Results: Forty-eight studies totaling 118 patients met inclusion criteria. Chemotherapy in combination with surgery and/or radiation exhibited the best overall survival when compared to monotherapy and no treatment (P < .001). However, most patients (66%) received either monotherapy or no therapy. The number and location of metastases among the 3 treatment groups did not significantly differ (P = .85). Treatment modality remained significantly associated with overall survival on multivariable analysis (P < .001). Platinum-based chemotherapy was most commonly utilized but did not provide a survival benefit when compared with all other regimens (P = .88)., Conclusion: Distant metastases with esthesioneuroblastoma portend a poor prognosis. Chemotherapy in combination with surgery and/or radiation was associated with improved overall survival. Further research into the optimal systemic therapeutic regimen for patients with distant metastases is critical., (© 2018 Wiley Periodicals, Inc.)

Objective: To quantify the rate of late intracranial recurrences among esthesioneuroblastoma patients treated with surgical resection and postoperative radiation., Study Design: Retrospective review., Methods: All patients receiving definitive-intent therapy for esthesioneuroblastoma between March 1995 and September 2015 were reviewed. Presenting disease extent was categorized based on radiologic, operative, and pathologic findings. Between-group survival differences were assessed using Kaplan-Meier method and log-rank test. Multivariate analyses were performed using Cox proportional hazards model., Results: Of 38 patients initially treated at our institution, 53% (20 of 38) presented with intracranial extension. At a median follow-up of 90 months (range, 6-199), 37% (14 of 38) recurred; 5- and 8-year disease-free survival rates were 69% and 54%; and overall survival rates were 81% and 72%, respectively. Among these patients, the dura was the most commonly involved site of relapse (8), followed by local (6), regional (5), and distant extracranial (3) sites; and five patients had ≥ two categories of failure. Eight-year dural disease-free survival was 57% versus 90% (P = 0.017) and 0% versus 87% (P < 0.0001), with and without intracranial extension and subtotal resection, respectively. Of six patients treated at recurrence, five (83%) experienced dural-based failure such that, among all 44 patients, 13 (65%) of 20 recurrences involved the dura. After dural recurrence, the median survival time was 42 months (range, 12-125); salvage treatments were effective in rare cases of isolated low-volume recurrence., Conclusion: Esthesioneuroblastoma patients presenting with intracranial extension are at substantial and unique risk for long-term dural-based relapse., Level of Evidence: 4. Laryngoscope, 128:2226-2233, 2018., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Olfactory neuroblastoma (ONB) is a kind of rare and complex head and neck tumor. The reports on this field are very scarce due to the low morbidity. Here, we summarized the clinical features and prognosis of ONB through analysis of 10 cases, and determined the phosphorylation status of some molecules known to be involved in carcinogesis such as Akt, Erk, Stat3 and Stat5 in ONB tissue. Ten ONB patients were recruited in this study, 6 male and 4 female, ranging from 26 to 66 years old. In the 10 cases, 6 were diagnosed as late T stage (T 3 /T 4 ), 6 were at late Kadish stage (C/D) and 3 were at high Hyams grade (Ⅲ), which indicated a poorer prognosis. Patient characteristics-gender and tumor features were evaluated with respect to the overall survival (OS) through univariate analysis. The result indicated that the OS of male is obviously higher than that of female after a series of combined treatment. The OS of ONB patients in the late stage or high grade is lower than those in early stages or low grade. Moreover, p-Akt, p-Erk, p-Stat3 and p-Stat5 was detected in 5 (50%), 9 (90%), 7 (70%) and 0 patients (0%), respectively, suggesting the former 3 molecules might be potential biomarkers for diagnosis of ONB., (Copyright © 2018. Published by Elsevier GmbH.)

The aim of this study was to report incidence and patient characteristics of olfactory neuroblastoma (ONB) at a tertiary cancer institution during a 16-year period. A retrospective review was conducted on patients with ONB treated at Rigshospitalet, Copenhagen from 2000 to 2016 covering Eastern Denmark. Patient demographics, symptoms, stage, pathology-reports, treatment, and outcome were extracted from the patient records and the Danish pathology register. The tumours were graded both histologically and clinically using Hyam's and Kadish classifications, respectively. We identified a total of 14 patients (ten males, four females, median age 57 years, range 17-81 years). Four patients were in Kadish stage A, one stage B, and seven stage C. According to Hyam's classification, two tumours were grade I, nine grade II, and three grade III. All patients were treated with surgery, eight in combination with radiotherapy, where one received proton therapy, and one a combination with chemotherapy. At a median follow-up time of 58 months, the 5-year overall survival was 90% (95% CI 61; 99). ONB is a rare disease; complete radical surgery alone or combined with radiotherapy offered good oncologic control and outcome. Long-term follow-up of ONB should be mandatory., (© 2018 APMIS. Published by John Wiley & Sons Ltd.)

Objective: Compare outcomes of patients with olfactory neuroblastoma (ONB) without skull base involvement treated with and without resection of the dura and olfactory bulb., Methods: Retrospective review of ONB patients treated from 1992 to 2013 at the MD Anderson Cancer Center (The University of Texas, Houston, Texas, U.S.A.). Primary outcomes were overall and disease-free survival., Results: Thirty-five patients were identified. Most patients had Kadish A/B. tumors (97%), Hyams grade 2 (70%), with unilateral involvement (91%), and arising from the nasal cavity (68%). Tumor involved the mucosa abutting the skull base in 42% of patients. Twenty-five patients (71%) received surgery and radiation, whereas the remainder had surgery alone. Five patients (14%) had bony skull base resection, and eight patients (23%) had resection of bony skull base, dura, and olfactory bulb. Surgical margins were grossly positive in one patient (3%) and microscopically positive in four patients (12%). The 5- and 10-year overall survival were 93% and 81%, respectively. The 5- and 10-year disease-free survival (DFS) were 89% and 78%, respectively. Bony cribriform plate resection was associated with better DFS (P = 0.05), but dura and olfactory bulb resection was not (P = 0.11). There was a trend toward improved DFS in patients with negative resection margins (P = 0.19). Surgical modality (open vs. endoscopic) and postoperative radiotherapy did not impact DFS., Conclusion: Most Kadish A/B ONB tumors have low Hyams grade, unilateral involvement, and favorable survival outcomes. Resection of the dura and olfactory bulb is not oncologically advantageous in patients without skull base involvement who are surgically treated with negative resection margins and cribriform resection., Level of Evidence: 4. Laryngoscope, 128:1274-1280, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

We retrospectively reviewed the cases of 85 patients with primary sinonasal malignancies who had undergone endoscopic surgery with curative intent achieved by "regional resection." Our goal was to assess the efficacy of endoscopic surgical treatment vis-à-vis traditional open surgery. Kaplan-Meier data analysis revealed that the 1-, 3-, and 5-year disease-specific survival rates were 82, 60, and 49%, respectively. Multivariate Cox model survival analysis revealed that male sex, certain pathologic types of cancer (i.e., undifferentiated carcinoma, olfactory neuroblastoma, and rhabdomyosarcoma), and T3/T4 category negatively impacted survival (adjusted hazard ratios: 3.601, 0.012, 0.287, 0.068, and 0.339, respectively; p < 0.05 for all). We also performed a separate analysis of 47 patients who had category T3 or T4 cancer to determine if the type of surgical approach is a prognostic factor. For this, we identified 20 new patients who had undergone open resection, and we compared them to 27 of our endoscopically treated patients who had similar clinical characteristics. We found that the type of surgical approach did not appear to be a prognostic factor (p > 0.10), although those patients who had undergone endoscopic resection had significantly shorter hospital stays (p < 0.001). We conclude that patients with primary sinonasal malignancies who are treated with endoscopic surgery have acceptable survival rates and therefore endoscopic surgery is justified in the hands of highly experienced surgeons in selected cases.

Background: Given the particularities of olfactory neuroblastoma (ONB) and the lack of studies on the subject, a multicenter collaborative study was conducted to assess treatment strategy., Methods: Fifty-three patients with ONB were included from the French Rare Head and Neck Cancer Expert Network (REFCOR) database: 16T1, 8T2, 19T3, and 10T4. All cases were treated endoscopically with skull base removal and repair in 26 cases (49%) and without external craniotomy., Results: The overall survival (OS) and disease-free survival (DFS) rates at 5 years were 87% and 71%, respectively, with mean follow-up of 45.4 ± 26.5 months. The complication rate was 18.8% with 4 cases of meningitis. Pathological analysis showed positive margins in 26.8%, notably on the dura-mater and periorbita, without impairment of OS or DFS. Forty-eight patients received adjuvant radiotherapy on T ± N. Ten patients had a recurrence (18.9%). Six patients died of their disease. Prophylactic neck irradiation seemed to reduce the recurrence rate., Conclusion: Exclusively endoscopic treatment proved efficient and reliable in a large controlled series., (© 2018 Wiley Periodicals, Inc.)

Olfactory neuroblastoma (ONB) is a potentially curable disease, despite being an aggressive malignancy with a poor natural history. Our goal was to evaluate management outcomes for patients with ONB treated at our institution. Our prospective database for brain tumors and the pathology registry of head and neck cancers at Oslo University Hospital were searched to identify all patients treated for ONB between 1998 and 2016. Variables extracted from these databases, supplemented by retrospective chart reviews, underwent thorough analysis. All cases were formally re-examined by a dedicated head and neck pathologist. Twenty patients were identified. Follow-up was 100%. Mean follow-up was 81.5 months for the entire cohort and 120.3 months for patients with no evidence of disease. Fourteen patients underwent treatment of choice including craniofacial resection (CFR) with or without radiotherapy (XRT). Six patients could only receive less extensive treatment; three patients underwent lateral rhinotomy (LR) with or without XRT after being deemed medically unsuitable for CFR, while another three patients received only supportive, non-surgical treatment (due to positive lymph node status in two and to extensive tumor size in one case). Overall and disease-specific survival rates were 100% after 10 years of follow-up when negative surgical margins were achieved by CFR. Positive margins were associated with poorer outcome with no patients surviving longer than 44 months. Long-term survival was also achieved in two cases among patients not eligible for CFR: one case after radical LR and one case after radio-chemotherapy. Advanced disease at presentation (tumor size ≥40 mm, Kadish grades C and D, or TNM IVa and IVb) and positive surgical margins were correlated to significantly dismal survival. Our study suggests that CFR with or without adjuvant XRT is safe and leads to excellent long-time overall and disease-specific survival. Negative surgical margins, tumor size <40 mm, Kadish stage A/B, and TNM stages I-III are independent prognostic predictors of outcome.

Background: Advanced-stage olfactory neuroblastoma requires multimodal therapy for optimal outcomes. Debate exists over endoscopic endonasal surgery in this situation. Stage-matched open and endoscopic surgical therapy were compared., Methods: Patients from 6 cancer institutions were assessed. Stratification included dural involvement, Kadish stage, nodal disease, Hyams' grade, approach, and margin status. At follow-up, local control, nodal status, and evidence of distant metastases were recorded with any subsequent therapy. Statistical analyses to identify risk factors for developing recurrence and survival differences were performed., Results: One hundred nine patients were assessed (age 49.2 ± 13.0 years; 46% women) representing Kadish A stage (10%), Kadish B stage (25%), and Kadish C stage (65%). The majority of the patients (61.5%) underwent endoscopic resection, 53.5% within Kadish C stage. Within-stage survival analysis favored endoscopic subgroup for Kadish C stage (log-rank P = .017) nonsignificant for Kadish B stage (log-rank P = .39)., Conclusion: Stage-matched survival was better for the endoscopically treated group compared to the open surgery group, with high negative margin resections obtained., (© 2017 Wiley Periodicals, Inc.)

Background: Given the rarity of esthesioneuroblastoma, it is difficult to validate a staging system. The purpose of this study was to investigate the utility of the Kadish staging system in esthesioneuroblastoma using the National Cancer Database (NCDB)., Methods: One thousand one hundred sixty-seven patients with esthesioneuroblastoma were identified from the NCDB., Results: Five-year survival was 80.0% for Kadish A, 87.7% for Kadish B, 77.0% for Kadish C, and 49.5% for Kadish D. Kadish B had higher survival than Kadish A. More Kadish B patients received surgery with adjuvant therapy than Kadish A patients (41.6% vs 32.5%; P = .0038) and also had more positive margins (21.6% vs 11.3%; P = .03). There was no difference in age distribution, sex, race, or neck dissection status between the 2 groups., Conclusion: Kadish B had greater survival than Kadish A, but the treatment characteristics could not account for this difference. The utility of early-stage Kadish staging is uncertain and requires further study., (© 2017 Wiley Periodicals, Inc.)

Background: Olfactory neuroblastoma is a rare sinonasal malignancy, with poorly defined treatment protocols. Management at a tertiary centre was retrospectively evaluated to inform future treatment and follow up., Methods: Cases treated with curative intent (2000-2014) were included. Data were collected, and overall and disease-free survival rates were calculated., Results: Eleven cases were identified, with a median follow up of 87 months. One patient was Kadish stage A, one was stage B, eight were stage C and one was stage D. The latter patient underwent chemoradiotherapy alone. The remaining patients proceeded to: endoscopic-assisted wide local excision (n = 2), anterior craniofacial resection (n = 4) or endoscopic craniofacial resection (n = 4). No patients had primary nodal disease or elective neck treatment. One patient had neoadjuvant chemoradiation. Six patients had post-operative radiotherapy; three received adjuvant chemotherapy. Two patients had late cervical node failure, and proceeded to neck dissection and post-operative radiotherapy. Two patients had late local recurrence. Ten-year overall and disease-free survival rates were 68.2 and 46.7 per cent, respectively., Conclusion: Longer-term follow up is supported given the incidence of late regional and local recurrence. Prophylactic treatment of cervical nodes in locally advanced disease is an area for further investigation.

Purpose: Olfactory neuroblastoma or esthesioneuroblastoma is a rare entity among head and neck neoplasms. In this paper, we report the experience of our institution and compare it with a comprehensive review of the literature., Patients and Methods: We retrospectively analysed clinical and treatment data of patients referred to the Lyon Sud University Hospital (France) for histologically proven olfactive esthesioneuroblastoma., Results: Ten patients treated between 1993 and 2015 have been analysed. Disease stage at diagnosis, according to the Kadish staging system, was C in 90% of cases. Median follow-up was 136 months. Ten-year overall survival was 90%. Five- and ten-year progression-free survival were 70% and 50%. Nine patients (90%) underwent surgical resection first. Seven of the nine patients who underwent resection (77%) received adjuvant three-dimensional (3D)-conformal radiotherapy (n=7), intensity-modulated radiotherapy (n=1), or volumetric arctherapy (n=1). The mean dose to the tumour volume was 61Gy. None of the patients received elective nodal irradiation. Two patients received concurrent chemotherapy. Five patients (50%) presented with disease recurrence, which was local (n=1), nodal (n=2) and cerebral (n=2)., Conclusion: Our results are consistent with the literature. Because of the lack of prospective study and the low number of cases in the literature, each institution's experience is of the utmost important to improve standardised management of these tumours., (Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Ion beam therapy has enabled us to treat formerly untreatable malignant tumors. The aim of the present study was to investigate the long-term follow-up course of patients with head and neck cancers who received ion beam therapy. The subjects were 8 patients (3 men and 5 women aged 43-78 years) with head and neck cancers who visited our department from 2006 to 2015 and received ion beam therapy. Six patients received carbon ion beam therapy, and the other two patients received proton beam therapy. The medical records of the patients were retrospectively analyzed. The primary site was the nasal and paranasal sinuses in six cases, nasopharynx in one case, and external auditory canal in one case. The histological type was olfactory neuroblastoma, malignant melanoma, and adenoid cystic carcinoma in two cases each, and chondrosarcoma and squamous cell carcinoma in one case each. The exposure dose ranged from 64 to 70.4 GyE. The average follow-up period was 42.0 months. Early adverse events were generally mild, and complete therapeutic response was obtained in all cases. However, five patients developed severe late complications including craniospinal dissemination, osteoradionecrosis of the maxilla and skull base, brain necrosis, and loss of eyesight. Three patients died of distant metastasis, local recurrence and/or brain necrosis within 2 years, and four patients have been surviving with distant metastasis or severe late complications. Ion beam therapy exhibits outstanding antitumor effects, but the severe late complications of the therapy must also be recognized.

Purpose: Although adjuvant radiation to the tumor bed has been reported to improve the clinic outcomes of esthesioneuroblastoma (ENB) patients, the role of elective neck irradiation (ENI) in clinically node-negative (N0) patients remains controversial. Here, we evaluated the effects of ENI on neck nodal relapse risk in ENB patients treated with radiation therapy as a component of multimodality treatment., Methods and Materials: Seventy-one N0 ENB patients irradiated at the University of Texas MD Anderson Cancer Center between 1970 and 2013 were identified. ENI was performed on 22 of these patients (31%). Survival analysis was performed with focus on comparative outcomes of those patients who did and did not receive ENI., Results: The median follow-up time for our cohort is 80.8 months (range, 6-350 months). Among N0 patients, 13 (18.3%) developed neck nodal relapses, with a median time to progression of 62.5 months. None of these 13 patients received prophylactic neck irradiation. ENI was associated with significantly improved regional nodal control at 5 years (regional control rate of 100% for ENI vs 82%, P < .001), but not overall survival or disease-free survival. Eleven patients without ENI developed isolated neck recurrences. All had further treatment for their neck disease, including neck dissection (n = 10), radiation (n = 10), or chemotherapy (n = 5). Six of these 11 patients (54.5%) demonstrated no evidence of further recurrence with a median follow-up of 55.5 months., Conclusion: ENI significantly reduces the risk of cervical nodal recurrence in ENB patients with clinically N0 neck, but this did not translate to a survival benefit. Multimodality treatment for isolated neck recurrence provides a reasonable salvage rate. The greatest benefit for ENI appeared to be among younger patients who presented with Kadish C disease. Further studies are needed to confirm these findings., Competing Interests: The authors declare no conflict of interests, (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objectives/hypothesis: To review the literature on neck recurrence in esthesioneuroblastoma., Study Design: PubMed database., Methods: A PubMed database search was performed using keywords "esthesioneuroblastoma," "olfactory neuroblastoma," and "esthesioneuroblastoma neck metastasis." Articles written in English with greater than 10 subjects that had data regarding the association of neck recurrence and mortality and/or the association of neck recurrence with Kadish stage were included for analysis., Results: Thirteen studies met inclusion criteria with information regarding the association of neck recurrence and mortality, and 15 studies had data associating neck recurrence and Kadish stage. The neck recurrence rate was 14.1% in studies analyzing mortality. Among those patients who developed regional metastases, mortality was 60%. Of patients without regional recurrence, the mortality rate from disease was 26% (P < 0.0001) and overall mortality was 32% (P < 0.0001). The rate of neck recurrence within each Kadish stage was 0%, 11%, 21%, and 18% for Kadish stages A, B, C, and D, respectively. The trend toward an increased incidence of neck recurrence from stage A to stage D is statistically significant, with P value 0.003., Conclusion: The rate of neck recurrence in esthesioneuroblastoma is close to 15%. There is a strong association of recurrence with Kadish stage B and C. Mortality from disease in patients with recurrence in cervical lymph nodes is significant when compared to those who never develop neck disease. Prospective studies are needed to evaluate a potential role for elective neck dissection versus elective neck radiation for patients with esthesioneuroblastoma., Level of Evidence: N/A. Laryngoscope, 126:1373-1379, 2016., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Surgical resection followed by radiotherapy can be considered like the optimal treatment modality for limited esthesioneuroblastoma. However, therapeutic management of locally advanced tumors remains a challenge. The aim of our study was to access and compare the oncologic results of the different treatment modalities in advanced esthesioneuroblastoma. We performed a systematic review using the Medline, and Cochrane database in accordance with PRISMA criteria and included all the cases of advanced esthesioneuroblastoma published between 2000 and 2013. We also retrospectively included 15 patients with an advanced esthesioneuroblastoma managed at our tertiary care medical center. Long-term survival rates defined as the time from diagnosis or randomization to the date of death or last follow-up were evaluated for each treatment with Kaplan-Meier survival curve analyses. 283 patients have been included. The mean follow-up was 78 months. Five-year highest survival rates were obtained in patients treated by surgery associated with radiotherapy. Ten-year highest survival rates were obtained in patients treated by the association of surgery, radiotherapy and chemotherapy (p = 0.0008). Within the surgical group, 5-year highest survival rates were obtained in patients treated by endoscopic resection (p = 0.003). Surgical resection combined with radiotherapy offers the gold standard of care. Adjuvant chemotherapy seems to improve the long-term survival in patients with locally advanced esthesioneuroblastoma. Endoscopic resection in advanced tumors should be discussed on a case-by-case basis.

Introduction: Sinonasal tumors are chemotherapy responsive which frequently present in advanced stages making NACT a promising option for improving resection and local control in borderline resectable and locally advanced tumours. Here we reviewed the results of 25 such cases treated with NACT., Materials and Methods: Sinonasal tumor patients treated with NACT were selected for this analysis. These patients received NACT with platinum and etoposide for 2 cycles. Patients who responded and were amenable for gross total resection underwent surgical resection and adjuvant CTRT. Those who responded but were not amenable for resection received radical CTRT. Patients who progressed on NACT received either radical CTRT or palliative radiotherapy., Results: The median age of the cohort was 42 years (IQR 37-47 years). Grades 3-4 toxicity with NACT were seen in 19 patients (76%). The response rate to NACT was 80%. Post-NACT surgery was done in 12 (48%) patients and radical chemoradiation in 9 (36%) patients. The 2-year progression free survival and overall survival were 75% and 78.5%, respectively., Conclusion: NACT in sinonasal tumours has a response rate of 80%. The protocol of NACT followed by local treatment is associated with improvement in outcomes as compared to our historical cohort.

Objective: Esthesioneuroblastoma (ENB) is an uncommon malignant tumor. During the past decade, endoscopic approaches have been gradually applied in treating skull base tumors. However, the experience in using this approach to treat ENB is still limited. Kadish staging and Dulguerov staging are common methods used for ENB staging, but it remains unclear as to which method is better. In this study, we reviewed our experiences with endoscopic surgeries for ENB and analyzed the prognostic roles of the two staging methods., Methods: A total of 24 patients with ENB treated with only endoscopic endonasal surgery between January 2001 and March 2012 were included. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method and early and advanced stages were compared using the log-rank test. The prognostic roles of the two staging methods were also analyzed., Results: Amongst the 24 patients, 19 patients presented with newly diagnosed ENB, and 5 patients presented with recurrent disease. The three-year OS and DFS rates were 82% and 70.8%, respectively. Four patients (16.6%) died from recurrence of the tumor. Dulguerov staging predicted OS with significant differences (P=0.042), whereas Kadish staging predicted DFS with significant differences (P=0.020) between the early and advanced stages., Conclusions: The present study showed experiences that purely endoscopic endonasal surgery for ENB showed successful survival results with remarkably decreased complications. Dulguerov staging and Kadish staging play different prognostic roles in patients treated with purely endoscopic endonasal resection based on various end points., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: Esthesioneuroblastoma is an uncommon malignancy of the head and neck for which there is no defined treatment protocol. The purpose of this study is to report our experience with the treatment and patterns of failure of this disease., Methods and Materials: From 1994 to 2012, 37 previously unreported patients with esthesioneuroblastoma were evaluated, and 32 eventually treated for cure at 2 academic medical centers. All patients were staged with Kadish criteria. The mean and median follow-ups were 96.1 and 76.5 months respectively (range 6-240 months)., Results: The Kadish stage was A in 6 patients, B in 13 patients, and C in 13 patients. Four patients were initially treated with concurrent chemo-radiation therapy. Twenty-eight patients were treated with primary surgery. Two (2) underwent open medial maxillectomy and 26 underwent craniofacial resection (open - 17, endoscopic - 9). Three patients received curative surgical resection only. Seven patients failed either within the cranial axis or distantly, 6 of the 7 are dead of disease, 10-194 months following initial treatment. Six patients had isolated neck recurrences, 4/6 were salvaged with neck dissection and additional chemo-radiation and remain alive 30-194 months following initial treatment. Estimated overall survival rate at 10 years was 78% based on Kadish and T stages., Conclusion: In this retrospective analysis of 32 patients, Kadish stage C and stage T3/T4 tumors were associated with worse outcome. Total radiation dose of 60 Gy, margin status, patient age, were not found to have significant prognostic value., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Olfactory neuroblastoma (ONB) is a rare tumor originating from olfactory epithelium. Here we retrospectively analyzed the long-term treatment outcomes and toxicity of radiotherapy for ONB patients for whom computed tomography (CT) and three-dimensional treatment planning was conducted to reappraise the role of radiotherapy in the light of recent advanced technology and chemotherapy., Methods: Seventeen patients with ONB treated between July 1992 and June 2013 were included. Three patients were Kadish stage B and 14 were stage C. All patients were treated with radiotherapy with or without surgery or chemotherapy. The radiation dose was distributed from 50 Gy to 66 Gy except for one patient who received 40 Gy preoperatively., Results: The median follow-up time was 95 months (range 8-173 months). The 5-year overall survival (OS) and relapse-free survival (RFS) rates were estimated at 88% and 74%, respectively. Five patients with stage C disease had recurrence with the median time to recurrence of 59 months (range 7-115 months). Late adverse events equal to or above Grade 2 in CTCAE v4.03 were observed in three patients., Conclusion: Multimodal therapy including radiotherapy with precise treatment planning based on CT simulation achieved an excellent local control rate with acceptable toxicity and reasonable overall survival for patients with ONB.

Esthesioneuroblastoma (ENB) is derived from the specialized olfactory neuroepithelium. Hyams grading and Kadish staging have been used to prognosticate and to guide treatment decisions. In this study, we sought to validate the prognostic utility of these systems in a large ENB cohort. We retrospectively analyzed the records of patients with ENB who had been evaluated and treated at our institution. The association of grade and stage with prognostic outcome was assessed; the Kaplan-Meier estimator was used to generate 5-year OS and DFS curves. Out of 124 cases we identified, 121 were assessed for grading and 109 for staging. Review of the tissue samples revealed that 62 % of tumors were low grade (I/II) and 21 % were high grade (III/IV); 17 % of tumors were metastasis. The OS rate was 75 % at 5 years. The DFS was 60 % at 5 years. The OS was significantly worse for metastatic ENB (low-grade ENB vs metastatic ENB p = 0.01598); the DFS was significantly worse for high grade versus low grade ENB. Of the 109 cases that had been staged, 16 % were stage A, 33 % stage B, 43 % stage C, and 8 % stage D. In the A, B, and C groups, there were no significant differences between recurrence, distant metastasis, or 5-year survival rates. Statistical significance was not reached with the T, N, M and overall staging system. Age cutoff of 65 years reliably predicted OS. High grade of ENB was significantly associated with poor outcome, while advanced stage was not associated with poor outcome in this large cohort. Grading should certainly be considered in prognostication and treatment decisions for ENB.

Importance: There is a need for larger studies characterizing the effect of tumor grade on survival for patients with esthesioneuroblastoma., Objective: To investigate prognostic factors for survival in patients diagnosed with esthesioneuroblastoma, including emphasis on tumor grade., Design, Setting, and Participants: Retrospective, population-based cohort study of patients in the Surveillance, Epidemiology, and End Results (SEER) tumor registry who were diagnosed with esthesioneuroblastoma from January 1, 1973, to January 1, 2010. The last date of survival follow-up was 2013., Main Outcomes and Measures: Overall and disease-specific survival., Results: The cohort included 281 patients with a mean age of 52 years. There were 154 males (54.8%) and 127 females (45.2%). Kaplan-Meier analysis demonstrated an overall and disease-specific survival rate of 61% and 70% at 5 years and 50% and 64% at 10 years, respectively. Multivariable Cox regression analysis showed that advanced tumor grade and modified Kadish stage (hazard ratio, 4.930; 95% CI, 2.635-9.223; P = .001) portended worse disease-specific survival, and radiation therapy (hazard ratio, 0.499; 95% CI, 0.272-0.916; P = .03) improved disease-specific survival. Patients with low-grade tumors (grades I and II) demonstrated an overall and disease-specific survival rate of 84% and 92% at 5 years and 67% and 87% at 10 years, respectively. Multivariable analysis of low-grade tumors only revealed receiving surgery (P = .004) as an independent positive predictor of disease-specific survival. High-grade tumors (grades III and IV) demonstrated overall and disease-specific survival of 40% and 50% at 5 years and 34% and 43% at 10 years, respectively. Multivariable analysis of high-grade tumors showed modified Kadish stage (hazard ratio, 2.025; 95% CI, 1.430-2.866; P < .001) predicted worse disease-specific survival, and radiation therapy (hazard ratio, 0.433; 95% CI, 0.228-0.864; P = .02) independently predicted improved disease-specific survival., Conclusions and Relevance: Here, to our knowledge, we report the largest study investigating prognostic factors for survival, with the inclusion of tumor grade, in patients diagnosed with esthesioneuroblastoma. Patients with high-grade tumors had substantially worse survival rates than patients with low-grade tumors. Multivariable analysis revealed only receiving surgery as an independent predictor of disease-specific survival for patients with low-grade tumors, while modified Kadish stage and postoperative radiation therapy were significant factors in predicting disease-specific survival in patients with high-grade tumors. This study highlights the growing evidence that tumor grade should be a key factor in predicting survival in patients with esthesioneuroblastoma, and that adjuvant radiation therapy improves survival rates among patients with high-grade, but not low-grade, tumors.

Conclusions: Endoscopic techniques seem to be safe approaches for the treatment of esthesioneuroblastomas (ENBs). However, they are intended for selected patients and require extensive experience in base of the skull surgery., Objectives: ENB is a rare tumor of the nasal cavity. The craniofacial approaches remain the gold standard of treatment in multiple centers. Endoscopic endonasal approaches were progressively developed. The main objective of this work was to study the overall survival and recurrence-free period for patients with ENB who underwent endoscopic resection., Methods: We performed a retrospective study from 1996 to 2014, reviewing the patients treated by endonasal endoscopic surgery for ENB., Results: Eight patients benefited from endoscopic surgical resection. According to the Kadish classification, one patient was stage A, three patients were stage B, and four patients were stage C. According to the Dulguerov classification, one patient was stage T1, five patients were stage T2, and two were stage T4. Reconstruction of the base of the skull was performed in three patients. No postoperative complications were noted. The mean follow-up period was 95 months. The 5-year overall survival was 87.5% and the 5-year recurrence-free survival was 75%. To date, there have been no local recurrences but two patients had lymph node recurrences. Seven patients are disease-free and one is deceased.

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.

Objective: The Hyams grading system has been extensively used to predict prognosis in patients with esthesioneuroblastoma (ENB). However, most studies showing prognostic correlation group grading into I/II versus III/IV, essentially comparing low versus high grade. In addition, these studies include patients with variable treatment regimens, including some that were treated with chemoradiation alone. We aimed to determine whether additional histologic variables correlate with outcome with regard to disease free and overall survival in a series of patients universally treated with anterior skull base resection and +/- adjuvant chemoradiation., Study Design: A retrospective review of 27 patients with ENB was performed., Methods: The sections of tumor from these 27 patients were studied and reviewed with attention to percentage lobularity, degree of pleomorphism, degree of neurofibrillary matrix, and degree of apoptosis. In addition, the presence or absence of rosettes, necrosis, calcification, spindle cells, gland hyperplasia, and bone invasion were noted. Finally, the number of mitoses per high power field and the nature of chromatin (fine vs coarse) were recorded. The histopathologic features of these 27 ENBs were reviewed and correlated with clinical outcome., Results: There were 11 patients with recurrence (40.7% recurrence). There were 5 deaths (81.5% survival). The study cohort's mean overall survival was 158 months and the mean disease-free survival was 70.6 months. In terms of overall survival, necrosis and mitosis (#/10hpf) were significant but not when multivariate analysis was performed, these were not individually significant. In terms of disease-free survival, mitosis (#/10hpf) was significant but not on multivariate analysis. Gland hyperplasia was found to be a positive prognostic variable, associated with longer overall and disease-free survival, but only in combination with no spindle features and without necrosis., Conclusions: An updated histologic grading system may provide more valuable prognostic information in patients with esthesioneuroblastoma treated with a standardized treatment paradigm.

Objective: To study the oncological outcome of the patients with unresectable locally advanced primary head and neck cancers invading the skull base, treated with particle radiotherapy., Methods: Fifty-seven patients with unresectable primary head and neck cancers invading the skull base received proton or carbon ion radiotherapy as definitive treatment at Hyogo Ion Beam Medical Center between 2003 and 2009. Forty-seven patients were treated with proton radiotherapy and 10 patients were treated with carbon ion radiotherapy. A retrospective review was performed with clinical charts and recorded imagings., Results: With a median follow-up of 32 months, the 3-year actual survival and local progression-free rates of all the patients were 61 and 56%, respectively. The 3-year actual survival rates of adenoid cystic carcinoma, squamous cell carcinoma, olfactory neuroblastoma, adenocarcinoma and malignant melanoma were 83, 44, 75, 0 and 38%, respectively. The 3-year actual local control rates of adenoid cystic carcinoma, squamous cell carcinoma, olfactory neuroblastoma, adenocarcinoma and malignant melanoma were 63, 31, 83, 50 and 0%, respectively. Distant metastasis was observed in 13 of 25 patients in adenoid cystic carcinoma, two of 14 patients in squamous cell carcinoma, one of six patients with olfactory neuroblastoma, two of four patients with adenocarcinoma, three of four patients with malignant melanoma and two of three patients with undifferentiated carcinoma. Mucositis and dermatitis were seen as acute toxicities. The most common late toxicity was visual disorder. Grades 2, 3 and 4 visual disorders were observed in seven, five and two patients, respectively., Conclusions: Proton and carbon ion radiotherapy resulted in satisfactory local control in patients with locally advanced unresectable primary head and neck cancers invading the skull base.

Background: Esthesioneuroblastoma is a rare cancer of the anterior cranial base that arises in the region of the olfactory rootlets. The purpose of this study was to review the long-term outcomes of patients diagnosed with esthesioneuroblastoma (ENB) treated at a single institution to determine factors associated with improved disease control and survival., Methods: A retrospective review of 70 patients with ENB treated at the University of Texas MD Anderson Cancer Center between 1992 and 2007 was undertaken. Survival and recurrence was analyzed and compared using the Kaplan-Meier method and log-rank statistics., Results: Seventy patients were reviewed. The majority (77%) had T3 or T4 disease at presentation, 38% identified as modified Kadish stage C or D. Ninety percent of patients received surgical resection as part of their treatment, and 66% received postoperative radiation or chemoradiation. The median follow-up was 91.4 months (7.6 years). Forty-eight percent of patients developed recurrent disease and the median time to recurrence was 6.9 years. Overall and disease-specific median survival was 10.5 and 11.6 years, respectively. Patients who were treated with surgery alone had a median disease-specific survival of 87.9 months, whereas those who were treated with surgery and postoperative radiation had a median disease-specific survival of 218.5 months (p = .047)., Conclusion: Patients with ENB can achieve favorable long-term survival, even if disease is locally advanced. Survival is improved considerably when surgical resection is followed by postoperative radiation. However, recurrence rates and mortality remain high, and therefore long-term observation in these patients is warranted., (Copyright © 2013 Wiley Periodicals, Inc.)

Esthesioneuroblastoma is a rare tumor of the olfactory epithelium. This report analyzed 11 children and adolescents treated in a single institution between 1982 and 2002. For 9 patients, therapy consisted of an initial course of chemotherapy before surgical resection and postoperative radiotherapy, for 1 patient an initial course of chemotherapy before radiotherapy and for another resection before radiotherapy with no chemotherapy. Response to chemotherapy was assessed in 9 patients of whom 6 achieved a complete or a partial remission. Ten patients are long-term survivors. The 5-year actuarial disease-free survival and overall survival rate was 91% (95% confidence interval, 62%-98%). Our study indicates that esthesioneuroblastoma is sensitive to chemotherapy and supports the role of combined modalities including neoadjuvant chemotherapy, surgery, and radiation therapy.