Esthesioneuroblastoma a Population-Based Analysis of Survival and Prognostic Factors

ORIGINAL ARTICLE Esthesioneuroblastoma A Population-Based Analysis of Survival and Prognostic Factors

Daniel Jethanamest, MD; Luc G. Morris, MD; Andrew G. Sikora, MD, PhD; David I. Kutler, MD

Objectives: To investigate the characteristics associ- plied to 261 patients. Kaplan-Meier analysis showed the ated with survival in esthesioneuroblastoma and to de- overall and disease-specific survival rates at 10 years to termine whether the modified Kadish staging system can be 83.4% and 90%, respectively, for patients with stage predict outcome. A disease; 49% and 68.3% for patients with stage B disease; 38.6% and 66.7% for patients with stage C disease; Design: Retrospective population-based cohort study. and 13.3% and 35.6% for patients with stage D disease. Log-rank test comparisons found Kadish stage (PϽ.01), Subjects: All patients in the Surveillance, Epidemiol- treatment modality (PϽ.002), lymph node status (PϽ.01), ogy, and End Results tumor registry diagnosed as hav- and age at diagnosis (PϽ.001) to be significant predic- ing esthesioneuroblastoma (1973-2002). tors of survival. Cox regression analysis confirmed that Kadish stage remained a significant predictor of disease- Main Outcome Measures: The modified Kadish stage specific survival. and the overall and disease-specific survival rates were determined. Conclusion: The modified Kadish staging system, lymph node status, treatment modality, and age are useful pre- Results: The cohort included 311 patients with a mean dictors of survival in patients who present with esthe- age of 53 years and a unimodal age distribution. The over- sioneuroblastoma. all 5- and 10-year survival rates were 62.1% and 45.6%, respectively. The modified Kadish staging system was ap- Arch Otolaryngol Head Neck Surg. 2007;133:276-280

STHESIONEUROBLASTOMA tablished: it has an approximately equal sex (ENB) is a rare tumor of the distribution; it affects a wide range of age nasal cavity that is believed groups; and, over time, it can locally ex- to be derived from the ol- tend to involve the surrounding paranasal factory neuroepithelium. It sinuses, cribriform plate, and orbits.5,6 The wasE was first described by Berger et al1 in most common site of metastasis is the cer- 1924, but because of the uncommon na- vical lymph nodes (10%-33% of patients), ture of the disease, its clinical character- while sites of distant metastasis, including istics and its impact on survival remain dif- the lungs, brain, and bone, are less com- ficult to study. This tumor has also often mon.3,7 The disease usually occurs in the been referred to as an olfactory neuroblas- fifth to sixth decades of life, although it is toma, although the exact cell of origin has unclear whether there is a unimodal or a bi- 2 5,6 Author Affiliations: not yet been proved. One review of the modal peak in incidence by age. Department of Otolaryngology, world literature through 1997 found 945 The first and most commonly refer- New York University School of unique cases, while another review from enced staging system was developed by Medicine, New York, NY the Armed Forces Institute of Pathology Kadish et al.8 This system divides tumors (Drs Jethanamest and Morris); reported 200 cases.3,4 Esthesioneuroblas- into 3 groups: group A lesions are lim- Department of Head and Neck toma reportedly represents only 3% to 6% ited to the nasal cavity; group B lesions in- Surgery, The University of Texas of all cancers in the nasal cavity and pa- volve the nasal cavity and paranasal si- M. D. Anderson Cancer Center, ranasal sinuses, although the true inci- nuses; and group C lesions extend beyond Houston (Dr Sikora); and Department of dence is difficult to determine, as contem- the nasal cavity and paranasal sinuses. The Otorhinolaryngology, Weill porary histologic techniques are likely modification of this staging system by 5 9 Medical College of Cornell increasing detection. Morita et al established group D for tu- University, New York Although ENB is uncommon, some con- mors with regional (cervical lymph node) (Dr Kutler). sistent features of this disease have been es- or distant metastases. Other staging sys-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 tems have also been used, but no single staging classifi- nant cancer (excluding any patients with second primary cation has been universally adopted for this tumor to date, malignancies). All data were extracted from the SEER*Stat soft- as the prognostic utility of each system has not been ware program, and a commercially available statistical pack- proved. Part of the difficulty in assessing clinical behav- age (SPSS Version 13.0; SPSS Inc, Chicago, Ill) was used to per- ior and survival outcomes for ENB lies in the rarity of form Kaplan-Meier survival analysis with applicable log-rank tests. Cox multivariate regression analysis was then per- the disease as well as in the difficulty of amassing cases formed, incorporating race, stage, sex, age at diagnosis, year in single-institution studies. At present, the largest re- of diagnosis, SEER geographic registry, and treatment modali- port of survival with ENB has involved a cohort of 50 pa- ties used. tients, with other large series averaging almost 30 patients.10,11 To obtain meaningful estimates of survival in ENB, and the prognostic factors that influence patient RESULTS outcome, we analyzed a large cohort of cases from the Surveillance, Epidemiology, and End Results (SEER) na- The cohort included 311 patients (mean age, 53 years). tional cancer registry.12 The age distribution was found to be unimodal, with the majority of patients between 40 and 70 years of age (Figure 1). There were 170 men (55%) and 141 women METHODS (45%); 83% of the patients were white, 6% were black, and 11% were of other race (Figure 2). The overall sur- A retrospective cohort study was performed using the SEER tu- vival rate was 62.1% at 5 years and 45.6% at 10 years. mor registry (National Cancer Institute, Bethesda, Md). The Sufficient clinical data at the time of diagnosis were avail- National Cancer Institute does not require institutional re- able to apply the modified Kadish staging system to 261 view board approval for this deidentified data set. The public- patients; 50 patients were excluded because of incom- use database from SEER 13 (1973-2002) was used to extract plete staging information. A total of 45 patients (17.2%) appropriate cases.12 The SEER registry has been successfully presented with stage A disease, 130 (49.8%) with stage used to study survival outcomes in cases involving various ma- B disease, 10 (3.8%) with stage C disease, and 76 (29.1%) lignancies, including those of the nasal cavity, and has proved 13 with stage D disease. The overall mean survival time was particularly useful in cases of uncommon diseases. 133.4 months (95% confidence interval [CI], 111.0- The SEER database codes information regarding the primary site and extent of disease. All patients diagnosed as hav- 155.7) in this group of 261 patients. The overall mean ing ENB from 1973 to 2002 (histologic type International Clas- survival time for patients with stage A disease was 145.6 sification of Diseases for Oncology, Third Edition, code 9522) with months (95% CI, 129.0-162.2), 149.5 months (95% CI, a site-specific code indicating that the primary tumor origi- 119.0-180.0) for those with stage B disease, 72.5 months nated in the nasal cavity or paranasal sinuses were identified (95% CI, 32.3-112.7) for those with stage C disease, and and included in the study. One case involving a histologic- 53.7 months (95% CI, 27.3-80.0) for those with stage D type ENB located in the adrenal gland was considered a cod- disease (Table). ing error and was excluded from our analysis. Kaplan-Meier analysis demonstrated the overall and No ENB-specific staging information, such as Kadish stag- disease-specific survival rates at 10 years to be 83.4% and ing, was available for these cases. However, related disease in- 90%, respectively, for patients with stage A disease; 49% formation, including SEER historic stage and American Joint Committee on Cancer stage, was available for a majority of cases. and 68.3% for those with stage B disease; 38.6% and 66.7% The SEER database describes the historic stage of each case as for those with stage C disease; and 13.3% and 35.6% for localized, regional, or distant. The cases of ENB that origi- those with stage D disease (Figure 3 and Figure 4). nated in the nasal cavity or cranial nerve (not otherwise speci- All pairwise log-rank comparisons between stages were fied) and that did not involve adjacent organs or tissue were statistically significant (PϽ.01) except for those involv- considered Kadish stage A. Any of these cases that were coded ing stage C disease (owing to the small size of this sub- as anything beyond “localized” disease were ambiguous and were group [n=10]). excluded from analysis. Stage B included all tumors that origi- Lymph node status at the time of diagnosis was avail- nated from the maxillary, ethmoid, frontal, sphenoid, and ac- able in 130 cases. Of these cases, 112 (86.2%) presented cessory sinuses that did not invade superstructures or involve with no lymph node involvement, 16 (12.3%) pre- further contiguous extension. Also, tumors that originated in the superior nasopharynx and extended into paranasal si- sented with regional involvement (submental, subman- nuses and those that extended from the nasal cavity into adja- dibular, internal jugular, retropharyngeal, cervical [not cent organs and structures were also considered stage B. Tu- otherwise specified], and regional [not otherwise speci- mors that included extent of disease beyond the sinuses, fied]), and 2 (1.5%) presented with distant metastases. including the orbit or intracranial extension, were considered Survival differed significantly based on the presence of stage C. Finally, any cases with “distant” disease were consid- lymph node metastases at the time of diagnosis (log- ered group D. Any case that did not provide data for extent of rank test, PϽ.01; Figure 4). disease could not be staged and was excluded from analysis. Treatment modality data were available for 274 cases, The modified Kadish stage was successfully determined in 261 revealing that 73 cases (26.7%) were treated with sur- of 311 cases. gery alone, 26 (9.5%) with radiotherapy alone, 170 (62%) In analyzing causes of death, the database provided information about the site of disease but not diagnosis-specific codes. with both surgery and radiotherapy, and 5 (1.8%) with Disease-specific deaths were therefore defined as any deaths neither treatment. Kaplan-Meier analysis in these groups caused by tumors in the following locations: nose, nasal cav- (Figure 5) demonstrated that the longest duration of ity, and middle ear; nasopharynx, other oral cavity, and phar- mean survival was in patients who received both mo- ynx; brain and other nervous system; or miscellaneous malig- dalities (216.8 months) (95% CI, 188.6-245.0), fol-

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20 No. of Cases 15

0 00 01-04 05-09 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 ≥85 Age (Interval) at Time of Diagnosis, y

Figure 1. Age distribution.

Laterality data was present for 179 patients, with an 1.0 even distribution of 48.6% left-sided, 46.4% right- sided, and 5.0% bilateral disease. The most common site of disease was the nasal cavity (n=212), followed by the 0.8 ethmoid (n=43) and accessory (n=21) sinuses. Cases were drawn from 12 of the possible 13 geographic reg- 0.6 istries in the SEER database.

0.4 COMMENT Cumulative Survival Stage The rarity of ENB has made accurate assessment of sur- 0.2 A B vival and prognostic strength of various staging systems C difficult. The SEER registries collectively provide a popu- D 0 lation-based database of patients with cancer compa-

0402060 80 100 120 rable to the national population with regard to socioeco- Months nomic status and education. In addition to allowing analysis of a larger patient cohort, the cohort in this database may also permit a more generalizable description Figure 2. Kaplan-Meier overall survival curve (using modified Kadish stage). of survival and prognostic factors than cohorts based at specialized tertiary referral centers. lowed by those who received surgery alone (208.1 Some of the basic characteristics of our study popula- months) (95% CI, 155.7-260.6), radiotherapy alone (92.8 tion, such as the mean age of 53 years and the wide range months) (95% CI, 64.9-120.8), and neither therapy (53.7 of patient ages, are in accord with previously published stud- months) (95% CI, 10.0-33.9), but log-rank tests found ies. Many authors report means and median peak inci- significance only between the groups receiving radio- dences in patients between the ages of 43.6 and 55.4 years, therapy alone and those with combined modality treat- although others have supported a bimodal peak in inci- ment (PϽ.002). Age at diagnosis was examined and found dence around the second and sixth decades of life, with 1 to be significant in univariate analysis (PϽ.001). Sex study reporting a mean age of 27 years in a set of 21 pa- (P=.15), race (P=.55), SEER geographic registry (P=.44), tients.7,10,14,15 The results of our study strongly favor a uni- and year of diagnosis (P=.89) were not statistically sig- modal distribution, with the majority of patients between nificant prognostic factors. Cox multivariate regression the ages of 45 and 64 years and only 22 of 301 patients in analysis was performed to adjust for interaction be- the 10- to 24-year-old range (Figure 1). This age distribu- tween covariates and confirmed that stage remained a sig- tion is in agreement with 2 recent studies that reported uni- nificant predictor of disease-specific survival (PϽ.001). modal peaks in the fourth and fifth decades of life.5,10 Treatment modality also remained a statistically signifi- The need for a robust staging system has led to the cant factor in the multiviariate model (PϽ.05). development of alternatives to the Kadish or modified

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Overall Disease-Specific Mean Survival Time, mo Modified Kadish Stage Sample Size, No. Survival, % Survival, % (95% Confidence Interval) A 45 83.4 90.0 145.6 (129.0-162.2) B 130 49.0 68.3 149.5 (119.0-180.0) C 10 38.6 66.7 72.5 (32.3-112.7) D 76 13.3 35.6 53.7 (27.3-80.0)

1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4 Disease-Specific Survival Disease-Specific Survival Stage 0.2 A 0.2 B Lymph Nodes C Negative D Positive 0.0 0.0

0402060 80 100 120 0402060 80 100 120 Months Months

Figure 3. Kaplan-Meier disease-specific survival curve (using modified Figure 4. Kaplan-Meier curve of disease-specific survival (by lymph node Kadish stage). status).

Kadish staging systems. Biller et al15 first proposed a system based on the TNM type of classification in 1990, and 1.0 Dulguerov et al16 proposed a refined TNM system in 1992. Some of the inadequacies of the Kadish system named by these authors include the inability of the Kadish group- 0.8 ings to effectively stratify patients, with few patients fall- ing into group A and very different types of spread being 0.6 consolidated in group C. Still, some authors have found acceptable prognostic utility with this staging system.10,17 Indeed, Dias et al18 compared the staging sys- 0.4

tems of Kadish, Biller, and Dulguerov and colleagues in Disease-Specific Survival a group of 35 patients and found that the Kadish system Treatment 0.2 Both Surgery and was the only classification that yielded a statistically sig- Radiotherapy Radiotherapy Alone nificant discrimination between stages. Unfortunately, Surgery Alone limitations in the detail of site data extracted from 0.0 the SEER database, such as a lack of specific coding for 0402060 80 100 120 involvement of the cribriform plate or superior ethmoid Months cells, prevented the application of these staging systems to our data set and a formal comparison of stag- Figure 5. Kaplan-Meier curve of disease-specific survival (by treatment ing systems. modality: surgery, radiotherapy, or both). In a meta-analysis of case series between 1990 and 2000, the overall 5-year survival rate in 26 studies was 45% (SD, 22%), compared with our study’s estimated sur- 97 cases between 1967 and 1977, Elkon et al7 found a vival rate of 62.1%.19 The meta-analysis found the 10- favorable 3-year overall survival rate in patients with stage year survival rate to be 52% (SD, 27%), which is com- A or B disease (88.9% and 83.3%, respectively), while pa- parable to our study’s 10-year survival rate of 45.3%. A tients with stage C disease had only a 52.9% survival rate study of all patients with ENB in Denmark between 1978 at 3 years. Recently, the University of Virginia Health Sys- and 2000 (N=40) found the overall or crude survival rate tem updated a series of 50 cases and reported higher dis- at 5 years to be 61%.20 Morita et al9 studied 49 patients ease-free survival rates of 86.5% and 82.6% at 5 and 15 and found a 5-year survival rate of 69%. In a review of years; all patients received multimodality treatment in-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 cluding craniofacial resection, radiotherapy, and chemo- Study concept and design: Morris. Acquisition of data: therapy for stage C disease.11 Jethanamest. Analysis and interpretation of data: Cervical lymph node metastases are commonly stud- Jethanamest, Morris, and Sikora. Drafting of the manu- ied in cases of ENB, as the management of the neck in script: Jethanamest and Morris. Critical revision of the patients who present without apparent nodal involve- manuscript for important intellectual content: Morris, Sikora, ment is not clear. The literature reports a 10% to 33% and Kutler. Statistical analysis: Jethanamest, Morris, and incidence of neck metastasis, which is similar to the 15.2% Sikora. Administrative, technical, and material support: in our study. Nodal status has been reported to be one Jethanamest. Study supervision: Sikora and Kutler. of the most important prognostic factors in survival, a Financial Disclosure: None reported. finding that is consistent with the clear impact on disease- specific survival that was shown in the present study (Figure 4) (PϽ.001).10,18,19 Surgical treatment of ENB now REFERENCES commonly includes craniofacial resection, although no clear consensus for overall management, including ra- 1. Berger L, Luc G, Richard D. The olfactory esthesioneuroepithelioma. Bull Assoc diotherapy and chemotherapy, currently exists. Our data Franc Etude Cancer. 1924;13:410-421. 2. Bradley PJ, Jones NS, Robertson I. Diagnosis and management of esthesio- revealed improved survival with multimodality treat- neuroblastoma. Curr Opin Otolaryngol Head Neck Surg. 2003;11: ment as opposed to radiotherapy alone, which is consis- 112-118. tent with previous studies.19 3. Broich G, Pagliari A, Ottaviani F. 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