Keywords
neuroblastoma - adrenal - nonadrenal - survival outcomes - prognostic factors - population-based
study - pediatric oncology
Introduction
Neuroblastoma (NB) is a highly aggressive form of pediatric cancer originating from
neural crest–derived cells.[1]
[2] Up to 90% of NB cases are diagnosed by the age of 5 years. It is notably responsible
for 15% of all pediatric cancer-related fatalities in the first year of life alone.[1] NB may arise in any structure of neural crest origin, predominantly within the adrenal
medulla or the paraspinal ganglia.[3]
[4] Other primary sites include the abdomen/retroperitoneum, neck, thorax, and pelvis.[5] NB is broadly categorized into adrenal and nonadrenal NBs due to the abundance of
adrenal tumors.[1] NB exhibits a wide genetic diversity,[4] with tumors combining chromosomal gains or losses with candidate driver mutations.[6]
[7]
[8]
The diverse primary tumor sites coupled with genetic variance contribute to a wide
array of clinical manifestations and outcomes. These range from highly aggressive,
treatment-resistant metastatic forms to more benign cases that in certain instances
may undergo spontaneous regression.[9] Other factors such as staging, age at diagnosis, histological characteristics, tumor
size, and genetic makeup are also influential in determining the clinical course and
outcome of NB.[10] Consequently, attempts have been made to categorize NB cases into stratified risk
groups to inform treatment protocols and prognostic estimations more effectively.[3]
[4]
[10]
[11]
[12]
[13]
In the recent years, significant strides were made in our understanding of the molecular
biology and pathogenesis of the tumor, allowing the development of more targeted treatment
modalities and improving the survival of these patients significantly.[2]
[14]
[15]
[16]
[17]
[18] Small studies showed an association between the location of NB and survival.[19]
[20] This association remains poorly understood.
The primary aim of this study is to analyze the survival outcomes in pediatric patients
with NB in the United States, with a specific focus on the impact of the primary tumor
site—adrenal versus nonadrenal from 1975 up till 2016.
Methodology
Data Source
The Surveillance, Epidemiology, and End Results (SEER) database was used for this
study. The SEER program is sponsored by the National Cancer Institute (NCI) and collects
data on cancer incidence and mortality from 22 population-based registries covering
approximately 48% of the U.S. population since 1973 (http://seer.cancer.gov/seerstat). Data were obtained from the SEER-18 registries (November 2020 submission) using
SEER*stat software (8.3.8).
Study Population
Data were examined from 1975 to 2016 to identify patients with primary NB. We included
pediatric patients (0–20 years) with the International Classification of Disease for
Oncology (3rd edition) codes: 9500: Neuroblastoma, NOS and 9490: Ganglioneuroblastoma.
Year of diagnosis was specified from 1975 to 2016. Only first primary tumors were
included. On initial screening, we identified 4,744 patients. We excluded cases with
no histological confirmation, no active follow-up (death certificate only), alive
with zero survival months, incomplete survival dates, and/or unknown cause of death.
A total of 4,553 cases were included in the final study. No duplicate cases were found
in our study population.
Outcome was categorized as “alive,” “dead attributable to this cancer diagnosis,”
or “dead from other cause.” Race was categorized as white, black, or others including
American Indian, Alaska Native, Asian, Pacific Islander, and unknown. Year of diagnosis
of the tumor was split into two groups (those diagnosed before the year 2000 and those
diagnosed in the year 2000 or later) to account for changes in treatment era. Other
variables including sex, age at diagnosis, staging, and follow-up were also collected.
Statistical Analysis
Frequency, survival data, and patient characteristics were obtained using SEER*Stat
software (8.3.6) case listing session. Data were entered into IBM SPSS statistical
package v.27 (SPSS Inc, Chicago, IL, United States). Descriptive statistics including
mean, standard deviation, and percentages were used to detail patients' characteristics.
Overall survival was calculated from the time of diagnosis to the time of event or
last follow-up using Kaplan–Meier product limit curves and log-rank testing. The effects
of continuous variables on survival were assessed using Cox proportional hazards regression.
After univariable analysis was performed, factors with p-values of less than 0.05 were entered into a multivariable model. Proportional hazards
assumption was evaluated by log-rank Kaplan–Meier plots. Hazard ratio (HR) and 95%
confidence intervals (CIs) were reported for all significant factors in the multivariable
model.
For further statistical analysis of the data, chi-squared test was used to compare
categorical variables, whereas Fischer's exact test was used when the frequency was
less than 5. t-test and analysis of variance (ANOVA) test were used as appropriate to compare continuous
data. The Kruskal–Willis test was used instead of ANOVA when data were not normally
distributed. All statistical tests were two sided. A p-value of less than 0.05 was considered statistically significant.
Results
Frequency Distributions by Primary Site
The distribution of various demographic and clinical variables was examined based
on the primary site of NB. [Table 1] summarizes these variables.
A significant difference was observed in gender distribution between adrenal and nonadrenal
cases. Males comprised 55.7% of adrenal cases compared to 49.6% in nonadrenal cases
(p < 0.001). White patients were more likely to have nonadrenal NB compared to other
races (p = 0.006). A higher percentage of adrenal NB was diagnosed after the year 2000, compared
to nonadrenal NB (71.3 vs. 62.1%; p < 0.001). Regarding disease stage, adrenal cases were more likely to present at a
distant stage (73.1%) than nonadrenal cases (34.7%; p < 0.001). Males were more likely present at a distant stage than females (p = 040). They were also more likely to present with undifferentiated (grade IV) tumor
than females (p = 0.003). While no significant difference was observed in the surgical intervention
rates between the two groups (p = 0.359), adrenal cases were significantly more likely to receive radiotherapy (31.5
vs. 19.7%; p < 0.001) and chemotherapy (76.3 vs. 58.5%; p < 0.001) compared to nonadrenal cases.
Table 1
Description of the cohort characteristics stratified by location
Variable
|
Primary site
|
p-value
|
Adrenal
|
Nonadrenal
|
Gender
|
Male
|
1,111 (55.7%)
|
1,238 (49.6%)
|
<
0.001
|
Female
|
885 (44.3%)
|
1,258 (50.4%)
|
Race
|
Whites
|
1,536 (77.5%)
|
1,982 (80.5%)
|
0.006
|
Blacks
|
258 (13%)
|
308 (12.5%)
|
Others[a]
|
189 (9.5%)
|
172 (7.0%)
|
Stage
|
Local
|
32 (14.1%)
|
323 (30.9%)
|
< 0.001
|
Regional
|
29 (12.8%)
|
361 (34.5%)
|
Distant
|
166 (73.1%)
|
363 (34.7%)
|
Grade
|
Well differentiated; grade I
|
33 (3.5%)
|
95 (9.4%)
|
< 0.001
|
Moderately differentiated; grade II
|
16 (1.7%)
|
30 (3%)
|
Poorly differentiated; grade III
|
668 (70.2%)
|
679 (67%)
|
Undifferentiated; grade IV
|
235 (24.7%)
|
210 (20.7%)
|
Year of diagnosis
|
< 2000
|
573 (28.7%)
|
946 (37.9%)
|
< 0.001
|
> 2000
|
1,423 (71.3%)
|
1,550 (62.1%)
|
Surgery
|
Surgery performed
|
1,497 (75.9%)
|
1,829 (74.7%)
|
0.359
|
Surgery not performed
|
475 (24.1%)
|
619 (25.3%)
|
Radiotherapy
|
Received
|
628 (31.5%)
|
492 (19.7%)
|
< 0.001
|
Not received/unknown
|
1,368 (68.5%)
|
2,004 (80.3%)
|
Chemotherapy
|
Received
|
1,522 (76.3%)
|
1,459 (58.5%)
|
< 0.001
|
Not received/unknown
|
474 (23.7%)
|
1,037 (41.5%)
|
Note: Bold font indicates statistically significant values (p < 0.05).
a Others: Hispanics, pacific islanders, and Asians.
Survival Analysis
Survival rates were generally higher for nonadrenal cases compared to adrenal NBs.
Specifically, the 2- and 5-year survival rates were 87 and 80%, respectively, for
nonadrenal cases compared to 77 and 65%, respectively, for adrenal cases. [Table 2] summarizes the 2- and 5-year survival stratified by the NB site.
Univariate survival analysis revealed that nonadrenal site, female sex, white race,
and cases diagnosed after 2000 were associated with improved survival in all cases,
while those who received chemotherapy and radiotherapy had lower overall survival.
When stratified by site, female sex was associated with improved survival in nonadrenal
NBs but not in adrenal cases. Similarly, white race was associated with improved survival
in nonadrenal NBs only ([Table 3]).
Cox multivariate analysis revealed that adrenal origin was associated with worse survival
(HR: 1.63; CI: 1.457–1.823). Surgical intervention and more recent year of diagnosis
were associated with improved survival outcomes in all groups. Female sex was significantly
associated with better survival in nonadrenal NBs only, while race did not emerge
as a significant prognostic factor in any of the three groups ([Table 4]).
Table 2
Two- and five-year survival stratified by tumor site
Variable
|
Interval
|
Cumulative % of survival at the end of interval
|
Adrenal
|
Nonadrenal
|
Primary site
|
2 y
|
77
|
87
|
5 y
|
65
|
80
|
Year of diagnosis
|
< 2000
|
2 y
|
64
|
79
|
5 y
|
53
|
72
|
> 2000
|
2 y
|
83
|
91
|
5 y
|
71
|
86
|
Race
|
White
|
2 y
|
78
|
87
|
5 y
|
66
|
81
|
Black
|
2 y
|
78
|
84
|
5 y
|
64
|
75
|
Other
|
2 y
|
72
|
84
|
5 y
|
59
|
78
|
Chemotherapy
|
Administered
|
2 y
|
73
|
81
|
5 y
|
58
|
71
|
No/unknown
|
2 y
|
92
|
94
|
5 y
|
90
|
93
|
Radiotherapy
|
Administered
|
2 y
|
72
|
75
|
5 y
|
53
|
62
|
No/unknown
|
2 y
|
80
|
89
|
5 y
|
71
|
85
|
Surgery
|
Performed
|
2 y
|
82
|
92
|
5 y
|
70
|
87
|
Not performed
|
2 y
|
62
|
70
|
5 y
|
51
|
62
|
Table 3
Univariate (Kaplan–Meier) survival analysis based on tumor site
Variable
|
Overall
|
Adrenal
|
Nonadrenal
|
Mean survival (95% CI)
|
p-value
|
Mean survival (95% CI)
|
p-value
|
Mean survival (95% CI)
|
p-value
|
Primary site
|
Adrenal
|
292 (280–305)
|
< 0.001
|
|
|
|
|
Nonadrenal
|
375 (366–385)
|
Demographics
|
Sex
|
Male
|
334 (323–344)
|
0.004
|
286 (270–302)
|
0.416
|
368 (355–381)
|
0.02
|
Female
|
350 (339–361)
|
297 (279–315)
|
383 (370–396)
|
Race
|
White
|
347 (339–356)
|
< 0.001
|
296 (282–310)
|
0.089
|
382 (371–392)
|
0.005
|
Black
|
309 (287–331)
|
283 (252–314)
|
332 (303–361)
|
Other
|
306 (277–335)
|
253 (216–291)
|
350 (309–391)
|
Treatments
|
Surgical treatment
|
Performed
|
373 (365–381)
|
< 0.001
|
316 (302–330)
|
< 0.001
|
414 (405–424)
|
< 0.001
|
Not performed
|
250 (234–267)
|
221 (197–245)
|
272 (250–294)
|
Radiotherapy
|
Administered
|
261 (246–277)
|
< 0.001
|
228 (205–251)
|
< 0.001
|
286 (264–308)
|
< 0.001
|
No/unknown
|
370 (361–378)
|
319 (305–333)
|
401 (391–410)
|
Chemotherapy
|
Administered
|
290 (280–300)
|
< 0.001
|
249 (235–263)
|
< 0.001
|
323 (309–337)
|
< 0.001
|
No/unknown
|
439 (430–449)
|
414 (395–433)
|
448 (438–458)
|
Year of diagnosis
|
< 2000
|
299 (287–311)
|
< 0.001
|
237 (217–256)
|
< 0.001
|
334 (320–349)
|
< 0.001
|
> 2000
|
156 (153–159)
|
141 (136–146)
|
171 (167–175)
|
Abbreviation: CI, confidence interval.
Note: Bold font indicates statistically significant values (p < 0.05).
Table 4
Cox multivariate regression analysis of factors associated with survival of patients
with neuroblastoma
Variable
|
Overall
|
Adrenal
|
Nonadrenal
|
p-value
|
Hazard ratio (95% CI)
|
p-value
|
Hazard ratio (95% CI)
|
p-value
|
Hazard ratio (95% CI)
|
Primary site
|
Nonadrenal
|
< 0.001
|
1.0 (ref)
|
–
|
–
|
Adrenal
|
1.63 (1.457–1.823)
|
Demographics
|
Sex
|
Male
|
0.049
|
1.0 (ref)
|
0.535
|
1.0 (ref)
|
0.028
|
1.0 (ref)
|
Female
|
0.895 (0.802–0.999)
|
0.955 (0.824–1.106)
|
0.831 (0.705–0.981)
|
Race
|
White
|
0.094
|
1.0 (ref)
|
0.415
|
1.0 (ref)
|
0.188
|
1.0 (ref)
|
Black
|
0.064
|
1.159 (0.992–1.355)
|
0.26
|
1.13 (0.913–1.399)
|
0.132
|
1.193 (0.948–1.5)
|
Other
|
0.172
|
1.141 (0.944–1.379)
|
0.398
|
1.108 (0.874–1.405)
|
0.224
|
1.215 (0.888–1.663)
|
Treatments
|
Surgical treatment
|
No/unknown
|
< 0.001
|
1.0 (ref)
|
< 0.001
|
1.0 (ref)
|
< 0.001
|
1.0 (ref)
|
Performed
|
0.471 (0.42–0.529)
|
0.566 (0.482–0.664)
|
0.385 (0.324–0.457)
|
Radiotherapy
|
No/unknown
|
< 0.001
|
1.0 (ref)
|
< 0.001
|
1.0 (ref)
|
< 0.001
|
1.0 (ref)
|
Administered
|
1.576 (1.403–1.77)
|
1.402 (1.198–1.64)
|
1.752 (1.471–2.089)
|
Chemotherapy
|
No/unknown
|
< 0.001
|
1.0 (ref)
|
< 0.001
|
1.0 (ref)
|
< 0.001
|
1.0 (ref)
|
Administered
|
2.905 (2.444–3.453)
|
3.102 (2.383–4.04)
|
2.681 (2.129–3.376)
|
Year of diagnosis
|
< 2000
|
< 0.001
|
1.0 (ref)
|
< 0.001
|
1.0 (ref)
|
< 0.001
|
1.0 (ref)
|
> 2000
|
0.532 (0.476–0.595)
|
0.559 (0.480–0.650)
|
0.508 (0.428–0.603)
|
Abbreviation: CI, confidence interval.
Note: Bold font indicates statistically significant values (p < 0.05).
Discussion
In the present study, we conduct a comprehensive analysis of survival rates in adrenal
and nonadrenal pediatric NBs in the United States. Among the most important findings
were the higher survival rates in nonadrenal NBs, marked improvements in survival
rates, and hazard reduction for diagnoses made post-2000 and cases undergoing surgery.
The presented study found that nonadrenal NB cases had significantly better survival
rates compared to adrenal cases after adjusting for sex, race, year of diagnosis,
and treatment modality. These findings are consistent with previous studies that have
also reported better outcomes in nonadrenal NB cases.[5]
[20] The explanation for this disparity is that adrenal NB is often associated with negative
prognostic markers such as metastasis at diagnosis, presence of MYC-N amplification,[20]
[21] 1p loss, 11q loss, 17q gain, or DNA copy number alterations.[21]
[22] Adrenal cases predominantly manifested at a distant stage (73.1%), in contrast to
nonadrenal cases (34.7%). Adrenal cases were also more likely to present with an undifferentiated
grade. The significant divergence in tumor stage and grade suggests that adrenal NBs
may inherently be more aggressive or have delayed clinical manifestations, leading
to advanced-stage presentation, and necessitating more aggressive diagnostic and treatment
methods.[21] It is worth noting that stage and grade analysis was limited due to the unavailability
of related data in many cases.
Adrenal cases underwent radiotherapy and chemotherapy more frequently than nonadrenal
cases (31.5 vs. 76.3% and 19.7 and 58.5%, respectively), consistent with previously
reported studies.[23] Chemotherapy and radiotherapy were associated with lower survival rates as these
treatments are reserved for intermediate- to high-risk NB cases.[24] Conversely, surgical intervention showed the best survival outcomes, likely due
to the fact that it is recommended as the frontline treatment in low-risk NBs.[25]
Both adrenal and nonadrenal NB cases exhibited an overall balanced sex distribution,
although adrenal NB showed a slight predominance in males (55.7%). The analysis further
showed that females have a higher mean survival time than males. When stratified by
site, this difference was statistically significant in nonadrenal NB only. Overall,
the influence of sex on NB survival is not clear. While some studies have found that
sex is not a significant prognostic factor,[26] others reported that the association between sex and survival is mediated by the
stage of disease.[27] In our study, males were more likely to present with adrenal NB, distant stage,
and undifferentiated grade than females, potentially explaining the survival difference.
Further analysis of prognostic markers and genetic mutations between males and females
is warranted.
Similarly, race was associated with survival in nonadrenal NB only. White patients
may have higher survival compared to other races, although this difference was not
significant on multivariate analysis. A previous study found that black patients with
NB have a higher prevalence of high-risk disease than white patients.[28] Another study suggested that the poorer outcomes might be due to higher incidence
of high-risk NB among black patients.[29] According to a recent study, no association between race and survival was concluded.
Nevertheless, the survival rates of patients treated during 2000 to 2004 and 2005
to 2015 showed improvement compared to those treated prior to 2000, suggesting reduction
of the racial disparity in survival rates.[26] Around the year 2000, there were significant changes in the understanding and management
of NB.[14]
[30] Some of the major changes that occurred around this time includes the development
of more intensive, multimodality approaches to treat patients who are classified as
high risk.[12] The discovery of genetic alterations that drive tumor growth resulted in the development
of targeted therapies that exploit these alterations.[14] Further prognostic refinement might be attributed to the development of the International
Neuroblastoma Risk Group Staging System (INRGSS), which was first proposed in 2009.[11] Multiple biologic and immunologic agents were developed over the recent years for
treatment of NB. For example, dinutuximab and eflornithine were approved for high-risk
NB by the Food and Drug Administration (FDA) in March 2015[31] and December 2023,[32] respectively. These multimodal approaches have significantly increased long-term
survival, with recent studies reporting long-term survival up to 50% compared with
15% prior to their implementation.[33]
[34]
[35]
[36]
[37]
While this study offers valuable insights, it is not without limitations. The database
provides limited information on the status of radiotherapy and chemotherapy treatments,
which consequently restricts the extent to which definitive conclusions can be drawn
concerning these variables. Additionally, the SEER database lacks data on adjunctive
therapies that may have been administered in conjunction with primary treatments,
thereby potentially impacting the interpretation of treatment efficacy. The SEER database
accounts for approximately 48% of cancer cases in the United States, which may limit
the generalizability of our findings. Moreover, the absence of tumor grading and staging
information for a significant proportion of cases limits the comprehensiveness of
the study.
Conclusion
In summary, this study establishes the primary tumor site as a significant predictor
of survival outcomes in pediatric NB in the United States. We provide a stratified
analysis of risk factors associated with adrenal versus nonadrenal NBs. Survival rates
of patients with NB continues to improve over the past years owing to improved diagnostic
and treatment modalities.