Keywords
neuroblastoma - INRG stage MS - outcome - stage 4S
Introduction
Stage 4S neuroblastoma was first described in 1971 by D'Angio et al and referred to
very young patients with otherwise stage I or II disease, but with metastasis in the
liver, skin, or bone marrow.[1] The International Neuroblastoma Risk Group (INRG) staging system has also reclassified
4S as stage MS and sets a patient age upper limit here at 18 months.[2]
[3] Stage 4S neuroblastoma disease (MS stage) is typically characterized by an initial
phase of rapid tumor progression followed by spontaneous regression in most cases.[4] However, disease progression regardless of any therapy(s) deployed may be seen in
only a minority of patients and survival rates reported in the literature varyingly
range from 56 to 90% cases.[5]
[6]
[7]
[8]
[9]
There is evidence that very young age at diagnosis (<2 months),[10]
[11] life-threatening symptoms,[12] MYCN amplification,[11]
[13] and chromosome 1p deletions[13] are predictors of poor outcome in stage 4S neuroblastoma (stage MS). However, optimal
treatment strategies and their outcomes still remain poorly understood.[8]
Against this background, the aim of this systematic review study was to accurately
better define clinical outcomes of infants with stage 4S (stage MS) neuroblastoma
taking into account the different treatment modalities employed with the biological
features of this enigmatic neuroblastic tumor.
Materials and Methods
Identification and Selection of Studies
A comprehensive search of the published literature in MEDLINE, Embase, and Cochrane
database(s) was performed based on Preferred Reporting Items for Systematic Reviews
and Meta-Analyses guidelines.[14] Search was made using term “neuroblastoma” in combination with one of the following
keywords: “4S” or “IVS” or “stage 4S” or “MS” or “stage IVS” or “infant” or “neonate”
or “spontaneous regression” or “congenital.” All articles published up to May 15,
2020, were included in the review.
Inclusion and Exclusion Criteria
This study included all original articles reporting on outcomes of stage 4S (INRG
stage MS) neuroblastoma. Non-English articles and case reports (<3 patients) were
first excluded with title and abstract screening. Studies with no stage 4S patients
and/or survival data were also excluded ([Fig. 1]).
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses study selection
flow diagram.
Data Extraction and Analysis
Identified articles were independently reviewed by three authors, and final selection
was approved by the senior author. The data on the survival of patients with stage
4S (INRG stage MS) neuroblastoma were then extracted from the original publications.
Data on the treatment modalities of stage 4S (INRG stage MS) neuroblastoma, MYCN,
and chromosome 1p/11q deletion status were also included in the analyses where available.
Statistical Analysis
Chi-square and Fisher's exact tests were utilized to analyze categorical variables.
A significance level of p ≤ 0.05 (two-tailed) was set. Analyses were performed using JMP Pro, version 13.1.0
for Windows (SAS Institute Inc., Cary, North Carolina, United States).
Results
The original search through different databases retrieved 2,325 articles. A total
of 1,623 studies were evaluated in screening of titles and abstracts after duplicates
were excluded. Eighty-five articles met the inclusion criteria in screening and were
selected for full-text review. After full-text review of 85 articles, 37 articles
met the eligibility criteria and were selected for review ([Fig. 1]). The published studies covered the time period(s) from 1971 to 2020.
In total, there were 1,105 patients with stage 4S (INRG stage MS) neuroblastoma identified
with overall survival of 84%. The most common site of primary tumor location was the
adrenal gland with metastasis observed in the liver. MYCN status was fully reported
in 12 studies including 544 patients and MYCN amplification here carried 56% mortality.
Chromosome 1p/11q deletions were only reported in three studies and 133 patients with
1p/11q deletion carried a 40% fatality rate ([Table 1]).
Table 1
Association of molecular biology and survival in 4S neuroblastoma
|
Number of cases (n)
|
Deaths (n)
|
Mortality (%)
|
p-Value
|
|
MYCN amplification
|
36
|
20
|
55.6
|
<0.001
|
|
MYCN not amplified
|
498
|
53
|
10.6
|
|
Chromosome 1p/11q deletion
|
10
|
4
|
40.0
|
0.02
|
|
Normal chromosome 1p/11q
|
123
|
11
|
8.9
|
A total of 201 patients were managed by observation only with an 8.5% mortality. Surgical
resection of the primary tumor was performed on 153 patients with 6.5% fatality rate
and surgery with chemotherapy on 160 patients with 10% mortality. The above-mentioned
three treatment groups had significantly better outcome(s) compared with other treatment
modalities listed (p < 0.001) ([Table 2]). One hundred eighty-six patients were treated with chemotherapy only with 21% mortality.
Table 2
Survival of stage 4S neuroblastoma with different treatment modalities
|
Number of cases (n)
|
Deaths (n)
|
Mortality (%)
|
|
Observation
|
201
|
17
|
8.5
|
|
Surgery only
|
153
|
10
|
6.5
|
|
Surgery and chemotherapy
|
160
|
16
|
10.0
|
|
Chemotherapy only
|
186
|
39
|
21.0
|
|
Radiotherapy only
|
15
|
5
|
33.3
|
|
Surgery and radiotherapy
|
21
|
4
|
19.0
|
|
Radiotherapy and chemotherapy
|
42
|
12
|
28.6
|
|
Surgery, chemotherapy, and radiotherapy
|
27
|
9
|
33.3
|
|
Overall
|
1,105
|
174
|
15.7
|
Discussion
This systematic review demonstrates that stage 4S (INRG stage MS) neuroblastoma carries
the best prognosis in only those groups of patients amenable for observation only
or surgical resection of primary tumor with or without chemotherapy. Moreover, MYCN
amplification and chromosome 1p/11q deletion were both predictors of mortality.
Observation only was the most commonly used treatment for stage 4S neuroblastoma.
Spontaneous regression or differentiation to a ganglioneuroma phenotype is common
in stage 4S (INRG stage MS) neuroblastoma with “benign” molecular biology.[4] Here, most tumors can be treated with active observation only with modest outcome(s)
anticipated including stage 4S (INRG stage MS) neuroblastoma mortality ranging from
0 to 19%.[8]
[15]
[16]
[17]
[18]
Surgery with or without chemotherapy yielded excellent outcome(s) in stage 4S (INRG
stage MS) neuroblastoma according to the quality of published literature reviewed
here in this systematic review. Patients suitable for surgical resection of the offending
primary tumor only had the best outcome(s).[8]
[11]
[15]
[17] Those requiring neoadjuvant chemotherapy before definitive surgical resection had
also good outcomes with only 10% mortality.[11]
[15]
[19]
[20] Interestingly, those treated with surgical resection and radiotherapy with or without
chemotherapy likely “scaled up” to control fulminant liver metastases had significantly
worse outcome(s).
Patients with stage 4S (INRG stage MS) neuroblastoma treated with chemotherapy only
had significant mortality compared with those treated with observation or surgery.
Chemotherapy only was the second most common treatment identified in this systematic
review and reported mortality varied significantly ranging from 0 to 29%.[8]
[11]
[17]
[21] We postulate that the inferior outcome(s) associated with chemotherapy are most
likely reflective of the unfavorable anatomical site of tumor and/or their unique
molecular tumor characteristics.[22]
Radiotherapy alone was administered in 15 patients with 33% mortality (range: 0–100%).[12]
[17]
[19]
[23] This review of published studies therefore shows that radiotherapy alone is associated
with poor prognosis. Similarly, combination(s) of chemotherapy and radiotherapy were
likewise associated with a significant fatality rate of 29%.[1]
[11]
[12]
[17]
[23]
A lack of robust published data showing “evidence-based” selection criteria of deployed
therapy strategies for patients with stage 4S (INRG stage MS) neuroblastoma is a main
limitation of this current study. Fully comparing outcomes metrics of the varying
molecular characteristics of the stage 4S (INRG stage MS) tumors between treatment
groups were challenging due to limited information available. Finally, all included
studies analyzed were retrospective cohort populations.
Conclusion
In conclusion, this study therefore demonstrates that stage 4S (INRG stage MS) neuroblastoma
is associated with good outcome(s) in most cases. Molecular characteristics of the
4S (INRG stage MS) neuroblastic tumor are the best predictors of mortality. Those
patients amenable for observation or surgical resection of primary tumor appear to
have the best overall prognosis.
