Journal of Medicine and Medical Science Vol. 3(4) pp. 243-246, April 2012
Available online http://www.interesjournals.org/JMMS
Copyright © 2012 International Research Journals
Full Length Research Paper
Signs and symptoms of Neuroblastoma
Keikhaei B, Pedram M, Popak B, Heidari M, Hadadi N, Samadi B.
Research Center for Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences,
Ahvaz-Iran
Abstract
Neuroblastoma is one of the most common malignant tumors in children that derived from the
sympathetic nervous system. Neuroblastoma related symptoms are often non-specific, including poor
feeding, weight loss, lethargy and fever. In general, overt symptoms may not occur until the tumor has
reached a big size and/or developed metastases. Signs and symptoms of Neuroblastoma are protean
and many childhood oncologic and non-oncologic diseases can mimic the features of Neuroblastoma
symptoms. The purpose of this study was to assess the signs and symptoms of Neuroblastoma at
Shafa hospital in Khuzestan province. A retrospective review was done in Neuroblastoma patient's
documents who were admitted in Ahvaz Shafa hospital during 1991 March through 2008 March. The
paraffinic blocks of tumoral tissue were analysed for MYCN amplification by PCR in forty patients. Of
87 patients with Neuroblastoma, 43 (49.4%) was male and 44 (50.6%) was female. Mean age at
diagnosis was 52.2 months. Diagnosis was established in 5.7% up to 1 year of age, and 73.6% and 92%
up to 5 and 10 years of age respectively. Diagnosis was carried only in 26.4% of patients up to 2 years
of old out. Sixty nine (69%) had got abdominal mass crossed the midline in 60% of cases. Fever was
found in 62.1% of patients at diagnosis. Age at time of diagnosis of Neuroblastoma was significantly
higher than other literatures, which somehow related to patient’s delay to refer. MYCN amplification
was found from 3 to 2200, in 32 of the forty patients (80%).This study shows that most of the
Neuroblastoma patients present with advance stages. So, awareness of general population and
increase the knowledge of primary health professionals can provide the diagnosis at the earlier stages
of disease.
Keywords: Neuroblastoma,Sign,Symptom,MYCN amplification.
INTRODUCTION
Neuroblastoma, a neoplasm of the sympathetic nervous
system, is the second solid malignant tumor of childhood
(Weinstein et al., 2003; Rudolf, 2008; Schmidt et al.,
2008) and the most common tumor of infancy.
(Castleberry, 1997). Neuroblastoma accounts for 8% to
10% of all childhood cancers and for approximately 15%
of cancer deaths in children. It is a varied malignancy
with prognosis fluctuating from near uniform survival to
high risk for fatal death. (Park et al., 2008). The
distribution of cases is approximately equal between
males and females (it occurs slightly more frequently in
boys than girls) (Wood and Lowis, 2008).
*Corresponding Author E-mail: keikhaeib@yahoo.com
The incidence peaks at age 0 to 4 years, with a median
age of 23 months. (Park et al., 2008). About forty percent
of patients who present with clinical symptoms at
diagnosis are under 1 year of age, and less than 2% with
clinical symptoms are over the age of 10 years (Arul,
2007). Neuroblastoma serves as a model for the
prognostic value of biologic and clinical data and the
potential to modify therapy for patient cohorts at low,
intermediate, and high risk for recurrence. Overall
survival is excellent for patients who have low- and
intermediate-risk Neuroblastoma with a general trend
toward minimization of therapy. In contrast, a marked
intensification of therapy has led to only incremental
improvement in survival for high-risk disease because
less than 40% of high-risk patients survive. Tumor
aggressiveness and progression of Neuroblastoma is
characterized by chromosomal, DNA and molecular bio-
244 J. Med. Med. Sci.
logy markers. The MYCN oncogene seems to play an
important role in the biological features of
Neuroblastoma. MYCN amplification correlates with both
advanced disease stage and rapid tumor progression
(Morowitz et al., 2003; Weinstein et al., 2003; Lehara et
al., 2006). This report intends to describe the clinical
presentations of neuroblastoma.The publication of this
article may raise the clinician’s awareness of the
diagnosis and treatment of Neuroblastoma.
MATERIAL AND METHODS
All of the patients with final diagnosis of Neuroblastoma
admitted in Ahvaz Shafa hospital between 1991 March
through 2008 March were enrolled in this study provided
that they had INSS criteria. A questionnaire including
questions about the duration between start of symptoms
to diagnosis, the presenting symptoms and signs, stage
of disease, and laboratory findings was completed for
each patient. In this way, 87 patients entered the study.
Tumor samples in forty patients were collected and
analysed for MYCN amplification. In the first phase
Paraffin-fixed tissue sections were cut and then Paraffin
was liquefied in xylene. After precipitation of the sample
and removal of the supernatant, remaining xylene is
removed by washing with ethanol. In the next step, DNA
was extracted and quantitative PCR were performed.
Both genes (NAGK gene and MYCN oncogene) were
amplified by a first step of 120 seconds at 95 °C, followed
by 45 cycles of 30 seconds at 95 °C, 30 seconds at 60
°C, and 30 seconds at 72 °C. The degree of amplification
of each sample was derived from the ratio of the number
of molecules of MYCN to the number of molecules of
NAGK reference gene. Only samples in which the
MYCN/NAGK percentage was three and more were
measured as amplified for this oncogene. After gathering
data, statistical analysis was performed by SPSS 16.0.2.
Values were presented as means ± SD. Differences were
considered significant at p <0 .05.
RESULTS
Eighty-seven patients participated in this study. Forty-four
(50.6%) was female, and 43 (49.4%) was male. Mean
age at diagnosis was 52.2 ± 41.5 months (Minimum: 1.5
months, Maximum: 16 years). There was no significant
differences between male and female mean age (p =
.633) and male to female ratio (p = .915).
Sixty nine (69%) had got abdominal mass crossed the
midline in 60% of cases. Fever was found in 62.1% of
patients at diagnosis. The distribution of patients in
stages were 1.2% at stage I ,2.9% at stage II, 22.4% at
stageIII, 70.1% at stage IV, 3.4% in stage IVs.Symptoms
and signs of the patients are shown in table 1.
Bone pain and unilateral palpable mass were found
more frequent in females compared to males (p = .002, p
= .019 respectively).
Mediastinal mass was presented more common in
children older than 3 years of age (p = .001). Also
dyspnea, hypotonia, and weight loss occurred more
frequent in this age group (p = .031, p = .025, p = .031
respectively), but hypertension was found to be more
frequent under 3 years of old (p = .025).
Diagnosis was performed in 5.7% up to 1 year of age,
and 73.6% and 92% up to 5 and 10 years of age.
Diagnosis was carried only in 26.4% of patients up to 2
years of old out.
Average white blood cells count, ESR, and ferritin
level were 8565 ± 1720, 56 ± 14, and 486 ± 303
respectively. It seems that mean white blood cells count
was lower in stage III and IV.
Amongst the forty patients N-MYC amplification were
detected. There were 22 (55%) males and 18 (45%)
females. Of the 40 patients, 1(2.5%) were in stage II, 10
(25%) were in stage III disease, 27 (67.5%) were in stage
IV disease and 2 (5%) were in stage IV-s disease. N-myc
amplification was found in 32/40 (80%) of the patients. Of
these 32 patients with N-myc amplifications 9 (28.1%)
were ≤ 2.5 years of age, 16 (50%) were 2.6 -5 years of
age and 7 (21.9%) were >5 years of age. Fifteen (46.9%)
of the patients were males. While seventeen (53.1%) of
the patients were female. Nine (28.1%) patients were in
stage III, 21 (65.6%) were in stage IV, the remaining 2
(6.2%) were stages II and IV-s tumors. Ninety percent of
stage III and 77.8% of stage IV tumors included in the
study had N-myc amplification.
DISCUSSION
Despite current therapeutic advances, ongoing clinical
trials and basic science investigations, Neuroblastoma
remains a complex medical challenge with an
unpredictable clinical course and dismal overall outcome
for advanced-stage disease (Ishola and Chung,
2007).The distribution of disease is approximately equal
between males and females(Wood and Lowis, 2008).
Similarly in our study, one gender couldn’t outnumber the
other.
Neuroblastoma can present in various ways. The
location of the tumor, along with the presence or absence
of dissemination, leads to a wide spectrum of symptoms
and signs. One third of infants with Neuroblastoma have
a mediastinal primary tumor; adrenal or abdominal
primaries are much more common in older children. But
in our study, mediastina mass was found more frequent
in patients > 3 years of age. It can be merely due to
delayed diagnosis in our study. Neuroblastoma related
opsoclunos myoclonos, a Para neoplastic syndrome, was
occurred in 2% of patients. Similarly we found that 1.1%
of patients had this phenomenon (Ertle et al., 2008). We
found that about 22% of our patients, had hypertension.
Also, Johnston and colleagues found the hypertension as
Keikhaei et al. 245
Table 1. Initial signs and symptoms in neuroblastoma patients
Sign or symptom
Abdominal mass
Fever
Weight loss
Unilateral palpable mass
Horner’s syndrome
Raccoon’s eye
Exophthalmia
Ptosis
Opsoclonus myoclonos
Strabismus
Dyspnea
Vomiting
Abdominal pain
Abdominal palpable mass
Hepatomegaly
Massive Hepatomegaly
Constipation
Urinary retention
Low back pain
Limping
Lower extremity weakness
Hypotonia
Bladder
&
anal
sphincter
dysfunction
Lymph nodes enlargement
Bone pain
Pleural effusion
Intermittent attack of sweating
Hypertension
Diarrhea
Subcutaneous nodules
Leg edema
Number of patients presented
the signs or symptoms
Male
Female
Total
32
28
60
27
27
54
16
17
33
4
16
20
1
2
3
4
3
7
3
3
6
3
4
7
1
0
1
1
0
1
4
5
9
12
5
17
22
23
45
30
29
59
14
10
24
5
4
9
2
2
4
1
4
5
6
6
12
7
11
18
10
7
17
2
5
7
1
2
3
9
6
0
4
6
5
4
3
A rare sign, but it can arise up to 25% of patients
(Johnston et al., 1991).
In a study, 50% of Neuroblastoma cases were
diagnosed before the age of 2(Breslow and McCann,
1971). In another study by Goldsby, ninety percent of
children diagnosed with Neuroblastoma are less than 5
years old and the peak incidence is less than 2 years
(Goldsby and Matthay, 2004). In a review by Arul, he
concluded that the median age at diagnosis is 19 months;
36% of cases are <12 months old, 89% are <5 years old,
and 98% are <10 years old (Arul, 2007). Also other
authors believe that the mean age of Neuroblastoma
diagnosis is about 23 months (Park et al., 2008). But in
our study, mean age at time of diagnosis was 52.2
months (approximately 4.5 years), significantly higher
14
16
2
3
13
3
3
1
23
22
2
7
19
2
7
4
Percent of patients presented
the signs or symptoms
69%
62.1%
37.9%
23%
3.4%
8%
6.9%
8%
1.1%
1.1%
10.3%
19.5%
51.7%
67.8%
27.6%
10.3%
4.6%
5.7%
13.8%
20.7%
19.5%
8%
3.4%
26.4%
25.3%
2.3%
8%
21.8%
5.7%
8%
4.6%
than other literatures; only 5.7% cases were < 12 months,
and 26.4% were < 24 months. These findings completely
differ to the other study. Indeed, in our area, patients
refer to medical care units, after the symptoms
completely established. Also the first line general
physicians try to manage the patients themselves,
without any consultation; so many patients undergo
therapy with a different diagnosis and the diagnosis
couldn’t be established at the best time due to the lack of
primary health care knowledge about the Neuroblastoma.
In general, children aged <1 year at time of diagnosis
and/or with localized disease have an overall better
prognosis, mainly depending on the degree of tumor
resection, and they require little or no adjuvant therapy.
On the contrary, older children often show bone marrow
246 J. Med. Med. Sci.
involvement at diagnosis and the majorities die from
disease progression despite intensive multimodal
therapy(Vassal et al., 2008). Most of patients in our study
were in stage IV, because of diagnosis latency and cure
obtained in only one case.
So awareness of general population in Khuzestan
province and increase the knowledge of physicians can
provide the diagnosis at the earlier stage of disease,
before it disseminate s and make a exigent management.
Multiple factors such as gender, stage, and N-myc
amplification have effect on the median survival of
patients with Neuroblastoma. Our results showed that
survival had no difference in males with and without Nmyc amplification, but females without N-myc
amplification had longer survival comparing with those
females who had N-myc amplification. The analysis of
cumulative survival by Kaplan-Meier curves showed that
patients with MYCN amplification had a significantly
worse prognosis compared with patients in whom the
oncogene was not amplified (Fiorillo et al., 1982;
Sansone et al., 1991).
In conclusion, the presentation of Neuroblastoma in
our study is protean and 92.5% of patients presented with
advanced diseases and most of them had MYCN
oncogene amplification.
The prognosis of patients with MYCN amplification is
worse and need more aggressive treatment. The
detection of MYCN amplification in Neuroblastoma
patients is important for clinical evaluation and treatment
strategy.
ACKNOWLEDGMENT
The authors thank MS Rahimi and Mrs. Shane for
administrative help. This work was supported in part by
research funds of the Department of Thalassemia and
Hemoglobinopathy Center of Ahvaz Jundishapur of
Medical Sciences. The paper is issued from a thesis of
MS Hadadi and Mr. Heidari.
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