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Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study
YJPSU-59323; No of Pages 4 Journal of Pediatric Surgery xxx (xxxx) xxx
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Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study Zuopeng Wang a, Hongqiang Sun b, Kai Li a,⁎, Wei Yao a, Kuiran Dong a, YangYang Ma c, Shan Zheng a a b c
Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China Department of Pediatric Surgery, Shandong Dezhou People's Hospital, Shandong, China Department of Pathology, Children's Hospital of Fudan University, Shanghai, China
a r t i c l e
i n f o
Article history: Received 5 August 2019 Accepted 24 August 2019 Available online xxxx Key words: Neuroblastoma Stage 4S Prognostic factors Outcomes
a b s t r a c t Background: Stage 4S neuroblastoma is a unique category of metastatic disease in infants with a favorable outlook. The purpose of this study was to clarify the prognostic factors of patients with stage 4S neuroblastoma. Method: Data were retrospectively collected from infant patients with stage 4S neuroblastoma in our department from May 2000 to May 2018. Patient characteristics, operative variables, perioperative outcomes, overall survival (OS), and recurrence were evaluated. Univariate and multivariate analyses were performed to identify the prognostic factors of stage 4S neuroblastoma. Result: A total of 28 infant patients (71. 4% males) with a mean age of 3.7 ± 2.7 months were recruited. The involved metastatic sites included liver (n = 18), skin (n = 9), and bone marrow (n = 5). Nine patients received biopsy, and 14 patients underwent original lesions resection followed by postchemotherapy. Five patients accompanied with abdominal compartment syndrome (ACS) were given experiential chemotherapy. The followup time ranged from 12 M to 156 M, with a mean of 32 months. Twenty-two patients completed treatment and survived. Two patients were still under treatment. Four patients died, including three with ACS. No recurrence was observed. According to Kaplan–Meier method, the 5-year overall survival was 84.4%. ACS (p = 0.001) and chemotherapy sensitivity (p b 0.001) were associated with all causes of mortality of stage 4S neuroblastoma, while neuroblastoma liver metastasis (P = 0.107), skin metastasis (P = 0.137), bone marrow metastasis (P = 0.89), tumor radical resection (P = 0.202), prenatal diagnosis (P = 0.314), and younger than 2 months of age (P = 0.683) did not emerge as prognostic factors. Conclusion: ACS and chemotherapy sensitivity were highly important factors that had an association with the prognosis of stage 4S neuroblastoma. Type of study: Prognosis study. Level of evidence: Level IV. © 2019 Elsevier Inc. All rights reserved.
1. Background Neuroblastoma is the most common malignant solid tumor deriving from adrenal medulla and paravertebral sympathetic ganglia cells [1]. Neuroblastoma is remarkable for its broad spectrum of clinical behavior, ranging from spontaneous regression to inevitable progression and death. 4S neuroblastoma is defined by the International Neuroblastoma Staging System (INSS) as patients younger than 12 months of age with localized primary tumor (Stage I or II) and metastases confined to liver, skin, or bone marrow (b10%) [2]. Minimal chemotherapy or observation is a common treatment strategy for infants with stage 4S ⁎ Corresponding author at: Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wan yuanRoad, Shanghai 201102, People's Republic of China. Tel.: +86 21 64931212; fax: +86 21 64931211. E-mail address: [email protected] (K. Li).
neuroblastoma and usually achieves favorable outcomes [3]. However, a subgroup of them suffered a worse prognosis. We presented case series of infants who were diagnosed with stage 4S neuroblastoma. We aimed to evaluate specific clinical prognostic factors in stage 4S neuroblastoma and whether these predicted survival. 2. Methods Twenty-eight patients with a diagnosis of stage 4S neuroblastoma were admitted to the Children's Hospital of Fudan University between May 2005 and May 2018. We retrospectively reviewed the clinical documents of the patient characteristics, operative variables, perioperative outcomes, and overall survival (OS) subsequent to obtaining approval from the local Research Ethics Committee of our hospital. Written informed consent was obtained from the parents of each patient. Fisher test as univariate analysis and binary logistic regression analysis as multivariate analysis
https://doi.org/10.1016/j.jpedsurg.2019.08.031 0022-3468/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Z. Wang, H. Sun, K. Li, et al., Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.031
2
Z. Wang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
were performed to identify the prognostic factors of stage 4S Neuroblastoma. The Kaplan–Meier method was applied to estimate overall survival (OS). Data analysis was performed by SPSS 17.0 software. 3. Results 3.1. Demographics Twenty male and eight female patients with stage 4S neuroblastoma were identified. The ages on admission ranged between newborn and 10 months, with an average age of 3.7 months. Six patients were younger than 2 months of age at diagnosis. The involved anatomic sites including right adrenal gland (n = 14), left adrenal gland (n = 11), mediastinum (n = 3), liver metastasis (n = 18), skin metastasis (n = 9), and bone marrow metastasis (n = 5). 3.2. Clinical signs and symptoms The most common clinical symptom was skin lesion and showed in 9 patients (32.1%). The second most frequent symptom was abdominal mass observed in 8 patients (28.5%). Five patients (17.8%) were diagnosed with tumor by prenatal examination. Five patients (17.8%) had presentations of abdominal distension. One patient was referred to our hospital for jaundice. Computed tomography (CT) scan, abdominal ultrasound, and emission computed tomography (ECT) were performed to assess all these patients. The results revealed the primary localized tumors while excluding cephalothorax and bone metastasis. 3.3. Laboratory investigations The lactate dehydrogenase (LDH) average levels were 542 ± 330 IU/ L (range 228–1337 IU /mL). Neuron-Specific Enolase (NSE) ranged from 17 to 370 ng/ml with an average level of 125 ± 123 ng/ml. The median of serum ferritin (SF) was 147 ng/ml (range 22–904 ng/ml). Bone marrow aspiration revealed five patients had bone marrow metastasis. MYCN was amplified in one of the tumors tested. 3.4. Management and outcomes Nine patients received biopsy and 14 patients underwent original lesion resection followed by postchemotherapy. Five patients accompanied with abdominal compartment syndrome (ACS) were given experiential chemotherapy. The imaging studies of these patients showed rapid progression of hepatomegaly with nodularity, and periumbilical varices (Fig. 1A). 27 patients received moderately aggressive chemotherapy regimen from Children's Oncology Group (COG) with drugs of carboplatin, etoposide, cyclophosphamide, and
Fig. 2. K-M survival curve showed OS 84.4%.
Table 1 Results of intergroup mortality analysis. Groups
Yes
No
P
ACS Chemotherapy sensitivity Prenatal diagnosis Liver metastasis Skin metastasis Bone marrow metastasis MYCN amplification Tumor radical resection Younger than 2 months
60% (3/5) 7.6% (2/26) 0% (0/5) 22.2% (4/18) 0% (0/9) 20% (1/5) 0% (0/1) 0% (0/15) 16.7%(1/6)
4.3% (1/23) 100% (2/2) 17.3% (4/23) 0% (0/10) 21.1% (4/19) 13% (3/23) 14.8% (4/27) 12.5% (1/8) 32.4% (3/19)
0.001 0.001 0.314 0.107 0.137 0.89 0.831 0.348 0.683
doxorubicin. The one with MYCN(+) was in the high-risk group. Twenty-two patients completed treatment and survived. Two patients were still under treatment. Four patients died, two of them presenting no response to chemotherapy with no reduction of the tumor size, and three patients having ACS. The other two patients with ACS showed good response to chemotherapy. CT scans found continuing shrinkage of the adrenal tumors and the rapid involution of the liver with metastasis (Fig. 1B).The follow-up ranged from 12 m to 156 m, with a mean of 32 months. The five-year OS was 84.4% (Fig. 2). 3.5. Analysis of prognostic factors We analyzed intergroup mortality in our cohort (Table 1).The mortality rate in patents with ACS was significantly higher than without
Fig. 1. A: Liver metastasis and primary tumor, B: Involution of liver metastasis and primary tumor after 12 months.
Please cite this article as: Z. Wang, H. Sun, K. Li, et al., Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.031
Z. Wang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
3
Table 2 Results of binary logistic regression analysis. Groups
Coef.
Std. Err.
t
P
[95% Conf. Interval]
ACS Chemotherapy sensitivity Prenatal diagnosis Liver metastasis Skin metastasis Bone marrow metastasis MYCN amplification Younger than 2 months Total
0.0856687 -0.761028 -0.4520691 -0.0409395 -0.1077537 -0.0246842 -0.0399376 -0.1833237 2.982511
.1468583 .1874001 .1577074 .2639758 .1343685 .1062678 .1290501 .1330513 1.174901
0.58 -4.06 -2.87 -0.16 -0.80 -0.23 -0.31 -1.38 2.54
0.567 0.001 0.01 0.878 0.433 0.819 0.76 0.184 0.02
-0.2217094, 0.3930467 -1.153261, -0.3687951 -0.7821546, -0.1219837 -0.5934471, 0.5115682 -0.3889902, 0.1734827 -0.2471053, 0.1977369 -0.3100424, 0.2301673 -0.4618032, 0.0951559 0.5234154, 5.441606
ACS (p = 0.001). Significant difference existed in survival rate between the chemotherapy sensitivity and nonsensitivity group (progression during chemotherapy) (p b 0.001). No significant difference existed in survival rate among the following groups: liver metastasis vs no liver metastasis (p = 0.107); skin metastasis and no skin metastasis (p = 0.137); bone marrow metastasis and no bone marrow metastasis (p = 0.89); tumor resection and only biopsy group (p = 0.202); prenatal diagnosis and nonprenatal diagnosis(p = 0.314); age at younger than 2 months and age at older than 2 months (p = 0.683) (Table1). Logistic multivariate regression analysis suggested that ACS and chemotherapy sensitivity were the important factors in the mortality of stage 4S neuroblastoma (Table 2). 4. Discussion Stage 4S neuroblastoma represents 5% of neuroblastoma [4], which has been confirmed as having significantly better prognosis compared with historical results with INSS stage 4 neuroblastoma in children with age of younger than 12 months. Though stage 4S infants suffer metastases, most of them reach excellent outcomes with spontaneous regression in the majority [5], but 10% to 20% of infants die from early complications [6,7]. OS for patients with stage 4S neuroblastoma is about 85–92% in the literature [8]. In our cohort, OS is about 84.4%, which was consistent with the literature report. Thus, treatment has to be tailored accordingly. If the tumor does not cause threatening symptoms, a wait-and-see approach may be warranted [9,10]. Complications such as ACS usually require a chemotherapy approach. However, China implemented the family planning policy, and each family had only one child. Our department gave relatively conservative treatment to the children with stage 4S neuroblastoma. All the patients without ACS also received the medium-risk chemotherapy with informed consent from the parents. Radiotherapy has been attempted with rather unpredictable results and an unpredictable time course. Furthermore, questions of practicability make it appear outdated [11]. Twist et al. reported that despite the high rates of spontaneous regression in stage 4S, neuroblastoma, immediate intervention with chemotherapy should be administrated for the patients with evidence of rapid tumor growth after diagnosis to avoid development and, eventually, respiratory failure [3] [12]. We found ACS was an important prognostic factor for stage 4S patients with the mortality rate 60% (3/5) and consisting of 75% (3/4) deaths. Hsu and colleagues claimed neonates to be more likely to develop severe complications commonly owing to progressive liver size and to benefit from intensive surveillance and early therapeutic interventions [13]. For ACS patients, experiential chemotherapy was recommended in the early time. And Till et al. suggested liver transplantation as a potentially lifesaving measure in neuroblastoma stage 4S with ACS owing to diffuse metastases [14]. According to the literature, a subset of children with stage 4S neuroblastoma has biological indicators of poor prognosis, including MYCN amplification, chromosomal aberrations, diploidy, elevated neuron specific enolase, serum lactate-dehydrogenase, ferritin, and younger than 2 months of age [5,7,10,15,16]. However, the majority of patients in our cohort did not do the examination of chromosome aberrations and
diploidy in early time. MYCN amplification has been established as an extremely worse prognostic factor in infants with both stage 4S and stage 4 neuroblastoma by multiple center studies [10]. Only one patient with MYCN amplification in our group made it impossible to establish the association of MYCN with survival. And the age of younger than 2 months seemed not to be a prognostic variable in our study neither. The small size samples and short follow-up may be the potential reasons. 4S neuroblastoma in general is rather sensitive even to reduced toxicity chemotherapeutic regimens. However, a small subset of patients develops progressive disease even with chemotherapy [7,14]. Our research indicated chemotherapy sensitivity (p b 0. 001) was associated with all causes mortality of stage 4S neuroblastoma in our study, while neuroblastoma liver metastasis (P = 0. 107), skin metastasis (P = 0. 137), bone marrow metastasis (P = 0. 89), tumor radical resection (P = 0. 202), prenatal diagnosis (P = 0. 314), and younger than 2 months of age (P = 0. 683) did not emerge as prognostic factors. Perinatal diagnosis of neuroblastoma was significantly increased in the last 20 years owing to routine prenatal ultrasound [7]. The prior research suggested no improvement in prognosis for stage 4S patients by resection of the primary tumor [17]. Only 15 patients underwent primary tumor resection in our study. And our results supported that there was no significant difference in the mortality rate between the tumor resection group and only biopsy group. In conclusion, stage 4S neuroblastoma had a favorable outcome with OS 84.4%. ACS and chemotherapy sensitivity were highly important factors and may associate with the prognosis of stage 4S neuroblastoma. There was no significant difference in the mortality rate between tumor resection and only biopsy group. Further studies are needed to evaluate these prognostic factors as well as biological prognostic factors in the larger stage 4S neuroblastoma patient population and long term follow-up. Acknowledgments This study was sponsored by the Science and Technology Commission of Shanghai Municipality (15411961800, Kai Li) Personnel Training Program for Distinguished Medical Young Scholar (2017 Kai Li), New Hundred People Plan of Shanghai Health and Family Planning Commission (2017 BR052 Kai Li), and Shanghai Sailing Program (17YF1401400, Zuopeng Wang), Youth Fund of Shanghai Health and Family Planning Commission Clinical Research Special Plan (20184Y0212 Zuopeng Wang). References [1] Tsubota S, Kadomatsu K. Origin and initiation mechanisms of neuroblastoma. Cell Tissue Res. 2018;372:211–21. [2] Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993; 11:1466–77. [3] Twist CJ, Naranjo A, Schmidt ML, et al. Defining risk factors for chemotherapeutic intervention in infants with stage 4S neuroblastoma: a report from Children's Oncology Group study ANBL0531. J Clin Oncol. 2019;37:115–24. [4] D'Angio GJ, Evans AE, Koop CE. Special pattern of widespread neuroblastoma with a favourable prognosis. Lancet. 1971;1:1046–9. [5] Taggart DR, London WB, Schmidt ML, et al. Prognostic value of the stage 4S metastatic pattern and tumor biology in patients with metastatic neuroblastoma diagnosed between birth and 18 months of age. J Clin Oncol. 2011;29:4358–64.
Please cite this article as: Z. Wang, H. Sun, K. Li, et al., Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.031
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[6] Nickerson HJ, Matthay KK, Seeger RC, et al. Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer group study. J Clin Oncol. 2000;18:477–86. [7] Schiavetti A, Foco M, Ingrosso A, et al. Congenital stage 1 neuroblastoma evolved into stage 4s. J Pediatr Hematol Oncol. 2009;31:59–60. [8] Schneiderman J, London WB, Brodeur GM, et al. Clinical significance of MYCN amplification and ploidy in favorable-stage neuroblastoma: a report from the Children's Oncology Group. J Clin Oncol. 2008;26:913–8. [9] French AE, Irwin MS, Navarro OM, et al. Long-term hepatic outcomes in survivors of stage 4S and 4 neuroblastoma in infancy. Pediatr Blood Cancer. 2012;58:283–8. [10] Schleiermacher G, Rubie H, Hartmann O, et al. Treatment of stage 4s neuroblastoma —report of 10 years' experience of the French Society of Paediatric Oncology (SFOP). Br J Cancer. 2003;89:470–6. [11] Paulino AC, Mayr NA, Simon JH, et al. Locoregional control in infants with neuroblastoma: role of radiation therapy and late toxicity. Int J Radiat Oncol Biol Phys. 2002; 52:1025–31. [12] De Bernardi B, Pianca C, Boni L, et al. Disseminated neuroblastoma (stage IV and IVS) in the first year of life. Outcome related to age and stage. Italian Cooperative Group on Neuroblastoma CANCER-AM CANCER SOC. 1992;70:1625–33.
[13] Hsu LL, Evans AE, D'Angio GJ. Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of the vulnerable neonate. Med Pediatr Oncol. 1996;27:521–8. [14] Holsten T, Schuster T, Grabhorn E, et al. Liver transplantation as a potentially lifesaving measure in neuroblastoma stage 4S. Pediatr Hematol Oncol. 2017;34:17–23. [15] De Bernardi B, Gerrard M, Boni L, et al. Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol. 2009;27:1034–40. [16] Steele M, Jones NL, Ng V, et al. Successful liver transplantation in an infant with stage 4S(M) neuroblastoma. Pediatr Blood Cancer. 2013;60:515–7. [17] Katzenstein HM, Bowman LC, Brodeur GM, et al. Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience—a pediatric oncology group study. J Clin Oncol. 1998;16:2007–17.
Please cite this article as: Z. Wang, H. Sun, K. Li, et al., Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.031
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study Zuopeng Wang a, Hongqiang Sun b, Kai Li a,⁎, Wei Yao a, Kuiran Dong a, YangYang Ma c, Shan Zheng a a b c
Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China Department of Pediatric Surgery, Shandong Dezhou People's Hospital, Shandong, China Department of Pathology, Children's Hospital of Fudan University, Shanghai, China
a r t i c l e
i n f o
Article history: Received 5 August 2019 Accepted 24 August 2019 Available online xxxx Key words: Neuroblastoma Stage 4S Prognostic factors Outcomes
a b s t r a c t Background: Stage 4S neuroblastoma is a unique category of metastatic disease in infants with a favorable outlook. The purpose of this study was to clarify the prognostic factors of patients with stage 4S neuroblastoma. Method: Data were retrospectively collected from infant patients with stage 4S neuroblastoma in our department from May 2000 to May 2018. Patient characteristics, operative variables, perioperative outcomes, overall survival (OS), and recurrence were evaluated. Univariate and multivariate analyses were performed to identify the prognostic factors of stage 4S neuroblastoma. Result: A total of 28 infant patients (71. 4% males) with a mean age of 3.7 ± 2.7 months were recruited. The involved metastatic sites included liver (n = 18), skin (n = 9), and bone marrow (n = 5). Nine patients received biopsy, and 14 patients underwent original lesions resection followed by postchemotherapy. Five patients accompanied with abdominal compartment syndrome (ACS) were given experiential chemotherapy. The followup time ranged from 12 M to 156 M, with a mean of 32 months. Twenty-two patients completed treatment and survived. Two patients were still under treatment. Four patients died, including three with ACS. No recurrence was observed. According to Kaplan–Meier method, the 5-year overall survival was 84.4%. ACS (p = 0.001) and chemotherapy sensitivity (p b 0.001) were associated with all causes of mortality of stage 4S neuroblastoma, while neuroblastoma liver metastasis (P = 0.107), skin metastasis (P = 0.137), bone marrow metastasis (P = 0.89), tumor radical resection (P = 0.202), prenatal diagnosis (P = 0.314), and younger than 2 months of age (P = 0.683) did not emerge as prognostic factors. Conclusion: ACS and chemotherapy sensitivity were highly important factors that had an association with the prognosis of stage 4S neuroblastoma. Type of study: Prognosis study. Level of evidence: Level IV. © 2019 Elsevier Inc. All rights reserved.
1. Background Neuroblastoma is the most common malignant solid tumor deriving from adrenal medulla and paravertebral sympathetic ganglia cells [1]. Neuroblastoma is remarkable for its broad spectrum of clinical behavior, ranging from spontaneous regression to inevitable progression and death. 4S neuroblastoma is defined by the International Neuroblastoma Staging System (INSS) as patients younger than 12 months of age with localized primary tumor (Stage I or II) and metastases confined to liver, skin, or bone marrow (b10%) [2]. Minimal chemotherapy or observation is a common treatment strategy for infants with stage 4S ⁎ Corresponding author at: Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wan yuanRoad, Shanghai 201102, People's Republic of China. Tel.: +86 21 64931212; fax: +86 21 64931211. E-mail address: [email protected] (K. Li).
neuroblastoma and usually achieves favorable outcomes [3]. However, a subgroup of them suffered a worse prognosis. We presented case series of infants who were diagnosed with stage 4S neuroblastoma. We aimed to evaluate specific clinical prognostic factors in stage 4S neuroblastoma and whether these predicted survival. 2. Methods Twenty-eight patients with a diagnosis of stage 4S neuroblastoma were admitted to the Children's Hospital of Fudan University between May 2005 and May 2018. We retrospectively reviewed the clinical documents of the patient characteristics, operative variables, perioperative outcomes, and overall survival (OS) subsequent to obtaining approval from the local Research Ethics Committee of our hospital. Written informed consent was obtained from the parents of each patient. Fisher test as univariate analysis and binary logistic regression analysis as multivariate analysis
https://doi.org/10.1016/j.jpedsurg.2019.08.031 0022-3468/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: Z. Wang, H. Sun, K. Li, et al., Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.031
2
Z. Wang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
were performed to identify the prognostic factors of stage 4S Neuroblastoma. The Kaplan–Meier method was applied to estimate overall survival (OS). Data analysis was performed by SPSS 17.0 software. 3. Results 3.1. Demographics Twenty male and eight female patients with stage 4S neuroblastoma were identified. The ages on admission ranged between newborn and 10 months, with an average age of 3.7 months. Six patients were younger than 2 months of age at diagnosis. The involved anatomic sites including right adrenal gland (n = 14), left adrenal gland (n = 11), mediastinum (n = 3), liver metastasis (n = 18), skin metastasis (n = 9), and bone marrow metastasis (n = 5). 3.2. Clinical signs and symptoms The most common clinical symptom was skin lesion and showed in 9 patients (32.1%). The second most frequent symptom was abdominal mass observed in 8 patients (28.5%). Five patients (17.8%) were diagnosed with tumor by prenatal examination. Five patients (17.8%) had presentations of abdominal distension. One patient was referred to our hospital for jaundice. Computed tomography (CT) scan, abdominal ultrasound, and emission computed tomography (ECT) were performed to assess all these patients. The results revealed the primary localized tumors while excluding cephalothorax and bone metastasis. 3.3. Laboratory investigations The lactate dehydrogenase (LDH) average levels were 542 ± 330 IU/ L (range 228–1337 IU /mL). Neuron-Specific Enolase (NSE) ranged from 17 to 370 ng/ml with an average level of 125 ± 123 ng/ml. The median of serum ferritin (SF) was 147 ng/ml (range 22–904 ng/ml). Bone marrow aspiration revealed five patients had bone marrow metastasis. MYCN was amplified in one of the tumors tested. 3.4. Management and outcomes Nine patients received biopsy and 14 patients underwent original lesion resection followed by postchemotherapy. Five patients accompanied with abdominal compartment syndrome (ACS) were given experiential chemotherapy. The imaging studies of these patients showed rapid progression of hepatomegaly with nodularity, and periumbilical varices (Fig. 1A). 27 patients received moderately aggressive chemotherapy regimen from Children's Oncology Group (COG) with drugs of carboplatin, etoposide, cyclophosphamide, and
Fig. 2. K-M survival curve showed OS 84.4%.
Table 1 Results of intergroup mortality analysis. Groups
Yes
No
P
ACS Chemotherapy sensitivity Prenatal diagnosis Liver metastasis Skin metastasis Bone marrow metastasis MYCN amplification Tumor radical resection Younger than 2 months
60% (3/5) 7.6% (2/26) 0% (0/5) 22.2% (4/18) 0% (0/9) 20% (1/5) 0% (0/1) 0% (0/15) 16.7%(1/6)
4.3% (1/23) 100% (2/2) 17.3% (4/23) 0% (0/10) 21.1% (4/19) 13% (3/23) 14.8% (4/27) 12.5% (1/8) 32.4% (3/19)
0.001 0.001 0.314 0.107 0.137 0.89 0.831 0.348 0.683
doxorubicin. The one with MYCN(+) was in the high-risk group. Twenty-two patients completed treatment and survived. Two patients were still under treatment. Four patients died, two of them presenting no response to chemotherapy with no reduction of the tumor size, and three patients having ACS. The other two patients with ACS showed good response to chemotherapy. CT scans found continuing shrinkage of the adrenal tumors and the rapid involution of the liver with metastasis (Fig. 1B).The follow-up ranged from 12 m to 156 m, with a mean of 32 months. The five-year OS was 84.4% (Fig. 2). 3.5. Analysis of prognostic factors We analyzed intergroup mortality in our cohort (Table 1).The mortality rate in patents with ACS was significantly higher than without
Fig. 1. A: Liver metastasis and primary tumor, B: Involution of liver metastasis and primary tumor after 12 months.
Please cite this article as: Z. Wang, H. Sun, K. Li, et al., Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.031
Z. Wang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
3
Table 2 Results of binary logistic regression analysis. Groups
Coef.
Std. Err.
t
P
[95% Conf. Interval]
ACS Chemotherapy sensitivity Prenatal diagnosis Liver metastasis Skin metastasis Bone marrow metastasis MYCN amplification Younger than 2 months Total
0.0856687 -0.761028 -0.4520691 -0.0409395 -0.1077537 -0.0246842 -0.0399376 -0.1833237 2.982511
.1468583 .1874001 .1577074 .2639758 .1343685 .1062678 .1290501 .1330513 1.174901
0.58 -4.06 -2.87 -0.16 -0.80 -0.23 -0.31 -1.38 2.54
0.567 0.001 0.01 0.878 0.433 0.819 0.76 0.184 0.02
-0.2217094, 0.3930467 -1.153261, -0.3687951 -0.7821546, -0.1219837 -0.5934471, 0.5115682 -0.3889902, 0.1734827 -0.2471053, 0.1977369 -0.3100424, 0.2301673 -0.4618032, 0.0951559 0.5234154, 5.441606
ACS (p = 0.001). Significant difference existed in survival rate between the chemotherapy sensitivity and nonsensitivity group (progression during chemotherapy) (p b 0.001). No significant difference existed in survival rate among the following groups: liver metastasis vs no liver metastasis (p = 0.107); skin metastasis and no skin metastasis (p = 0.137); bone marrow metastasis and no bone marrow metastasis (p = 0.89); tumor resection and only biopsy group (p = 0.202); prenatal diagnosis and nonprenatal diagnosis(p = 0.314); age at younger than 2 months and age at older than 2 months (p = 0.683) (Table1). Logistic multivariate regression analysis suggested that ACS and chemotherapy sensitivity were the important factors in the mortality of stage 4S neuroblastoma (Table 2). 4. Discussion Stage 4S neuroblastoma represents 5% of neuroblastoma [4], which has been confirmed as having significantly better prognosis compared with historical results with INSS stage 4 neuroblastoma in children with age of younger than 12 months. Though stage 4S infants suffer metastases, most of them reach excellent outcomes with spontaneous regression in the majority [5], but 10% to 20% of infants die from early complications [6,7]. OS for patients with stage 4S neuroblastoma is about 85–92% in the literature [8]. In our cohort, OS is about 84.4%, which was consistent with the literature report. Thus, treatment has to be tailored accordingly. If the tumor does not cause threatening symptoms, a wait-and-see approach may be warranted [9,10]. Complications such as ACS usually require a chemotherapy approach. However, China implemented the family planning policy, and each family had only one child. Our department gave relatively conservative treatment to the children with stage 4S neuroblastoma. All the patients without ACS also received the medium-risk chemotherapy with informed consent from the parents. Radiotherapy has been attempted with rather unpredictable results and an unpredictable time course. Furthermore, questions of practicability make it appear outdated [11]. Twist et al. reported that despite the high rates of spontaneous regression in stage 4S, neuroblastoma, immediate intervention with chemotherapy should be administrated for the patients with evidence of rapid tumor growth after diagnosis to avoid development and, eventually, respiratory failure [3] [12]. We found ACS was an important prognostic factor for stage 4S patients with the mortality rate 60% (3/5) and consisting of 75% (3/4) deaths. Hsu and colleagues claimed neonates to be more likely to develop severe complications commonly owing to progressive liver size and to benefit from intensive surveillance and early therapeutic interventions [13]. For ACS patients, experiential chemotherapy was recommended in the early time. And Till et al. suggested liver transplantation as a potentially lifesaving measure in neuroblastoma stage 4S with ACS owing to diffuse metastases [14]. According to the literature, a subset of children with stage 4S neuroblastoma has biological indicators of poor prognosis, including MYCN amplification, chromosomal aberrations, diploidy, elevated neuron specific enolase, serum lactate-dehydrogenase, ferritin, and younger than 2 months of age [5,7,10,15,16]. However, the majority of patients in our cohort did not do the examination of chromosome aberrations and
diploidy in early time. MYCN amplification has been established as an extremely worse prognostic factor in infants with both stage 4S and stage 4 neuroblastoma by multiple center studies [10]. Only one patient with MYCN amplification in our group made it impossible to establish the association of MYCN with survival. And the age of younger than 2 months seemed not to be a prognostic variable in our study neither. The small size samples and short follow-up may be the potential reasons. 4S neuroblastoma in general is rather sensitive even to reduced toxicity chemotherapeutic regimens. However, a small subset of patients develops progressive disease even with chemotherapy [7,14]. Our research indicated chemotherapy sensitivity (p b 0. 001) was associated with all causes mortality of stage 4S neuroblastoma in our study, while neuroblastoma liver metastasis (P = 0. 107), skin metastasis (P = 0. 137), bone marrow metastasis (P = 0. 89), tumor radical resection (P = 0. 202), prenatal diagnosis (P = 0. 314), and younger than 2 months of age (P = 0. 683) did not emerge as prognostic factors. Perinatal diagnosis of neuroblastoma was significantly increased in the last 20 years owing to routine prenatal ultrasound [7]. The prior research suggested no improvement in prognosis for stage 4S patients by resection of the primary tumor [17]. Only 15 patients underwent primary tumor resection in our study. And our results supported that there was no significant difference in the mortality rate between the tumor resection group and only biopsy group. In conclusion, stage 4S neuroblastoma had a favorable outcome with OS 84.4%. ACS and chemotherapy sensitivity were highly important factors and may associate with the prognosis of stage 4S neuroblastoma. There was no significant difference in the mortality rate between tumor resection and only biopsy group. Further studies are needed to evaluate these prognostic factors as well as biological prognostic factors in the larger stage 4S neuroblastoma patient population and long term follow-up. Acknowledgments This study was sponsored by the Science and Technology Commission of Shanghai Municipality (15411961800, Kai Li) Personnel Training Program for Distinguished Medical Young Scholar (2017 Kai Li), New Hundred People Plan of Shanghai Health and Family Planning Commission (2017 BR052 Kai Li), and Shanghai Sailing Program (17YF1401400, Zuopeng Wang), Youth Fund of Shanghai Health and Family Planning Commission Clinical Research Special Plan (20184Y0212 Zuopeng Wang). References [1] Tsubota S, Kadomatsu K. Origin and initiation mechanisms of neuroblastoma. Cell Tissue Res. 2018;372:211–21. [2] Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993; 11:1466–77. [3] Twist CJ, Naranjo A, Schmidt ML, et al. Defining risk factors for chemotherapeutic intervention in infants with stage 4S neuroblastoma: a report from Children's Oncology Group study ANBL0531. J Clin Oncol. 2019;37:115–24. [4] D'Angio GJ, Evans AE, Koop CE. Special pattern of widespread neuroblastoma with a favourable prognosis. Lancet. 1971;1:1046–9. [5] Taggart DR, London WB, Schmidt ML, et al. Prognostic value of the stage 4S metastatic pattern and tumor biology in patients with metastatic neuroblastoma diagnosed between birth and 18 months of age. J Clin Oncol. 2011;29:4358–64.
Please cite this article as: Z. Wang, H. Sun, K. Li, et al., Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.031
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Please cite this article as: Z. Wang, H. Sun, K. Li, et al., Prognostic Factor Analysis of Stage 4S Neuroblastoma in Infant Patients: A Single Center Study, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.08.031