Eur J Cardiothorac Surg 2007;31:725-730. doi:10.1016/j.ejcts.2007.01.026
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Surgical treatment of malignant mediastinal neurogenic tumors in children
Chang Hyun Kanga,*,
Young Tae Kima,
Sang-Hoon Jeonb,
Sook-Whan Sungb,
Joo Hyun Kima
a Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University Hospital, Xenotransplantation Research Center, Clinical Research Institute, Seoul National University College of Medicine, Seoul, South Korea
b Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Kyeonggi-do, South Korea
Received 2 September 2006;
received in revised form 23 December 2006;
accepted 15 January 2007.
* Corresponding author. Address: Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, 28 Yongon-dong, Jongro-gu, Seoul 110-744, South Korea. Tel.: +82 2 2072 3010; fax: +82 2 762 3566. (Email: chkang{at}snu.ac.kr).
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Abstract
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Introduction: The aim of this study was to identify the role of surgical resection in the treatment of malignant mediastinal neurogenic tumors in children. Materials and methods: Thirty-eight consecutive children, who underwent surgical resection of a malignant mediastinal neurogenic tumor between 1986 and 2004, were included in this study. The tumor cell types were neuroblastoma in 23 patients (60.5%), ganglioneuroblastoma in 14 (36.8%), and malignant neuroepithelioma in 1 (2.6%). Surgery was performed for curative resection in localized tumors and salvage resection of residual mediastinal masses after chemotherapy in stage IV tumors. Of the 16 patients (42.1%) who underwent salvage resection, 14 had neuroblastoma and 2 ganglioneuroblastoma. Results: Mean patient age was 3.4 ± 3.0 years (1 month–13 years) and 26 patients (68.4%) were symptomatic at presentation. Adjacent structure invasion was found in eight patients (21.1%), invasion of chest wall in four, heart and vena cava in two, lung in one, and chest wall and lung in one. Complete gross resection was possible in 30 patients (78.9%) and there was no surgical mortality. Surgical morbidity occurred in 10 patients (26.3%) and Horner's syndrome was the most frequent complication (n
= 7). The 5-year survival was 95.2% for a localized tumor and 52.5% for a stage IV tumor (p
= 0.004). The significant risk factors of long-term survival were adjacent structure invasion (p
= 0.002) and a stage IV tumor (p
= 0.002) by multivariate Cox regression analysis. Conclusions: Surgical resection of localized malignant mediastinal neurogenic tumor in children showed good long-term survival, and salvage operations after chemotherapy showed acceptable long-term survival.
Key Words: Neuroectodermal tumors • Surgery • Survival
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1. Introduction
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Neurogenic tumor is the most common mediastinal tumor encountered in children. About 20% of these tumors are malignant, and neuroblastic tumors are the most common malignant neurogenic tumor type in children [1,2]. The clinical course of neuroblastic tumor varies and spontaneous regression is a well-known phenomenon in infantile neuroblastic tumor [3]. Metastatic dissemination is also common for neuroblastic tumors, which most commonly involves bone and liver [4]. Because of a diverse clinical course and prognosis, treatment is usually performed according to risk factors, which include age, stage, and biologic tumor markers [5]. Surgical resection is generally recommended in localized stage I and II and excellent results have been reported [6,7]. However, the role of surgery for the treatment of stage IV neuroblastic tumors remains controversial. Salvage resection of a primary localized tumor after chemotherapy has been reported in several studies [8–11]. However, no consensus has been established concerning the role of surgery in disseminated disease. Furthermore, although many reports are available concerning long-term survival of overall or abdominal neuroblastoma, studies that specifically address mediastinal neuroblastic tumor are scarce [12]. Therefore, most results of surgical treatment in neuroblastic tumor have derived from the results of abdominal neuroblastoma or mixed results of mediastinal and abdominal neuroblastoma. The aims of this study were: (1) to evaluate the roles of curative and salvage resection in malignant mediastinal neurogenic tumor and (2) to identify the risk factors of long-term survival in surgically resected mediastinal malignant neurogenic tumors.
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2. Materials and methods
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A retrospective study was conducted on children with a malignant neurogenic tumor. Thirty-eight children who underwent surgical resection from 1986 to 2004 were included in this study. During the study period, 111 children with a mediastinal tumor were operated on at the department of thoracic surgery at our hospital. Seventy-three children had a neurogenic tumor and 38 of them had a malignant neoplasm. The most common malignant neurogenic tumor was neuroblastoma (n
= 23; 60.5%), followed by ganglioneuroblastoma (n
= 14; 36.8%); one child had a malignant neuroepithelioma (2.6%). Routine preoperative evaluation included history taking, physical examination, blood laboratory tests, and a chest CT scan. Chest MRI was performed in seven patients in whom dumbbell-type tumor was suspected. The routine evaluation of the artery of Adamkiewicz was not performed in those cases. In cases with a resectable localized tumor, primary surgical resection was performed and tumor cell type was confirmed by postoperative pathologic evaluation. If a tumor showed an advanced nature or a metastatic lesion was suspected, an evaluation was performed for malignant neuroblastic tumor. Preoperative laboratory studies for a malignant neuroblastic tumor included ferritin, neuron-specific enolase, and urine catecholamine. MYCN gene copy evaluation was not performed in most of the study population in our series. This study was performed routinely from 2001 in our hospital. Needle aspiration biopsy was performed on all patients with a suspected malignant neoplasm. After confirmation of a malignant neuroblastic tumor by needle biopsy, bone scan, abdominal ultrasonography, magnetic resonance imaging, and bilateral bone marrow aspirate were added for staging. Abdominal cavity evaluation was performed by abdominal ultrasonography in those patients with advanced or metastatic tumors, but not performed routinely in all patients. The staging of malignant neuroblastic tumor was performed according to the International Neuroblastoma Staging System (INSS) [12].
Surgical resection targeted gross total resection. Microscopic clearance of tumor cells at resection margins was not evaluated in operation rooms; rather, the statuses of resection margins were determined by postoperative pathologic evaluations. In cases where complete resection was not possible, mass debulking was performed with residual gross tumor to avoid unacceptable postoperative morbidity. Dumbbell-shaped tumors were removed by combined operation with a neurosurgeon by thoracotomy and laminectomy. When a tumor protruded into the cervical area through the thoracic inlet, resection was performed by median sternotomy.
Follow-up was performed by attending surgeons or pediatric oncologists with a minimum interval of 3 months. Follow-up data obtained up to December 2005 were collected for analysis. Clinical data were obtained by reviewing medical records, and the survival statuses were confirmed by consulting the national death statistical database. Complete follow-up was possible in all patients. The median follow-up period was 74 months (3–183 months).
2.1 Statistical analysis
Statistical analysis was performed using SPSS statistical software (version 11.0, SPSS Inc., Chicago, IL). Continuous variables are expressed as means ± standard deviation, and discrete variables as numbers and ratios. Comparisons of continuous variables between groups were performed using the independent t-test and discrete variables were compared using Pearson's chi-square test or Fisher's exact test. Survival rates were calculated using the Kaplan-Meier method and differences between subgroups were compared using the log-rank test. Univariate analysis for risk factors of survival was performed using the log-rank test, and multivariate analysis using Cox's proportional hazard model. The variables included in the univariate and multivariate analyses were: sex, age under 1 year, symptoms, cell type, dumbbell tumor, local invasion of adjacent organs, residual tumor, stage, preoperative chemotherapy, postoperative complication, adjuvant chemotherapy, and adjuvant radiation therapy. A statistically significant difference was defined as having a p-value of <0.05.
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3. Results
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Patient clinical characteristics are listed in Table 1
. Thirty-eight patients with a malignant neurogenic tumor were included. The sex ratio was 1:1, median age was 3 years, and nine of the children (23.7%) were infants at the time of diagnosis. Symptomatic presentation occurred in 26 children (68.4%). 97.3% of the malignant neurogenic tumors were neuroblastic tumors, and there were 23 neuroblastomas and 14 ganglioneuroblastomas. The stages of the neuroblastic tumors were stage I in 13, IIA in 4, III in 4, IV in 14, and IVS in 2. Metastatic dissemination was identified preoperatively in 16 patients (42.1%). Metastatic sites are depicted in Table 2
. The most common metastatic site was bone in 10 patients (26.3%), followed by liver (n
= 2; 5.3%) and cervical lymph nodes (n
= 2; 5.3%).
Preoperative chemotherapy was performed in 19 patients (50.0%). Four patients with stage III and 14 with stage IV underwent preoperative chemotherapy, and 1 infant with stage IVS underwent preoperative chemotherapy. The mean number of chemotherapy cycles was 5.1 ± 0.8 (3–6 cycles). Surgery was performed by thoracotomy in 36 patients (94.7%) and by median sternotomy in 2 (5.3%). Invasion of an adjacent organ or structure was identified in eight patients (21.1%). Chest wall invasion was the most common site of local invasion and was identified in four patients (10.5%). Lung invasion was found in one patient (2.6%), lung and chest wall invasion in one (2.6%), inferior vena cava invasion in one (2.6%), and superior vena cava and main pulmonary artery in one (2.6%). Concomitantly performed operations were posterior laminectomy in two patients, wedge resection of the lung in two, chest wall resection and reconstruction in one, diaphragm resection and repair in one, and inferior vena cava partial resection and reconstruction in one. The tumor which invaded the inferior vena cava was resected under cardiopulmonary bypass support. Gross total resection was possible in 30 patients (78.9%). The stages of patients with a gross residual mass were IIA in four, III in one, and IV in three. There was no operative mortality. However, operative morbidity occurred in 10 patients (23.7%; Table 3
) Postoperative chemotherapy was performed in 33 patients (86.8%) and postoperative radiation therapy in 7 patients (18.4%). Autologous bone marrow transplantation was performed in one patient whose disease showed chemoresistant progression after surgical resection.
During the follow-up period, 11 patients (28.9%) succumbed to the disease or to treatment-related complications. Causes of death are listed in Table 4
. Tumor recurrence occurred in eight patients (21.1%) and six of these died due to progression of the recurred disease. The locations of recurrences were: bone in two, brain in two, supraclavicular lymph node in two, cervical lymph node in one, axillary lymph node in one, chest wall in one, and abdominal cavity in one. Two patients underwent a second operation for recurred disease, which occurred at an axillary lymph node and in brain, respectively. The overall 5-year survival and disease-free survival of malignant neurogenic tumor after surgical resection were 77.6% and 74.7%, respectively. The overall 5-year survival for those with localized disease (stage I, II, and III) was 95.2% and for those with metastatic disease (stage IV) 52.5% (p
= 0.004; Fig. 1
). The overall survivals according to INSS stage were 93.3% in stage I, 100% in stage IIA, 75.0% in stage III, and 52.5% in stage IV. The 5-year disease-free survivals of those with localized and metastatic disease were 90.2% and 52.5%, respectively (p
= 0.009) (Fig. 2
).
Univariate and multivariate analyses were performed to identify prognostic factors affecting overall survival. Univariate analysis revealed that invasion of an adjacent organ or structure (p
= 0.025), stage IV disease (0.014), and preoperative chemotherapy (p
= 0.0216) were significant risk factors of overall survival. Multivariate analysis using Cox's proportional hazard model identified adjacent organ or structure invasion (odd ratio (OR) 3.90, 95% confidence interval CI 1.08–14.0, p
= 0.002) and stage IV (OR 1.92, CI 1.14–3.22, p
= 0.002) as significant independent risk factors of overall survival (Table 5
).
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4. Discussion
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Pediatric neurogenic tumors have epidemiologic features that differentiate them from adult neurogenic tumors. Neurogenic tumors are the most common type of mediastinal tumors in children, and constitute 46.2% of these tumors versus 11.2% in the adult population [1]. About 20% of neurogenic tumors in children are malignant neoplasms and occur predominantly in the first 5 years of life; moreover, the histologic cell types are different according to age [1]. Neuroblastic tumors are the most common type of malignant neurogenic tumor in children and are classified as neuroblastomas or ganglioneuroblastomas, and neuroblastomas account for about 30% of malignant mediastinal tumors in children [2]. Ganglioneuroblastoma and neuroblastoma are categorized as sympathetic ganglia tumors, the benign type of which is known as ganglioneuroma. They originate from nerve cells rather than nerve sheaths and usually occur at sympathetic ganglia or adrenal glands. However, the sites most commonly affected by ganglioneuroblastoma and neuroblastoma differ. Ganglioneuroblastoma commonly occurs at sympathetic ganglia in the mediastinum, whereas neuroblastoma occurs in the abdominal cavity. Only 30% of neuroblastomas occur in the mediastinum [13].
Ganglioneuroblastoma is a transitional tumor that contains both malignant neuroblastomatous and benign ganglioneuromatous elements. Ganglioneuroblastomas are seen more often in older children and adolescents than neuroblastomas, and usually have less aggressive features than neuroblastoma. Moreover, about a half of ganglioneuroblastoma patients are asymptomatic and are discovered by routine chest X-ray examinations [14]. However, Kubota and colleagues [15] found no tendency for ganglioneuroblastoma to occur at a less advanced stage or with a differing age presentation or more favorable histology. Instead, they concluded that the absence of a MYCN amplification in ganglioneuroblastoma was related to a better prognosis. A study conducted by the Children's Cancer Group also confirmed that MYCN amplification is less likely in ganglioneuroblastoma, and therefore the prognosis of ganglioneuroblastoma was far better than that of neuroblastoma in their study [16]. Adam and colleagues [14] reported an 88% 5-year actuarial survival rate for ganglioneuroblastoma and found that prognosis was related to histologic growth pattern, age, and disease extent at diagnosis. However, ganglioneuroblastoma can also present at advanced stage like neuroblastoma when it is associated with a poor prognosis. In the present study, 36% of malignant neurogenic tumors were ganglioneuroblastomas. However, no favorable survival for ganglioneuroblastoma was identified by our survival analysis. By univariate analysis ganglioneuroblastoma was found to have an 84% 5-year survival rate versus 72% for neuroblastoma, which was not significantly different. In the present study, disease stage (especially the presence of a metastatic lesion) was a more significant risk factor than tumor cell type.
The treatment of neuroblastic tumor is performed on the basis of risk evaluation. Low-, intermediate-, and high-risk groups are defined according to patient age, INSS stage, MYCN status, Shimada histology, and tumor cell ploidy [17]. Localized resectable tumors of stage I, IIA, and IIB without MYCN amplification belong to the low-risk group. Patients in these groups are usually treated only surgically, whereas intermediate- and high-risk groups are treated using multimodality therapy. Perez and colleagues [7] performed a study on 374 stage I and II neuroblastoma patients who underwent surgery alone as a primary therapy. Overall survival rates for stage I and II were 99% and 98%, respectively. Moreover, although a significantly higher rate of recurrence was found among stage II patients, additional treatments, which included repeated surgery or multimodality treatments, successfully controlled disease recurrence. In addition, incomplete resection in stage I and II patients was not found to be a major determinant of overall survival. These findings were also identified in our study. Gross total resection was possible in 76.4% of patients with localized disease (INSS stage I and II), and the 5-year survival of these patients was 94.5%, which is comparable to other reports. However, 70.6% of patients with stage I or II in our study received postoperative chemotherapy, and the effects of postoperative chemotherapy on overall survival in cases of localized disease is unclear from the results of the present study.
The role of surgical resection in high-risk neuroblastoma patients (INSS stage IV and over 1 year old) is controversial. Because of the poor survival of these high-risk patients, multimodality treatment is a standard treatment. Intensive induction chemotherapy and subsequent consolidation therapy have improved overall and progression-free survivals in these patients [5]. However, the role of surgery in high-risk patients has not been accurately defined, although it is known that local progression can be prevented by surgical resection, its effect on overall survival is debatable. Several studies have concluded that complete surgical resection is not an absolute prerequisite for the long-term survival of high-risk patients. Kaneko and colleagues [8] reported that pre- and postoperative chemotherapy with intraoperative radiotherapy improved the relapse-free survival rate of stage III and IV neuroblastoma patients despite gross residual tumor in 8 of 14 surgical resections, and concluded that systemic intensive surgery for advanced neuroblastoma is no longer required. Castel and colleagues [9] found that although surgical resection achieved good local control, that complete resection of stage IV neuroblastoma did not significantly improve disease-free survival as compared with other lesser forms of resection. They also suggested that degree of resection does not influence the overall outcome of stage IV neuroblastoma patients.
However, other studies have concluded that complete primary tumor resection improves the overall survival of high-risk patients. In a study of 153 stage IV neuroblastoma patients reported by Escobar and colleagues [10], the authors indicated that an age of less than 1 year, a favorable pathology, and complete tumor removal significantly favored survival. Complete tumor resection was possible in 75% of survivors, but in only 25% of non-survivors. Another study also advocated the importance of complete resection for stage IV neuroblastoma. La Quaglia and colleagues [11] in their study of 141 stage IV neuroblastoma patients, found that the probability of local progression was 50% in unresected patients and 10% in patients who underwent gross total resection, and that overall survival rate showed a similar pattern (50% in resected patients and 11% in unresected patients). Thus, they concluded that gross total resection should be considered a necessary part of the management of stage IV neuroblastoma.
In our study, surgical resection was performed in 16 patients with stage IV malignant neuroblastic tumor, 2 of whom were infants. The overall 5-year survival rate was 52.5% and gross total resection was possible in 81.2%. Moreover, the presence of residual tumor was not found to influence overall long-term survival. In addition, it is unclear based on our results whether complete gross total resection improves overall survival. However, the combination of surgical resection and chemotherapy produced a favorable long-term outcome in stage IV neuroblastic patients. Therefore, it is our opinion that multimodality therapy including surgery and chemotherapy is an effective treatment modality in metastatic stage IV malignant neuroblastic tumor.
Mediastinal malignant tumors are relatively rare in children. During an 18-year period, surgical resection was performed in 38 patients with malignant neurogenic tumor at our institution and most of these were malignant neuroblastic tumors. Surgical treatment achieved excellent long-term survival for localized tumors and favorable results for metastatic stage IV malignant neuroblastic tumors irrespective of the completeness of gross total resection after preoperative chemotherapy. It is our opinion that surgery should be considered as a main treatment option for localized and stage IV malignant neuroblastic tumors in children.
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Appendix A
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Conference discussion
Dr E. Rendina (Rome, Italy): I was particularly interested in seeing that you have a case that infiltrated the inferior vena cava. It's very unusual to have intrathoracic tumors that infiltrate the inferior vena cava. Do you have details on the management of this very difficult case? Usually these tumors infiltrate also the right atrium and the liver. Do you have details on the treatment of this particular patient?
Dr Kang: In the preoperative evaluation of that patient we didn’t know that the tumor invaded the inferior vena cava, but after open thoracotomy, we found that the tumor invaded the inferior vena cava, so we started cardiopulmonary bypass, and with the assistance of a cardiac surgeon, the tumor was removed, including partial resection of the wall of the IVC. However it is not a usual practice in our hospital, if there is a direct cardiac invasion, they are not usually considered as candidates for surgical resection.
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Footnotes
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\#9734; Presented at the joint 20th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 14th Annual Meeting of the European Society of Thoracic Surgeons, Stockholm, Sweden, September 10–13, 2006.
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References
|
|---|
- Takeda S, Miyoshi S, Minami M, Matsuda H. Intrathoracic neurogenic tumors – 50 years’ experience in a Japanese institution. Eur J Cardiothorac Surg 2004;26:807-812.[Abstract/Free Full Text]
- Grosfeld JL, Skinner MA, Rescorla FJ, West KW, Scherer III LR. Mediastinal tumors in children: experience with 196 cases. Ann Surg Oncol 1994;1:121-127.[Abstract]
- Haas D, Ablin AR, Miller C, Zoger S, Matthay KK. Complete pathologic maturation and regression of stage IVS neuroblastoma without treatment. Cancer 1988;62:818-825.[CrossRef][Medline]
- DeLorimier AA, Bragg KU, Linden G. Neuroblastoma in childhood. Am J Dis Child 1969;118:441-450.[Medline]
- Weinstein JL, Katzenstein HM, Cohn SL. Advances in the diagnosis and treatment of neuroblastoma. Oncologist 2003;8:278-292.[Abstract/Free Full Text]
- Alvarado CS, London WB, Look AT, Brodeur GM, Altmiller DH, Thorner PS, Joshi VV, Rowe ST, Nash MB, Smith EI, Castleberry RP, Cohn SL. Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group Study. J Pediatr Hematol Oncol 2000;22:197-205.[CrossRef][Medline]
- Perez CA, Matthay KK, Atkinson JB, Seeger RC, Shimada H, Haase GM, Stram DO, Gerbing RB, Lukens JN. Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children's cancer group study. J Clin Oncol 2000;18:18-26.[Abstract/Free Full Text]
- Kaneko M, Iwakawa M, Ikebukuro K, Ohkawa H. Complete resection is not required in patients with neuroblastoma under 1 year of age. J Pediatr Surg 1998;33:1690-1694.[CrossRef][Medline]
- Castel V, Tovar JA, Costa E, Cuadros J, Ruiz A, Rollan V, Ruiz-Jimenez JI, Perez-Hernandez R, Canete A. The role of surgery in stage IV neuroblastoma. J Pediatr Surg 2002;37:1574-1578.[CrossRef][Medline]
- Escobar MA, Grosfeld JL, Powell RL, West KW, Scherer III LR, Fallon RJ, Rescorla FJ. Long-term outcomes in patients with stage IV neuroblastoma. J Pediatr Surg 2006;41:377-381.[CrossRef][Medline]
- La Quaglia MP, Kushner BH, Su W, Heller G, Kramer K, Abramson S, Rosen N, Wolden S, Cheung NK. The impact of gross total resection on local control and survival in high-risk neuroblastoma. J Pediatr Surg 2004;39:412-417.[CrossRef][Medline]
- Suita S, Tajiri T, Sera Y, Takamatsu H, Mizote H, Ohgami H, Kurosaki N, Hara T, Okamura J, Miyazaki S, Sugimoto T, Kawakami K, Tsuneyoshi M, Tasaka H, Yano H, Akiyama H, Ikeda K. The characteristics of mediastinal neuroblastoma. Eur J Pediatr Surg 2000;10:353-359.[CrossRef][Medline]
- Strollo DC, Rosado-de-Christenson ML, Jett JR. Primary mediastinal tumors: part II. Tumors of the middle and posterior mediastinum. Chest 1997;112:1344-1357.[Abstract/Free Full Text]
- Adam A, Hochholzer L. Ganglioneuroblastoma of the posterior mediastiuum: a clinicopathologic review of 80 cases. Cancer 1981;47:373-381.[CrossRef][Medline]
- Kubota M, Suita S, Tajiri T, Shono K, Fujii Y. Analysis of the prognostic factors relating to better clinical outcome in ganglioneuroblastoma. J Pediatr Surg 2000;35:92-95.[Medline]
- Goto S, Umehara S, Gerbing RB, Stram DO, Brodeur GM, Seeger RC, Lukens JN, Matthay KK, Shimada H. Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 2001;92:2699-2708.[CrossRef][Medline]
- Castleberry RP, Pritchard J, Ambros P, Berthold F, Brodeur GM, Castel V, Cohn SL, De Bernardi B, Dicks-Mireaux C, Frappaz D, Haase GM, Haber M, Jones DR, Joshi VV, Kaneko M, Kemshead JT, Kogner P, Lee RE, Matthay KK, Michon JM, Monclair R, Roald BR, Seeger RC, Shaw PJ, Shuster JJ. The International Neuroblastoma Risk Groups (INRG): a preliminary report. Eur J Cancer 1997;33:2113-2116.[CrossRef][Medline]
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Abstract
1. Introduction
