Statistical Framework in Support of a Revised Children's Oncology Group Neuroblastoma Risk Classification System.

PURPOSE: The International Neuroblastoma Risk Group (INRG) Staging System (INRGSS) was developed through international consensus to provide a presurgical staging system that uses clinical and imaging data at diagnosis. A revised Children's Oncology Group (COG) neuroblastoma (NB) risk classification system is needed to incorporate the INRGSS and within the context of modern therapy. Herein, we provide statistical support for the clinical validity of a revised COG risk classification system. PATIENTS AND METHODS: Nine factors were tested for potential statistical and clinical significance in 4,569 patients diagnosed with NB who were enrolled in the COG biology/banking study ANBL00B1 (2006-2016). Recursive partitioning was performed to create a survival-tree regression (STR) analysis of event-free survival (EFS), generating a split by selecting the strongest prognostic factor among those that were statistically significant. The least absolute shrinkage and selection operator (LASSO) was applied to obtain the most parsimonious model for EFS. COG patients were risk classified using STR, LASSO, and per the 2009 INRG classification (generated using an STR analysis of INRG data). Results were descriptively compared among the three classification approaches. RESULTS: The 3-year EFS and overall survival (± SE) were 72.9% ± 0.9% and 84.5% ± 0.7%, respectively (N = 4,569). In each approach, the most statistically and clinically significant factors were diagnostic category (eg, NB, ganglioneuroblastoma), INRGSS, MYCN status, International Neuroblastoma Pathology Classification, ploidy, and 1p/11q status. The results of the STR analysis were more concordant with those of the INRG classification system than with LASSO, although both methods showed moderate agreement with the INRG system. CONCLUSION: These analyses provide a framework to develop a new COG risk classification incorporating the INRGSS. There is statistical evidence to support the clinical validity of each of the three classifications: STR, LASSO, and INRG.

Clinical and biological features of neuroblastic tumors: A comparison of neuroblastoma and ganglioneuroblastoma.

Neuroblastoma (NB), ganglioneuroblastoma intermixed (GNBi) and ganglioneuroblastoma nodular (GNBn) are neuroblastic tumors that present with a wide range of symptoms and variable prognoses. We retrospectively reviewed the pretreatment clinical (age, sex and tumor stage) and biological (MYCN amplification; and levels of lactate dehydrogenase, ferritin and neuron-specific enolase) characteristics of 279 patients who were diagnosed with pathologically confirmed NB and GNB from January 2005 to December 2015. The median age at diagnosis increased with grade of differentiation (NB: 28.9 months; GNBn: 38.4 months; GNBi: 47.5 months; p < 0.01). NB patients were more frequently diagnosed with adrenal tumors and had a higher prevalence of abnormal serum ferritin at the time of diagnosis (60.0% vs. 40.0% vs. 12.0%, P<0.001), NSE (96.0% vs. 93.0% vs. 81.0%, P=0.013) when compared with GNBn and GNBi patients. The prevalence rates of disseminated tumors and MYCN amplified tumors were lower in the GNBi group than in the GNBn and NB groups (13.0% vs. 25.0% vs. 44.0%, P=0.002; 0 vs. 14.0% vs. 26.0%, P=0.032, respectively). The overall survival (OS) of patients with GNB was significantly better than that of patients with NB (GNBi: 100%, GNBn: 74.5±11.4%, NB: 50.8±4.5%, respectively; P<0.01). Our study revealed that both NB and GNB have a wide range of presentations, and clinicians should be aware of both typical and atypical symptoms and signs. Children with GNB (especially GNBi) were more likely to present favorable prognostic factors than their NB counterparts, which consequently lead to better outcomes and longer survival for these patients.

Neuroblastoma in the adult: the Italian experience with 21 patients.

BACKGROUND: Neuroblastoma in the adult is rare. No established therapeutic guidelines exist for these patients and the literature on this issue is scant and contradictory. MATERIALS AND METHODS: Between 1986 and 2011, 21 adults (18 to 38 y; median, 23) diagnosed with neuroblastoma were referred to our hospital. Three of the 21 were classified as neuroblastoma, not otherwise specified, 13 as neuroblastoma, schwannian stroma-poor, and 5 as ganglioneuroblastoma, nodular. Nine patients had a resectable (stage 1/2) and 6 an unresectable primary tumor (stage 3); 6 had disseminated disease (stage 4). RESULTS: Of 9 stage 1/2 patients, 6 underwent surgery alone (2 survive, 4 died), 2 received adjuvant chemotherapy (both survive), and 1 received radiation therapy (alive). Four of the 6 stage 3 patients received chemotherapy and died, 1 underwent partial tumor resection only and died, and 1 received radiation therapy after partial tumor resection and is alive. The 6 stage 4 patients received chemotherapy with/without radiotherapy, and all died. Event-free survival at 10 years was 33.3% for stage 1/2, 16.7% for stage 3, and 0% for stage 4 patients. The 10-year overall and event-free survival rates were 39.8% and 19.1%, respectively. CONCLUSIONS: The outcome of neuroblastoma in adults is poorer than in younger patients at all stages. The clinical course seems modestly influenced by therapy.

GLUT1 protein expression correlates with unfavourable histologic category and high risk in patients with neuroblastic tumours.

GLUT1 is a hypoxia-induced gene that has many biologically important functions, and the overexpression of the GLUT1 protein correlates with poor prognosis in several adult cancers. The clinical significance of the GLUT1 protein in peripheral neuroblastic tumours (NTs) has not been comprehensively documented. In the present retrospective study, immunohistochemical analyses revealed the presence of GLUT1 in 44/96 (46 %) NTs. Membranous GLUT1 was present in neuroblasts of 44/87 neuroblastomas (NBs) and nodular ganglioneuroblastomas (nGNBs) but was absent in ganglion cells. The presence of GLUT1 was significantly increased in NBs and nGNBs compared with maturing ganglioneuromas and intermixed ganglioneuroblastomas (P < 0.001). The proportion of NBs and nGNBs expressing GLUT1 was significantly increased in the high-risk and low/intermediate-risk groups compared with the very-low-risk group (P = 0.022) and the unfavourable compared with the favourable pathology prognostic group (P = 0.027). In the Cox regression analyses, GLUT1 expression indicated a worse overall survival (OS; hazard rate ratio (HR) 2.29, P = 0.053) and event-free survival (EFS; HR 1.68, P = 0.181) which was not attenuated by adjustment for the mitosis-karyorrhexis index and MYCN amplification (OS: adjusted HR 2.44, P = 0.053 and EFS: adjusted HR 1.63, P = 0.244). This indicated that GLUT1 protein expression was independent of mitosis-karyorrhexis index and MYCN amplification as a prognostic factor. Our data may have clinical significance because GLUT1 was also present in a higher proportion of high-risk NTs.

Copy number gain of MYCN gene is a recurrent genetic aberration and favorable prognostic factor in Chinese pediatric neuroblastoma patients.

BACKGROUND: Amplification of MYCN oncogene is an established marker indicating aggressive tumor progression of neuroblastoma (NBL). But copy number analyses of MYCN gene in ganglioneuroblastoma (GNBL) and ganglioneuroma(GN) is poorly described in the literature. In the study, we evaluated the copy number aberrations of MYCN gene in clinical samples of NBLs, GNBLs and GNs and analyzed their association with clinical outcome of the patients. METHODS: In this study, we analyzed MYCN gene and chromosome 2 aneusomy by using fluorescence in situ hybridization (FISH) method in a total of 220 patients with NBL, GNBL and GN cases. Kaplan-Meier curves were generated by using SPSS 12.0 software. RESULTS: Of 220 patients, 178 (81.0%) were NBLs, 32 (14.5%) were GNBLs and 10 (4.5%) were GNs. MYCN gain is a recurrent genetic aberration of neuroblastic tumors (71.8%, 158/220), which was found in 129 NBLs (58.6%, 129/220), 25 GNBLs (11.4%, 25/220) and 4 GN cases (1.8%, 4/220). However, MYCN amplification was only present in 24 NBL tumors (13.5%, 24/178) and 1 GNBL case (3.1%, 1/32). Kaplan-Meier survival analysis indicated that MYCN amplification is significantly correlated with decreased overall survival in NBLs (P=0.017). Furthermore, a better prognosis trend was observed in patients with MYCN gain tumors compared with those with MYCN gene normal copy number tumors and MYCN amplification tumors (P=0.012). CONCLUSIONS: In summary, the frequency of MYCN amplification in NBLs is high and is rarely observed in GNBLs and GNs, which suggest MYCN plays an important role in neuroblastic tumors differentiation. MYCN gain appeared to define a subgroup of NBLs with much better outcome and classification of MYCN gene copy number alteration as three groups (amplification, gain and normal) can provide a powerful prognostic indicator in NBLs. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6417541528559124.

Characteristics and outcome of patients with ganglioneuroblastoma, nodular subtype: a report from the INRG project.

AIM: Describe characteristics and outcome of INRG patients with ganglioneuroblastoma, nodular subtype (GNBn). PATIENTS AND METHODS: Amongst 4071 patients in the INRG database with known INPC histological category, 232 patients with GNBn were identified. Patients were categorised by clinical, pathological and genetic characteristic. For event-free survival (EFS) and overall survival (OS), Kaplan-Meier curves and lifetables were generated, and the outcome of subgroups was compared using log rank test. RESULTS: Patients with GNBn were older (83% >18 months), a higher proportion had unfavourable INPC pathology (83%), and rarely had MYCN gene amplified tumours (2%). Otherwise, the distribution of clinical and biological risk factors including stage, ferritin, initial treatment, grade of NB differentiation, MKI, 11q, 1p, and 17q were similar between patients with GNBn and the overall INRG cohort. EFS and OS were 54%±5% and 68%±5%, respectively. A cohort with superior outcome was identified: OS for GNBn patients younger than 18 months was 95%±5% (n=39) and for GNBn patients with stage 1, 2, 3, 4s was 95%±3% (n=125). Conversely, a poor outcome sub-group could also be identified: OS for stage 4 was 35%±7% (n=107). CONCLUSIONS: Patients with GNBn tumours are rare and have a very heterogeneous outcome. Except for LDH and MKI, the factors prognostic in the overall NB cohort are also prognostic in patients with GNBn. Similar to the overall NB cohort, patients with GNBn older than 18 months of age, with stage 4 disease represent a high-risk sub-group and should be considered for aggressive treatment upfront.

High anaplastic lymphoma kinase immunohistochemical staining in neuroblastoma and ganglioneuroblastoma is an independent predictor of poor outcome.

Anaplastic lymphoma kinase (ALK) mutations occur in 3% to 11% of neuroblastoma (NBL) cases and are associated with high ALK levels. However, high ALK levels appear to be a mutation-independent hallmark of NBL. Evidence about the prognostic relevance of ALK mutations and ALK tumor positivity in patients with NBL has been inconclusive. In this study, we investigated the prognostic relevance of ALK positivity by IHC and ALK mutation status by PCR sequencing in 71 NBL, 12 ganglioneuroblastoma (GNBL), and 20 ganglioneuroma samples in a multivariate model. ALK mutations were present in 2 of 72 NBL and 2 of 12 GNBL samples, which all contained many ALK-positive cells (>50%). In addition, half of all NBL samples showed ALK positivity in most (>50%) of tumor cells, whereas half of the GNBL showed staining in <20% of the tumor cells. In most ganglioneuroma samples, a low percentage of tumor cells stained positive for ALK, which mainly involved ganglion cells. Higher percentages of ALK-positive cells in NBL and GNBL patient samples correlated with inferior survival in univariate and multivariate analyses with established prognostic factors, such as stage, age, and MYCN status. In conclusion, ALK positivity by IHC is an independent, poor prognostic factor in patients with GNBL and NBL. ALK IHC is an easy test suitable for future risk stratification in patients with NBL and GNBL.

Hedgehog signaling pathway in neuroblastoma differentiation.

PURPOSE: The hedgehog (Hh) signaling pathway is activated in some adult cancers. On the other hand, the Hh signaling pathway plays an important role in the development of the neural crest in embryos. The aim of this study is to show the activation of Hh signaling pathway in neuroblastoma (NB), a pediatric malignancy arising from neural crest cells, and to reveal the meaning of the Hh signaling pathway in NB development. METHODS: This study analyzed the expression of Sonic hedgehog (Shh), GLI1, and Patched 1 (Ptch1), transactivators of Hh signaling pathway, by immunohistochemistry in 82 NB and 10 ganglioneuroblastoma cases. All 92 cases were evaluated for the status of MYCN amplification. RESULTS: Of the 92 cases, 67 (73%) were positive for Shh, 62 cases (67%) were positive for GLI1, and 73 cases (79%) were positive for Ptch1. Only 2 (10%) of the 20 cases with MYCN amplification were positive for Shh and GLI1, and 4 cases (20%) were positive for Ptch1 (MYCN amplification vs no MYCN amplification, P ≦ .01). The percentage of GLI1-positive cells in the cases with INSS stage 1 without MYCN amplification was significantly higher than that with INSS stage 4. Of 72 cases without MYCN amplification, 60 were GLI1-positive. Twelve cases were GLI1-negative, and the prognosis of the GLI1-positive cases was significantly better than that of the GLI1-negative cases (P = .015). CONCLUSIONS: Most of NBs without MYCN amplification were positive for Shh, GLI1, and Ptch1. In the cases without MYCN amplification, the high expression of GLI1 was significantly associated with early clinical stage and a good prognosis of the patients. In contrast to adult cancers, the activation of the Hh signaling pathway in NB may be associated with the differentiation of the NB.

[Improved survival in children with neuroblastoma]. / Forbedret overlevelse hos børn med neuroblastom.

INTRODUCTION: The aims of the present study were to analyze whether changes in incidence and mortality rates have taken place in Denmark during the period 1981-2005, and whether the distribution of known prognostic factors has changed during this period. MATERIAL AND METHODS: A total of 206 children below 15 years of age with neuroblastoma or ganglioneuroblastoma who were diagnosed in Denmark between 1981 and 2005. RESULTS: The incidence was 8.68 per million children below 15 years of age (world standard 9.6) and 43.5 per million children below 12 months of age and these incidences have remained unchanged since 1970. The mortality rate has decreased steadily during the study period. The prognostic factors age, stage and site of primary tumour did not change during the study period and were not different from those reported by others. 32% of the children were below 12 months of age at diagnosis. 53% of the children had metastatic disease. The overall 5-year survival increased over the study period from 38% in 1981-1985 to 69% in 2001-2005. A significant increase in the survival of children > 12 months of age with stage 4 disease was also observed. Relapse/disease progression more than three years from diagnosis occurred in only 2% of patients. The median time from relapse to death was three months. CONCLUSION: The survival of children with neuroblastoma in Denmark has increased significantly over the last 25 years.

Outcome prediction and risk assessment by quantitative pyrosequencing methylation analysis of the SFN gene in advanced stage, high-risk, neuroblastic tumor patients.

The aim of our study was to identify threshold levels of DNA methylation predictive of the outcome to better define the risk group of stage 4 neuroblastic tumor patients. Quantitative pyrosequencing analysis was applied to a training set of 50 stage 4, high risk patients and to a validation cohort of 72 consecutive patients. Stage 4 patients at lower risk and ganglioneuroma patients were included as control groups. Predictive thresholds of methylation were identified by ROC curve analysis. The prognostic end points of the study were the overall and progression-free survival at 60 months. Data were analyzed with the Cox proportional hazard model. In a multivariate model the methylation threshold identified for the SFN gene (14.3.3sigma) distinguished the patients presenting favorable outcome from those with progressing disease, independently from all known predictors (Training set: Overall Survival HR 8.53, p = 0.001; Validation set: HR 4.07, p = 0.008). The level of methylation in the tumors of high-risk patients surviving more than 60 months was comparable to that of tumors derived from lower risk patients and to that of benign ganglioneuroma. Methylation above the threshold level was associated with reduced SFN expression in comparison with samples below the threshold. Quantitative methylation is a promising tool to predict survival in neuroblastic tumor patients. Our results lead to the hypothesis that a subset of patients considered at high risk-but displaying low levels of methylation-could be assigned at a lower risk group.

Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG.

BACKGROUND: The International Neuroblastoma Pathology Classification (INPC) was the first to clearly define prognostic subgroups in ganglioneuroma (GN) and ganglioneuroblastoma (GNB). PROCEDURE: Histopathology and tumor resectability of 552 GN/GNB cases from the Children's Cancer Group (CCG) and Children's Oncology Group (COG) neuroblastoma studies were reviewed. The results were analyzed along with clinical information and biological data of the cases. RESULTS: According to the INPC, 300 tumors were classified into the Favorable Histology (FH) group and 252 were into the Unfavorable Histology (UH) group. Tumors in the FH group included 43 ganglioneuroma-maturing (GN-M), 198 ganglioneuroblastoma-intermixed (GNB-I), and 59 ganglioneuroblastoma-nodular, favorable subset (GNB-N-FS), and were often (91%) resected completely by single or multiple surgical procedures. Patients with the FH tumors had an excellent prognosis with no tumor-related deaths. The UH group included ganglioneuroblastoma-nodular, unfavorable subset (GNB-N-US) tumors. Patients with the UH tumors had a high incidence (53%) of distant metastasis at the time of diagnosis, and their prognosis significantly depended on clinical stage (5-year EFS: 80.1% for non-stage 4 patients; 16.7% for stage 4 patients): Complete primary tumor resection was not beneficial to those GNB-N-US patients, regardless of whether metastasis was present or not. MYCN amplification was detected in four tumors in the FH group and six tumors in the UH group. The majority (160/191, 84%) of GN-M and GNB-I tumors had a diploid pattern determined by flow cytometry. CONCLUSIONS: Stringent application of the INPC along with clinical staging was critical for prognostic evaluation of the patients with this group of tumors.

Surgical treatment of malignant mediastinal neurogenic tumors in children.

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.

Thoracic neuroblastoma: outcome of incomplete resection.

The prognosis for thoracic neuroblastoma has been documented as good, but the reasons have not been elucidated. We reviewed our experience of patients with thoracic neuroblastoma who were treated over the past decade. Among 102 patients treated for neuroblastoma at our hospital between December 1987 and June 1997, 20 patients had thoracic neuroblastoma (stage 1: nine, stage 2: five, stage 3: three, stage 4: three). Tumor characteristics and survival rate were compared between thoracic and nonthoracic neuroblastoma. The surgical margin was positive in 13 of the 20 patients with thoracic neuroblastoma. However, local recurrence was observed in only one patient who later underwent complete resection. All patients survived 4-14 years of follow-up. Among those over 1 year old, thoracic neuroblastoma was detected at an earlier stage than in their nonthoracic counterparts (stages 1 and 2 vs. 3 and 4: 6/3 vs. 1/17, p=0.003), and the 5-year survival rate was better than in their nonthoracic counterparts (100% vs. 44.5%, p=0.015). The incidence of ganglioneuroblastoma was significantly higher in the thoracic group at the age of >1 year ( p=0.003). In six of nine patients from the thoracic group who were >1 year old, small areas of ganglioneuroma were identified in the tumor tissue. There was a stronger tendency for the maturation of neuroblastoma into ganglioneuroma in the thoracic group. Complete resection is not required for thoracic neuroblastoma regardless of the patient's age.

Epidemiology of neuroblastoma: analysis of a single institution.

BACKGROUND: Neuroblastoma is the fourth most frequent cancer among all pediatric neoplasms Epidemiological studies may shed more light on the disease and aid in improving treatment of patients with neuroblastoma. PATIENTS AND METHODS: Epidemiology data are presented for 333 children with neuroblastoma or ganglioneuroblastoma and 11 children with ganglioneuroma who were treated at the Institute of Mother and Child in Warsaw, Poland, from 1962 to 1996. RESULTS: Analysis of the stage of the disease, age, sex and survival of children with neuroblastoma demonstrated comparable distribution of good and intermediate stages versus the stages with a poor prognosis. CONCLUSION: Comprehensive analysis of epidemiological data on the stage of cancer, age, sex and survival in patients with neuroblastoma provides a basis for better prognosis of the disease and cost-efficient treatment.

Tumor de la médula suprarenal como causa de muerte súbita

Se presenta el caso de una muerte súbita diagnosticada en un individuo de 27 años de edad, masculino, del grupo racial predominantemente europoide, con antecedentes de salud conocidos. Se realiza la necropsia médico-legal encontrando un tumor de médula suprarrenal denominado ganglioneuroblastoma, productor de catecolaminas, las que al provocar una descarga adrenérgica conducen a la muerte, tal y como se describe en la literatura consultada. El estudio toxicológico aportó resultados negativos a sustancias tóxicas exógenas. Se considera una causa de muerte súbita de interés dada su incidencia y la importancia de su diagnóstico histopatológico...(AU)

Relationship between histopathological features, MYCN amplification, and prognosis: a UKCCSG study. United Kingdom Children Cancer Study Group.

Histological sections from 231 patients with neuroblastoma were reviewed and morphological features and their relationship to age, stage, MYCN amplification (in 128 tumours by Southern analyses), and clinical outcome (based on Shimada risk grouping) determined. Stage 4 disease was associated with poorly differentiated and undifferentiated tumours (P = 0.001), an MKI of >2% (P< 0.001), and Shimada unfavourable histology (UHi) P< 0.0001. In univariate analysis MKI was significant in predicting a poorer relapse-free survival (RFS), low vs. intermediate and high (P< 0.001). Age, MYCN amplification, and Shimada UH also emerged as significant variables. There was a higher proportion of MYCN-amplified tumours with Shimada UH (P = 0.03), and this group had a decreased RFS (P = 0.002). In patients with Shimada FH, MYCN amplification did not significantly predict a poor prognosis. In those with stage 4 disease, Shimada classification was not significant in predicting survival (P = 0.97); the same was true for those over the age of 1 year (P = 0.66). In multivariate analysis, MYCN amplification and Shimada UH both emerged as independent prognostic factors. In conclusion, morphological features assigned some subsets of patients to prognostic risk groups. Most MYCN-amplified tumours have unfavourable histology and a poorer prognosis. However, in patients with stage 4 disease and those over the age of 1 year, other factors that may influence prognosis should be determined.

Neuroblastoma: changing incidence and survival in young people aged 0-24 years. A report from the North of England Young Persons' Malignant Disease Registry.

BACKGROUND AND PROCEDURE: Population based data for neuroblastoma in children and young adults under 25 years at diagnosis were ascertained from the Northern Region Young Persons' Malignant Disease Registry for the period 1968-1995. Age-standardised incidence rates were calculated (ASR) and changes in incidence and survival were investigated. Over the study period 144 patients were registered, of these 136 were children under 15 years at diagnosis (median age: 2.2 years, ASR: 8.6 cases per million children per year), and 8 were 15-24 years (ASR 0.6). RESULTS AND CONCLUSIONS: Incidence of childhood neuroblastoma in the North of England increased significantly over time; ASRs were 5.8 for 1968-1981 and 9.5 for 1982-1995 (rate ratio: 1.6, 95%; CI 1.2-2.3). The increase in incidence was seen in both infants and older children, and in both low stage and advanced disease. Overall 5 year survival was 15% for 1968-1981 and 40% for 1982-1995 (P < 0.0001). Significant improvements in survival were documented across different stage and age-groups, including those over 1 with stage 4 disease (0% versus 18%, P < 0.0001). Further research is needed to investigate the reasons for the increasing incidence of neuroblastoma.

Histopathology defines prognostic subsets of ganglioneuroblastoma, nodular.

BACKGROUND: Ganglioneuroblastoma, nodular (GNBn) is a rare subtype of the family of neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) that are classified in the unfavorable histology group according to the International Neuroblastoma Pathology Classification (Shimada system). Tumors of this subtype have been considered to represent a prototypic example of biologically and clinically nonaggressive (Schwannian stroma-rich and stroma-dominant) components combined with biologically and clinically aggressive nodular (Schwannian stroma-poor) components. However, detailed histopathologic analysis as well as thorough prognostic evaluation of patients with this subtype has not been reported. METHODS: Pathology slides and reports from a total of 70 GNBn patients from the Children's Cancer Group (CCG)-3881 and CCG-3891 studies were reviewed. Sixty-eight tumors were classified in the favorable subset (FS) or the unfavorable subset (US) based on the evaluation of nodular components by applying the same histopathologic criteria (patient age, grade of neuroblastic differentiation, mitosis-karyorrhexis index) that are used for neuroblastomas in the International Neuroblastoma Pathology Classification. Patient prognosis as well as clinical and biologic characteristics within the subsets were analyzed, and the results were compared with those from 654 non-GNBn patients who were enrolled in the same CCG studies during the same period. RESULTS: Patients with GNBn tumors, usually diagnosed at age > 1 year, had a significantly lower overall 5-year event free survival (EFS) rate than patients with non-GNBn subtypes (44.7% EFS vs. 65.0% EFS; P = 0. 0073). A significant difference in the outcome of the patients between the FS (22 patients; 86.1% EFS; 95.0% survival rate) and the US (46 patients; 29.0% EFS; 40.7% survival rate) of the GNBn subtype (P < 0.0005) was shown. When the cohort of patients with GNBn tumors was subdivided into FS and US, the outcomes were similar to those of patients with tumors of favorable histology (397 patients; 90.5% EFS; 97.6% survival rate) and with tumors of unfavorable histology (257 patients; 27.0% EFS; 35.7% survival rate) of the non-GNBn type. The patients with US tumors frequently (63.0%) presented with distant metastasis. CONCLUSIONS: The current study demonstrates that the nodular components in GNBn tumors are not always aggressive. The prognosis of these patients can be determined by the analysis of age-linked histopathologic features.

Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group 'Survey' 1982-1992.

In 1982 the European Neuroblastoma Study Group (ENSG) established a prospective registry for patients with newly diagnosed neuroblastoma ('The ENSG Survey'). Clinical information was collected primarily to: (a) establish an ENSG database; and (b) investigate prognostic factors in neuroblastoma. This paper summarises the results of the survey. By 1992, 1277 patients with a median age of 26 months (range: 0-289 months), gender ratio of 1.19 M:F had been registered from 30 centres. The median follow-up of survivors is 9.7 years (range: 1-14 years). Overall 5-year survival (S) is 45% (95% CI 42-48%), and event-free survival (EFS) is 43% (95% CI 40-45%). For both survival and EFS the key established prognostic factors, stage and age, are highly significant (P<0.001). In particular, patients under 1 year of age at diagnosis, whatever the disease stage, had a more favourable prognosis than older patients; stage 2 (EFS 93% (95% (CI 85-97) versus 76% (95% CI 67-86), P=0.02), stage 3 (EFS 91% (95% CI 82-96) versus 52% (95% CI 44-60), P<0.001) and stage 4 (EFS 59% (95% CI 48-69) versus 16% (95% CI 13-19), P<0.001). Multivariate analysis established that the anatomical location of the primary tumour (i.e. abdominal versus other sites) and primary tumour volume also conferred a statistically significant difference. In stage 4 disease the 20% of patients without demonstrable bone marrow involvement had a more favourable prognosis than those with infiltrated marrow (EFS 36% (95% CI 13-19) versus 16% (95% CI 29-45), P<0.001). Urine catecholamine metabolite levels (raised versus normal), histology (ganglioneuroblastoma versus neuroblastoma) and gender had no significant effect on outcome after stage and age were accounted for. 5-year survival following first relapse is only 5.6% (95% CI 2.8-8.4). This ENSG Survey provides secure data for future comparisons with new prognostic factors and treatment programmes.

Analysis of the prognostic factors relating to better clinical outcome in ganglioneuroblastoma.

PURPOSE: To elucidate the precise reason for the better prognosis in ganglioneuroblastoma (GNB) than in neuroblastoma (NB), the prognostic factors (age at diagnosis, stage at diagnosis, primary site, N-myc amplification, Shimada classification, and ploidy) were analyzed. METHODS: A retrospective analysis of the 57 neuroblastoma cases (20 GNB cases and 37 NB cases), that had not been detected by mass screening over the past 19 years at the authors' institute, was carried out. RESULTS: A Kaplan-Meier analysis of the 5-year survival rates were 67.2% and 35.1% in cases of GNB and NB, respectively, and these rates were significantly higher in GNB (logrank test; P = .04631). No significant differences were seen between GNB and NB regarding the rate in patients 1 year of age or older (95.0% v 78.4%; P = .1005), the rate of advanced cases (60.0% v 78.4%, P = .1406), the rate of an unfavorable histology (Shimada classification, 54.5% v 68.4%, P = .4473), or the diploid pattern rate (75.0% v 76.9%, P = .9200). However, N-myc amplification was found exclusively in NB (amplified cases per examined cases; 15/31), and all cases with N-myc amplification died. When the 5-year survival rate was evaluated in the patient without N-myc amplification between GNB and NB, no significant difference was observed (logrank test; P = .8568). CONCLUSION: The better prognosis in patients with GNB was thus thought to be exclusively related to an absence of N-myc amplification.