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.

2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors.

The clinical course of neuroblastoma is more heterogeneous than any other malignant disease. Most low-risk patients experience regression after limited or even no chemotherapy. However, more than half of high-risk patients die from disease despite intensive multimodal treatment. Precise patient characterization at diagnosis is key for risk-adapted treatment. The guidelines presented here incorporate results from national and international clinical trials to produce recommendations for diagnosing and treating neuroblastoma patients in German hospitals outside of clinical trials.

Radiation-Induced Schwannomas and Neurofibromas: A Systematic Review.

OBJECTIVE: Radiation-induced benign peripheral nerve sheath tumors are uncommon late complications of irradiation. We conducted the largest systematic review of individual patient data. METHODS: We performed a systematic search of PubMed databases and compiled a comprehensive literature review. Kaplan-Meier analysis was used to investigate survival, and statistical significance was assessed with a log-rank test. RESULTS: We analyzed 40 cases of radiation-induced benign peripheral nerve sheath tumors. The histologic distributions were 28 schwannomas, 11 neurofibromas, and 1 ganglioneuroma. The average age of radiation exposure for development of primary lesions was 14.9 ± 15.5 years, and the latency period between radiotherapy to the onset of secondary tumors was 24.5 ± 12.7 years. The average irradiation dose delivered was 26.3 ± 20.3 Gy. The median overall survival for all cases was not reached (95% confidence interval, 22-not reached) months, with 10-year survival rates of 65.2%. Surgical negative margin was a positive prognostic factor for radiation-induced benign peripheral nerve sheath tumors. CONCLUSIONS: The risk of incidence of secondary benign peripheral nerve sheath tumors in patients treated with radiotherapy should be considered in long-term follow-up periods. At present, complete surgical resection is the main stay for the treatment of radiation-induced benign peripheral nerve sheath tumors.

Galectin-3 is a marker of favorable prognosis and a biologically relevant molecule in neuroblastic tumors.

Childhood neuroblastic tumors are characterized by heterogeneous clinical courses, ranging from benign ganglioneuroma (GN) to highly lethal neuroblastoma (NB). Although a refined prognostic evaluation and risk stratification of each tumor patient is becoming increasingly essential to personalize treatment options, currently only few biomolecular markers (essentially MYCN amplification, chromosome 11q status and DNA ploidy) are validated for this purpose in neuroblastic tumors. Here we report that Galectin-3 (Gal-3), a ß-galactoside-binding lectin involved in multiple biological functions that has already acquired diagnostic relevance in specific clinical settings, is variably expressed in most differentiated and less aggressive neuroblastic tumors, such as GN and ganglioneuroblastoma, as well as in a subset of NB cases. Gal-3 expression is associated with the INPC histopathological categorization (P<0.001) and Shimada favorable phenotype (P=0.001), but not with other prognostically relevant features. Importantly, Gal-3 expression was associated with a better 5-year overall survival (P=0.003), and with improved cumulative survival in patient subsets at worse prognosis, such as older age at diagnosis, advanced stages or NB histopathological classification. In vitro, Gal-3 expression and nuclear accumulation accompanied retinoic acid-induced cell differentiation in NB cell lines. Forced Gal-3 overexpression increased phenotypic differentiation and substrate adherence, while inhibiting proliferation. Altogether, these findings suggest that Gal-3 is a biologically relevant player for neuroblastic tumors, whose determination by conventional immunohistochemistry might be used for outcome assessment and patient's risk stratification in the clinical setting.

Ganglioneuroma: to operate or not to operate.

INTRODUCTION: Ganglioneuroma (GN) is a benign, differentiated variety of neurogenic tumor. It is often asymptomatic and may be diagnosed by serendipity. Surgical removal is the treatment of choice. However, it has been suggested that postoperative complications and sequelae might outweigh the benefits of this approach. The purpose of the present study was to examine these issues in a large experience of neural tumors. METHODS: Patients treated between 1992 and 2012 were retrospectively reviewed. Modern imaging, measurement of catecholamine metabolite excretion and metaiodobenzylguanidine were used for workup. Surgical treatment aimed at complete resection. Complications and sequelae were recorded. Literature was searched for regrowth or malignant transformation of GN. RESULTS: Of 227 patients with neural tumors, 24 were GN patients (12 abdominal, 11 thoracic and 1 cervical with 8 dumbbell extensions). Six children were symptomatic (three with abdominal pain and mass, one with stridor or dysphonia, and one each with anisocoria and opsomyoclonus). However, 18 (75%) were asymptomatic and the diagnosis was incidental. Several tumors were large and involved more than one body space. There were no neurologic symptoms in eight cases with dumbbell extension. Complete resection was achieved in 20 children (83%) whereas gross residual was left in four. Postoperative complications were: Horner syndrome (3 patients), mild scoliosis (1 patient), adhesive bowel obstruction (1 patient) and acute urinary retention (1 patient). There was no evidence of either regrowth or malignant behavior in residual masses left in place after follow-up of 84 (1-194) months. CONCLUSIONS: There were a limited number of general minor complications in this series that did not include cases of regrowth or malignant transformation. However, these unfavorable events were occasionally reported in the literature. Since diagnosis of GN cannot be ascertained before removal of the mass, this should remain the aim of the treatment, although limiting the chances of complications to a minimum even if incomplete resection is the price to pay. Nonoperative attitudes should not be recommended in all cases, but they are certainly justified in some.

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.

VEGF-C, VEGF-D and VEGFR-3 expression in peripheral neuroblastic tumours.

AIMS: More than 50% of neuroblastomas (NBs) present with haematogenous and/or lymphatic metastasis; however, little is known about the clinicopathological significance in NBs of the key lymphangiogenesis growth factors vascular endothelial growth factor (VEGF)-C and VEGF-D and the receptor VEGFR-3. METHODS AND RESULTS: Ninety-three NBs and nine ganglioneuromas (GNs) were immunostained for VEGF-C, VEGF-D and VEGFR-3. VEGF-C and VEGF-D were present in 76% and 82% of the NBs, respectively. There was no significant difference in VEGF-C expression between NBs and GNs. VEGF-D expression was significantly higher in NBs compared with GNs and in MYCN-amplified NBs. VEGFR-3 tumoral cell expression (VEGFR-3c), present in 48% of the NBs, was significantly higher in NBs from children ≥ 18 months at presentation and those belonging to a high-risk group. VEGFR-3 lymphovascular density was increased significantly in NBs compared with GNs and in NBs associated with adverse clinicopathological and biological factors. Lymphovascular invasion, assessed in VEGFR-3-stained vessels, was present in ∼50% of NBs. Cox regression analyses demonstrated that VEGFR-3c expression was associated with a significantly shorter event-free survival and that its effect was independent of the important pathological variable, mitosis-karyorrhexis index. CONCLUSIONS: VEGF-D and VEGFR-3 up-regulation support tumour progression in NB and VEGFR-3c may provide a useful prognostic marker in NBs.

Podoplanin lymphatic density and invasion correlate with adverse clinicopathologic and biological factors and survival in neuroblastomas.

Neuroblastoma (NB) is a challenging problem in oncology, as the majority of patients have lymphatic and/or hematogenous metastases at diagnosis. We investigated the prognostic significance of lymphatic density (LD) and invasion (LI) in NBs using the lymphatic endothelial marker podoplanin (PDPN). A total of 77 neuroblastic tumors and 9 ganglioneuromas (GNs) were immunostained for PDPN using D2-40 antibody. Intratumoral lymphatics were identified in 87% (67/77) of NBs and 7/9 GNs. The LD counts were significantly higher (P<0.01) in NBs (median=19.6, range=0.00 to 89.3) than in GNs (median=10.2, range=0 to 18.7). LI, assessed in D2-40-stained lymphatics, was present in 52/67 (78%) NBs. LDs were significantly higher in NBs from patients with adverse clinical factors (advanced-stage, high-risk group, primary abdominal compared with extra-abdominal sites), biological factors (MYCN amplification, 1p deletion, 17q gain), and distant lymph node metastases. LDs and LI were also significantly higher in NBs belonging to an unfavorable pathology prognostic group and in those with a high mitosis-karyorrhexis index. High LD and the presence of LI correlated with a shorter event-free survival in univariable analyses. High LD and the presence of LI were also associated with worse overall survival, although the association was less strong. In conclusion, increased LDs and the presence of LI correlated with adverse clinicopathologic and biological factors and survival. These findings suggest that PDPN has the potential to provide valuable prognostic information to clinicians for risk assessment in NBs.

Angiogenin up-regulation correlates with adverse clinicopathological and biological factors, increased microvascular density and poor patient outcome in neuroblastomas.

AIMS: As new biomarkers are urgently needed to identify children with high-risk neuroblastoma (NB), we studied the contribution of angiogenin (ANG) to angiogenesis and its association with clinicopathological and biological features and patient outcome in NB. METHODS AND RESULTS: Ninety NBs and 12 ganglioneuromas (GNs) were immunostained for ANG and CD31. ANG expression in NB tumoral cells (ANG scores) and vessels [ANG microvascular density (MVD)] and total MVD (CD31 MVD) were determined. The ANG score was significantly greater in NBs than in GNs (P = 0.015) and in NBs from children with stage 4 tumours, high-risk disease, unfavourable pathology (P < 0.001 for each), MYCN amplification (P = 0.003), and 1p deletion (P = 0.002). ANG scores correlated with ANG MVD and CD31 MVD (P < 0.001 for each). Total ANG and CD31 protein levels, measured with a sensitive enzyme-linked immunosorbent assay, were highly correlated (P = 0.003). High ANG scores were associated with decreased overall and event-free survival (log-rank test, P = 0.025 and P = 0.018, respectively). High ANG MVD was associated with decreased overall and event-free survival (log-rank test, P = 0.009 and P = 0.026, respectively). High CD31 MVD was associated with decreased event-free survival (P = 0.045). CONCLUSIONS: The strong correlation of ANG up-regulation with total MVD and adverse clinicopathological and biological factors indicates that ANG supports growth and progression in NB.

Morbidity after ganglioneuroma excision: is surgery necessary?

INTRODUCTION: Ganglioneuroma (GN), the benign form of peripheral neuroblastic tumour, is often asymptomatic and the diagnosis can be incidental. Our aim was to evaluate the incidence of complications after surgical treatment following diagnosis of this tumour. MATERIAL AND METHODS: 24 consecutive children were diagnosed with GN in our centre between January 1989 and December 2009. All patients had negative urinary catecholamines and/or biopsy confirming the diagnosis of GN. Data are reported as mean ± SD. RESULTS: Age at diagnosis was 73 ± 43 months. The most common presentation was respiratory symptoms and/or abdominal pain; 9 (38%) patients were asymptomatic. Tumour location was in the chest (n=14), abdomen (n=7), or pelvis (n=3). 23 children (9 asymptomatic) were operated on; 1 child with a thoracic mass did not undergo surgery because of severe neurological impairments from birth unrelated to GN. 13 children (4 asymptomatic) had a thoracotomy, 8 children (4 asymptomatic) had laparotomy, and 2 (1 asymptomatic) underwent perineal resection. A macroscopically complete surgical excision was performed in 17 cases (74%) and a macroscopically near-complete excision in 6 (26%). At histological examination, resection margins contained tumour in 10 patients (43%) and were free of tumour in the remaining 13 (57%). 7 children (30%) had complications after surgery including 3 patients with Horner's syndrome (which persisted in 2), 1 with chylothorax, 1 with pneumothorax, 1 with pain in the arm, and 1 who developed adhesive intestinal obstruction. 2 children received adjuvant chemotherapy. We re-evaluated the histology specimens according to the International Neuroblastoma Pathology Classification and found that the diagnosis of GN was confirmed in 20 cases (83%), while intermixed ganglioneuroblastoma (iGNB) was diagnosed in 4 patients (17%). At 33.5 ± 40 months (range 1-137) follow-up, all 24 patients, including the child not operated on and the children with incomplete resection or iGNB, are alive with no tumour progression or recurrence. CONCLUSIONS: GN excision is associated with postoperative complications which can be persistent and may affect the quality of life of survivors. In our series we did not observe tumour progression in spite of incomplete excision. The rationale for GN excision should be revisited.

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.

Up-to-date monitoring of childhood cancer long-term survival in Europe: tumours of the sympathetic nervous system, retinoblastoma, renal and bone tumours, and soft tissue sarcomas.

BACKGROUND: Prognosis for most types of childhood tumours has improved during the last few decades. In this article we estimate up-to-date period survival for less common, but important childhood malignancies in Europe. METHODS: Using the database of the Automated Childhood Cancer Information System we calculated period estimates of 10-year survival for the 1995-1999 period for children aged 0-14 years diagnosed during 1985-1999 with tumours of the sympathetic nervous system (NS), retinoblastoma, renal tumours, bone tumours and soft tissue sarcomas in four European regions. RESULTS: Ten-year period survival for 1995-1999 was 66% in children with tumours of the sympathetic NS, 96% for retinoblastoma, 87% for renal tumours, 58% for bone tumours and 61% for soft tissue sarcomas. The higher period estimates, as compared with cohort and complete estimates indicate recent improvement in survival for tumours of the sympathetic NS and to a lesser extent for retinoblastoma and renal tumours. Region-specific period survival estimates were lowest for Eastern Europe for renal, bone and soft tissue tumours, but not for the other two tumour groups. CONCLUSION: There have been further improvements in the 1990s in long-term survival of children diagnosed with several malignancies, albeit to a different extent in different European regions.

[Surgical management of retrorectal tumors]. / Prise en charge chirurgicale des tumeurs rétrorectales.

Retrorectal tumors (RRT) constitute an anatomical grouping of various tumors of different nature, both benign and malignant. The diversity of their presentation, surgical management, and prognosis are illustrated by five clinical cases. A simple categorization would distinguish vestigial tumors (whether cystic or solid), congenital nonvestigial tumors such as chordoma, and tumors of neural or bony origin. Imaging by CT scan and by MRI will usually determine the nature of the tumor and its relationship to the surrounding anatomical structures. The principle of treatment is complete removal with free margins. The surgical approach may be posterior, anterior or combined depending on the nature and the size of the lesion and on how high it is situated relative to the second sacral vertebra. Complete resection may be both difficult and bloody. Sacral segments may need to be resected either for reasons of surgical approach or to obtain clear margins. Rectal resection is rarely necessary. The prognosis of these lesions depends on the nature of the tumor and particularly on the quality and completeness of the resection.

Low occurrence of familial neuroblastomas and ganglioneuromas in five consecutive GPOH neuroblastoma treatment studies.

Familial neuroblastoma is of special interest in view of the oncogenesis of this tumour with its early manifestation in childhood. The inheritance seems to follow an autosomal-dominant mendelian trait with incomplete penetrance. Familial neuroblastomas and ganglioneuromas have not been reported in detail within large treatment studies. A retrospective clinicopathological survey of patients reported to the German neuroblastoma treatment studies over 24 years was performed. Among 2863 patients (2752 neuroblastomas, 111 ganglioneuromas) included in five consecutive trials, only 22 hereditary cases in ten families were observed. Neuroblastomas were found in 18 patients and ganglioneuromas in four, accounting for less than one percent of all cases. Six patients with neuroblastomas had localised disease, seven had stage 4, three had stage 4S, and stage was unknown in two patients. Two families had three affected patients. Contrary to previous reports, age distribution and number of primary tumours in patients with familial data confirm the low prevalence of familial neuroblastoma and may help in counselling the affected families.

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.

[Neurogenic tumors of the mediastinum]. / Tumori neurogeni del mediastino; neurogenic tumors of mediastinum.

Neurogenic neoplasms represent approximately 20% of the space-occupying lesions in the mediastinum. They are primary tumors originating from structures belonging to the peripheral or sympathetic nervous system, they are most commonly diagnosed in subjects in the age range between 10 and 30 years. Benign forms are significantly more frequent than malignant forms, an observation that was confirmed by our own experience; whether these tumors have a predilection for the male or female sex cannot be concluded from the various case series studied to date. Surgical resection can be considered the treatment of choice on the basis of the long-term results, which are greatly satisfactory in benign tumors and encouraging in the malignant variants.

[Impact of complete resection on survival of patients with large neuroblastoma]. / Influencia de la resección completa en la supervivencia de pacientes con neuroblastomas extensos.

UNLABELLED: The aim of our study is to assess the role of complete resection after chemotherapy in stage 3 and 4 (INSS) neuroblastoma. MATERIAL AND METHODS: We treated in the period 1990-1997 a group of 71 infants and children with neural tumors. There were 63 neuroblastomas (median age: 24.8 +/- 25 months, median 18). 47 were abdominal, 13 thoracic, 2 pelvic and 1 cervical. Survival rate (Kaplan-Meier) in patients with or without complete resection of the tumor were assessed (Mantel Cox). RESULTS: 14 of 17 patients with stage 3 tumors and only 8 of 23 with stage 4 survive. All patients with stage 3 undergoing complete resection are alive, whereas only 4 of 7 with incomplete resection survive (p < 0.01). In contrast, the effort and risk of resection do not appear to be worth in stage 4. Two kidneys, one spleen and a portion of the pancreas were removed to perform complete tumor removal. CONCLUSIONS: Complete resection in stage 3 neuroblastoma after chemotherapy improves survival, and radical surgery seems justified even if neighboring structures have to be removed. Radical surgery does not seem to be useful in stage 4 neuroblastoma.

Mediastinal tumors of peripheral nervous system origin.

A wide spectrum of benign and malignant tumors of peripheral nervous system origin can arise in the mediastinum. These neoplasms are more frequent in the posterior mediastinum and can develop from peripheral nerves, sympathetic and parasympathetic ganglia, and neural tube embryonic remnants. The clinicopathologic features of mediastinal schwannomas, melanotic schwannomas, neurofibromas, ganglioneuromas, granular cell tumors, malignant tumors of peripheral nerve sheath origin, malignant melanocytic tumors of peripheral nerve sheath origin, neuroblastomas, ganglioneuroblastomas, and pigmented neuroectodermal tumors of infancy are reviewed.

High levels of expression and nuclear localization of interleukin-1 beta converting enzyme (ICE) and CPP32 in favorable human neuroblastomas.

Neuroblastomas frequently show spontaneous regression and differentiation, which may at least partly be regulated by signaling through nerve growth factor and its receptors, TRK-A and p75LNTR. We studied 52 neuroblastic tumors to test whether the cell death-related proteases, interleukin-1 beta converting enzyme (ICE), CPP32, and Ich-1, were involved in the regression of the tumors. High levels of expression of ICE and CPP32 were significantly correlated with a high level of TRK-A expression, single copy of N-myc, younger age, lower stages, and better prognosis. The immunohistochemical studies and Western analyses as well as the terminal dUTP-biotin nick end labeling (TUNEL) method revealed that both ICE and CPP32 were translocated from the cytoplasm into the nuclei in regressing, apoptotic tumor cells. Our results suggest that ICE and CPP32 cysteine proteases may play an important role in regulating the apoptotic process of the favorable neuroblastomas.