Adolescent- and adult-onset neuroblastic tumor: A retrospective multicenter observational study of patients diagnosed in France between 2000 and 2020.

BACKGROUND: Adult- and adolescent-onset neuroblastomas are rare, with no established therapy. In addition, rare pheochromocytomas may harbor neuroblastic components. This study was designed to collect epidemiological, diagnostic and therapeutic data in order to better define the characteristics of malignant peripheral neuroblastic tumors (MPNT) and composite pheochromocytomas (CP) with MPNT. PROCEDURE: Fifty-nine adults and adolescents (aged over 15 years) diagnosed with a peripheral or composite neuroblastic tumor, who were treated in one of 17 institutions between 2000 and 2020, were retrospectively studied. RESULTS: Eighteen patients with neuroblastoma (NB) or ganglioneuroblastoma (GNB) had locoregional disease, and 28 patients had metastatic stage 4 NB. Among the 13 patients with CP, 12 had locoregional disease. Fifty-eight percent of the population were adolescents and young adults under 24 years of age. The probability of 5-year event-free survival (EFS) was 40% (confidence interval: 27%-53%). CONCLUSIONS: Outcomes were better for patients with localized tumor than for patients with metastases. For patients with localized tumor, in terms of survival, surgical treatment was the best therapeutic option. Multimodal treatment with chemotherapy, surgery, radiotherapy, and immunotherapy-based maintenance allowed long-term survival for some patients. Adolescent- and adult-onset neuroblastoma appeared to have specific characteristics associated with poorer outcomes compared to pediatric neuroblastoma. Nevertheless, complete disease control improved survival. The presence of a neuroblastic component in pheochromocytoma should be considered when making therapeutic management decisions. The development of specific tools/resources (Tumor Referral Board, Registry, biology, and trials with new agents or strategies) may help to improve outcomes for patients.

Successful endoscopic approach for peripheral neuroblastic tumors in children.

BACKGROUND: Recently, reports of endoscopic approaches for neuroblastoma, ganglioneuroblastoma, and ganglioneuroma (peripheral neuroblastic tumor; PNTs) have been increasing. This study aimed to clarify the indications for endoscopic surgery for PNTs. METHODS: Pediatric patients who underwent endoscopic surgery for PNTs at our institution were included in this study. Image-defined risk factors (IDRFs) were analyzed using preoperative computed tomography (CT). RESULTS: Twenty-four patients underwent endoscopic surgery for PNTs. The diagnoses included neuroblastoma (n = 11), ganglioneuroma (n = 10), and ganglioneuroblastoma (n = 3). Regarding the tumor site, there were 18 cases of adrenal tumors, five cases of mediastinal tumors, and one case of retroperitoneal tumors. Image-defined risk factors were positive in eight cases (contacted with a renal vessel, n = 6; compression of principal bronchi, n = 2). Complete resection was accomplished in 21 cases (14 of 16 IDRF-negative cases and seven of eight IDRF-positive cases). All patients survived without recurrence during the follow-up period. CONCLUSIONS: The CT findings of contact with renal vessels and compression of principal bronchi do not seem to be indicators of incomplete resection. An endoscopic approach to PNTs in pediatric patients is feasible with a good prognosis if patients are selected strictly.

Ganglioneuroblastoma intermixed: Clinicopathological implications of diagnosis at presentation and genomic correlations.

BACKGROUND: Ganglioneuroblastoma intermixed (GNBI) is classified as "favorable" histology by International Neuroblastoma Pathology Classification system. However, the International Neuroblastoma Risk Group (INRG) stratifies patients using wider clinicopathological and cytogenetic/molecular parameters. While the diagnosis of GNBI is typically made on resected tumor, it may sometimes be rendered on initial biopsy. We studied GNBI noted at diagnosis to evaluate its correlation with INRG staging and other clinicopathological and molecular features. METHODS: In this retrospective study, clinical, radiological, pathological, cytogenetic, and molecular information from patients with GNBI at diagnosis seen between 1995 and 2021 was analyzed. INRG staging was performed. RESULTS: Of the 15,827 neuroblastoma specimens, GNBI was noted in 237 patients. Of these, 53 had the initial pathological diagnosis of GNBI; median follow-up 3.5 (range: 0.2-14) years. Disease was locoregional in 41 (77%, 16 stage L1 and 25 L2); none relapsed. Twelve (23%) had metastatic disease at presentation; six (50%) relapsed, and two died of disease. MYCN was amplified in two metastatic tumors. Six of 31 (19%) tumors tested had recurrent cytogenetic abnormalities and nonrecurrent somatic gene mutations in 10/23 (43%). The presence of any adverse molecular/cytogenetic findings was associated with metastatic disease (p < .05). For patients with localized GNBI undergoing both biopsy and resection, GNBI was diagnosed in both in 17/19 (90%). CONCLUSIONS: Localized GNBI at diagnosis has excellent long-term clinical outcome even without cytotoxic therapy. For localized GNBI, a biopsy sample is adequate to make the diagnosis. When associated with metastasis at diagnosis, prognosis is poorer, possibly due to associated adverse biological features.

Ganglioneuroblastoma in a Child With Neurofibromatosis Type 1: A Case Report and Literature Review.

Neurofibromatosis type 1 (NF1) is a genetic condition commonly associated with a predisposition to tumor development. Affected individuals have an increased risk of benign and malignant tumors of the central and peripheral nervous system. Though pediatric patients with NF1 have an increased risk of tumors such as optic gliomas and neurofibromas during childhood, neuroblastic tumors are less often observed in this population. We report a rare case of a 5-year-old female with ganglioneuroblastoma intermixed and known history of NF1 and review the existing literature on the occurrence of ganglioneuroblastoma in pediatric patients with NF1.

Identification and validation of radiomic features from computed tomography for preoperative classification of neuroblastic tumors in children.

BACKGROUND: To identify radiomic features that can predict the pathological type of neuroblastic tumor in children. METHODS: Data on neuroblastic tumors in 104 children were retrospectively analyzed. There were 14 cases of ganglioneuroma, 24 cases of ganglioneuroblastoma, and 65 cases of neuroblastoma. Stratified sampling was used to randomly allocate the cases into the training and validation sets in a ratio of 3:1. The maximum relevance-minimum redundancy algorithm was used to identify the top 10 of two clinical features and 851 radiomic features in portal venous-phase contrast-enhanced computed tomography images. Least absolute shrinkage and selection operator regression was used to classify tumors in two binary steps: first as ganglioneuroma compared to the other two types, then as ganglioneuroblastoma compared to neuroblastoma. RESULTS: Based on 10 clinical-radiomic features, the classifier identified ganglioneuroma compared to the other two tumor types in the validation dataset with sensitivity of 100.0%, specificity of 81.8%, and an area under the receiver operating characteristic curve (AUC) of 0.875. The classifier identified ganglioneuroblastoma versus neuroblastoma with a sensitivity of 83.3%, a specificity of 87.5%, and an AUC of 0.854. The overall accuracy of the classifier across all three types of tumors was 80.8%. CONCLUSION: Radiomic features can help predict the pathological type of neuroblastic tumors in children.

Brain and Spinal Cord Tumors of Embryonic Origin.

Embryonal tumors (ETs) of the central nervous system (CNS) comprise a large heterogeneous group of highly malignant tumors that predominantly affect children and adolescents. Currently, the neoplasms classified as ET are the medulloblastoma (MB), embryonal tumors with multilayered rosettes (ETMR), medulloepithelioma (ME), CNS neuroblastoma (NB), CNS ganglioneuroblastoma (GNB), atypical teratoid/rhabdoid tumors (AT/RT), and CNS embryonal tumors with rhabdoid features. All these tumors are classified as malignant-grade IV neoplasms, and the prognosis of patients with these neoplasms is very poor. Currently, except for the histological classification of MB, the recently utilized WHO classification accepts a novel molecular classification of MBs into four distinct molecular subgroups: wingless/integrated (WNT)-activated, sonic hedgehog (Shh), and the numerical Group3 and Group 4. The combination of both histological and genetic classifications has substantial prognostic significance, and patients are categorized as low risk with over 90% survival, the standard risk with 75-90% survival, high risk with 50-75% survival, and very high risk with survival rate lower than 50%. Children under three years are predominantly affected by AT/RT and represent about 20% of all CNS tumors in this age group. AT/RT is typically located in the posterior fossa (mainly in cerebellopontine angle) in 50-60% of the cases. The pathogenesis of this neoplasm is strongly associated with loss of function of the SMARCB1 (INI1, hSNF5) gene located at the 22q11.23 chromosome, or very rarely with alterations in (SMARCA4) BRG1 gene. The cells of this neoplasm resemble those of other neuronal tumors, and hence, immunochemistry markers have been utilized, such as smooth muscle actin, epithelial membrane antigen, vimentin, and lately antibodies for INI1. ETMRs are characterized by the presence of ependymoblastic rosettes formed by undifferentiated neuroepithelial cells and neuropil. The tumorigenesis of ETMRs is strongly related to the amplification of the pluripotency factor Chr19q13.41 miRNA cluster (C19MC) present in around 90% of the cases. Additionally, the expression of LIN28A is a highly sensitive and specific marker of ETMR diagnosis, as it is overexpressed in almost all cases of ETMR and is related to poor patient outcomes. The treatment of patients with ETs includes a combination of surgical resection, radiotherapy (focal or craniospinal), and chemotherapeutic agents. Currently, there is a trend to reduce the dose of craniospinal irradiation in the treatment of low-risk MBs. Novel targeted therapies are expected in the treatment of patients with MBs due to the identification of the main driver genes. Survival rates vary between ET types and their subtypes, with ganglioneuroblastoma having over 95% 5-year survival rate, while ATRT is probably linked with the worst prognosis with a 30% 5-year survival rate.

Blueberry muffin baby secondary to ganglioneuroblastoma.

We report the case of a neonate presenting with the clinical features of blueberry muffin syndrome caused by ganglioneuroblastoma, a rare variant of neuroblastoma. This syndrome may be the only visible manifestation of a neonatal tumor and highlights the importance of early recognition and initiation of therapy to reduce mortality.

Ganglioneuroblastoma Presenting as Obstructive Sleep Apnea in a 5-Year-Old Boy.

The authors present an interesting case of ganglioneuroblastoma, a tumor of the sympathetic chain, presenting as severe obstructive sleep apnea in a healthy 5-year-old boy. The patient's initial polysomnogram demonstrated an apnea-hypopnea index (AHI) of 86 events/hour. He underwent an adenotonsillectomy at an outside hospital and his repeat AHI was still 62. The patient was nonobese and nonsyndromic appearing, which made his incredibly high AHI perplexing. He underwent sleep endoscopy and direct laryngoscopy for further evaluation, which demonstrated a large mass in the left posterior pharynx. He then underwent surgical excision with a resolution of his obstructive sleep apnea.

Paediatric metastatic ganglioneuroblastoma on 68Ga-DOTA NOC PET-CT.

68Ga-DOTA NOC PET-CT imaging has been shown to have high accuracy for the evaluation of neuroendocrine tumours. We report a case of a 3-year-old boy who presented with a right paravertebral soft tissue mass. Biopsy showed ganglioneuroblastoma. The patient was referred for 68Ga-DOTA NOC for staging. 68Ga-DOTA NOC PET/CT images showed somatostatin-avid large right paravertebral soft tissue mass representing the primary lesion, along with increased radiotracer localization at multiple metastatic lytic bone lesions in the axial and appendicular skeleton. 68Ga-DOTA NOC PET-CT is helpful in the evaluation of the disease extent of neuroendocrine tumours including ganglioneuroblastoma.

Refractory Stage M Ganglioneuroblastoma With Bone Metastases and a Favorable, Chronic Course of Disease: Description of a Patient Cohort.

Refractory stage M neuroblastoma (NB) is associated with a poor prognosis and a progressive course of disease. Here, we describe a unique group of patients with a discrepant clinical course. Seven histologically confirmed ganglioneuroblastoma (GNB) (n=6) and differentiating NB (n=1) patients were identified who were diagnosed with stage M disease based on iodine-123-metaiodobenzylguanidine avid bone metastases. Six patients started on high-risk treatment, without tumor response (stable disease). Treatment was discontinued before the start of consolidation treatment because of refractory response in all patients. Unexpectedly, after cessation of treatment no progression of disease occurred. In 2 patients, the primary tumors expanded (>25%) very slowly during 1.5 and 3 years, and remained stable thereafter. Metabolically, a slow decrease of urinary homovanillic acid and vanillylmandelic acid levels and iodine-123-metaiodobenzylguanidine avidity was observed. All patients are alive with presence of metastatic disease after a median follow-up of 17 years (range: 6.7 to 27 y). Interestingly, at diagnosis, 6 patients were asymptomatic, 6 patients had GNB morphology, and 5 patients had meningeal metastases. These are all features seen in only a small minority of stage M patients. This GNB entity illustrates the clinical heterogeneity of neuroblastic tumors and can be used to further study the developmental origin of different NB subtypes.

A Metastatic Neuroblastic Tumor in a 28-Month-old Boy: Unusual Spontaneous Regression From Neuroblastoma to Ganglioneuroma?

Neuroblastoma with bone metastasis is well known to have an extremely poor prognosis. We experienced the case of a patient with adrenal ganglioneuroblastoma (GNB) with metastases of subcutaneous nodules, a lymph node, and multiple bones. A pathologic examination of tumors from different sites revealed both GNB and ganglioneuroma. A genetic comparison between these tumors identified the same molecular signatures, suggesting the possibility of spontaneous differentiation in the remaining GNB. The patient has been healthy without aggressive chemotherapy, and the patient's pathologic urinary catecholamines normalized. Even if unusual, we have to recognize probable spontaneous differentiation from neuroblastoma to GNB and then to ganglioneuroma, even in sites of bone metastasis.

Mediastinal neuroblastoma, ganglioneuroblastoma, and ganglioneuroma: Pathology review and diagnostic approach.

Neuroblastic tumors are a group of tumors of the sympathetic ganglia and adrenal medulla that derive from primordial neural crest cells. These tumors include neuroblastoma, intermixed ganglioneuroblastoma, nodular ganglioneuroblastoma, and ganglioneuroma. Neuroblastomas are the most common extracranial solid tumor arising in childhood and may occur in different anatomic sites. Neuroblastic tumors are common mesenchymal tumors of the mediastinum. Herein, we describe advances in our understanding of neuroblastic tumor biology. Pathologists should be aware of diagnostic challenges associated with these tumors to ensure correct histologic diagnosis and appropriate clinical management. We describe updated mediastinal neuroblastic tumor pathology, focusing on morphological, immunohistochemical, and molecular features and differential diagnoses.

Unresectable thoracic neuroblastic tumors: Changes in image-defined risk factors after chemotherapy and impact on surgical management.

PURPOSE: Neuroblastoma management in children is multimodal and depends on multiple factors, including the possibility of complete surgical resection. Image-defined risk factors (IDRFs) are used to assess the feasibility of primary surgery. We studied the changes in IDRFs after neoadjuvant chemotherapy for thoracic neurogenic tumors. METHODS: We performed a multicenter review of 27 patients presenting with unresectable thoracic neurogenic tumors. Patients received neoadjuvant chemotherapy, according to their risk group. IDRF at diagnosis and before surgery were retrospectively analyzed by a radiologist and a surgeon, blind to the initial assessment. Surgical and oncologic outcomes were reviewed. RESULTS: None of the patients presented MYCN amplification, and 78 IDRFs were identified at diagnosis. Vascular IDRFs were the most frequent, with 28 vascular IDRFs detected in 18 patients, 22 of which disappeared after chemotherapy. Reductions of tumor volume were associated with a regression of IDRFs. Patients undergoing minimally invasive surgery had smaller tumor volumes than those undergoing open surgery, and no vascular IDRF. Two patients received two additional courses of chemotherapy to reduce tumor volume sufficiently for surgery. One patient with ganglioneuroblastoma underwent early surgery due to a lack of response to initial chemotherapy. CONCLUSION: Tumor volume reduction with neoadjuvant chemotherapy eliminates most IDRF in thoracic neurogenic tumors. Vascular IDRF are rapidly resolved at this site, making surgical resection and minimally invasive surgery possible.

Importance of Magnetic Resonance Imaging With Diffusion-weighted Imaging in Guiding Biopsy of Nodular Ganglioneuroblastoma: A Case Report.

BACKGROUND: Nodular ganglioneuroblastoma is a rare peripheral neuroblastic tumor of variable prognosis. Accurate diagnosis, staging, and risk categorization can be particularly challenging in patients with nodular ganglioneuroblastoma due to the inherent heterogeneity of these lesions. CASE PRESENTATION: We illustrate the use of diffusion-weighted magnetic resonance imaging to identify tumor nodules and guide tumor biopsy in an almost 5-year-old boy with a large abdominal tumor. CONCLUSIONS: Diffusion-weighted magnetic resonance imaging was successful in detecting and guiding biopsy of a poorly differentiated neuroblastoma nodule within the context of a well-differentiated ganglioneuroma, allowing the diagnosis and characterization of a ganglioneuroblastoma nodular, thus influencing the child's prognosis and treatment.

Harlequin syndrome associated with ganglioneuroblastoma-induced Horner syndrome.

A 1-year-old boy presented with a 4-month history of hypertension, ptosis of the right upper eyelid, left hemifacial sweating, and flushing. He was diagnosed with Harlequin syndrome associated with Horner syndrome. Computed tomography revealed a mass lesion in the right superior mediastinum. Therefore, the patient underwent total tumor resection. Histological examination demonstrated ganglioneuroblastoma. The MYCN oncogene was not amplified, and the mitosis-karyorrhexis index was low. Accordingly, radiation and chemotherapy were not performed. No recurrence was observed within 8 months after surgery, and the patient's blood pressure was normalized. However, the ptosis, hemifacial sweating, and flushing persisted.

Retrospective accuracy analysis of MRI based lesion size measurement in neuroblastic tumors: which sequence should we choose?

BACKGROUND: MR imaging of neuroblastic tumors is widely used for assessing the effect of chemotherapy on tumor size. However, there are some concerns that MRI might falsely estimate lesion diameters due to calcification and fibrosis. Therefore, the aim of our study was to compare neuroblastic tumor size based on MRI measurements to histopathology measurements of the resected specimens as standard of reference. METHODS: Inclusion criteria were diagnosis of a neuroblastic tumor, MR imaging within 100 days to surgery and gross total resection without fragmentation of the tumor between 2008 and 2019. Lesion diameters were measured by two radiologists according to RECIST 1.1 in axial plane in T2w turbo spin echo (TSE), diffusion-weighted imaging (DWI), and in T1w pre- and postcontrast sequences. Furthermore, the largest lesion size in three-dimensions was noted. The largest diameter of histopathology measurements of each specimen was used for comparison with MRI. RESULTS: Thirty-seven patients (mean age: 5 ± 4 years) with 38 lesions (neuroblastoma: n = 17; ganglioneuroblastoma: n = 11; ganglioneuroma: n = 10) were included in this retrospective study. There was excellent intra-class correlation coefficient between both readers for all sequences (> 0.9) Tumor dimensions of reader 1 based on axial MRI measurements were significantly smaller with the following median differences (cm): T1w precontrast - 1.4 (interquartile range (IQR): 1.8), T1w postcontrast - 1.0 (IQR: 1.9), T2w TSE: -1.0 (IQR: 1.6), and DWI -1.3 (IQR: 2.2) (p < 0.001 for all sequences). However, the evaluation revealed no significant differences between the three-dimensional measurements and histopathology measurements of the resected specimens regardless of the applied MRI sequence. CONCLUSIONS: Axial MRI based lesion size measurements are significantly smaller than histopathological measurements. However, there was no significant difference between three-dimensional measurements and histopathology measurements of the resected specimens. T2w TSE and T1w postcontrast images provided the lowest deviation and might consequently be preferred for measurements.

Suprasellar central nervous system ganglioneuroblastoma: a case in a 9-year-old child and review of the literature.

PURPOSE: Intracranial ganglioneuroblastomas are incredibly rare neuroectodermal tumors with only 8 described cases total, 5 of those having imaging findings METHODS: Here we present a 9-year-old female patient with 4 months progressive headaches, personality changes, and vomiting. We also present a review of the current literature of intracranial ganglioneuroblastomas. RESULTS: Imaging demonstrated a partially calcified suprasellar mass measuring 4.6 × 6.3 × 5 cm composed of both solid and cystic components, diagnosed to be a ganglioneuroblastoma, with mass effect on the lateral and 3rd ventricles, with a midline shift of right to left of 6-7 mm. She was treated with subtotal surgical resection, an intensive chemotherapeutic regimen, and radiation and has no residual disease on imaging 1 year and 4 months status post-surgery. CONCLUSION: To our knowledge, this is the first case of a ganglioneuroblastoma to mimic a craniopharyngioma based upon imaging findings and suprasellar location. As these cases are extremely rare, an optimal therapeutic regimen has not been defined. However, a combination of surgical resection, chemotherapy, and radiation therapy can be effective, as shown here with successful treatment and no evidence of residual disease.

High Oct4 expression: implications in the pathogenesis of neuroblastic tumours.

BACKGROUND: Neuroblastic tumours (NBTs) are paediatric solid tumours derived from embryonic neural crest cells which harbour their own cancer stem cells (CSC). There is evidence indicating that CSC may be responsible for tumour progression, chemotherapy resistance and recurrence in NBTs. Oct4 is a transcription factor which plays a key role in mammal embryonic development and stem cell fate regulation. The aim of the study is to elucidate the clinical significance of Oct4 in NBTs. METHODS: We studied Oct4 expression in 563 primary NBTs using digital image quantification. Chi-square test was applied to analyse the correlation between histopathology and the Oct4+ cell percentage. Survival analysis was carried out with Kaplan-Meier curves and log-rank test. Additionally, a multivariate Cox regression analysis with the stepwise backwards (Wald) method was undertaken to calculate the impact of Oct4 expression level on survival. RESULTS: We found that tumours with a high proportion of cells expressing Oct4 correlated statistically with undifferentiated and poorly differentiated neuroblastoma / nodular ganglioneuroblastoma, and that Oct4 expression was not present in ganglioneuroma (p < 0.05). Statistical analysis also indicated a relationship between high Oct4 expression levels, high-risk patients according to the International Neuroblastoma Risk Group pre-treatment classification parameters, larger blood vessels and low survival rates. CONCLUSIONS: These results suggest that the Oct4 gene may regulate NBT pathogenic differentiation pathways, and should thus be considered as a target for knockdown when developing novel therapies for high-risk NBT patients.

Ganglioneuroblastoma Arising in an Ovarian Dermoid Cyst: First Report in the Literature.

The development of a somatic neoplasm within an ovarian dermoid cyst (mature cystic teratoma) is a rare, but well described, phenomenon which occurs in approximately 1% of all cases. Any of the tissue components of a dermoid cyst has the potential to undergo neoplastic transformation with carcinoid tumors and squamous cell carcinomas being among the most common neoplasms. We report a case of a ganglioneuroblastoma arising within an ovarian dermoid cyst, an association which, as far as we are aware, has not been described previously.

Results of a prospective clinical trial JN-L-10 using image-defined risk factors to inform surgical decisions for children with low-risk neuroblastoma disease: A report from the Japan Children's Cancer Group Neuroblastoma Committee.

BACKGROUND: The present study sought to reduce the incidence of treatment complications of low-risk neuroblastoma by using image-defined risk factors (IDRFs) to inform the timing of surgical resection. PROCEDURES: Eligible patients included children (<18 years of age) with stage 1 or 2 disease, children (<365 days of age) with stage 3 disease, and infants with stage 4S disease. In IDRF-negative cases, treatment was completed with surgical resection alone. In IDRF-positive cases, the timing of surgery was determined based on the IDRFs after low-dose chemotherapy with 2-3 of the following four drugs: vincristine, cyclophosphamide, pirarubicin, and carboplatin. The outcome measures were overall survival, progression-free survival, and adverse events. This study was registered with the UMIN Clinical Trials Registry (number 000004355). RESULTS: Of the 60 patients screened between 2010 and 2013, 58 eligible patients were enrolled; 32 were identified as IDRF negative at diagnosis while 26 were identified as IDRF positive and underwent induction chemotherapy. The 3-year overall and progression-free survival rates of the 58 patients were 100% and 82.8% (95% confidence interval: 70.3-90.3), respectively. Neutropenia was the most frequently reported grade 3 or 4 chemotherapy-related form of toxicity (41.7%). With regard to surgical complications, 2.5% of all patients developed pleural effusion and ascites as early complications, while only 2.5% developed renal atrophy as a long-term complication. No fatal toxicities were observed. CONCLUSION: Using IDRFs to inform surgical decision making for the treatment of low-risk neuroblastoma improved prognosis and reduced the incidence of long-term complications.