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.

Primary intracranial pediatric ganglioneuroblastoma-report of two cases and review of an unusual masquerader.

Ganglioneuroblastoma (GNB) is a rare neurogenic tumor with a predilection for extracranial sites. Its primary intracranial occurrence is anecdotal, with less than ten cases reported in pediatric literature. We report two cases of this unusual entity. The first was a 1-year-old boy who presented with a progressive scalp swelling that radiologically appeared to be a mesenchymal tumor. The tumor was resected completely, and its histopathological examination was suggestive of a pigmented GNB. The clinico-radiological presentation and melanin pigmentation of the tumor were unique features of the case. The second case was a 7-year-old girl who presented with left hemiparesis and raised intracranial pressure due to a large right parietal intraparenchymal tumor that histologically proved to be a GNB. The child succumbed to disease progression a month after undergoing near-total resection of the tumor. Analysis of our cases in the light of a literature review reveals that pediatric intracranial GNBs have diverse clinico-radiological features and can easily be confused for commoner pathologies in both intra- and extra-axial locations.

High-Titer Anti-ZSCAN1 Antibodies in a Toddler Clinically Diagnosed with Apparent Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome.

Severe obesity in young children prompts for a differential diagnosis that includes syndromic conditions. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) syndrome is a potentially fatal disorder characterized by rapid-onset obesity associated with hypoventilation, neural crest tumors, and endocrine and behavioral abnormalities. The etiology of ROHHAD syndrome remains to be established, but recent research has been focusing on autoimmunity. We report on a 2-year-old girl with rapid-onset obesity during the first year of life who progressed to hypoventilation and encephalitis in less than four months since the start of accelerated weight gain. The patient had a high titer of anti-ZSCAN1 antibodies (348; reference range < 40), and the increased values did not decline after acute phase treatment. Other encephalitis-related antibodies, such as the anti-NDMA antibody, were not detected. The rapid progression from obesity onset to central hypoventilation with encephalitis warns about the severe consequences of early-onset ROHHAD syndrome. These data indicate that serial measurements of anti-ZSCAN1 antibodies might be useful for the diagnosis and estimation of disease severity. Further research is needed to determine whether it can predict the clinical course of ROHHAD syndrome and whether there is any difference in antibody production between patients with and without tumors.

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.

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.

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.

Intracranial leptomeningeal CNS ganglioneuroblastoma. First report and review of the literature.

BACKGROUND: CNS ganglioneuroblastoma in an extremely rare embryonal tumour, specifically in the pediatric population. Bad prognosis is documented due to aggressiveness and absence of protocolized treatment at the moment. CLINICAL DESCRIPTION: We present the case of a 5-year-old boy who presented with sudden loss of consciousness. CT scan was performed showing a large posterior fossa lesion with several intraventricular focal lesions, suggesting metastases, the largest one located inside the III ventricle. The patient underwent a posterior fossa resection of the lesion and a subtotal resection of the III ventricle lesion, with adjuvant chemotherapy. The evolution was poor and the patient finally died 3 months after diagnosis. CONCLUSION: Ganglioneuroblastoma is extremely likely to recur quickly and extensively. There is little knowledge about treatment options but is documented that gross total resection followed by adjuvant radiotherapy and chemotherapy is the best management in these patients.

Ewing Sarcoma Displaying Extensive Well Differentiated Neuroblastomatous Differentiation: A Case Report.

INTRODUCTION: A tumor with EWSR1/FLI fusion displaying extensive well differentiated neuroblastomatous differentiation is presented. CASE REPORT: A nine-year-old female patient had a thoracic vertebra 8 paraspinal mass. The lesion was resected incompletely. Histopathologically, a small round cell tumor with gangliomatous differentiation was seen. This was initially diagnosed as an intermixed ganglioneuroblastoma. In the completion surgery biopsy material, the small round cell component was more prominent. Immunohistochemistry for both samples showed membrane positivity for CD99 and nuclear positivity for NKX2.2 in the small round cell component of the tumor. Molecular analysis revealed EWSR1/FLI fusion. The diagnosis then considered a "Ewing Sarcoma Displaying Extensive Well Differentiated Neuroblastomatous Differentiation". CONCLUSION: Tumors with the EWSR1/FLI fusion may show neuroblastomatous differentiation. We chose to treat this as an Ewing Sarcoma (ES). Recognition of this phenomenon in ES cases may prevent a possible misinterpretation and a failure in oncologic treatment.

Great mimicker - a case of occult melanoma displaying ganglioneuroblastic differentiation.

Melanomas are known for their diverse morphological features, presenting a diagnostic challenge for pathologists. Uncommon variations of melanoma can exhibit distinct cytological and histomorphological characteristics, including ganglioneuroblastic differentiation. However, this phenomenon is extremely rare, with only a few documented cases. Here, we present a unique case of an occult metastatic melanoma with ganglioneuroblastic differentiation developing in a 76-year-old male. The diagnosis was based on histopathology, immunophenotyping, and molecular testing, which revealed SOX10 positivity and an NRAS mutation. Notably, classic melanoma markers HMB45 and melan-A were negative, highlighting the importance of considering alternative markers. This case emphasizes the significance of immunohistochemistry and molecular investigation in diagnosing melanomas with unusual features and identifying appropriate candidates for immune checkpoint therapy. Additionally, the occurrence of ganglioneuroblastic differentiation further supports a shared histogenetic origin from the neural crest. Improved understanding of such rare variants contributes to accurate diagnosis and optimal management of melanoma patients.

Composite phaeochromocytomas-a systematic review of published literature.

INTRODUCTION: Composite phaeochromocytoma is a tumour containing a separate tumour of neuronal origin in addition to a chromaffin cell tumour. This study reports on two cases from a single centre's records and presents a systematic literature review of composite phaeochromocytomas. METHODS: In addition to describing 2 case reports, a systematic search of the Medline database from inception up to April 2020 was done for human case reports on composite phaeochromocytomas. Relevant titles and/or abstracts were screened, and full texts were reviewed to identify appropriate studies. Data was extracted and a descriptive analysis of presentation, clinical features, management strategies and outcomes was performed. The quality of included studies was assessed using a critical appraisal checklist. RESULTS: There were 62 studies included, with a total of 94 patients. Of 91 patients where data was available, the median (range) age of patients was 48 (4-86) years. Of 90 patients where information was provided, 57% were female. In at least 28% of patients, a genetic cause was identified. Common presenting features include abdominal pain, palpable mass, cardiovascular and gastrointestinal symptoms. The most common tumour component with phaeochromocytoma is ganglioneuroma; other components include ganglioneuroblastoma, neuroblastoma and malignant peripheral nerve sheath tumours. In patients with follow-up data (n=48), 85% of patients were alive and well at a median (range) follow-up time of 18 (0.5-168) months. CONCLUSION: Composite phaeochromocytoma is a rare tumour, with a significant genetic predisposition. This review summarises available epidemiological data, which will be useful for clinicians managing this rare condition.

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.

Incidence of Horner syndrome associated with neuroblastic disease.

PURPOSE: Horner syndrome (HS) manifests in unilateral ptosis, miosis, enophthalmos, and anhedonia. It is most commonly caused by trauma or surgical procedures, but can also occur in pediatric patients as a result of tumors, especially neuroblastoma (NBL). The objective of this study was to analyze the incidence of HS in patients diagnosed with NBL. METHODS: A retrospective analysis of data collected at the Department of Pediatric Oncology, Hematology, and Transplantology from 2004 to 2019 was performed. The study group included 119 patients younger than 18 years old, with 62 girls and 57 boys. All of them were diagnosed with a neuroblastic tumor. RESULTS: Among the 119 patients, eight children (6.72%) were diagnosed with HS associated with NBL. Three of these patients presented to the clinic with HS, whereas HS developed after the surgical procedure to remove the tumor in four patients. The adrenal gland was the most frequent localization of the tumor. However, HS occurred more frequently in patients with mediastinum tumors. As a presenting symptom, HS occurred in 2 of 11 cases (18.18%) with mediastinum localization. All of the patients with HS were younger than 2 years old. CONCLUSION: Investigation of the cause of isolated HS is crucial because it can be the first symptom of NBL. However, the surgical procedure itself increases the risk of HS as a complication of NBL 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.

Neurogenic Tumors of the Mediastinum.

Neurogenic tumors represent a broad ill-defined category of neoplasms that includes tumors of Schwann cell and/or neuroblastic derivation, as well as neoplasms that typically develop in the central nervous system, but rarely present in ectopic sites including the mediastinum. Neurogenic tumors may occur at many different anatomic sites, but the mediastinum represents a uniquely challenging site given the complex anatomy. Additionally, some of these neoplasms may present with multicentric involvement in the context of genetic syndromes, including NF1, NF2 and schwanomatosis. Most of these develop in posterior structures, often in association with paraspinal structures. Fine needle biopsy/small biopsies play an important role in the diagnosis of these neoplasms, given its record of safety and the increased applicability of ancillary testing to these smaller samples at the present time. In this review we focus on the major categories of neurogenic tumors that may be encountered in the mediastinum, including schwannoma, neurofibroma, malignant peripheral nerve sheath tumors, ganglioneuroma and ganglioneuroblastoma, as well as rarer members of this category. We discuss diagnostic approaches applicable to small cytologic and tissue samples and relevant differential diagnoses.

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.

Congenital malformation syndromes associated with peripheral neuroblastic tumors: A systematic review.

Malformation syndromes with predisposition to peripheral neuroblastic tumors (pNT), including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, may provide clues to critical mutations influencing pNT development. Our objective was to identify and characterize features of pNT associated with specific malformation syndromes. A systematic review of the literature was performed using MEDLINE, Scopus, and Web of Science. We identified 154 of 1014 papers that met eligibility, comprising 207 cases. The patient's age, tumor histology, and frequency of multiple primary tumors varied by malformation syndrome. Genomic studies and systematized reporting are necessary to elucidate cancer risk and the distinct clinical and biological pNT patterns within syndromes.

INSM1 Expression in Peripheral Neuroblastic Tumors and Other Embryonal Neoplasms.

Insulinoma-associated protein 1 (INSM1) is a transcription factor that functions in neuroepithelial tissue development and shows expression in neuroendocrine neoplasms. Given the role of INSM1 in controlling differentiation of the sympatho-adrenal lineage, we hypothesized that INSM1 expression would define a subset of neuroblastic tumors. This study aimed to characterize the immunohistochemical profile of INSM1 in a cohort of peripheral neuroblastic tumors and compare INSM1 expression in these tumors to that seen in other embryonal neoplasms, using both tissue microarrays and whole-slide histologic sections. INSM1 showed nuclear expression in 39/50 (78%) peripheral neuroblastic tumors, including 27/32 (84%) neuroblastomas, 9/9 (100%) ganglioneuroblastomas, and 3/9 (33%) ganglioneuromas. Altogether, 70% of peripheral neuroblastic tumors showed anti-INSM1 immunoreactivity in more than 20% of tumor nuclei. Although no non-neuroblastic tumors in this study exhibited INSM1 expression in more than 20% of nuclei, focal or patchy staining was identified in 7/14 (50%) rhabdomyosarcomas, 7/22 (32%) nephroblastomas, and 4/20 (20%) Ewing sarcomas. The absence of INSM1 expression in peripheral neuroblastic tumors was restricted to undifferentiated and poorly differentiated neuroblastomas, as well as mature ganglioneuromas, mimicking the transient INSM1 expression seen in sympatho-adrenal differentiation during normal development. No significant association between MYCN amplification status and INSM1 expression was observed. We found that all 3 INSM1-negative neuroblastoma patients with available follow-up were alive at a median of 15 years, in comparison to 9 of 13 INSM1-positive neuroblastoma patients living at a median of 5 years. Additional studies are needed to determine whether INSM1 expression is indicative of a clinically significant differentiation state in neuroblastoma.

Ganglioneuroblastoma in children.

INTRODUCTION: Neuroblastoma ranks third among pediatric malignancies. CASE REPORT: The case of a 3-year-old child is presented, who suddenly had frequent, unproductive, emetic cough; fever; and weight loss. Lung X-ray showed an opacity situated in the posterior superior mediastinum. Thoracic ultrasound revealed a slightly inhomogeneous, hypoechoic mass located in the posterior superior mediastinum. Computed tomography evidenced a tumor mass with homogeneous appearance in the costo-vertebral groove. Histological examination confirmed the diagnosis of ganglioneuroblastoma. CONCLUSION: Although history and clinical examination provided few elements, diagnosis was made based on imaging and histopathological examination.

Cytopathological spectrum of peripheral neuroblastic tumours in fine needle aspiration cytology and categorisation as per International Neuroblastoma Pathology Classification.

OBJECTIVE: The aim of this analysis was to describe the cytopathology spectrum of peripheral neuroblastic tumours (NTs) including neuroblastoma (NB), ganglioneuroblastoma (GNB) and ganglioneuroma (GN). Feasibility of applying the International Neuroblastoma Pathology Classification (INPC) to further subtype NTs in cytology was evaluated. METHODS: All peripheral NTs reported on fine needle aspiration during 2011-2015 were retrieved and detailed cytomorphological evaluation was performed. Based on INPC criteria, NBs were further categorised as undifferentiated, poorly differentiated and differentiating subtypes. Mitotic-karyorrhectic index was evaluated. Immunocytochemistry on cell blocks was reviewed wherever available. MYCN amplification by fluorescence in situ hybridisation was performed in 11 cases on smears. RESULTS: A total of 90 cases including 83 NBs, six GNB and one GN were evaluated. The age range was 12 days-12 years, with 55 males and 45 females. Both the primary and metastatic locations were aspirated. Applying the INPC criteria, there were 61 poorly differentiated, 14 undifferentiated, eight differentiating NB and six GNB. Immunocytochemistry on cell blocks showed positivity for at least two neuronal markers in NB. Mitotic-karyorrhectic index was high in 63, low in 22 and intermediate in two cases, respectively. MYCN amplification by fluorescence in situ hybridisation was feasible on smears and was amplified in 6 out of 11 cases tested. CONCLUSION: Peripheral NT types including NB, GNB and GN have distinctive cytomorphology. NBs can be further subtyped as undifferentiated, poorly differentiated and differentiating subtypes as per INPC criteria.

Characteristics and management of ganglioneuroma and ganglioneuroblastoma-intermixed in children and adolescents.

BACKGROUND: Ganglioneuromas (GNs) usually demonstrate favorable histological and clinical features. Surgery is often performed due to clinical symptoms and/or theoretical concerns that GN may transform into neuroblastoma (NB); however, several studies have identified significant GN-surgical morbidities. OBJECTIVES: We compared the natural history, biological and clinical features of GN and ganglioneuroblastoma-intermixed (GNB-I) managed by surgery or observation to inform management and surveillance. PROCEDURES: This retrospective study includes patients (n = 67) with histological diagnosis of GN (50/67) and GNB-I (17/67) at the Hospital for Sick Children between 1990 and 2014. Clinical, pathological features, tumor dimensions, and management were recorded. RESULTS: Median age and maximal tumor diameter were 6 years (1.3-17.8) and 6.3 cm (1.4-16.9), respectively. Of the 67 patients, 46 (69%) had upfront surgery and 21 (31%) were observed. Of the 21 observed patients 4 later underwent resection. There were post-operative complications in 15 of the 50 (30%) surgical patients. The presence of imaging-defined risk factors correlated with complications (P = 0.005). Observed patients were older (median 8.4 vs. 5.3 years) and diagnosed more recently. Median growth was 0.3 cm/year and 6 of 21 had progressive disease (PD). At median follow-up of 2.2 years (0.2-14.3), all patients were alive and for those with evaluable imaging there were 27 complete and 10 partial responses, 19 stable and 6 PD. Pathology classification changed at resection for three cases, but no GN was reclassified to NB. CONCLUSIONS: GN and GNB-I have a slow growth rate and resection can be associated with significant morbidity. Watch and wait approaches should be considered for some GN and GNB-I.