Ganglioneuroma

BackgroundGanglioneuroma (GN) and ganglioneuroblastoma intermixed (GNBI) are mature variants of neuroblastic tumors (NT). It is still discussed whether incomplete resection of GN/GNBI impairs the outcome of patients.MethodsClinical characteristics and outcome of localized GN/GNBI were retrospectively compared to localized neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) registered in the German neuroblastoma trials between 2000 and 2010.ResultsOf 808 consecutive localized NT, 162 (20 %) were classified as GN and 55 (7 %) as GNBI. GN/GNBI patients presented more often with stage 1 disease (68 % vs. 37 %, p 2 cm. No progression occurred after subtotal resection. Two patients died of treatment, none of tumor progression.ConclusionsGN/GNBI account for one quarter of localized NT and differ from immature tumors in their clinical features. Chemotherapy is not effective. Subtotal resection appears to be a sufficient treatment.Trial registrationClinicalTrials.gov identifiers - NB97 (NCT00017225; registered June 6, 2001); NB2004 (NCT00410631; registered December 11, 2006).

BackgroundRapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients.MethodsWe sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons.ResultsThe analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations.ConclusionsClinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.

Several unique features of neuroblastoma (NB), including the capacity for spontaneous regression and maturation to benign pathology, suggest that genes that regulate cellular proliferation, survival and differentiation may be involved in directing clinical tumour aggressiveness. The in situ expression of Bcl-2, Rb, p21, p53 and Bax proteins, as well as the proliferation marker proliferating cell nuclear antigen (PCNA) were examined immunocytochemically in a selection of 38 stage- and outcome-identified NB tumours. Apoptotic cells were identified morphologically and by a DNA fragmentation labelling technique (TUNEL). Although the tumour cell density of Bcl-2, p53, Bax, PCNA and TUNEL positivity correlated with patient survival, a spatially organized expression pattern was further recognized in stroma-poor differentiating tumours. Immature tumour cells adjacent to thin fibrovascular stroma are proliferating, as evidenced by PCNA positivity, and often express Bcl-2. At increasing distance from this fibrovascular stroma, intermediately differentiated tumour cells express Rb, while with more advanced differentiation, proliferation ceases and Bcl-2 immunoreactivity is lost. The most differentiated tumour cells, which often express p53, and occasionally p21 and Bax, lie adjacent to TUNEL-positive, morphologically apoptotic cells. This spatial organization in favourable outcome NB tumours suggests that physiological regulation of differentiation and apoptosis may be involved in tumour regression.

Low-pass whole-genome sequencing (LP-WGS) of circulating tumor DNA (ctDNA) is increasingly recognized for its utility in identifying somatic copy-number aberration (CNA). In this study, we analyzed LP-WGS ctDNA data from 73 pediatric patients with neuroblastic tumor and 11 healthy controls to explore diagnostic value of ctDNA CNA burden (including the genotypings) with a customized bioinformatics workflow. We found that a high baseline ctDNA CNA burden [tumor DNA fraction (TFx) ≥0.2%] was present in 36 of 41 patients (87.80%) with neuroblastoma, six of 22 patients (27.27%) with ganglioneuroblastoma, and three of 10 patients (30%) with ganglioneuroma. High baseline ctDNA CNA burden could predict high-risk neuroblastic tumors with an area under curve (AUC) of 0.95, sensitivity of 94.12%, and specificity of 100%. Frequent chromosomal copy-number changes, including chr17q gain, chr7 gain, chr3p loss, and chr11q loss, were found in ctDNA. Gain of chr17q demonstrated the highest diagnostic value with an AUC of 0.92, indicating strong sensitivity and specificity for detecting high-risk neuroblastic tumors. The homologous recombination deficiency score in the high- and intermediate-risk groups was significantly elevated compared with those in the low-/very low-risk group. The TFx levels and segmental alterations significantly decreased in patients with neuroblastic tumor who underwent chemotherapy, from median TFx = 13.82% before treatment to 0.24% after treatment (P SignificanceOur results support the development of ctDNA CNA analysis as a robust and minimally invasive approach for early detection, molecular diagnosis, and risk stratification of peripheral neuroblastic tumors.