Peripheral neuroblastic tumors (PNTs) are the most common extracranial solid tumors in early childhood.They represent a spectrum of neural crest derived tumors including neuroblastoma, ganglioneuroblastoma and ganglioneuroma. PNTs exhibit heterogeneity due to interconverting malignant cell states described as adrenergic/nor-adrenergic or mesenchymal/neural crest cell in origin. The factors determining individual patient levels of tumor heterogeneity, their impact on the malignant phenotype, and the presence of other cell states are unknown. Here, single-cell RNA-sequencing analysis of 4267 cells from 7 PNTs demonstrated extensive transcriptomic heterogeneity. Trajectory modelling showed that malignant neuroblasts move between adrenergic and mesenchymal cell states via a novel state that we termed a "transitional" phenotype. Transitional cells are characterized by gene expression programs linked to a sympathoadrenal development, and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature was highly predictive of poor prognosis when compared to adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identified a similar transitional H3K27-acetylation super-enhancer landscape, supporting the concept that PNTs have phenotypic plasticity and transdifferentiation capacity. Additionally, examination of PNT microenvironments, found that neuroblastomas contained low immune cell infiltration, high levels of non-inflammatory macrophages, and low cytotoxic T lymphocyte levels compared with more benign PNT subtypes. Modeling of cell-cell signaling in the tumor microenvironment predicted specific paracrine effects toward the various subtypes of malignant cells, suggesting further cell-extrinsic influences on malignant cell phenotype. Collectively, our study reveals the presence of a previously unrecognized transitional cell state with high malignant potential and an immune cell architecture which serve both as potential biomarkers and therapeutic targets.Introduction Peripheral neuroblastic tumors (PNTs) represent a spectrum of tumors derived from the neural crest and account up to 8-10% of all pediatric malignancies. A salient feature of PNTs is a heterogeneous clinical course ranging from spontaneous regression to persistent disease progression 1 . Histologically, PNTs comprise four variants, including neuroblastoma (NB), ganglioneuroblastoma nodular (GNBn), ganglioneuroblastoma intermixed (GNBi), and ganglioneuroma (GN) 1 . GN and GNBi are low-grade in nature and usually curable by surgical resection alone 2 . In contrast, the most common subtype; NB is often lethal. Despite intensive treatments, the long-term survival of high-risk NB is less than 50% 3 .Around half of high-risk patients relapse after initial treatment response, and salvage therapies for relapsed patients are rarely effective 1 . Moreover, genomics studies comparing longitudinal samples f...

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Neuroblastoma (NB) is one of the most common extracranial malignant solid tumors in childhood, and over 90% of NBs are diagnosed in children under the age of 10 years old. For patients between 14 and 18 years old or older than 18 years, due to the rarity of NB, few studies have been performed in this population. Defined "adolescent cases" as individuals in 14-18 years old and "adult cases" as older than 18 years old, we reported five NB cases of adolescents and adults in our hospital. 137 cases presented a review of published literature on this topic. Clinicopathological factors and treatment modalities used of the 142 patients were assessed for their prognostic value. Better outcomes were found in adolescent patients rather than adult patients (p = 0.012). Patients diagnosed with neuroblastoma or ganglioneuroblastoma (nodular type) (p = 0.006) and with distant metastasis (p < 0.001) were characterized by poor outcomes. Distant metastasis was an independent adverse influencing factor for overall survival in adolescent and adult NB patients. Regarding treatment modalities, complete surgical resection was a significant factor improving the survival for such patients (p < 0.001). For patients with distant metastasis, a significantly longer progressionfree survival with chemotherapy than without chemotherapy (p = 0.038), whereas chemotherapy did not show an advantage on patients with localized disease (p = 0.039). The prognosis of NB in adolescent and adult patients was worse than that in children. These two groups also showed heterogeneity in clinical factors, genetic factors, and treatment tolerance. The rarity of adolescent and adult NB can lead to misdiagnosis and incorrect management. Further optimization of chemotherapy regimens and dosage for adolescent and adult NB patients is needed. The anti-GD2 immunotherapy may be an effective approach for treatment. Key words: neuroblastoma; adolescent and adult; outcome; heterogeneity; treatment Neuroblastoma (NB), an embryonic tumor originating from the sympathetic nervous system, is one of the most common extracranial malignant solid tumors in childhood and accounts for 7% of all childhood malignancies [1]. As a typical tumor of early childhood, over 90% of NB are diagnosed in children under the age of 10 years old [2]. The current risk classification of NB is based on the Children's Oncology Group (COG) guidelines [3]. It takes into account diagnosis, tumor stage, pathological characteristics, and genetic alterations, such as amplification of