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The presence of large cells having simultaneously increased cytoplasmic and nuclear volume accompanied by prominent nucleoli; i.e., differentiating neuroblasts and ganglion cells, is well documented in peripheral neuroblastic tumors (pNTs), and considered as one of the signs of tumor maturation and an indication of a better prognosis of the patient...
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... first and most complete, prognostically significant and biologically relevant "in depth" morphological clas- sification of the pNTs was established in 1999 and modi- fied in 2003 by the International Neuroblastoma Patholo- gy Committee ( Table 1). 1,2 The International Neuroblas- toma Pathology Classification (INPC) distinguishes four basic categories: (1) neuroblastoma (Schwannian stroma- poor) -NB, (2) ganglioneuroblastoma, intermixed (Schwannian stroma-rich) -GNBi, (3) ganglioneuroma (Schwannian stroma-dominant) -GN, and (4) gan- glioneuroblastoma, nodular (composite, Schwannian stroma-rich/stroma-dominant and stroma-poor) -GNBn. ...
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... 21 Other genetic alterations MYCN amplification is the most significant genetic alteration affecting NB prognosis, correlating strongly with undifferentiated or poorly differentiated histology, high MKI and nuclear hypertrophy or 'bull's eye' nucleoli. 22 For any stage, the prognosis is worse if the tumour harbours MYCN amplification, and these patients are regarded as high risk regardless of other prognostic factors (Fig. 3). [23][24][25] Up to 15% of NBs harbour activating point mutations or amplifications of ALK at diagnosis, and ALK mutations are further enriched on disease relapse. ...
... Neuroblastic tumors arise from primitive cells of the sympathetic nervous system and are composed of three histological subtypes: neuroblastoma, ganglioneuroblastoma (GNB), and ganglioneuroma [1,2]. These three tumors vary in terms of malignancy, with neuroblastomas being the most malignant of the three and the most common extracranial solid tumor in childhood [3,4]. ...
... While these imaging techniques can serve a fundamental role in helping localize and visualize a possible GNB when present, a definitive diagnosis cannot be made until a histopathological analysis is performed due to the great similarity the three neuroblastic tumors display on imaging. According to the International Neuroblastoma Pathology Committee, GNBs are classified into two groups, GNB intermixed (stroma rich) and GNB nodular (stroma poor) [2]. GNB intermixed is characterized by the presence of intermixing neuroblastic and ganglion cells while GNB nodular expresses a stroma poor/neuroblastic nodular component that is normally hemorrhagic/necrotic and coexisting with a stroma rich or stroma dominant component [9]. ...
Ganglioneuroblastomas (GNBs) are a rare subtype of neoplastic tumors that arise from the autonomic nervous system and contain both mature gangliocytes and immature neuroblasts. The primary age group affected by GNBs is the pediatric population, with less than 50 cases of adult GNBs existing in the literature. To the authors' best knowledge, only 21 cases of GNBs arising in the adrenal glands of adults have been reported. Herein we present a literature review examining the symptoms, treatment type, age, and sex of adults, and the presence of tumor metastases and calcification from the 21 cases reported in the literature.
... The most common primary site of NB is the adrenal medulla (40%) and abdominal ganglia (25%), but NB can also occur in the sympathetic ganglia of the thorax (15%), pelvis (5%), and neck (3-5%) (2). The histologic types of malignant NB can be divided into ganglioneuroblastoma (GNB) and neuroblastoma (3). NB is the most common extracranial solid tumor in children, accounting for approximately 8% of all of the malignancies in children, with an incidence rate of approximately 0.013-0.014%, ...
Background: Neuroblastoma (NB), considered the most common non-intracranial solid tumor in children, accounts for nearly 8% of pediatric malignancies. This study aimed to develop a simple and practical nomogram to predict event-free survival (EFS) in NB patients and establish a new risk stratification system.
Method: In this study, 763 patients primarily diagnosed with neuroblastoma in the TARGET database were included and randomly assigned to a training set (70%) and a validation set (30%) in a 7:3 ratio. First, the independent prognostic factors of EFS for NB patients were identified through univariate and multivariate Cox regression analyses. Second, a nomogram was created based on these factors and was validated for calibration capability, discriminative and clinical significance by C-curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Finally, we developed a new risk stratification system for NB patients based on the nomogram.
Result: The univariate Cox analysis demonstrated that NB patients with age at diagnosis > 318 days, INSS stage 4, DNA diploidy, MYCN amplification status, and COG high-risk group had a relatively poor prognosis. However, according to the multivariate Cox regression analysis, only age, INSS stage, and DNA ploidy were independent predictive factors in NB patients regarding EFS, and a nomogram was created based on these factors. The AUC values of the ROC curves for the 3-, 5-, and 10-year EFS of this nomogram were 0.681, 0.706, and 0.720, respectively. Additionally, the AUC values of individual independent prognostic factors of EFS were lower than those of the nomogram, suggesting that our nomogram had higher predictive reliability for prognosis. In addition, a new risk stratification system was developed to better stratify NB patients and provide clinical practitioners with a better reference for clinical decision-making.
Conclusion: NB patients’ EFS could be predicted more accurately and easily through the constructed nomogram and event-occurrence risk stratification system, helping clinicians to better differentiate NB patients and develop individualized treatment plans to maximize patient benefits.
... The presence of very large nucleoli in LCN can be considered a sign for sustaining a highly increased MYC-family protein expression. Though nuclear morphology (enlargement, open chromatin pattern, prominent nucleolar formation) of LCN cells is often similar to that of differentiating neuroblasts, these two cell types should be strictly distinguished [12]. LCN is composed of neoplastic cells, though they are larger than conventional neuroblastic cells, with scanty cytoplasm and no or limited neurite projection, so that the tumor is evaluated as either undifferentiated or poorly differentiated subtype. ...
Two rare cases of large cell neuroblastoma (LCN) are reported. Case 1 (8-year-old male) showed the appearance of Neuroblastoma, poorly differentiated subtype with a high MKI (Mitosis-Karyorrhexis Index) and Case 2 (7-year-old male) was Neuroblastoma, undifferentiated subtype with a low MKI. Both cases were classified into the Unfavorable Histology Group according to the International Neuroblastoma Pathology Classification and their tumors were characteristically composed of neuroblastic cells with enlarged and often pale or vacuolated nuclei containing one or few prominent nucleoli. While LCN is a phenotypical variant of MYC-driven neuroblastoma overexpressing MYC-family protein, the two tumors presented in this report had different molecular characteristics: One had n-MYC oncogene amplification with n-MYC protein overexpression (Case 1), and the other had c-MYC protein overexpression without genomic amplification (Case 2). It was also noted that the tumor cells in Case 2 demonstrated “aberrant” desmin expression by immunostaining.
... have histopathological and genetic characteristics similar to those of other MYCN-amplified embryonic tumors, such as neuroblastoma, 3,5,6 even though the tumor features a retinoblastoma-associated gene expression profile. 7 In oncogenic-driven retinoblastoma, MYCN is focally amplified with >28 copies, spanning 1 to 5 Mb and encompassing neighboring genes. ...
Purpose:
MYCNOS (MYCN opposite strand) is co-amplified with MYCN in pediatric cancers, including retinoblastoma. MYCNOS encodes several RNA variants whose functions have not been elucidated in retinoblastoma. Thus, we attempted to identify MYCNOS variants in retinoblastoma and aimed to decipher the role of MYCNOS variant 1 (MYCNOS1) on the activity of MYCN-amplified retinoblastoma.
Methods:
The profiles of MYCNOS variants and MYCN status were determined in 17 retinoblastoma tissues, cell lines, retinas, and retinal organoids. A functional study of MYCNOS1 expression was conducted in patient-derived tumor cells and in retinoblastoma cell lines via short hairpin RNA-mediated gene silencing. We carried out MYCN expression, cell viability, cell cycle, apoptosis, soft agar colony formation, and transwell assays to examine the role of MYCNOS1 in MYCN and cell behaviors. We analyzed a transcriptome of MYCN-amplified retinoblastoma cells deficient for MYCNOS1 and, finally, tested the responses of these cells to chemotherapeutic agents.
Results:
Expression of MYCNOS1 was associated with the expression and copy number of MYCN. Knockdown of MYCNOS1 caused instability of the MYCN protein, leading to cell cycle arrest and impaired proliferation and chemotaxis-directed migration in MYCN-amplified retinoblastoma cells in which RB1 was intact. MYCNOS1 expression was associated with gene signatures of photoreceptor cells and epithelial-mesenchymal transition. MYCNOS1 silencing enhanced the response of retinoblastoma cells to topotecan but not carboplatin.
Conclusions:
MYCNOS1 supports progression of retinoblastoma. Inhibition of MYCNOS1 expression may be necessary to suppress MYCN activity when treating MYCN-amplified cancers without RB1 mutation.
... The mature IRG of EGFP control fish consists mainly of tyrosine hydroxylase (TH)-expressing chromaffin cells (Fig. 1, D to G). By contrast, all MYCN-transformed neuroblastoma cell populations, with or without mutations in the arid1aa or arid1ab gene, included TH-expressing, undifferentiated, small round tumor cells with hyperchromatic nuclei (Fig. 1, H to O), similar to (26). Together, these findings demonstrate synergism between arid1aa or arid1ab deficiency and MYCN overexpression in both mosaic and stable zebrafish lines, thus strengthening the case for a tumor suppressor role of arid1aa and arid1ab during neuroblastoma tumorigenesis. ...
Mutations in genes encoding SWI/SNF chromatin remodeling complexes are found in approximately 20% of all human cancers, with ARID1A being the most frequently mutated subunit. Here, we show that disruption of ARID1A homologs in a zebrafish model accelerates the onset and increases the penetrance of MYCN-driven neuroblastoma by increasing cell proliferation in the sympathoadrenal lineage. Depletion of ARID1A in human NGP neuroblastoma cells promoted the adrenergic-to-mesenchymal transition with changes in enhancer-mediated gene expression due to alterations in the genomic occupancies of distinct SWI/SNF assemblies, BAF and PBAF. Our findings indicate that ARID1A is a haploinsufficient tumor suppressor in MYCN-driven neuroblastoma, whose depletion enhances tumor development and promotes the emergence of the more drug-resistant mesenchymal cell state.
... Based on a pathologist's review of the tumors, they are consistent with a classification of large cell/nucleolar NBL of the poorly differentiated subtype. 16,21 The large cell/nucleolar NBL subclassification of neuroblastoma is strongly associated with N-Myc amplification and is speculated to be a consequence of N-Myc overexpression. 16,21 This subtype is also a highly aggressive variant of NBL with very poor outcome that is proposed to be a developmentally immature stem cell-like NBL. ...
... 16,21 The large cell/nucleolar NBL subclassification of neuroblastoma is strongly associated with N-Myc amplification and is speculated to be a consequence of N-Myc overexpression. 16,21 This subtype is also a highly aggressive variant of NBL with very poor outcome that is proposed to be a developmentally immature stem cell-like NBL. 21,22 The second set of tumors was negative for Synaptophysin, Phox2B, Map2, TH and Chromogranin A. By hematoxylin and eosin staining, the tumors showed features of osteosarcoma with extensive osteoid throughout the tumors and were designated as osteosarcomas (Figure 3b, right). ...
... 16,21 This subtype is also a highly aggressive variant of NBL with very poor outcome that is proposed to be a developmentally immature stem cell-like NBL. 21,22 The second set of tumors was negative for Synaptophysin, Phox2B, Map2, TH and Chromogranin A. By hematoxylin and eosin staining, the tumors showed features of osteosarcoma with extensive osteoid throughout the tumors and were designated as osteosarcomas (Figure 3b, right). During craniofacial development, NCC-derived osteoblasts form the bone and cartilage of the face and neck. ...
Neuroblastoma (NBL) is an embryonal cancer of the sympathetic nervous system (SNS), which causes 15% of pediatric cancer deaths. High-risk NBL is characterized by N-Myc amplification and segmental chromosomal gains and losses. Owing to limited disease models, the etiology of NBL is largely unknown, including both the cell of origin and the majority of oncogenic drivers. We have established a novel system for studying NBL based on the transformation of neural crest cells (NCCs), the progenitor cells of the SNS, isolated from mouse embryonic day 9.5 trunk neural tube explants. Based on pathology and gene expression analysis, we report the first successful transformation of wild-type NCCs into NBL by enforced expression of N-Myc, to generate phenotypically and molecularly accurate tumors that closely model human MYCN-amplified NBL. Using comparative genomic hybridization, we found that NCC-derived NBL tumors acquired copy number gains and losses that are syntenic to those observed in human MYCN-amplified NBL including 17q gain, 2p gain and loss of 1p36. When p53-compromised NCCs were transformed with N-Myc, we generated primitive neuroectodermal tumors with divergent differentiation including osteosarcoma. These subcutaneous tumors were metastatic to regional lymph nodes, liver and lung. Our novel experimental approach accurately models human NBL and establishes a new system with potential to study early stages of NBL oncogenesis, to functionally assess NBL oncogenic drivers and to characterize NBL metastasis.Oncogene advance online publication, 1 May 2017; doi:10.1038/onc.2017.128.
... 20 Indeed, the large nucleolar neuroblastoma subtype has prominent nucleoli and very little discernible cytoplasm and is highly associated with a deteriorating clinical course and MYCN gene amplification. [21][22][23] Several nucleolar factors, including RNA polymerase I (POLI) and BYSL, are dysregulated in human cancer, and inhibition of RNA POLI has been shown to be an effective therapeutic strategy in certain cancers. [24][25][26] Haploinsufficiency of RPL24, RPL39 and EIF6, factors involved in the ribosome biogenesis pathway, have been shown to suppress oncogeneinduced transformation. ...
... Tumor cells in these TgDEF; MYCN compound transgenic fish have sympathoadrenal precursor cells with an increased nucleolar size and a higher proliferative fraction than found in TgMYCN single transgenic fish (Figures 4o and t and Supplementary Figure S4v). In childhood neuroblastoma, the Shimada group has identified a subtype characterized by large and prominent nucleoli called 'large nucleolar neuroblastoma', 22 which is highly associated with MYCN amplification and a poor prognosis. 23 Here we show that these neuroblastomas with MYCN amplification also have high levels of expression of DEF, which is an essential component of the multi-protein complex called the SSU processome and required for processing of the pre-rRNA into the 18 s rRNA. ...
The nucleolar factor, digestive organ expansion factor (DEF), has a key role in ribosome biogenesis, functioning in pre-ribosomal RNA (pre-rRNA) processing as a component of the small ribosomal subunit (SSU) processome. Here we show that the peripheral sympathetic nervous system (PSNS) is very underdeveloped in def-deficient zebrafish, and that def haploinsufficiency significantly decreases disease penetrance and tumor growth rate in a MYCN-driven transgenic zebrafish model of neuroblastoma that arises in the PSNS. Consistent with these findings, DEF is highly expressed in human neuroblastoma, and its depletion in human neuroblastoma cell lines induces apoptosis. Interestingly, overexpression of MYCN in zebrafish and in human neuroblastoma cells results in the appearance of intermediate pre-rRNAs species that reflect the processing of pre-rRNAs through Pathway 2, a pathway that processes pre-rRNAs in a different temporal order than the more often used Pathway 1. Our results indicate that DEF and possibly other components of the SSU processome provide a novel site of vulnerability in neuroblastoma cells that could be exploited for targeted therapy.
... In particular, the current International Neuroblastoma Pathology Classification guidelines identify a NBL subset with favorable prognosis using quantification of Schwannian stroma 3,4 . ...
Neuroblastoma (NBL) is a heterogeneous tumor characterized by a wide range of clinical manifestations. A high tumor cell differentiation grade correlates to a favorable stage and positive outcome. Expression of the hypoxia inducible factors HIF1-α (HIF1A gene) and HIF2-α (EPAS1 gene) and/or hypoxia-regulated pathways has been shown to promote the undifferentiated phenotype of NBL cells. Our hypothesis is that HIF1A and EPAS1 expression represent one of the mechanisms responsible for the lack of responsiveness of NBL to differentiation therapy. Clinically, high levels of HIF1A and EPAS1 expression were associated with inferior survival in two NBL microarray datasets, and patient subgroups with lower expression of HIF1A and EPAS1 showed significant enrichment of pathways related to neuronal differentiation. In NBL cell lines, the combination of all-trans retinoic acid (ATRA) with HIF1A or EPAS1 silencing led to an acquired glial-cell phenotype and enhanced expression of glial-cell differentiation markers. Furthermore, HIF1A or EPAS1 silencing might promote cell senescence independent of ATRA treatment. Taken together, our data suggest that HIF inhibition coupled with ATRA treatment promotes differentiation into a more benign phenotype and cell senescence in vitro. These findings open the way for additional lines of attack in the treatment of NBL minimal residue disease.
... MYCN amplification is a hallmark of aggressive clinical behavior for patients with pNTs. In contrast to conventional neuroblastoma with a typical salt-and-pepper nucleus, MYCNamplified tumors are often characterized by the presence of one or few prominent nucleoli (8)(9)(10) . Recently, in our report describing genotype-phenotype discordant neuroblastomas, we suggested that those prominent nucleoli could be the putative site of RNA synthesis/accumulation critical for protein expression (11) . ...
... Our study clearly demonstrated that the majority of NBUD tumors had prominent nucleoli, and showed the feature of so-called "Large cell neuroblastoma" (16) . These tumors were often associated with poor prognostic factors, such as older age (≥18 months old) at diagnosis, metastatic disease, MYCN amplification, a diploid pattern, 1pLOH, and a high MKI (8)(9)16) . Patients with NBUD had a poor clinical outcome that was not significantly influenced by the presence/absence of those prognostic factors except for MYCN status and the combination of MYCN status with the presence/absence of prominent nucleoli. ...
This study sought to investigate biological/clinicopathological characteristics of neuroblastoma, undifferentiated subtype (NBUD).
This study examined 157 NBUD cases filed at the Children's Oncology Group Neuroblastoma Pathology Reference Laboratory, and survival rates of the patients were analyzed with known prognostic factors. Immunostainings for MYCN and MYC protein were performed on 68 tumors.
NBUD cases had a poor prognosis (48.4% ± 5.0% 3-year event-free survival [EFS]; 56.5% ± 5.0% overall survival [OS]), and were often associated with high mitosis-karyorrhexis index (MKI, 65%), prominent nucleoli (PN, 83%), ≥ 18 months of age (75%), MYCN amplification (MYCN-A, 83%), diploid pattern (63%), and 1pLOH (loss of heterozygosity (72%). However, these prognostic indicators, except for MYCN status, had no significant impact on survival. Surprisingly, EFS for patients with MYCN-A tumors (53.4% ± 5.6%) was significantly better (P = .0248) than for patients with MYCN-nonamplified (MYCN-NA) tumors (31.7% ± 11.7%), with MYCN-NA and PN (+) tumors having the worst prognosis (9.3% ± 8.8%, P = .0045). Immunohistochemically, MYCN expression was found in 42 of 48 MYCN-A tumors. In contrast, MYC expression was almost exclusively found in the MYCN-NA tumors (9 of 20) especially when they had PN (8 of 11). Those patients with only MYC-positive tumors had the worst EFS (N = 8, 12.5% ± 11.7%) compared with only MYCN-positive (N = 39, 49.9% ± 17.7%) and both negative tumors (N = 15, 70.0% ± 17.1%) (P = .0029). High MKI was often found in only MYCN-positive (30 of 38) but rarely in only MYC-positive (2 of 8) tumors.
NBUD represents a unique subtype of neuroblastoma associated with a poor prognosis. In this subtype, MYC protein expression may be a new prognostic factor indicating more aggressive clinical behavior than MYCN amplification and subsequent MYCN protein expression. Cancer 2013. © 2013 American Cancer Society.
