Neuroblastoma (NBL)

Neuroblastoma, an embryonal cancer of neural crest arise from the sympathetic ganglion 1).

Shows metastases frequently at diagnosis.

May occur anywhere in the sympathetic nervous system, most commonly from adrenal gland (40%), followed by sympathetic ganglia of thoracic (15%), cervical (5%) and pelvic regions (5%). Neoplasms under this rubric include:

1. neuroblastomas: the most undifferentiated and aggressive in this group.

2. ganglioneuroblastomas

3. ganglioneuromas.

Olfactory neuroblastomas are called esthesioneuroblastomas.

Delloye-Bourgeois and colleagues demonstrate that neuroblastoma cell lines and patient-derived xenografts engraft and adopt a metastatic program in chick embryos. They identify Sema3C as a candidate switch that regulates metastatic spread 2).


Is the most malignant tumor in children and most common solid tumor in infants accounting for 8-10% of all childhood malignancies (about 8.7 million/year). It affects primarily children younger than 10 years of age. About 50% are below the age of 2 years. It occurs more frequently in boys than in girls (1.2:1). It originates from the neural crest cell, which normally gives rise to the adrenal medulla and sympathetic ganglia anywhere from the neck to the pelvis. It occurs in the abdomen in about 70% of cases (45% in adrenal medulla and 25% in sympathetic ganglia) 3).

Malignant tumors that have increased frequency in neurofibromatosis: neuroblastoma, ganglioglioma, sarcoma, leukemia, Wilm’s tumor, breast cancer 4).


NBL consists of nests of neuroblasts (undifferentiated small round cells) separated by fine fibrovascular septa (stroma) and showing Rosette formation in about one-third of cases. In about 5-10% of cases, some neuroblasts show differentiation into mature ganglion cells and the tumor is classified as ganglioneuroblastoma; however, in adolescents and young adults, the tumor is formed of mature ganglion cells separated by collagenous stroma and called ganglioneuroma and this is the most benign type of NBL. NBL and ganglioneuroblastoma were classified by Shimada and recently by International Neuroblastoma Pathology Classification into favorable and unfavorable histology tumors according to the degree of neuroblasts differentiation and stromal development (stroma-rich and stroma-poor) 5).

Amplification of the MYC family member, MYCN, is found in ∼25% of cases and correlates with high-risk disease and poor prognosis. Currently, amplification of MYCN remains the best-characterized genetic marker of risk in neuroblastoma. This article reviews roles for MYCN in neuroblastoma and highlights recent identification of other driver mutations. Strategies to target MYCN at the level of protein stability and transcription are also reviewed 6).

Patients with NBL may show genetic abnormalities in the form of deletion in the short arm of chromosome one and amplification of genes of chromosome two (called N myc gene amplification) and this is considered a poor prognostic factor of the disease 7).

Clinical presentation

May present with abdominal mass, local or radicular pain, or (with high thoracic or cervical tumors) Horner’s syndrome. Spinal cord compression may occur from invasion through the neural foramen, and scoliosis may occur. Catecholamine precursors (homovanillic acid (HVA), vanillylmandelic acid (VMA) and dopamine) may be excreted and cause HTN (can be assayed in urine). Periorbital tumor metastases may produce raccoon’s eyes (usually unilateral ecchymosis and proptosis). Many of the low-grade tumors regress spontaneously and never present.

Opsoclonus-myoclonus syndrome: in peds, usually indicates neuroblastoma.

The most common clinical presentation of abdominal NBL in children is a large flank mass; however, other rare presentations may include pelvic NBL, bilateral, pelviabdominal, and neonatal NBL, other manifestations may associate with the tumor mass-like metastatic lesions in bone or liver, pallor, abdominal pain, weight loss, and fever. NBL is a biologically active tumor secreting vanillylmandelic acid (VMA) and homovanillic acid, or other metabolites such as catecholamines, neuron-specific enolase (NSE), and vasoactive intestinal peptides in some cases 8).

Horner’s syndrome 2nd order neuron (preganglionic)

Etiologies of dysfunction: lateral sympathectomies, significant chest trauma, apical pulmonary neoplasms (Pancoast tumor), high thoracic or cervical neuroblastoma.


NBL can be diagnosed radiologically by ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) with different sensitivities and specificities.

Three major staging systems are used for staging of NBL: Evans staging system (1971), Pediatric Oncology Group (1983) system, and the widely used International Neuroblastoma Staging System (INSS 1988).


Treatment of NBL is a multimodality therapy composed of surgery, chemotherapy, and radiotherapy either in combination or separate depending on disease stage, patient age, genetic abnormalities, tumor biology, and histological classifications 9) see esthesioneuroblastoma.

Arsenic trioxide (As2O3), known as pi-shuang and the most toxic compound in traditional Chinese medicine, has been used as an antitumor agent for thousands of years. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a natural phenol that has significant anti-bacterial, anti-fungaI and antiaging activities. A study of Yen et al. from TaichungTaiwan, aimed to examine the combined anticancer effects of As2O3 and resveratrol against human neuroblastoma SK-N-SH cells, and elucidate the underlying intracellular signaling.

SK-N-SH cells were treated with an extremely low-dose (2-4 μM) of As2O3 alone or combined with 75 μg/ml resveratrol for further comparisons. Cell viability, apoptotic signaling as well as synergistic cytotoxic effects were estimated using the MTT assay, microscopy observation, flow cytometric analysis for loss of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS), and typical quantitative western blotting analysis. Student’s t-test, and one- and two-way analysis of variance (ANOVA) were used for examination of significant differences.

The combined treatment was more effective than single treatment of As2O3 or resveratrol alone in suppressing cell viability, which correlated with the elevation of ROS levels. The intracellular mechanisms of cytotoxicity of As2O3 plus resveratrol were revealed as ROS accumulation and relative decrease of MMP, leading to activation of caspase-3 and -9, but not of caspase-1, -7 and-8. Combination treatment reduced the expression of B-cell lymphoma 2 (BCL2), BH3 interacting domain death agonist (BID), and BCL-x/L.

Combined treatment at extremely low concentration of two agents from natural products, As2O3 and resveratrol, has high potential as a cocktail of anticancer drugs for neuroblastoma 10).

Yang et al tested antitumor effects of sorafenib (≤ 10 µM) on four human neuroblastoma cell lines, CHLA255, CHLA171, CHLA90 and SK-N-AS. Sorafenib inhibited cell proliferation and induced apoptosis of neuroblastoma tumor cells in a dose-dependent manner. Sorafenib inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) proteins at Tyr705 in these cells, associated with inhibition of phosphorylated JAK2, an upstream kinase that mediates STAT3 phosphorylation. Expression of a constitutively-activated STAT3 mutant (pSTAT3-C) partially blocked the antitumor effects of sorafenib on neuroblastoma cells. Sorafenib also inhibited the phosphorylation of STAT3 induced by IL-6 and sphingosine-1-phosphate (S1P), a recently identified regulator for STAT3, in these tumor cells. Moreover, sorafenib downregulated phosphorylation of MAPK (p44/42) in neuroblastoma cells, consistent with inhibition of their upstream regulators MEK1/2 11).


Iniguez et al. used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling, and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies 12).


Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diag- nosis, staging, and response to treatment. J Clin Oncol. 1993; 11:1466–1477

Zheng T, Ménard M, Weiss WA. Neuroblastoma Metastases: Leveraging the Avian Neural Crest. Cancer Cell. 2017 Oct 9;32(4):395-397. doi: 10.1016/j.ccell.2017.09.012. PubMed PMID: 29017050.

Brodeur GM, Marris JM. Neuroblastoma. In: Pizzo, Poplack BG, editors. Principles and Practice of Pediatric Oncology. 5 th ed. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 933-70

Sharif S, Moran A, Huson SM, Iddenden R, Shenton A, Howard E, Evans DG. Women with neurofibro- matosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. JMed Genet. 2007; 44:481–484

Shimada H, Umehara S, Monobe Y, Hachitanda Y, Nakagawa A, Goto S, et al. International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: A report from the Children’s Cancer Group. Cancer 2001;92:2451-61.

Huang M, Weiss WA. Neuroblastoma and MYCN. Cold Spring Harb Perspect Med. 2013 Oct 1;3(10):a014415. doi: 10.1101/cshperspect.a014415. PubMed PMID: 24086065.

Bowman LC, Castleberry RP, Cantor A, Joshi V, Cohn SL, Smith EI, et al. Genetic staging of unresectable or metastatic neuroblastoma in infants: A pediatric oncology group study. J Natl Cancer Inst 1997;89:373-80.

Park JR, Eggert A, Caron H. Neuroblastoma: Biology, prognosis, and treatment. Hematol Oncol Clin North Am 2010;24:65-86.

Yen CM, Tsai CW, Chang WS, Yang YC, Hung YW, Lee HT, Shen CC, Sheu ML, Wang JY, Gong CL, Cheng WY, Bau DT. Novel Combination of Arsenic Trioxide (As(2)O(3) Plus Resveratrol in Inducing Programmed Cell Death of Human Neuroblastoma SK-N-SH Cells. Cancer Genomics Proteomics. 2018 Nov-Dec;15(6):453-460. doi: 10.21873/cgp.20104. PubMed PMID: 30343279.

Yang F, Jove V, Buettner R, Xin H, Wu J, Wang Y, Nam S, Xu Y, Ara T, DeClerck YA, Seeger R, Yu H, Jove R. Sorafenib inhibits endogenous and IL-6/S1P induced JAK2-STAT3 signaling in human neuroblastoma, associated with growth suppression and apoptosis. Cancer Biol Ther. 2012 May;13(7):534-41. doi: 10.4161/cbt.19603. Epub 2012 May 1. PubMed PMID: 22406995

Iniguez AB, Alexe G, Wang EJ, Roti G, Patel S, Chen L, Kitara S, Conway A, Robichaud AL, Stolte B, Bandopadhayay P, Goodale A, Pantel S, Lee Y, Cheff DM, Hall MD, Guha R, Davis MI, Menard M, Nasholm N, Weiss WA, Qi J, Beroukhim R, Piccioni F, Johannessen C, Stegmaier K. Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling. Cancer Cell. 2018 Dec 10;34(6):922-938.e7. doi: 10.1016/j.ccell.2018.11.005. PubMed PMID: 30537514.

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