Neuroblastoma (NB) is the most frequently-occurring extracranial childhood tumor. It is classified as an embryonal neuroendocrine tumor, originating from neural crest progenitor cells (Matthay et al. 2016). Hence, it can occur anywhere along the sympathetic nervous system, including the superior cervical, paraspinal, and celiac ganglia; the majority arise in the adrenal glands (Maris et al. 2010). Due to the high variability in its presentation, clinical signs and symptoms at presentation can range from benign palpable mass with distension to major illness from substantial tumor spread. Although overall increases in five-year event-free survival have been reported, subgroup-specific analysis of mortality has revealed discordance between the high cure rates for the more benign low-risk forms and little improvement in the high-risk groups (Maris et al. 2007; Linabery et al. 2008). Thus, the impetus for the development of targeted therapeutics in the intensive management of high-risk groups is strong.
Risk factors for the acquisition of mutations in key genes leading to neuroblastoma have yet to be identified although exposures during conception and pregnancy are a topic of investigation. Neuroblastoma can develop either sporadically or be transmitted in the germline. Most familial cases of neuroblastoma occur due to the inheritance of highly penetrant mutations in either the ALK or PHOX2B genes (Mosse et al. 2008; Maris et al. 2010). A small subset of familial NB demonstrates autosomal dominant inheritance (Knudson et al. 1972). Although up to 15% of sporadic cases of neuroblastoma arise from mutations in ALK, more common transforming mutations involve polymorphisms in BARD1 (2q35), LIN28B (6q16.3), or FLJ22536 (6p22.3). Cytogenetic aberrations can further include loss of chromosome 1p and 11q, copy number variation in 1q21, and gain of 17q (Maris et al. 2008; Capasso et al. 2009; Diskin et al. 2012; Matthay et al. 2016). Notably, amplification of MYCN oncogene is seen in approximately 25% of patients and is associated with the poorest prognosis; 17q gain and 1p loss correlate with MYCN amplification (Heukamp et al. 2012; Matthay et al. 2016).
Neuroblastoma is the most common tumor of the sympathetic nervous system (97%) and the most common malignancy of infancy with a median age of diagnosis of 17 months (London et al. 2005). It accounts for 15% of pediatric cancer-related deaths (Althoff et al. 2015). The annual incidence of neuroblastoma in the United States is approximately 650 cases, i.e., 10.2 per million children (65 per million infants), with little change (0.4%) over time (Maris et al. 2010). While an overall improvement in five-year mortality has been noted between 1975 through 2005, subgroup specific mortality paints a different picture.
Given the wide areas populated by neural crest cells, neuroblastoma can present in the neck, chest, abdomen, or pelvis. With the most frequent site of origin being the adrenal medulla, patients often present with a solid abdominal mass. With involvement of the superior cervical ganglia, aside from a neck mass, Horner syndrome (ptosis, miosis, anhydrosis) can be observed. If tumor involves the spinal cord, cord compression or paralysis may be seen (Maris et al. 2010). Furthermore, tumor behavior can range from spontaneous regression to widespread dissemination at presentation (Maris et al. 2007). With over half of all neuroblastoma patients having hematogenous spread at diagnosis, the disease can involve the bone and bone marrow (56% and 71%, respectively), followed by lymph nodes (31%), and lungs (3%) (Cheung et al. 2013; Teitz et al. 2013). Non-specific clinical signs include fever, weight loss, and fatigue. Thus, signs and symptoms, which can range from an asymptomatic palpable mass to significant critical illness, are highly variable and dependent upon factors now linked with prognosis.
The widespread variability in neuroblastoma tumor behavior is linked to multiple factors now linked with patient prognosis. Classic prognostic categorization by Children’s Oncology Group (COG) divides patients into four groups based on patient age, post-surgical stage, MYCN amplification, histology, and DNA ploidy (Maris et al. 2007):
However, COG classification of neuroblastoma has differed from the European SIOPEN and other cooperative groups. In 2004, the International Neuroblastoma Risk Group (INRG), a task force of pediatric neuroblastoma experts worldwide, met with the primary aim of developing a consensus approach to neuroblastoma risk stratification pre-treatment (Cohn et al. 2009). Using patient age, tumor stage, tumor grade and differentiation, tumor histology, MYCN amplification, cytogenetic aberrations in 11q, and DNA ploidy, the group defined 16 pre-treatment groups broadly divisible into four prognostic subgroups based on five-year event-free survival (EFS):
Over 50% of newly diagnosed neuroblastoma are very-low or low-risk (Cohen et al. 2009). Negative prognostic markers include age older than 18 months, metastasis at diagnosis, and presence of MYCN amplification, 1p loss, 11q loss, 17q gain, or DNA copy number alterations (Cohn et al. 2009; Matthay et al. 2016).
Diagnostic evaluation relies not only on a careful history and physical, but also on biochemical, histologic, and radiographic analyses. Histologic confirmation is required to establish a diagnosis of neuroblastoma. Histologically, small round pale blue cells, known as Homer Wright pseudo rosettes, can be seen; these are similarly seen in Wilm's tumor and Ewing sarcoma, leading to their common group categorization as small blue cell tumors (Matthay et al. 2016). If a biopsy sample is tumor positive, DNA ploidy and MYCN gene status are further evaluated. Since neuroblastoma cells originate from neural crest cells destined to differentiate into sympathetic peripheral neurons, cells often produce catecholamines; break-down product of these catecholamines are homovanillic acid (HVA) and vanillylmandelic acid (VMA). Thus, in over 90% of neuroblastoma, elevation in these catecholamine breakdown products in urine is diagnostic (LaBrosse et al. 1980). Preliminary imaging is preferentially conducted with MRI for good resolution and surgical excision planning. Further exploiting sympathetic neuronal uptake of mIBG (metaiodobenzylguanidine), due to its analogous nature to norepinephrine, the extent of neuroblastoma metastasis can be delineated with a mIBG scan with high accuracy and quality (Vik et al. 2009). To complete tumor staging, bone marrow biopsies are required (Matthay et al. 2016). Of note, common paraneoplastic conditions associated with neuroblastoma include opsoclonus myoclonus syndrome and intractable secretory diarrhea due to vasoactive intestinal peptide (VIP) secretion (Kaplan et al. 1980; Brunklaus et al. 2012).
Given the heterogeneity in tumor location, grade, and stage at diagnosis, treatment modalities include simple observation, surgical resection, chemotherapy, radiation therapy, stem-cell transplantation, and immunotherapy. Patients with low-risk NB have localized tumor, some (infants) with a high propensity for spontaneous tumor regression (Matthay et al. 1998). Thus, children with small tumors (less than 5 cm) can simply be observed with imaging done every six to 12 weeks to monitor tumor growth, thus avoiding surgery in the young infant altogether (Matthay et al. 2016). For larger, localized tumors, in patients past infancy, surgical resection is pursued. For patients younger than 18 months of age, the observational approach is currently under international investigation by COG (NCT02176967) and SIOPEN (NCT01728155) cooperative groups. For children who present with symptoms, limited chemotherapy is given without surgical palliation or radiation therapy (Matthay et al. 2016). The intermediate-risk group presents with localized metastasis, i.e., to the lymph node or bone marrow (in infants). They are usually managed with chemotherapy alone and possible surgical resection if able (Baker et al. 2010). The high-risk group has the worst prognosis and presents with widespread metastatic disease to the bone marrow, bone, lungs, and liver. They receive induction chemotherapy to reduce tumor burden at both the primary and metastatic locations, followed by maximal surgical resection, followed by myeloablative chemotherapy and stem-cell transplantation. After that, patients are managed on a combination of maintenance chemotherapy and immunotherapy (Park et al. 2013). A monoclonal antibody, dinutuximab (Unituxin), that attaches to a carbohydrate molecule (GD2) on the surface of many neuroblastoma cells, is being used as an immunotherapy drug for neuroblastoma treatment. Dinutuximab treatment is reported to improve the two-year event-free survival of high-risk neuroblastoma patients from 46% to 66% (Yu et al. 2010).