Neuroblastoma: Symptoms and Treatment

Neuroblastoma is a malignant tumor of immature cells of the sympathetic nervous system, most commonly arising in the adrenal glands and paravertebral sympathetic ganglia of the thoracic and abdominal cavities. It is one of the most common solid tumors in young children: most cases are diagnosed before age 5, with a median age of 18-24 months. Neuroblastoma is characterized by marked biological heterogeneity, ranging from spontaneously regressing forms in infants to aggressive, high-risk variants with metastases. [1]

The evolution of approaches to staging and treatment is associated with the introduction of the INRG/INSS systems, molecular risk stratification (MYCN amplification, 1p/11q deletions, ploidy, etc.) and the expansion of the therapeutic arsenal: induction "dense" chemotherapy, high-dose therapy with autologous hematopoietic cell transplantation, radionuclide MIBG therapy, maintenance differentiation therapy with retinoids, and immunotherapy with anti-GD2 antibodies (dinutuximab, naxitamab). All this improves the survival of some patients, although in high-risk cases it remains insufficient. [2]

Diagnosis is based on a combination of imaging (ultrasound, magnetic resonance imaging, and computed tomography), metaiodobenzylguanidine (MIBG) scintigraphy, biopsy with histology/immunohistochemistry, bone marrow metastasis testing, and laboratory assessment of catecholamine metabolites (vanillylmandelic and homovanillic acids). The current INRG system defines stages prior to treatment based on "image-defined risk factors" (IDRFs), which helps plan surgery and assess risk. [3]

Despite the lack of specific primary prevention, timely diagnosis of symptoms (painless abdominal/neck mass, bone pain, weight loss, neurological manifestations, diarrhea, hypertension) and referral to specialized centers increase the chances of a favorable outcome. Pareneoplastic opsoclonus-myoclonus-ataxia syndrome requires active screening for neuroblastoma. [4]

Code according to ICD-10 and ICD-11

The correct coding of neuroblastoma depends on the location of the primary tumor and the use of additional codes (morphology). ICD-10 uses codes based on topography (e.g., malignant tumor of the adrenal gland - C74.x; peripheral nerves/sympathetic system - C47.x or C49.x as appropriate; for rare localizations - the corresponding CNS/organs sections). For the prefixes "neuroblastoma/sympathioblastoma", the topical section and clinical documentation are used. [5]

In ICD-11, the main section for malignant neuroepitheliomatous tumors of the peripheral nerves/autonomic nervous system is block 2C40 (with clarifying subcategories by localization), and the morphological type "neuroblastoma, unspecified" is designated by the expansion code XH85Z0. In oncoregistries, the morphological code ICD-O-3.2 "9500/3 - Neuroblastoma, NOS" is often recorded in parallel. [6]

Table 1. Coding examples

System	What are we encoding?	Code	Comment
ICD-10	Malignant tumor of the adrenal gland (indication of "neuroblastoma" in the diagnosis)	C74.90 / C74.x	Specify the part of the adrenal gland if possible. [7]
ICD-10	Peripheral nerves/autonomic nervous system	C47.x / C49.x	The choice depends on the anatomical area. [8]
ICD-11	Malignant neuroepitheliomatous neoplasms of peripheral nerves/ANS	2C40.*	Topographic detailing by subsections. [9]
ICD-11	Morphology (extension code)	XH85Z0	"Neuroblastoma, NOS." [10]
ICD-O-3.2	Morphological type	9500/3	Used in oncoregistries. [11]

Epidemiology

Neuroblastoma is the most common solid extracranial tumor of childhood and the most common malignant tumor in infants. Approximately 600–800 new cases are reported annually in the United States, with a peak incidence in children under 2 years of age. Incidence varies by region and ethnic group. [12]

Incidence estimates range from 7-13 cases per million children (0-14 years) per year, although individual registries vary in incidence due to methodology and coverage. In children under 1 year of age, the incidence rate may exceed 25% of all newly diagnosed neuroblastomas. Gender differences are moderate. [13]

Five-year survival varies significantly by risk group: for low and intermediate risk, it is often ≥90-95%, while for high risk, it is approximately 50-60%, even with multimodal treatment. Improvements are associated with intensified therapy and the introduction of anti-GD2 immunotherapy, but the need for new strategies remains high. [14]

Rare clinical scenarios include antenatally detected tumor (via fetal ultrasound) and opsoclonus-myoclonus-ataxia syndrome; approximately 50% of children with this syndrome eventually develop neuroblastoma. These subtypes often have different biology and prognosis. [15]

Table 2. Key epidemiological indicators

Indicator	Meaning
New cases in the US/year	~600-800 [16]
Age of peaks	1-2 years; most up to 5 years [17]
Incidence (0-14 years)	~7-13 per 1 million/year (varies) [18]
Proportion of children <1 year of age among all NB	≥25% in a number of estimates [19]
5-year survival: low/intermediate risk	≥90-95% [20]
5-year survival: high risk	~50-60% (centers are variable) [21]

Reasons

A single, universal cause of neuroblastoma has not been established. The tumor arises from embryonic neural crest cells that differentiate into the sympathetic nervous system and adrenal medulla. A significant number of cases are associated with chromosomal rearrangements and driver mutations that affect proliferation, differentiation, and apoptosis. [22]

A small proportion of patients have a hereditary predisposition. In familial observations, anomalous activation of the ALK pathway (heterozygous missense variants in the tyrosine kinase domain) plays a central role, while variants in PHOX2B play a lesser role. Familial cases account for approximately 1-2% of all neuroblastomas. In sporadic tumors, somatic activating mutations of ALK are detected in approximately 8-10% of patients. [23]

In addition to point mutations, segmental chromosomal abnormalities are important: MYCN amplification, deletions of 1p and 11q, and gain of 17q are associated with a more aggressive course and higher risk. Pleidiploidy/diploidy and DNA index also influence the prognosis in infants. [24]

Environmental factors (nutrition, pregnancy, infections) have not been consistently linked to neuroblastoma risk in large studies; parents are unable to implement convincing "preventive" lifestyle modifications. This underscores the importance of early recognition of symptoms and genetic counseling for families with a history of neuroblastoma. [25]

Risk factors

Key risk factors include the presence of familial cases of neuroblastoma, carriage of pathogenic variants in the ALK or PHOX2B genes, as well as certain tumor and patient characteristics (age, molecular markers) that determine risk stratification and treatment tactics. [26]

ALK/PHOX2B variants are inherited in an autosomal dominant manner, with a 50% chance of being passed on to offspring if a parent is affected. If clinical suspicion is present, genetic counseling and targeted testing are recommended, including discussion of surveillance programs for at-risk children. [27]

Unfavorable factors include age ≥18 months at diagnosis, MYCN amplification, 1p/11q deletions, bone/bone marrow/liver metastases, and unfavorable INPC histology. These features constitute a “high risk” classification according to the INRG/COG systems and determine the need for treatment escalation. [28]

Paraneoplastic opsoclonus-myoclonus-ataxia syndrome, on the contrary, is often associated with small tumor volume, early stages of INRG and absence of MYCN amplification, but is accompanied by a high risk of neurological sequelae requiring separate immunomodulatory therapy and rehabilitation. [29]

Table 3. Risk factors and their clinical significance

Factor	Frequency/Characteristic	Clinical significance
Family history of NB	~1-2% of all cases	Consider ALK/PHOX2B testing, observed since childhood. [30]
ALK (germinal/somatic)	~75% familial; ~9% sporadic	Potential targeted therapy with ALK inhibitors in relapse. [31]
PHOX2B (germinal)	Rarely	Associated dysautonomia/hypoventilation; screening. [32]
Age ≥18 months	Often seen in aggressive forms	High risk indicator according to INRG. [33]
MYCN amp; 1p/11q del; +17q	Aggressive biology	Worsens the prognosis; affects the choice of therapy. [34]
OMAS syndrome	2-3% NB; ~50% of children with OMAS have NB	Small local tumors; high risk of neuroneological consequences. [35]

Pathogenesis

The tumor arises from the neural crest through impaired sympathoblast differentiation. Genetic drivers (MYCN amplification, ALK mutations) activate oncogenic pathways, supporting proliferation and preventing maturation into ganglion cells. Segmental chromosomal rearrangements cause genomic instability and resistance to therapy. [36]

The tumor microenvironment, including immune cells, vascular, and stromal elements, influences clinical behavior. Neuroblastoma cells express ganglioside GD2, making them vulnerable to anti-GD2 antibodies that trigger complement- and cell-mediated cytotoxic responses. [37]

Transcriptional regulation of sympathetic nervous system development involves PHOX2B and other factors; dysregulation of the NF-κB/Nrf2 pathway influences resistance to oxidative stress and chemoresistance. This explains the variable sensitivity of tumors to therapy and the interest in combined strategies targeting the stress response and differentiation. [38]

In infants, some tumors exhibit spontaneous differentiation or apoptosis (INRG MS stage), which is associated with features of the maturing sympathetic series and genomic characteristics (absence of MYCN amplification, favorable ploidy). [39]

Symptoms

The clinical presentation depends on the location. The most common onset is a painless, palpable abdominal mass, loss of appetite, weight loss, and low-grade fever. With retroperitoneal localization, constipation, diarrhea, abdominal pain, and increased blood pressure due to catecholamine activity are possible. [40]

With mediastinal localization, cough, stridor, and respiratory failure are observed. Paravertebral growth can lead to spinal cord compression (paresis, sensory disturbances, pelvic dysfunction), requiring urgent decompression and steroid therapy. [41]

Metastatic lesions of the bones and bone marrow cause bone pain, lameness, anemia, thrombocytopenia, and weakness. In infants with stage MS, hepatosplenomegaly and cutaneous metastases are noted. [42]

A special clinical form is opsoclonus-myoclonus-ataxia syndrome with chaotic saccades, myoclonus and ataxic disturbances; it requires immediate oncologic search. [43]

Classification, forms and stages

Historically, the postoperative INSS system was used. The current standard is the preclinical INRGSS system, which defines stages before treatment based on imaging data and the presence of "image-defined risk factors" (IDRFs) indicating the technical difficulty of radical resection. [44]

Table 4. Stages of INRGSS (before treatment)

Stage	Definition
L1	Localized tumor without IDRF, within one anatomical "compartment". [45]
L2	Locoregional tumor with ≥1 IDRF. [46]
M	Distant metastases (except MS). [47]
MS	Metastatic disease in children <18 months with skin/liver/bone marrow involvement only. [48]

Risk stratification (low, intermediate, high) takes into account stage, age, MYCN, segmental aberrations, and histology (INPC). It determines the scope of therapy – from surgery with observation to an intensive multimodal program. [49]

Histologically, neuroblastoma, ganglioneuroblastoma and more mature variants (ganglioneuroma) are distinguished; unfavorable histology is associated with a worse prognosis. [50]

Complications and consequences

Local complications include spinal cord compression, airway obstruction in mediastinal locations, vascular invasion, necrosis, and hemorrhage within the tumor. Endocrine-metabolic manifestations include hypertension, hyperhidrosis, and diarrhea (secretion of vasoactive intestinal peptide). [51]

Systemic complications include bone pain and pathological fractures, pancytopenia due to bone marrow infiltration, and liver failure due to massive lesions in infants. Infectious complications and toxicity of therapy increase with the intensification of protocols. [52]

After treatment, late effects are significant: cardiotoxicity of anthracyclines, sensorineural hearing loss after platinum, endocrine disorders, secondary malignancies, neurocognitive consequences of radiation/high-dose therapy. A long-term follow-up program is necessary. [53]

In OMAS, even with a favorable oncological profile, up to 60-70% of children have long-term neurological and cognitive sequelae requiring multidisciplinary rehabilitation. [54]

When to see a doctor

1. If a child develops a painless tumor-like mass in the abdomen/neck, persistent bone pain, lameness, unexplained weight loss, prolonged fever, or high blood pressure, it is necessary to consult a pediatrician/oncologist. 2) In case of acute neurological symptoms (weakness in the legs, sensory disturbances, urinary disorders) - urgently, due to the risk of spinal cord compression. [55]
2. Symptoms of OMAS (chaotic rapid eye movements, myoclonus, gait instability) require immediate oncologic investigation, including imaging and MIBG scanning. 4) Families with known ALK/PHOX2B variants or multiple relatives with neuroblastoma are advised to have genetic counseling and a surveillance plan. [56]

Even with “banal” complaints in young children, keep the threshold for further examination low: early detection of a localized tumor increases the likelihood of organ-preserving treatment. [57]

Diagnostics

The initial stage includes a clinical examination, basic blood tests (complete blood count, biochemistry), and urine collection for catecholamine metabolites—vanillylmandelic and homovanillic acids (elevated in most patients). An initial ultrasound examination helps detect the tumor mass and guide further imaging. [58]

Imaging: Magnetic resonance imaging is preferred for assessing local extent, vascular/spinal cord relationships, and identification of IDRFs; computed tomography is useful for bone structures and calcifications. The key "functional" method is MIBG (I-123) scintigraphy, which reveals foci accumulating a norepinephrine analog; in MIBG-negative tumors, fluorodeoxyglucose PET is used. [59]

Morphological verification: trephine biopsy/core biopsy of the tumor under imaging guidance or surgical biopsy. Histology/immunohistochemistry, assessment of the histological type (INPC) and molecular markers (MYCN, 1p/11q, ploidy) are mandatory. The standard is bone marrow examination (aspiration from both ridges + biopsy) to detect metastases. [60]

Staging and risk stratification: Based on INRGSS (L1/L2/M/MS), age, biomarkers and histology, a risk group (low/intermediate/high) is determined, which directly influences the scope of treatment - from observation to an intensive program with transplantation and immunotherapy. [61]

Table 5. Main diagnostic tests and their role

Study	What does it give?	When shown
Urine for VMA/GVK	Biochemical marker of catecholamine production	To all those suspected of having NB. [62]
MRI/CT	Precise anatomy, IDRFs, surgical planning	All; MRI preferred for soft tissue/spinal canal. [63]
MIBG scintigraphy	Search for primary/metastases, response assessment	Standard; if MIBG is negative - PET-CT. [64]
Tumor biopsy	Diagnosis, INPC, molecular markers	All before starting specific therapy. [65]
Bone marrow examination	Metastases, staging	All; 2 aspirations + biopsies. [66]

Differential diagnosis

Neuroblastoma is differentiated from other retroperitoneal tumors in children (nephroblastoma/Wilms tumor, hepatoblastoma, rhabdomyosarcoma) by age, biochemical markers (VMA/GVK), the nature of calcifications on CT, MIBG accumulation, and immunohistochemistry (GD2, NB84). [67]

In mediastinal localization, differentiation from lymphomas and teratomas is important; in paravertebral growth, from nerve sheath tumors. In infants with hepatomegaly and cutaneous infiltrates (MS), hemato-oncological diseases should be excluded. [68]

OMAS must be distinguished from post-infectious cerebellitis and autoimmune encephalitis; half of children with OMAS have neuroblastoma, so even with a normal brain MRI, a systemic oncologic search with MIBG is needed. [69]

Finally, mature ganglioneuromas/ganglioneuroblastomas require morphological verification, since management tactics from observation to surgery and (rarely) systemic treatment vary. [70]

Treatment

Treatment depends strictly on the risk group. Low-risk (often L1 without unfavorable markers): observation or organ-preserving resection in the case of symptoms/growth is possible, since a significant proportion of tumors in infants regress. The goal is a cure with minimal toxicity, avoiding excessive chemotherapy and radiation. [71]

Intermediate risk (often L2 without MYCN amplification): a combination of moderate-intensity induction chemotherapy followed by an attempt at definitive resection. Transplantation can often be avoided. Regimens include platinum, alkylating agents, anthracyclines, and etoposide, with dynamic response assessment by MIBG/MRI. [72]

High-risk (age ≥18 months and/or MYCN amplification and/or M stage): multistage program. Induction chemotherapy “compresses” the tumor mass and metastases, increasing resectability. Surgery is followed by consolidation with high-dose therapy and autologous hematopoietic cell transplantation to eradicate minimal residual disease. [73]

Radiation therapy is used to control the tumor bed after resection in high-risk patients and in cases of painful bone lesions or spinal cord compression. Doses and fields are planned taking into account age and potential late toxicities. [74]

Maintenance differentiation therapy with isotretinoin (13-cis-retinoic acid) is the standard treatment after transplantation for high-risk patients. It reduces the risk of relapse by "promoting" residual blast cells to mature. [75]

Immunotherapy with anti-GD2 antibodies has become a cornerstone of the maintenance phase. The combination of dinutuximab with GM-CSF and isotretinoin significantly improves relapse-free and overall survival compared with isotretinoin alone. A positive effect on event-free and overall survival has been confirmed in real-world clinical practice. The role of interleukin-2 depends on the protocol and the benefit/toxicity ratio. [76]

Naxitamab is another anti-GD2 antibody used primarily in relapsed/refractory settings, including GM-CSF; comparative efficacy assessments with dinutuximab are ongoing, and the choice depends on the indication, availability, and toxicity profile. [77]

Radionuclide therapy with 131I-MIBG is an option for MIBG-positive relapsed/refractory disease; it is combined with chemotherapy or used as a bridge to transplantation. It allows for targeted irradiation of tumor cells that absorb MIBG and reduces tumor burden in systemic metastases. [78]

Targeted therapy with ALK inhibitors (cryozotinib/lorlatinib, etc.) is being considered in patients with activating ALK mutations, most often in relapsed patients. Data are accumulating in clinical trials; profound responses have been observed in some cases. Target selection requires molecular profiling of the tumor. [79]

Intensive protocols are associated with toxicity (pain during anti-GD2 infusion, neuropathy, cytopenias, infections, mucositis, cardiotoxicity, ototoxicity). Therefore, treatment is carried out in reference centers with supportive care, infection prevention, hearing/cardiac monitoring, and psychosocial and neurocognitive support programs. [80]

Table 6. Major therapeutic blocks and goals

Stage	Compound	Target
Induction	Platinum, alkylating agents, anthracyclines, etoposide	Reduce mass, increase resectability. [81]
Surgery	Organ-/function-preserving resection	Local control with minimal risk of complications (IDRFs). [82]
Consolidation	High-dose therapy + autotransplantation	Eradication of minimal residual disease. [83]
Radiation	Irradiation of the bed/lesions	Local pain control/palliation. [84]
Support	Isotretinoin ± anti-GD2 (dinutuximab/naxitamab) ± GM-CSF	Reducing the risk of relapse, destroying the remainder. [85]
Relapse	131I-MIBG, targets (ALK), research	Disease control, preparation for next steps. [86]

Prevention

There is no specific primary prevention for neuroblastoma: no proven modifiable risk factors have been identified. Screening programs to determine catecholamine metabolites in the population have not reduced mortality and are not recommended. The primary focus is early recognition of symptoms and timely referral. [87]

Families with familial cases or identified germline variants of ALK/PHOX2B are advised to receive genetic counseling, discussion of reproductive options, and individualized child care, including periodic examinations and imaging at a referral center. [88]

Secondary prevention of relapse is achieved through standardized protocols of maintenance therapy (retinoids, anti-GD2) and strict monitoring of minimal residual disease, which indirectly reduces the risk of late events. [89]

It is important for parents to be aware of potential late effects of treatment and to participate in survivorship care programs (vaccinations, cardiac and audio monitoring, endocrine monitoring, cognitive support). [90]

Forecast

The prognosis is determined by the risk group: in low and intermediate risk groups, 5-year overall survival is usually ≥90-95%. In the high-risk group, despite intensification, 5-year survival remains around 50-60%, although in certain cohorts and with a complete response to induction, the rates are higher. The introduction of anti-GD2 immunotherapy has improved early survival and event-free survival. [91]

Unfavorable prognostic factors include age ≥18 months, MYCN amplification, segmental aberrations (1p/11q/17q), widespread metastases, and unfavorable histology. In contrast, infants with MS stage and a favorable genomic profile may experience spontaneous regression and excellent outcome. [92]

The long-term outlook also depends on the toxicity of therapy. Follow-up programs are aimed at early detection of cardiovascular, auditory, endocrine, and neurocognitive sequelae, as well as secondary neoplasms. [93]

Ongoing clinical trials are evaluating the optimal placement of immunotherapy (including pre-transplant use), the role of MIBG in consolidation, new antibody and cellular approaches, and targets (ALK and others), offering hope for further improvement in outcomes. [94]

FAQ

Is this an "adrenal" tumor?
Most often, yes, from the adrenal medulla, but neuroblastoma also arises along the sympathetic chain of the neck/chest/abdomen/pelvis. The site influences coding and surgical tactics. [95]

Why is a MIBG scan necessary?
Most neuroblastomas accumulate MIBG, which allows for the identification of all lesions, assessment of treatment response, and planning of MIBG therapy in case of relapse. If the tumor is MIBG-negative, PET-CT is used. [96]

What is anti-GD2 therapy and why is it important?
Neuroblastoma cells express GD2. Anti-GD2 antibodies (dinutuximab/naxitamab) "mark" the cells for the immune system and improve survival in high-risk patients after transplantation or relapse. [97]

Is it possible to target mutations?
For ALK mutations, ALK inhibitors are considered (usually in the context of trials or in relapse). The decision is made by a multidisciplinary team after molecular profiling. [98]

Is it true that some children's tumors "go away" on their own?
Yes, infants with advanced MS sometimes experience regression without intensive therapy, but the decision to monitor requires strict criteria and observation in a specialized center. [99]

Additional tables

Table 7. Prognostic markers

Marker	Unfavorable	Comment
MYCN amplification	High	High risk criterion. [100]
Deletion 1p/11q	Unfavorable	Associated with relapse/resistance. [101]
+17q	Adverse	Often together with other aberrations. [102]
Ploidy (hyperdiploidy in infants)	Favorable	Related to regression/best answer. [103]

Table 8. Common differential diagnoses

Localization	Possible "double"	What makes it different
Retroperitoneal space	Wilms' tumor	Age, MIBG positivity, VMA/GVK. [104]
Mediastinum	Lymphomas, teratomas	PET behavior, markers, histology. [105]
Paravertebral	Nerve sheath tumors	MRI image, histology. [106]

Table 9. Symptoms and red flags

Symptom	What is it due to?	Action
Painless mass in the abdomen	Primary adrenal/paraganglion tumor	Urgent imaging and analysis. [107]
Bone pain/lameness	Bone metastases	Staging, pain relief, systemic therapy. [108]
Hypertension/diarrhea	Catecholamines/VIP	Drug control + treatment NB. [109]
OMAS	Paraneoplastic immune response	Oncosearch + immunomodulation. [110]