Approach

As neuroblastoma can occur anywhere along the sympathetic nervous system, signs and symptoms depend on the location of the original tumour and any sites of metastases.

The tumour's ability to metabolise catecholamines may also contribute to symptomatology.

Diagnosis is confirmed by unequivocal histology from tumour tissue by light microscopy, or by unequivocal evidence of neuroblastoma cells on bone marrow aspiration and biopsy in the setting of increased urine catecholamines.[27]

History

The vast majority of neuroblastomas are diagnosed in children younger than 5 years of age, and nearly all patients are diagnosed by the time they are 10 years of age. ACS: key statistics about neuroblastoma Opens in new window​ The median age at diagnosis is 17 months.​[12]​​​​

A family history of neuroblastic tumours may be present 1% to 2% of patients.[13] A few medical conditions, some of which are related to aberrant neural crest development, predispose a patient to developing neuroblastoma, including Turner syndrome, Hirschsprung's disease, congenital central hypoventilation syndrome, and neurofibromatosis type 1.[17][28]

Presenting symptoms can be a direct result of mass effect of the primary lesion (e.g., constipation, abdominal distention) or the result of metastases (e.g., bone pain); however, patients with localised disease may be asymptomatic.

Abdominal distention (caused by the presence of a large abdominal mass) is the most common symptom.[29][30]​​​ In the UK, the National Institute for Health and Care Excellence (NICE) recommend very urgent referral (an appointment within 48 hours) for specialist assessment for neuroblastoma in children with a palpable abdominal mass or an unexplained enlarged abdominal organ.[31]

Constipation, usually secondary to the mass effect of an abdominal tumour, is also a common presenting symptom. Patients with tumour secretion of vasoactive intestinal protein (VIP), a paraneoplastic syndrome associated with neuroblastoma, may present with intractable secretory diarrhoea, although this is uncommon.[9]

Patients (or carer) commonly report general systemic symptoms such as decreased appetite, weight loss, fussiness (in infants), fatigue, or abdominal, bone, or back pain. These symptoms may indicate metastatic spread.

Clinical presentation may differ between infants and older children. Infants may sometimes present with either an asymptomatic adrenal mass detected on routine prenatal ultrasound, or in the case of patients <18 months with stage MS disease (International Neuroblastoma Risk Group Staging System), severe hepatomegaly secondary to liver metastases.[2][32]​ Skin nodules are also more common in infants compared with older children.

Physical examination

Presenting signs will depend on the location of the primary lesion and the presence of any metastases. A large abdominal mass is commonly felt on palpation of the abdomen.[29][30]

If the primary lesion is in the upper portion of the thoracic outlet or cervical sympathetic chain, patients will often present with:[1][5][6]

  • Horner's syndrome (characterised by ptosis, miosis, anhidrosis) due to sympathetic nerve compression

or

  • Superior vena cava syndrome (characterised by dyspnoea, facial swelling, cough, distended neck/chest veins, oedema of the upper extremities) due to mass effect on the vascular system

If the tumour extends into the spinal canal, patients may initially present with signs of spinal cord compression including loss of bowel and bladder function, lower-extremity weakness, and back pain.

Hypertension may be present, but is uncommon. It occurs due to mass effect of an abdominal tumour, which may compromise renal vasculature resulting in alterations of the renin-activating system pathway, or may be a result of tumour-associated catecholamine secretion.[1][25]

Opsoclonus-myoclonus ataxia (OMA; also known as opsoclonus-myoclonus syndrome), a paraneoplastic syndrome associated with neuroblastoma, occurs in <3% of patients with neuroblastoma.[33] In patients with OMA, nearly one half will be diagnosed with neuroblastoma; therefore, all children with OMA should be evaluated for neuroblastoma.[34] Rapid, dancing eye movements, rhythmic jerking of limbs/trunk, and ataxia are pathognomonic for OMA.[8]

​Signs of metastatic spread may be evident on examination

Specific signs will depend on the location of the metastases, the most common sites being lymph nodes, bone marrow, bone, liver, skin, orbits, and dura. Patients with orbital metastases may present with periorbital ecchymosis (commonly referred to as panda eyes). Palpable subcutaneous skin nodules are another common sign associated with metastatic spread, but occur mainly in infants.[35][36]​​ If the disease has spread to the bone marrow, pallor, infections, and bleeding may be present as a result of pancytopenia. Hepatomegaly may be noted with metastatic spread to the liver.

Initial investigations

Initial investigations for all patients with suspected neuroblastoma include a full blood count, serum electrolytes, renal function, and liver function tests. Lactate dehydrogenase may be considered.[37]

Because neuroblastoma arises from the sympathetic nervous system, specific tests to look for the presence of catecholamine metabolism may form part of the initial work-up.[37] Testing for the catecholamine degradation products, homovanillic acid (HVA) and vanillylmandelic acid (VMA), is required for diagnosis if bone marrow is the only diagnostic tissue obtained. HVA and VMA are secreted by the majority of tumours and can be detected in the patient's urine.[26] This test is highly sensitive and specific for neuroblastoma.

Urinary catecholamine levels are no longer recommended for the assessment of treatment response (due to influence of diet and lack of standardisation).[37][38]​​

Initial imaging studies

Ultrasound of the abdomen should form part of the work-up in all patients with suspected neuroblastoma. If a mass is detected on ultrasound, further imaging should include a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the abdomen, and may reveal a heterogeneous mass (possibly with calcifications). If there is intraspinal extension of the tumour, MRI is preferred over CT.[37][Figure caption and citation for the preceding image starts]: CT scan of the abdomen showing paraspinal neuroblastomaFrom the personal collection of Dr Jason Shohet [Citation ends].com.bmj.content.model.Caption@2c89593b[Figure caption and citation for the preceding image starts]: CT scan showing a thoracic paraspinal neuroblastoma wrapping around the spineFrom the personal collection of Dr Jason Shohet [Citation ends].com.bmj.content.model.Caption@5d62f3e4

Guidelines recommend biopsy for most patients if upfront resection is not indicated.[37] The tissue sample may be obtained by percutaneous needle or incisional biopsy of the primary tumour, or bone marrow aspiration and biopsy if bone marrow metastasis is suspected.[39]

Definitive diagnosis requires one of the following:[27]

  • Unequivocal histological diagnosis from tumour tissue by light microscopy.

  • Unequivocal evidence of neuroblastoma cells on bone marrow aspiration and biopsy in the setting of increased urine catecholamines.

Evaluation of tumour tissue

Key for risk stratification. Amplification of v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN) is associated with aggressive (high-risk) disease. Therefore, tumour tissue must be evaluated for MYCN.[40] Segmental chromosomal aberrations may be associated with aggressive disease (depending upon other factors).[37] Evaluation of DNA ploidy may be required to guide treatment duration. Bilateral bone marrow aspirates and trephine biopsies may be of diagnostic value when, in rare cases, marrow is the only source of tumour material.[37]

Investigations for metastatic disease

Neuroblastoma commonly presents with metastases. As such, a comprehensive evaluation for metastases is recommended in all patients for whom there is a high suspicion for neuroblastoma, or in patients who have been diagnosed with neuroblastoma.

123-Iodine-metaiodobenzylguanidine (MIBG) scintigraphy is recommended for the assessment of metastatic disease.[37] Thyroid protection with potassium iodide should be given prior to all MIBG infusions, whether therapeutic or diagnostic.[41][Figure caption and citation for the preceding image starts]: 123-iodine-metaiodobenzylguanidine (MIBG) scintigraphy showing multifocal bony metastasesFrom the personal collection of Dr Jason Shohet [Citation ends].com.bmj.content.model.Caption@6222ea85

18-Fluorodeoxyglucose (FDG)-PET should be obtained in the absence of 123-I-MIBG uptake or in patients with suspected mixed-avidity disease.[37]

Staging

In order to standardise staging internationally, irrespective of surgery, the International Neuroblastoma Risk Group (INRG) developed a staging system based on image-defined risk factors (IDRFs).[2] IDRFs are determined at the time of diagnosis, prior to surgery.

See the Diagnostic criteria section for further detail on the various staging systems.

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