Neuroblastoma is the most common extracranial solid tumor in infancy, accounting for approximately 15% of pediatric deaths from oncologic causes.1,2 Neuroblastoma is an umbrella term encompassing neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. These tumors are comprised of neuroblasts, primitive undifferentiated sympathetic cells, and stroma, and can arise anywhere along the sympathetic chain.3 The median age at diagnosis is approximately 16 months, with 95% of neuroblastomas diagnosed by 7 years of age.4 Common tumor sites are: the adrenal glands (35%), extra-adrenal retroperitoneum (30% to 35%), and posterior mediastinum (20%).5 Given the wide range of histopathology, the natural progression of neuroblastoma is quite variable, with some tumors undergoing spontaneous regression, and others progressing to death. Even with recent advanced treatment regimens, patients with metastatic neuroblastoma have a poor 3-year, event-free survival of about 60%, despite multimodal therapy.6
A few staging strategies have been developed to stratify patients and help deliver appropriate therapy based on individual risk. The International Neuroblastoma Staging System (INSS), developed in 1988 and modified in 1993, was the first widely used staging system to standardize the extent of disease in neuroblastoma patients.7 The INSS is a surgical staging system, with stages 1-3 defined by the extent of surgical excision of tumor, and stage 4 representing metastatic disease. However, pretreatment risk assessments and comparisons across clinical trials were difficult given its reliance on surgical outcomes, which can vary across surgeons. In 2009, the International Neuroblastoma Risk Group established the INRG Staging System (Table 1), which standardized neuroblastoma staging in a presurgical manner.4,8 The INRG staging system incorporates image-defined risk factors (IDRFs) (Tables 2, 3) as well as other genetic and biomolecular markers to risk stratify patients. IDRFs are tumor imaging features, such as involvement of vasculature or other critical organs that have been associated with risk of resecting neuroblastoma. Tumors without an IDRF are considered L1, whereas a tumor with an IDRF is L2. Metastatic disease is stage M, as in the INSS. Stage MS applies to patients with metastatic disease confined to the skin, liver and/or bone marrow in patients 18 months or younger. This differs from the INSS stage 4S, which has an age cutoff of 12 months. In both staging systems, metastatic disease must be iodine-123 metaiodobenzylguanidine (MIBG) negative with less than 10% of total nucleated cells identified as malignant on bone marrow smears or biopsy.7,8
A variety of imaging modalities are employed during the initial diagnosis of neuroblastoma.9 Ultrasound is often the first imaging study ordered when there is suspicion of a mass. Ultrasound is advantageous due to the lack of radiation or need for sedation; however, it is insufficient for the evaluation of IDRFs according to the INRG staging system. This is due to poor interobserver reproducibility as well as limited assessment of highly calcified tumors due to posterior acoustic shadowing. As outlined in the INRG,8 CT or MR are mandatory imaging studies to assess for the extent of tumor and to document IDRFs. CT is widely available and can be performed rapidly often without the need for sedation. It also has higher resolution than MR and is the best modality to evaluate for airway compression or lung parenchymal involvement. MR has better soft-tissue contrast and is the best modality to evaluate spinal canal extension; however, it is not as widely available as CT and often requires sedation. MIBG is a norepinephrine analog that demonstrates uptake in approximately 90% of neuroblastomas10 and is mandatory for the evaluation of metastatic disease. A variety of MIBG scoring systems have been published and are reviewed in the INRG Task Force publication by Matthay et al.11 F-18 fluorodeoxyglucose (FDG) PET/CT is occasionally used when MIBG is not widely available or for MIBG negative tumors; however, studies have been inconclusive, and its use is not clearly defined. Some studies have shown higher sensitivity than MIBG for soft-tissue lesions12 and stage 1 or 2 disease.13 Other studies have shown lower overall and event free survival in tumors with higher SUVmax.14
The IDRF is a central component to the INRG Staging System. As the name implies, IDRFs are imaging features associated with a high risk of surgical complication. To create uniformity and aid in reproducibility across clinical trials, a lexicon has been suggested to describe tumor IDRFs.15 As stated in the INRG,8 either CT or MR can be used to determine IDRFs, with usage based on local availability and clinician or radiologist preference.
Separation – “visible layer, usually fat, is present between the tumor and the neighboring structure.”15 An IDRF is not present if there is separation.
Contact – “no visible layer is present between the tumor and the neighboring structure.” 15 For an artery, contact occurs when less than 50% of the vessel circumference is enveloped by tumor. For a vein, the term flattened is used to describe when a vein is decreased in diameter, but the lumen remains partly visible. An IDRF is not present if there is contact, except for renal vessels (see Invasion).
Encasement – “neighboring structure is surrounded by the tumor.” 15 For an artery, encasement requires more than 50% of the vessel circumference to be enveloped by tumor. For a vein, encasement is present when the lumen is no longer visible. An IDRF is present if there is encasement.
Compression – “tumor is in contact with the airways and causes the short axis of the airway to be reduced.” 15 This only applies to airways. An IDRF is present if there is compression.
Infiltration – “extension into a neighboring organ, causing the margins between the tumor and the infiltrated structure to be lacking or ill defined.” 15 This applies to vital structures other than vessels. An IDRF is present if there is infiltration.
Invasion – This term applies to tumor relationship with the renal pedicle, as studies have shown that surgical resection of a tumor with renal invasion often requires nephrectomy or leads to segmental renal infarction.16 Invasion is present if the tumor is in contact (see above) with the renal artery, renal vein, or renal pelvis. An IDRF is present if there is invasion.
Multiple body compartments – Tumors that involve multiple contiguous body compartments are considered IDRF positive (Figure 1). Multifocal primary neuroblastomas are rare. They may be familial or seen in patients with syndrome-associated neuroblastic tumors. When found, multifocality should be documented and each neoplasm should be staged according to the greatest extent of disease. Multifocality alone is not considered IDRF.
Neck – Primary cervical neuroblastoma is uncommon, occurring less than 5% of the time.3 Cervical neuroblastomas arise from the superior cervical sympathetic chain, and tumors that encase the carotid or vertebral arteries, encase the jugular vein, compress the airway, and/or infiltrate the skull base are considered IDRF positive.
Cervicothoracic junction – Similar to cervical neuroblastoma, tumors that encase the major vessels (subclavian, carotid, and/or vertebral) or compress the trachea are considered IDRF positive. Additionally, tumors encasing the brachial plexus roots are IDRF positive.
Thorax – Thoracic neuroblastomas account for approximately 20% of neuroblastomas3 and arise from the paraspinal sympathetic chain in the posterior mediastinum. In addition to encasement of the aorta and trachea, tumors that involve the lower mediastinum, infiltrating the costo-vertebral junction between T9 and T12, are also considered IDRF positive. This is because injury to the anterior spinal artery may result in spinal cord infarction.
Thoraco-abdominal junction – Tumors that encase the aorta and/or vena cava are IDRF positive.
Abdomen and pelvis – The vast majority of neuroblastomas arise from the abdomen and pelvis,3 originating in the adrenal glands or from the sympathetic ganglia or sympathetic fibers along the aorta and major branches. Vascular involvement is common, and encasement of the origin of the celiac artery and/or superior mesenteric artery, aorta, inferior vena cava, or iliac vessels are considered IDRF positive. As stated above, the risk of renal complications is high, so renal invasion is also considered IDRF positive. Additional IDRFs are listed in Table 2.
Spinal – The paraspinal course of the sympathetic ganglion chain commonly enables tumor extension into the spinal canal common. Spinal IDRF positive features include 1) invasion of more than one-third of the spinal canal (on axial plane) (Figure 2), 2) perimedullary leptomeningeal spaces that are effaced, and/or 3) abnormal spinal cord signal.
Neuroblastoma is a common pediatric malignancy with a wide range of biological behaviors, from spontaneous regression to progressive disease and death. Optimal treatment requires personally tailored treatment regimens based on individual patient risk. The INRG staging system is a robust and widely used staging system that incorporates image-defined risk factors to stratify patients in treatment categories according to risk.
Sung A, Rubin EM, Lai H. Review of Image-Defined Risk Factors in Neuroblastoma. J Am Osteopath Coll Radiol. 2021;10(3):15-20.