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Neuroblastoma Treatment (PDQ®)

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Stage Information for Neuroblastoma

Staging Evaluation
        Metaiodobenzylguanidine (mIBG) scan
        Other staging tests and procedures
International Neuroblastoma Staging Systems
        International Neuroblastoma Staging System (INSS)
        International Neuroblastoma Risk Group Staging System (INRGSS)

Staging Evaluation

A thorough evaluation for metastatic disease is performed before therapy initiation. The following studies are typically performed:[1]

Metaiodobenzylguanidine (mIBG) scan

Before resection of the primary tumor, bone involvement is assessed by mIBG scan, which is applicable to all sites of disease, and by technetium-99 scan if the results of the mIBG scan are negative or unavailable.[2,3] Approximately 90% of neuroblastomas will be mIBG avid. It has a sensitivity and specificity of 90% to 99% and is equally distributed between primary and metastatic sites.[4] Although iodine 123 (123I) has a shorter half-life, it is preferred over131I because of its lower radiation dose, better quality images, less thyroid toxicity, and lower cost.

Imaging with 123I-mIBG is optimal for identifying soft tissue and bony metastases and is superior to 18F-fluorodeoxyglucose positron emission tomography–computerized tomography (PET-CT) in a prospective comparison.[5] Baseline mIBG scans performed at diagnosis provide an excellent method for monitoring disease response and performing posttherapy surveillance.[6]

A retrospective analysis of paired mIBG and PET scans in 60 newly diagnosed neuroblastoma patients demonstrated that for International Neuroblastoma Staging System (INSS) stages 1 and 2 patients, PET was superior at determining the extent of primary disease and more sensitive for detection of residual masses. In contrast, for stage 4 disease, 123I-mIBG imaging was superior for the detection of bone marrow and bony metastases.[7]

Curie score and SIOPEN score

Multiple groups have investigated a semi-quantitative scoring method to evaluate disease extent and prognostic value. The most common scoring methods in use for evaluation of disease extent and response are the Curie and the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) methods.

  • Curie score: The Curie score is a semiquantitative scoring system developed to predict the extent and severity of mIBG-avid disease. The use of the Curie scoring system was assessed as a prognostic marker for response and survival with mIBG-avid, stage 4 newly diagnosed high-risk neuroblastoma (N = 280), treated on the Children’s Oncology Group (COG) protocol COG-A3973 (NCT00004188). Patients with a Curie score greater than 2 after induction therapy had a significantly worse event-free survival (EFS) than those with scores less than 2 (3-year EFS, 15.4% ± 5.3% for Curie score >2 vs. 44.9% ± 3.9% for Curie score ≤2; P < .001). A postinduction Curie score greater than 2 identified a cohort of patients at greater risk of an event, independent of other known neuroblastoma factors, including age, MYCN status, ploidy, mitosis-karyorrhexis index, and histologic grade.[8]

  • SIOPEN score: A retrospective study of 58 stage 4 patients from the German Pediatric Oncology Group compared the prognostic value of the Curie and SIOPEN scoring methods. At diagnosis, a Curie score of 2 or less and a SIOPEN score of 4 or less (best cutoff) at diagnosis were correlated to significantly better EFS and overall survival, compared with higher scores. After four cycles of induction, those with complete response by mIBG had a better outcome than those with residual uptake, but after six cycles, there was no significant difference.[9]

Other staging tests and procedures

Other tests and procedures used to stage neuroblastoma include the following:

  • Bone marrow aspiration and biopsy: Bone marrow is assessed by bilateral iliac crest marrow aspirates and trephine (core) bone marrow biopsies to exclude bone marrow involvement. To be considered adequate, core biopsy specimens must contain at least 1 cm of marrow, excluding cartilage. Bone marrow sampling may not be necessary for tumors that are otherwise stage 1.[10]

  • Lumbar puncture: Lumbar puncture is avoided because central nervous system (CNS) metastasis at diagnosis is rare,[11] and lumbar puncture may be associated with an increased incidence of subsequent development of CNS metastasis.[12]

  • Lymph node assessment: Palpable lymph nodes are clinically examined and histologically confirmed if indicated for staging.[1]

  • CT and magnetic resonance imaging (MRI) scan:
    • Three-dimensional (3-D) imaging of the primary tumor and potential lymph node drainage sites is done using CT scans and/or MRI scans of the chest, abdomen, and pelvis. Ultrasound is considered suboptimal for accurate 3-D measurements.

    • Paraspinal tumors may extend through neural foramina to compress the spinal cord. Therefore, MRI of the spine adjacent to any paraspinal tumor is part of the staging evaluation.

    • A brain/orbit CT and/or MRI is performed if clinically indicated by examination and/or uptake on mIBG scan.

International Neuroblastoma Staging Systems

International Neuroblastoma Staging System (INSS)

The INSS has replaced the previously used Evans and Pediatric Oncology Group (POG) staging systems. The INSS is described in Table 3 and represents the first step in harmonizing risk stratification worldwide. The INSS is a postoperative staging system that was developed in 1988 and used the extent of surgical resection to stage patients. This led to variability in stage assignments in different countries, and INSS staging was also affected by access to experienced pediatric surgeons. As a result of further advances in the understanding of neuroblastoma biology and genetics, a new risk classification system was developed that incorporates newer biological factors into the INSS and reaches consensus on the criteria for defining each of these guidelines.

INSS combines certain features of the previously used Evans and POG systems [1,13] and has identified distinct prognostic groups (refer to Table 3).[1,13-15]

Table 3. The International Neuroblastoma Staging System (INSS)
Stage/Prognostic Group Description 
mIBG = metaiodobenzylguanidine.
Stage 1Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (i.e., nodes attached to and removed with the primary tumor may be positive).
Stage 2ALocalized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.
Stage 2BLocalized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically
Stage 3Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.
Stage 4Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S.
Stage 4SLocalized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (by definition limited to infants younger than 12 months).[3] Marrow involvement should be minimal (i.e., <10% of total nucleated cells identified as malignant by bone biopsy or by bone marrow aspirate). More extensive bone marrow involvement would be considered stage 4 disease. The results of the mIBG scan, if performed, should be negative for disease in the bone marrow.

Controversy exists regarding the INSS staging system and the treatment of several small subsets of patients.[16-18] Risk group assignment and recommended treatment are expected to evolve as additional outcome data are analyzed. For example, the risk group for INSS stage 4, including patients aged 12 to 18 months, changed in 2005 for patients with MYCN-nonamplified status.[19-21]

International Neuroblastoma Risk Group Staging System (INRGSS)

The INRGSS is a preoperative staging system that was developed specifically for the INRG cellular classification system. The extent of disease is determined by the presence or absence of image-defined risk factors (IDRFs) and/or metastatic tumor at the time of diagnosis, before any treatment. IDRFs are surgical risk factors, detected by imaging, that make total tumor excision risky or difficult at the time of diagnosis.

The INRGSS simplifies stages into L1, L2, M or MS (refer to Table 4 for more information). Localized tumors are classified as stage L1 or L2 disease on the basis of whether one or more of the 20 IDRFs are present.[22] For example, in the case of spinal cord compression, an IDRF is present when more than one-third of the spinal canal in the axial plane is invaded, when the leptomeningeal spaces are not visible, or when the spinal cord magnetic resonance signal intensity is abnormal. By combining the INRGSS, preoperative imaging and biological factors, each patient has a risk stage defined that predicts outcome and dictates the appropriate treatment approach to be followed. The INRGSS has predictive value for lower stage patients, with stage L1 having a 5-year EFS of 90%, compared with 78% for L2.[22]

Most international protocols have begun to incorporate collection and use of IDRF in risk stratification and assignment of therapy.[23,24] It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and thereby facilitate comparisons of clinical trials conducted in different parts of the world.

Table 4. International Neuroblastoma Risk Group Staging Systema
Stage Description 
aAdapted from Monclair et al.[22]
L1 Localized tumor not involving vital structures as defined by the list of image-defined risk factorsa and confined to one body compartment.
L2 Locoregional tumor with presence of one or more image-defined risk factors.a
M Distant metastatic disease (except MS).
MS Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow.

  1. Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11 (8): 1466-77, 1993.  [PUBMED Abstract]

  2. Brisse HJ, McCarville MB, Granata C, et al.: Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project. Radiology 261 (1): 243-57, 2011.  [PUBMED Abstract]

  3. Taggart DR, London WB, Schmidt ML, et al.: Prognostic value of the stage 4S metastatic pattern and tumor biology in patients with metastatic neuroblastoma diagnosed between birth and 18 months of age. J Clin Oncol 29 (33): 4358-64, 2011.  [PUBMED Abstract]

  4. Howman-Giles R, Shaw PJ, Uren RF, et al.: Neuroblastoma and other neuroendocrine tumors. Semin Nucl Med 37 (4): 286-302, 2007.  [PUBMED Abstract]

  5. Papathanasiou ND, Gaze MN, Sullivan K, et al.: 18F-FDG PET/CT and 123I-metaiodobenzylguanidine imaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 52 (4): 519-25, 2011.  [PUBMED Abstract]

  6. Kushner BH, Kramer K, Modak S, et al.: Sensitivity of surveillance studies for detecting asymptomatic and unsuspected relapse of high-risk neuroblastoma. J Clin Oncol 27 (7): 1041-6, 2009.  [PUBMED Abstract]

  7. Sharp SE, Shulkin BL, Gelfand MJ, et al.: 123I-MIBG scintigraphy and 18F-FDG PET in neuroblastoma. J Nucl Med 50 (8): 1237-43, 2009.  [PUBMED Abstract]

  8. Yanik GA, Parisi MT, Shulkin BL, et al.: Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group. J Nucl Med 54 (4): 541-8, 2013.  [PUBMED Abstract]

  9. Decarolis B, Schneider C, Hero B, et al.: Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study. J Clin Oncol 31 (7): 944-51, 2013.  [PUBMED Abstract]

  10. Russell HV, Golding LA, Suell MN, et al.: The role of bone marrow evaluation in the staging of patients with otherwise localized, low-risk neuroblastoma. Pediatr Blood Cancer 45 (7): 916-9, 2005.  [PUBMED Abstract]

  11. DuBois SG, Kalika Y, Lukens JN, et al.: Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol 21 (3): 181-9, 1999 May-Jun.  [PUBMED Abstract]

  12. Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer 91 (8): 1510-9, 2001.  [PUBMED Abstract]

  13. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988.  [PUBMED Abstract]

  14. Castleberry RP, Shuster JJ, Smith EI: The Pediatric Oncology Group experience with the international staging system criteria for neuroblastoma. Member Institutions of the Pediatric Oncology Group. J Clin Oncol 12 (11): 2378-81, 1994.  [PUBMED Abstract]

  15. Ikeda H, Iehara T, Tsuchida Y, et al.: Experience with International Neuroblastoma Staging System and Pathology Classification. Br J Cancer 86 (7): 1110-6, 2002.  [PUBMED Abstract]

  16. Kushner BH, Cheung NK: Treatment reduction for neuroblastoma. Pediatr Blood Cancer 43 (6): 619-21, 2004.  [PUBMED Abstract]

  17. Kushner BH, Kramer K, LaQuaglia MP, et al.: Liver involvement in neuroblastoma: the Memorial Sloan-Kettering Experience supports treatment reduction in young patients. Pediatr Blood Cancer 46 (3): 278-84, 2006.  [PUBMED Abstract]

  18. Navarro S, Amann G, Beiske K, et al.: Prognostic value of International Neuroblastoma Pathology Classification in localized resectable peripheral neuroblastic tumors: a histopathologic study of localized neuroblastoma European Study Group 94.01 Trial and Protocol. J Clin Oncol 24 (4): 695-9, 2006.  [PUBMED Abstract]

  19. Schmidt ML, Lal A, Seeger RC, et al.: Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 23 (27): 6474-80, 2005.  [PUBMED Abstract]

  20. London WB, Castleberry RP, Matthay KK, et al.: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23 (27): 6459-65, 2005.  [PUBMED Abstract]

  21. George RE, London WB, Cohn SL, et al.: Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 23 (27): 6466-73, 2005.  [PUBMED Abstract]

  22. Monclair T, Brodeur GM, Ambros PF, et al.: The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 27 (2): 298-303, 2009.  [PUBMED Abstract]

  23. Cecchetto G, Mosseri V, De Bernardi B, et al.: Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 23 (33): 8483-9, 2005.  [PUBMED Abstract]

  24. Simon T, Hero B, Benz-Bohm G, et al.: Review of image defined risk factors in localized neuroblastoma patients: Results of the GPOH NB97 trial. Pediatr Blood Cancer 50 (5): 965-9, 2008.  [PUBMED Abstract]