Neuroblastoma: clinical and biological approach to risk stratification and treatment

Abstract

Neuroblastoma is the most common extra-cranial solid tumor of childhood and the most common in the first year of life. It is a unique malignancy in that infants often present with either localized or metastatic disease that can spontaneously regress without intervention while older children can succumb to the disease after months to years of arduous therapy. Given this wide range of outcomes, the International Neuroblastoma Risk Group was created to stratify patients based on presenting characteristics and tumor biology in order to guide intensity of treatment strategies. The goal has been to decrease therapy for low-risk patients to avoid long-term complications while augmenting and targeting therapies for high-risk patients to improve overall survival. The international risk stratification depends on age, stage, histology, MYCN gene amplification status, tumor cell ploidy and segmental chromosomal abnormalities. Treatment for asymptomatic low-risk patients with an estimated survival of > 98% is often observation or surgical resection alone, whereas intermediate-risk patients with an estimated survival of > 90% require moderate doses of response-adjusted chemotherapy along with resection. High-risk patients undergo multiple cycles of combination chemotherapy before surgery, followed by consolidation with myeloablative autologous hematopoietic stem cell transplantation and local radiation and finally immunotherapy with differentiation therapy as maintenance phase. With this approach, outcome for patients with neuroblastoma has improved, as the field continues to expand efforts in more targeted therapies for high-risk patients.

Keywords: Clinical presentation; Neuroblastoma; Pediatric oncology; Risk classification; Treatment.

Figure 1. Skin Metastasis in Infant with Stage MS Neuroblastoma

A) Skin metastasis in neuroblastoma can be seen in stage MS disease, consisting of subcutaneous nodules with a bluish hue. B) Fine needle aspirate of a skin metastasis showing histology consistent with neuroblastoma, here showing a Homer-Wright rosette pattern.

Figure 2. Imaging in Neuroblastoma

Imaging in neuroblastoma must be multimodal to accurately locate and characterize the primary tumor with cross-sectional imaging and locate metastatic disease with MIBG. A) An MRI showing a paraspinal mass invading the spinal canal across many thoracic levels, causing spinal cord compression. Also note the metastatic involvement of multiple vertebral bodies. B) ¹²³I-metaiodobenzylguanidine (MIBG) scan showing the primary thoracic tumor and revealing wide spread metastatic disease involving the bones. C) Single-photon emission computed tomography (SPECT) combining MIBG and CT to better localize the MIBG uptake.

Figure 3. International Neuroblastoma Risk Group (INRG) Consensus Pretreatment Classification Schema

Reprinted with permission. ©2009 American Society of Clinical Oncology. All rights reserved. Cohn, S et al: J Clin Oncol 27(2), 2009: 289–297. This is the original published INRG risk classification. All blank fields represent any value. GN, ganglioneuroma; GNB, ganglioneuroblastoma; Amp, amplified; NA, not amplified.

Figure 4. Event Free Survival Based on Risk Stratification (reproduced with permission from (Park, et al., 2013))

Patients with high risk disease have significantly worse event free survival than those with low or intermediate risk disease. Event free Kaplan-Meier survival curves from the time of diagnosis for children enrolled on Children’s Oncology Group, Children’s Cancer Group or Pediatric Oncology Group studies between 1990 and 2010. Risk stratification based on INRG risk classification.

Figure 5. Treatment Overview for Neuroblastoma by Risk Classification

Patients with low risk disease are often managed with surgical resection or observation alone with tumors likely to spontaneously regress that are not causing symptoms. Intermediate patients are treated with chemotherapy with the number of cycles dependent on their response as well as surgical resection of the primary tumor. High risk disease requires intensive multimodal therapy, including chemotherapy, surgery, myeloablation, radiation, immunotherapy and differentiation therapy.