Abstract/Text: The clinical hallmark of neuroblastoma is heterogeneity, with the likelihood of cure varying widely according to age at diagnosis, extent of disease, and tumour biology. A subset of tumours will undergo spontaneous regression while others show relentless progression. Around half of all cases are currently classified as high-risk for disease relapse, with overall survival rates less than 40% despite intensive multimodal therapy. This Seminar focuses on recent advances in our understanding of the biology of this complex paediatric solid tumour. We outline plans for the development of a uniform International Neuroblastoma Risk Group (INRG) classification system, and summarise strategies for risk-based therapies. We also update readers on new discoveries related to the underlying molecular pathogenesis of this tumour, with special emphasis on advances that are translatable to the clinic. Finally, we discuss new approaches to treatment, including recently discovered molecular targets that might provide more effective treatment strategies with the potential for less toxicity.

Abstract/Text: BACKGROUND: The International Neuroblastoma Pathology Classification was established in 1999 for the prognostic evaluation of patients with neuroblastic tumors (NTs).
METHODS: Pathology slides from 746 NTs (the Children's Cancer Group [CCG]-3881 and CCG-3891 studies) were evaluated according to the International Classification. First, prognostic effects of the morphologic indicators (grade of neuroblastic differentiation: undifferentiated [U], poorly differentiated [PD] and differentiating [D]; and mitosis-karyorrhexis index [MKI]: low [L-MKI], intermediate [I-MKI], and high [H-MKI]) for tumors in the neuroblastoma (NB) category were tested. Then, prognostic significance of the International Classification for all NTs in four categories (neuroblastoma [NB]; ganglioneuroblastoma, intermixed [GNBi]; ganglioneuroma [GN]; and ganglioneuroblastoma, nodular [GNBn]) was analyzed. Finally, age distribution of the patients in the four categories as well as three subtypes (based on the grade of differentiation) in the NB category was compared.
RESULTS: There were 630 NB tumors, 30 GNBi tumors, 10 GN tumors, and 76 GNBn tumors. In the NB category, prognostic effects of the indicators (three grades of differentiation and three mitosis-karyorrhexis index [MKI] classes: low [L], intermediate [I], and high [H]) were affected significantly by the age of the patients. The age-linked evaluation of the indicators according to the International Classification successfully distinguished two prognostic subgroups: the favorable histology (FH) subgroup (PD/D and L/I-MKI tumors in patients age < 1.5 years, D and L-MKI tumors in patients ages 1.5-5.0 years; 90.4% 5-year event free survival [EFS]) and the unfavorable histology (UH) subgroup (U and/or H-MKI tumors in patients of any age, PD and/or I-MKI tumors in patients ages 1.5-5.0 years, any grade of differentiation, and any MKI class in patients age > or = 5 years; 26.9% EFS) (P < 0.0001). The International Classification also distinguished the FH group (FH subgroup with NB, GNBi, and GN tumors) and the UH group (UH subgroup with NB and GNBn tumors) for all NTs (90.8% EFS and 31.2% EFS, respectively; P < 0.0001) and provided independent prognostic information on both patient age and disease stage (P < 0.0001). Among patients with FH tumors, the median ages of patients with the PD and D subtype tumors in the NB category were 0.43 years (range, 0-1.50 years) and 1.50 years (range, 0.02-4.65 years), respectively, and the median ages of patients with GNBi and GN tumors were 3.51 years (range, 0.96-14.85 years) and 4.80 years (range, 1.94-17.05 years), respectively. In contrast, patients with UH tumors generally were older when they were diagnosed, and with median ages of 2.99 years (range, 1.30-8.84 years) for patients with U subtype tumors, 2.59 years (range, 0.0-12.57 years) for patients with PD subtype tumors, 2.16 years (range, 0.35-9.90) for patients with D subtype tumors, and 3.26 years (range, 0.57-15.90 years) for patients with GNBn tumors.
CONCLUSIONS: This study confirmed the prognostic significance of the International Classification, substantiated age-linked prognostic effects of the morphologic indicators for patients with the tumors in the NB category, and supported the concept of an age-appropriate framework of maturation for patients with the tumors in the FH group.

Copyright 2001 American Cancer Society.

Abstract/Text: The clinical hallmark of neuroblastoma is heterogeneity, with the likelihood of cure varying widely according to age at diagnosis, extent of disease, and tumour biology. A subset of tumours will undergo spontaneous regression while others show relentless progression. Around half of all cases are currently classified as high-risk for disease relapse, with overall survival rates less than 40% despite intensive multimodal therapy. This Seminar focuses on recent advances in our understanding of the biology of this complex paediatric solid tumour. We outline plans for the development of a uniform International Neuroblastoma Risk Group (INRG) classification system, and summarise strategies for risk-based therapies. We also update readers on new discoveries related to the underlying molecular pathogenesis of this tumour, with special emphasis on advances that are translatable to the clinic. Finally, we discuss new approaches to treatment, including recently discovered molecular targets that might provide more effective treatment strategies with the potential for less toxicity.