Pathology of peripheral neuroblastic tumors: an update

Abstract

The International Neuroblastoma Pathology Classification, which is used to distinguish the Favorable Histology (FH) and Unfavorable Histology (UH) Groups among peripheral neuroblastic tumors, has been incorporated into the Children’s Oncology Group (COG) neuroblastoma clinical trials and plays a significant role in patient stratification and protocol assignment. Since the survival rate of patients in the UH Group is still very low, we have been continuously investigating biologically relevant relationships between molecular alterations leading to a poor prognosis of the patients and their histological/cytological manifestations. First, we established a new concept of MYC-driven neuroblastoma and demonstrated that either n-MYC or c-MYC oncoprotein overexpression has a more direct prognostic impact than genomic amplification. In this subgroup of UH neuroblastomas, nucleolar hypertrophy is found to be the sign for sustaining higher levels of n-MYC/c-MYC oncoprotein expression. In addition to MYC-driven neuroblastomas, we are proposing to include telomere-related gene alterations, such as telomere reverse transcriptase (TERT) overexpression and alternative lengthening of telomere (ALT) phenotype activated by the loss of the alpha-thalassemia/mental retardation syndrome X-linked (ATRX) protein, for identifying new subgroups in the UH neuroblastomas. Classifying/stratifying the patients in the UH neuroblastomas into four subgroups, namely, MYC, TERT, ALT and Null, on the basis of immunohistochemically identifiable and actionable/druggable targets could lead to future precision pathway-targeting therapies.