Histologic Response to Induction Chemotherapy in High-Risk Neuroblastoma.
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INTRODUCTION: Tumor histology at diagnosis is used in conjunction with other prognostic features to risk stratify patients with neuroblastoma and to assign therapy regimens. In patients with high-risk disease, adjustment of therapy is tailored to treatment response, largely based on disease imaging following induction chemotherapy and resection of the primary tumor. The goals of this study were to (i) quantify changes in histologic features in the primary tumor between diagnosis and resection, and (ii) assess the prognostic capability of such alterations. METHODS: Tumor histology from paired samples at diagnosis and resection was evaluated from 94 patients with high-risk neuroblastoma enrolled in Children's Oncology Group (COG) trials from 2001 to 2013. Presence of Schwannian stroma, neuropil, degree of differentiation, mitosis karyorrhexis index (MKI), necrosis, and percentage of neuroblastic cells were annotated. Changes in tumor histology between diagnosis and resection were analyzed for association with overall survival (OS) and progression-free survival (PFS). RESULTS: Significant changes between diagnosis and resection were observed in all histologic parameters (p < 0.01), suggesting a more phenotypically differentiated tumor following induction therapy. A higher percentage of intermediate-high MKI in tumor cells at diagnosis was associated with a lower PFS and OS (p < 0.05). No other histologic factor was associated with survival at diagnosis or resection. The tumor percentage of intermediate-high MKI decreased by a mean of 75% from diagnosis to resection (p < 0.0001). The shift from intermediate/high MKI at diagnosis to low MKI at resection had a PFS hazard ratio (HR) of 2.1 (95% CI: 0.9, 4.9; p = 0.0908) and OS HR = 2.3 (95% CI: 0.9, 5.9; p = 0.0773). CONCLUSION: Our findings suggest that primary neuroblastoma tumors undergo a significant morphologic shift following induction chemotherapy to a differentiated, less mitotically active phenotype. However, the alterations are not prognostic of patient outcome either at resection alone, or when the change from diagnosis to resection is considered.