Demystifying neuroblastoma malignancy through fractal dimension, entropy, and lacunarity

Neuroblastoma is a pediatric solid tumor with a prognosis associated with histology and age of the patient, which are the parameters of the well-established current classification (Shimada classification). Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor. Therefore, there is a continuous need to stratify the children suffering from this tumor. A mathematical and computational approach is proposed to enable automatic and precise cancer diagnosis on the histological slide.We targeted the complexity of neuroblastoma by calculating its image entropy (S), fractal dimension (FD), and lacunarity (λ) in a combined mathematical code. First, we tested the proposed method for patient-derived glioma images. It allowed distinguishing between normal brain tissue, grade II, and grade III glioma, which harbor different outcomes.In neuroblastoma, our analysis of image's FD, S, and λ combined with a machine learning algorithm automatically predicted tumor malignancy with a receiver operating characteristic curve of 0.82. FD, S, and λ distinguish between neuroblastoma and ganglioneuroma, but they only partially differentiate between the normal samples and the other classes. Ganglioneuroma, the most differentiated form, and poorly-differentiated neuroblastoma display different values of FD, S, and λ.FD, S, and λ of imaging recognize groups in neuroblastic tumors. We suggest that future studies including these features may challenge the current Shimada classification of neuroblastoma with categories of favorable and unfavorable histology. It is expected that this methodology could trigger multicenter studies and potentially find practical use in the clinical setting of children's hospitals worldwide.