Improved risk stratification by PET-based intratumor heterogeneity in children with high-risk neuroblastoma

Abstract

Purpose: The substratification of high-risk neuroblastoma is challenging, and new predictive imaging biomarkers are warranted for better patient selection. The aim of the study was to evaluate the prognostic role of PET-based intratumor heterogeneity and its potential ability to improve risk stratification in neuroblastoma.

Methods: Pretreatment ¹⁸F-FDG PET/CT scans from 112 consecutive children with newly diagnosed neuroblastoma were retrospectively analyzed. The primary tumor was segmented in the PET images. SUVs, volumetric parameters including metabolic tumor volume (MTV) and total lesion glycolysis (TLG), and texture features were extracted. After the exclusion of imaging features with poor and moderate reproducibility, the relationships between the imaging indices and clinicopathological factors, as well as event-free survival (EFS), were assessed.

Results: The median follow-up duration was 33 months. Multivariate analysis showed that PET-based intratumor heterogeneity outperformed clinicopathological features, including age, stage, and MYCN, and remained the most robust independent predictor for EFS [training set, hazard ratio (HR): 6.4, 95% CI: 3.1-13.2, p < 0.001; test set, HR: 5.0, 95% CI: 1.8-13.6, p = 0.002]. Within the clinical high-risk group, patients with a high metabolic heterogeneity showed significantly poorer outcomes (HR: 3.3, 95% CI: 1.6-6.8, p = 0.002 in the training set; HR: 4.4, 95% CI: 1.5-12.9, p = 0.008 in the test set) compared to those with relatively homogeneous tumors. Furthermore, intratumor heterogeneity outran the volumetric indices (MTVs and TLGs) and yielded the best performance of distinguishing high-risk patients with different outcomes with a 3-year EFS of 6% vs. 47% (p = 0.001) in the training set and 9% vs. 51% (p = 0.004) in the test set.

Conclusion: PET-based intratumor heterogeneity was a strong independent prognostic factor in neuroblastoma. In the clinical high-risk group, intratumor heterogeneity further stratified patients with distinct outcomes.

Keywords: 18F-FDG; PET/CT; intratumor heterogeneity; neuroblastoma; pediatric; radiomics.

Figure 1

Flowchart shows study population selection, with exclusion criteria.

Figure 2

Receiver-operating characteristic curve analysis for the prediction of MYCN amplification according to a model composed of two texture features.

Figure 3

Kaplan–Meier event-free survival (EFS) curves in children with neuroblastoma having neither, one, or both imaging risk factors—GLRLM_RLNU ≥1,828 and Histogram_Entropy ≥3.3—in the training set (A) and the test set (B).

Figure 4

Kaplan–Meier curves for EFS in children with high-risk neuroblastoma in the training set according to (A) metabolic tumor volume (MTV) with a cutoff value of 120 ml; (B) MTV41% with a cutoff value of 65 ml; (C) total lesion glycolysis (TLG) with a cutoff value of 426 g; (D) TLG41% with a cutoff value of 141 g; (E) rad-risk.

Figure 5

Kaplan–Meier curves for EFS in children with high-risk neuroblastoma in the test set according to (A) MTV with a cutoff value of 120 ml; (B) MTV41% with a cutoff value of 65 ml; (C) TLG with a cutoff value of 426 g; (D) TLG41% with a cutoff value of 141 g; (E) rad-risk.

Figure 6

Two patients with a high-risk neuroblastoma and high or low intratumor heterogeneity. Both patients had amplified MYCN and stage 4 diseases. (A–D) A 20-month-old girl with a highly heterogeneous FDG uptake in the primary tumor (high rad-risk). She progressed 21 months after diagnosis. (E–H) A 5-year-old boy with a relatively homogeneous FDG uptake (low rad-risk). The patient remained recurrence free within 5 years of follow-up.