Whole-tumoral metabolic heterogeneity in 18F-FDG PET/CT is a novel prognostic marker for neuroblastoma

Abstract

Background: Neuroblastoma (NB) is a highly heterogeneous tumor, and more than half of newly diagnosed NB are associated with extensive metastases. Accurately characterizing the heterogeneity of whole-body tumor lesions remains clinical challenge. This study aims to quantify whole-tumoral metabolic heterogeneity (WMH) derived from whole-body tumor lesions, and investigate the prognostic value of WMH in NB.

Methods: We retrospectively enrolled 95 newly diagnosed pediatric NB patients in our department. Traditional semi-quantitative PET/CT parameters including the maximum standardized uptake value (SUVmax), the mean standardized uptake value (SUVmean), the peak standardized uptake value (SUVpeak), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured. These PET/CT parameters were expressed as PSUVmax, PSUVmean, PSUVpeak, PMTV, PTLG for primary tumor, WSUVmax, WSUVmean, WSUVpeak, WMTV, WTLG for whole-body tumor lesions. The metabolic heterogeneity was quantified using the areas under the curve of the cumulative SUV-volume histogram index (AUC-CSH index). Intra-tumoral metabolic heterogeneity (IMH) and WMH were extracted from primary tumor and whole-body tumor lesions, respectively. The outcome endpoints were overall survival (OS) and progression-free survival (PFS). Survival analysis was performed utilizing the univariate and multivariate Cox proportional hazards regression. The optimal cut-off values for metabolic parameters were obtained by receiver operating characteristic curve (ROC).

Results: During follow up, 27 (28.4%) patients died, 21 (22.1%) patients relapsed and 47 (49.5%) patients remained progression-free survival, with a median follow-up of 35.0 months. In survival analysis, WMTV and WTLG were independent indicators of PFS, and WMH was an independent risk factor of PFS and OS. However, IMH only showed association with PFS and OS. In addition to metabolic parameters, the International Neuroblastoma Staging System (INSS) was identified as an independent risk factor for PFS, and neuron-specific enolase (NSE) served as an independent predictor of OS.

Conclusion: WMH was an independent risk factor for PFS and OS, suggesting its potential as a novel prognostic marker for newly diagnosed NB patients.

Keywords: 18F-FDG PET/CT; Intra-tumoral metabolic heterogeneity; Neuroblastoma; Prognosis; Whole-tumoral metabolic heterogeneity.

Fig. 1

The calculation process of AUC-CSH index and traditional metabolic parameters. Step1: Identify and outline the tumor lesions including primary lesion and metastases. Step2: Extract the tumor metabolic parameters. In this step, we classify the tumor lesions into two forms: primary lesion and whole-body lesions (including primary lesion and metastases). The whole-body lesions as a whole to participate in the subsequent AUC-CSH index. The whole-body lesions would be calculated for only one AUC-CSH index for whole-tumoral metabolic heterogeneity (WMH). Step 3: AUC-CSH index and traditional metabolic parameters based on primary lesion (IMH) and whole-body lesions (WMH) were calculated, separately

Fig. 2

Comparing intra-tumoral metabolic heterogeneity and whole-tumoral metabolic heterogeneity in different subgroups

Fig. 3

Survival curves based on optimal cut-off value

Fig. 4

Two representative NB patients with high and low WMH values; A: a 32-month-old girl with a relatively uniform FDG uptake in whole-body tumor (White arrow, IMH:0.443, WMH:0.470), was disease free survival 51.3 months after diagnosis; B: a 29-month-old girl with a heterogeneous FDG uptake in whole-body tumor (Red arrow, IMH:0.463, WMH:0.392), relapsed at 7.1 months, and died at 8.9 months after diagnosis