Discordance Between Histopathologic Grading and Dual-Tracer PET/CT Findings in Metastatic NETs and Outcome of Lu-DOTATATE PRRT: Does In Vivo Molecular PET Perform Better from the Viewpoint of Prediction of Tumor Biology?

Discordance between histopathologic grading and dual-tracer PET/CT (Ga-DOTATATE and F-FDG) findings in neuroendocrine tumors (NETs), though not typical, can be encountered in real-world scenarios. The aim of this study was to assess patients with discordance between World Health Organization (WHO) 2017 grade-predicted molecular PET/CT imaging and the actual dual-tracer PET/CT findings (by exploring their histopathologic, immunohistochemical, and molecular imaging characteristics), with a view toward identifying the prognostic determinants affecting outcome in a peptide receptor radionuclide therapy setup. Thirty-six patients with histopathologically proven inoperable, locally advanced or metastatic NETs, referred for peptide receptor radionuclide therapy, were included in this study. The cohort was divided into 2 broad population groups: those with discordance (between WHO 2017 grade-predicted molecular imaging and the dual-tracer PET/CT findings) and control (showing both F-FDG and GaDOTATATE uptake). The cohort was divided on the basis of dual-tracer PET/CT into 3 groups: metabolically inactive (non-F-FDG-avid) and somatostatin receptor (SSTR)-expressing tumors, metabolically active (F-FDG-avid) and non-GaDOTATATE-concentrating (non-SSTR-expressing) tumors, and matched imaging characteristics with the WHO 2017 grading system (showing both F-FDG- and GaDOTATATE-concentrating disease) for statistical analysis. Descriptive statistics were used to analyze categoric data; multivariate analysis was used to assess the correlation between different variables with progression-free survival (PFS) and overall survival (OS). Kaplan-Meier curves were used for survival analysis to calculate median survival and to analyze survival on the basis of WHO 2017 grading and dual-tracer PET. Cox proportional hazards regression analysis was used to determine predictors of survival (OS and PFS). Of the 36-patient cohort, 24 (66.7%) showed discordance and 12 (33.3%) were in the control group. Among those showing discordance: 14 (38.9%) had metabolically inactive and SSTR-expressing disease and the remaining 10 (27.8%) had F-FDG-concentrating and non-SSTR-expressing disease. Among those in the control group, 12 (33.3%) had intermediate-grade NETs and showed matched (Ga-DOTATATE- and F-FDG-concentrating lesions) disease. Multivariate analysis in patients with discordant findings showed a significant correlation of dual-tracer PET with OS, whereas no significant correlation could be established between WHO grade and OS in the discordant subgroups. No significant correlation could be appreciated between PFS and either dual-tracer PET or WHO grading. The Kaplan-Meier analysis and Cox analysis showed dual-tracer PET/CT imaging to be a significant prognostic determinant and predictor of outcome, respectively. In NET patients with discordance between the 2 parameters, dual-tracer PET/CT with F-FDG and Ga-DOTATATE performed better than WHO grading, differentiation status, and immunohistochemistry in prognosticating and predicting outcome.