Heterogeneity in intratumor correlations of ¹⁸F-FDG, ¹⁸F-FLT, and ⁶¹Cu-ATSM PET in canine sinonasal tumors

Intratumor heterogeneity in biologic properties and in relationships between various phenotypes may present a challenge for biologically targeted therapies. Understanding the relationships between different phenotypes in individual tumor types could help inform treatment selection. The goal of this study was to characterize spatial correlations of glucose metabolism, proliferation, and hypoxia in 2 histologic types of tumors. Methods: Twenty canine veterinary patients with spontaneously occurring sinonasal tumors (13 carcinomas and 7 sarcomas) were imaged with ¹⁸F-FDG, ¹⁸Flabeled 39-deoxy-39-fluorothymidine (¹⁸F-FLT), and ⁶¹Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone) ( ⁶¹Cu-ATSM) PET/CT on 3 consecutive days. Precise positioning and immobilization techniques coupled with anesthesia enabled motionless scans with repeatable positioning. Standardized uptake values (SUVs) of gross sarcoma and carcinoma volumes were compared by use of Mann-Whitney U tests. Patient images were rigidly registered together, and intratumor tracer uptake distributions were compared. Voxelbased Spearman correlation coefficients were used to quantify intertracer correlations, and the correlation coefficients of sarcomas and carcinomas were compared. The relative overlap of the highest uptake volumes of the 3 tracers was quantified, and the values were compared for sarcomas and carcinomas. Results: Large degrees of heterogeneity in SUV measures and phenotype correlations were observed. Carcinoma and sarcoma tumors differed significantly in SUV measures, with carcinoma tumors having significantly higher ¹⁸F-FDG maximum SUVs than sarcoma tumors (11.1 vs. 5.0; P 5 0.01) as well as higher ⁶¹Cu-ATSM mean SUVs (2.6 vs. 1.2; P 5 0.02). Carcinomas had significantly higher population-averaged Spearman correlation coefficients than sarcomas in comparisons of ¹⁸F-FDG and ¹⁸F-FLT (0.80 vs. 0.61; P 5 0.02), ¹⁸F-FLT and ⁶¹Cu-ATSM (0.83 vs. 0.38; P < 0.0001), and ¹⁸F-FDG and ⁶¹Cu-ATSM (0.82 vs. 0.69; P 5 0.04). Additionally, the highest uptake volumes of the 3 tracers had significantly greater overlap in carcinomas than in sarcomas. Conclusion: The relationships of glucose metabolism, proliferation, and hypoxia were heterogeneous across different tumors, with carcinomas tending to have high correlations and sarcomas having low correlations. Consequently, canine carcinoma tumors are robust targets for therapies that target a single biologic property, whereas sarcoma tumors may not be well suited for such therapies. Histology-specific PET correlations have farreaching implications for the robustness of biologic target definition.