Tumor Differentiation and the Role of Nuclear Medicine Scintigraphy and Therapy

Tumor differentiation is a biologic process that significantly influences molecular imaging patterns and therapeutic response. This review examines how tumor differentiation shapes theranostic strategy across thyroid, neuroendocrine, and prostate cancers, with particular attention to the inverse association between tumor differentiation and glucose metabolism. In thyroid and neuroendocrine tumors, well-differentiated disease retains tissue-specific transporters and receptors, such as the sodium-iodide symporter and somatostatin receptors, enabling function-based imaging and targeted therapy. Well-differentiated neuroendocrine tumors upregulate somatostatin receptor expression. Conversely, poorly differentiated tumors in these categories lose these specialized features and exhibit enhanced glycolytic metabolism, resulting in increased [¹⁸F]FDG uptake. In prostate cancer, the differentiation-metabolism relationship is more complex. Prostate-specific membrane antigen (PSMA) is a membrane protein expressed on the apical surface of endothelial cells in prostate and nonprostate tissue. It is weakly expressed in normal prostate tissue but upregulated in prostate cancer and several solid malignancies. Within prostate adenocarcinoma, PSMA expression generally increases with higher Gleason score and tumor aggressiveness, making dedifferentiating tumors and metastatic disease highly PSMA-avid on imaging and suitable for PSMA-targeted therapy. However, in treatment-emergent neuroendocrine prostate cancer, PSMA expression may be lost despite intense [¹⁸F]FDG uptake, reflecting lineage plasticity rather than classical dedifferentiation. This tumor-specific differentiation-driven model has significant implications for patient management, treatment planning, and prognosis. Understanding these tumor-specific differentiation patterns allows clinicians to optimize diagnostic imaging and therapeutic strategies in precision oncology and personalized medicine.