18F-FDG Uptake in Well-Differentiated Neuroendocrine Tumors Correlates with Both Ki-67 and VHL Pathway Inactivation

Abstract

Background:¹⁸F-FDG-PET scan positivity correlates with poor prognosis in neuroendocrine neoplasms (NEN). Glucose transporter 1 (GLUT1) and carbonic anhydrase 9 (CA9) are markers of aggressiveness in tumors. Together with von Hippel-Lindau protein (pVHL), they are involved in tumor cell metabolism via the hypoxia-inducible factor signaling pathway. The aim of this study was to compare, in a series of well-differentiated neuroendocrine tumors (NET), the ¹⁸F-FDG uptake and expression of the proliferation markers Ki-67, GLUT1, CA9, and pVHL. Patients and Methods: This retrospective study included 27 patients with well-differentiated NET. ¹⁸F-FDG-PET images were evaluated by the maximum standardized uptake value (SUV_max). GLUT1, CA9, and pVHL were analyzed by immunohistochemistry. Results: The NET were of pancreatic (n = 19), midgut (n = 4), duodenal (n = 1), esophageal (n = 1), rectal (n = 1), and pulmonary (n = 1) origin. Eight, 11, and 8 tumors were grade 1, 2, and 3, respectively. The mean/median Ki-67 index was 15/10% (1-60). The mean/median SUV_max was 6.2/5.2 (1.4-18.7). SUV_max correlated with greater tumor size (p = 0.03), higher expression of Ki-67 (p = 0.04), and lower expression of pVHL (p = 0.008). In the group of 16 NET with a low proliferative index (Ki-67 index <10%), 5/6 (83%) of the tumors with a high SUV_max had decreased pVHL expression (p = 0.0013). Conclusion: This study confirms that ¹⁸F-FDG-PET uptake correlates with both tumor size and proliferation in well-differentiated NET, and it highlights a subset of low-grade but ¹⁸F-FDG-PET-positive NET related to sporadic inactivation of the VHL pathway.

Prognostic value of a three-scale grading system based on combining molecular imaging with 68Ga-DOTATATE and 18F-FDG PET/CT in patients with metastatic gastroenteropancreatic neuroendocrine neoplasias

“…In the study of Garin et al [18,19], an SUVmax cutoff of 4.5 was used to define 18 F-FDG positivity, whereas Sansovini et al [21] applied an arbitrary SUVmax cutoff of 2.5 separating 18 F-FDG positive from 18 F-FDG negative lesions. Whether low 18 F-FDG uptake lesions represent an evolution step toward overt high uptake lesions or they just reflect a different pathophysiological underlying process (such as hypoxia [25]), remains to be investigated.…”

Position Statement on the Diagnosis, Treatment, and Response Evaluation to Systemic Therapies of Advanced Neuroendocrine Tumors, With a Special Focus on Radioligand Therapy

“…Although without any robust evidence, it is likely that the association of FDG-PET with more aggressive tumors and a higher proliferative index influenced this decision. 109 …”

Likely Common Role of Hypoxia in Driving18F-FDG Uptake in Cancer, Myocardial Ischemia, Inflammation and Infection

“…31 In well-differentiated neuroendocrine tumors, 18 F-FDG PET uptake correlates with both tumor size and proliferation. 32 A possible explanation is that proliferating tumor cells generate ATP from glucose at least to some extent through efficient oxidative phosphorylation, so less glucose is needed, thus resulting in with low accumulation of 18 F-FDG. Also, the necrotic tumor zones were associated with lower 18 F-FDG activity.…”