Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

FDG PET/CT accurately characterises adrenal tumours, with an excellent sensitivity and negative predictive values. Thus, a negative PET may predict a benign tumour that would potentially prevent the need for surgery of adrenal tumours with inconclusive conventional imaging.

Our objective was to evaluate 18 F-FDG PET uptake in patients with nonmetastatic and metastatic chromaffin-derived tumors. Methods: Twenty-eight consecutive unrelated patients with chromaffin tumors, including 9 patients with genetically determined disease, were studied. A combination of preoperative imaging work-up, surgical findings, and pathologic analyses was used to classify the patients into 2 groups: those with nonmetastatic disease (presumed benign, n 5 18) and those with metastatic tumors (n 5 10). 18 F-FDG PET was performed in all cases. Visual and quantitative analyses were individually graded for each tumor. Somatic mutations of the succinate dehydrogenase subunits B and D and Von-Hippel Lindau genes were also evaluated in 6 benign sporadic tumor samples. Results: All but 2 patients showed significantly increased 18 F-FDG uptake on visual analysis. The maximum standardized uptake value (SUVmax) ranged from 1.9 to 42 (mean 6 SD, 8.2 6 9.7; median, 4.6) in nonmetastatic tumors and 2.3 to 29.3 (mean 6 SD, 9.7 6 8.4; median, 7.4) in metastatic tumors. No statistical difference was observed between the groups (P 5 0.44), but succinate dehydrogenase-related tumors were notable in being the most 18 F-FDG-avid tumors (SUVmax, 42, 29.3,21,17, and 5.3). Succinate dehydrogenase and Von-Hippel Lindau-related tumors had a significantly higher SUVmax than did neurofibromatosis type 1 and multiple endocrine neoplasia type 2A syndrome-related tumors (P 5 0.02). 18 F-FDG PET was superior to 131 I-metaiodobenzylguanidine in all metastatic patients but one. By contrast, 18 F-FDG PET underestimated the extent of the disease, compared with 6-18 F-fluorodopa PET, in 5 patients with metastatic pheochromocytoma. However, succinate dehydrogenase mutations (germline and somatic) and functional dedifferentiation do not adequately explain 18 F-FDG uptake since most tumors were highly avid for 18 F-FDG. Conclusion: 18 F-FDG PET positivity is almost a constant feature of pheochromocytomas and paragangliomas. It may be considered a molecular signature of such tumors, although which aspect of the plethora of molecular changes associated with dedifferentiation, germline genetic defects, or the adaptive response to hypoxia is responsible for this characteristic requires further elucidation.

Our results suggest that tumour staging can be improved by combining (18)F-FDOPA and (18)F-FDG in the preoperative work-up of patients with abdominal and malignant PHEOs. (18)F-FDOPA is also an effective localization tool for neck PGLs. MIBG however, still has a role in these patients as MIBG and FDOPA images did not completely overlap.

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