Increased Thyroidal Activity on Routine FDG-PET/CT after Combination Immune Checkpoint Inhibition: Temporal Associations with Clinical and Biochemical Thyroiditis

Abstract

Background: FDG-PET/CT used for immune checkpoint inhibitor (ICI) response assessment can incidentally identify immune-related adverse events (irAEs), including thyroiditis. This study aimed to correlate the time course of FDG-PET/CT evidence of thyroiditis with clinical and biochemical evolution of thyroid dysfunction.

Methods: A retrospective review was performed by two independent blinded nuclear medicine physicians (NMPs) of thyroidal FDG uptake in 127 patients who underwent PET/CT between January 2016 and January 2019 at baseline and during treatment monitoring of combination ICI therapy for advanced melanoma. Interobserver agreement was assessed and FDG-PET/CT performance defined by a receiver-operating characteristic (ROC) curve using thyroid function tests (TFTs) as the standard of truth. Thyroid maximum standardized uptake value (SUVmax) and its temporal changes with respect to the longitudinal biochemistry were serially recorded.

Results: At a median of 3 weeks after commencing ICI, 43/127 (34%) had a diagnosis of thyroiditis established by abnormal TFTs. FDG-PET/CT was performed at baseline and at a median of 11 weeks (range 3-32) following the start of therapy. ROC analysis showed an area under the curve of 0.87 (95% CI 0.80, 0.94) for FDG-PET/CT for detection of thyroiditis with a positive predictive value of 93%. Among patients with biochemical evidence of thyroiditis, those with a positive FDG-PET/CT were more likely to develop overt hypothyroidism (77% versus 35%, p < 0.01). In the evaluation of the index test, there was an almost perfect interobserver agreement between NMPs of 93.7% (95% CI 89.4-98.0), kappa 0.83.

Conclusion: Increased metabolic activity of the thyroid on routine FDG-PET/CT performed for tumoral response of patients undergoing ICI therapy is generally detected well after routine biochemical diagnosis. Elevation of FDG uptake in the thyroid is predictive of overt clinical hypothyroidism and suggests that an ongoing robust inflammatory response beyond the initial thyrotoxic phase may be indicative of thyroid destruction.

Keywords: FDG-PET/CT; combination immunotherapy; endocrine toxicity; immune-related adverse event; interobserver agreement; ipilimumab and nivolumab; melanoma; thyroiditis.

Figure 1

Consort diagram outlining patient eligibility and summary of FDG-PET/CT and clinical findings.

Figure 2

Temporal evolution of thyroid FDG uptake in a patient with cICI related thyroiditis. Trans-axial and maximum intensity projection images of the thyroid gland demonstrated in sequence on CT scan (white arrows), fusion image (red arrows) and PET scan (black arrows). Normal thyroid appearance is demonstrated at baseline (A). A significant increase in FDG uptake is noted on the first on-treatment scan at three weeks (B). Panel (C,D) demonstrate partial and complete resolution at 6 weeks and 24 weeks, respectively.

Figure 3

Box plot SUVmax (blue) and % change of SUV max (red). Absolute SUVmax at the first on-treatment FDG-PET/CT, and % change in SUVmax with respect to baseline in patients where FDG-PET/CT-detected thyroiditis was documented by both NMPs (positive), by one NMP (equivocal) and by neither NMP (negative). Equivocal results were deemed to reflect nuanced reporting in the lower range of abnormality and were classified as negative in the analysis.

Figure 4

Receiver Operator Curves (ROC). (A) SUVmax at first follow up scan and (B) SUVmax% change with corresponding area under the ROC of 0.88 and 0.87, respectively.

Figure 5

Swimmer Plot demonstrating the timing of the first on-treatment FDG-PET/CT with respect to the thyroiditis diagnosis, typically represented by an early thyrotoxic phase followed by euthyroid and/or hypothyroid phase. Thyroid function tests were performed every 4–6 weeks or more frequently if clinically indicated. The horizontal black arrow represents an outlier, whereby the thyrotoxicosis was diagnosed 97 months after the first FDG-PET/CT.

Figure 6

Increased thyroid FDG uptake at baseline in a patient who developed cICI related thyroiditis. Trans-axial and maximum intensity projection images of the thyroid gland demonstrated in sequence on CT scan (white arrows), fusion image (red arrows) and PET scan (black arrows). A clear increase in thyroid FDG uptake is demonstrated at baseline (A), which had resolved completely on both on-treatment scans at 6 and 14 weeks (B,C). The patient was euthyroid at baseline and developed biochemical thyroiditis 10 days after commencement of cICI.

Figure 7

Diffuse skeletal muscle uptake of FDG in a patient with thyroiditis. Maximum intensity projection PET images at baseline (A) and on-treatment (B,C) demonstrate interval development of thyroiditis (red arrows) and diffuse skeletal muscle uptake (black arrows). The patient complained of progressive upper and lower limb weakness during the thyrotoxic phase, with a normal CK.