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Corn et al. J Cancer Metastasis Treat 2021;7:41 https://dx.doi.org/10.20517/2394-4722.2021.63 Page 11 of 19

[88]
More recently, Gossili et al. reported on their study of 341 patients with prostate cancer who had
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undergone Ga-PSMA PET/CT scanning, identifying 13 patients (4%) with incidental increased thyroid
uptake. The pattern of uptake was focal in seven, diffuse in five and diffuse-plus-focal in one. Malignancy
was confirmed in 2 patients (2/13, 15%), and both displayed focal uptake. This paper was the subject of a
commentary in Clinical Thyroidology by Santhanam and Cooper who noted the lack of sensitivity and
[89]
specificity of PSMA-based thyroid imaging but enunciated on some of the potential benefits of detecting
neovasculature in advanced metastatic radioiodine refractory thyroid cancer. They also recommended
further investigations in patients found to have focal thyroidal uptake on PSMA-based PET imaging,
namely thyroid ultrasound and biopsy. It is very likely that the true prevalence of PSMA-PETomas is higher
since the present application of this imaging modality is for prostate cancer, thereby excluding female
[87]
patients who are known to have an incidence of thyroid disorders .
Radiolabeled choline ( F or C) is another radiopharmaceutical with utility in imaging several solid
11
18
tumors [90,91] , including potential for imaging parathyroid adenomas and hyperplasia . Choline is a
[92]
precursor to the phosphatidylcholine that comprises much of the cellular membrane and is internalized into
[93]
the cell by choline kinase enzymes . Increased uptake is noted in conditions with high proliferative rates.
There are now reports of incidental thyroid uptake on radiolabelled choline PET/CT scans, mostly as case
[94]
reports. In a retrospective analysis by Ruiz-Esponda et al. , only 30 thyroid incidentalomas were identified
in a pool of 1197 radiolabelled choline PET/CT scans (2.5%). Of the 15 patients that underwent diagnostic
FNAC only one malignancy was identified, indicating that incidental thyroid lesions detected by this
method may have a lower likelihood of malignancy than those detected by FDG-PET/CT.

MUTATION ANALYSIS
Mutation analysis has garnered significant traction in recent years across various cancers as a method to
improve the characterization of tumors and associated prognosis. BRAF V600E is the commonest mutation
encountered in adults with thyroid cancer, occurring in close to 50% of patients with papillary thyroid
carcinoma . Studies have shown that a BRAF mutation in papillary thyroid cancer is associated with worse
[95]
outcomes [96,97] , commonly reported as a higher stage at diagnosis and more frequent distant metastases . A
[98]
higher risk of death has also been described with BRAF-mutated thyroid cancers, on the order of 2.66-fold
[99]
higher . It has been reported that male gender is a robust independent risk factor for PTC-specific
mortality in BRAF V600E patients but not in wild-type BRAF patients . Moreover, these same authors
[100]
[101]
identified age-associated mortality risk in PTC as dependent on BRAF status . In a study comparing PET-
detected papillary thyroid cancers to conventionally detected controls, Beck et al. described a higher rate
[40]
of BRAF mutations in the PET-detected cohort (78% vs. 41%, P = 0.05). In this report, the PET-detected
cancers were more commonly found in males (54% vs. 26%, P = 0.003) and higher stages (stage III 24% vs.
12%, stage IV 7% vs. 0%, P = 0.05). BRAF V600E mutation is associated with increased expression of glucose
[102]
transporters (GLUT-1) in papillary thyroid cancers , which may be responsible for the higher proportion
of BRAF mutations in PET-detected cancers. In agreement with this, several studies have shown
significantly higher SUV values in BRAF-mutated papillary thyroid cancers versus their BRAF-wild type
max
counterparts [42,103,104] .

GLUT transporter expression was also noted to be elevated in thyroid incidentalomas exhibiting loss of the
[105]
oncosuppressor gene PTEN . It was later confirmed by the same group that lack of PTEN expression in
thyroid cancer cells was responsible for GLUT-1 upregulation and glucose uptake . Aggressive, poorly
[106]
differentiated thyroid cancers have higher levels of GLUT-1 expression [20,107,108] , which is the predominant
isoform noted to be over-expressed with loss of PTEN expression . Increased expression of GLUT
[105]
proteins would be expected to correlate with increased cellular glucose, and thus FDG, uptake cancers