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Page 12 of 19 Corn et al. J Cancer Metastasis Treat 2021;7:41 https://dx.doi.org/10.20517/2394-4722.2021.63

cells [108,109] . This increased expression of GLUT transporters in both BRAF and PTEN mutated phenotypes
may give credence to the observation of PET-detected thyroid incidentalomas exhibiting more aggressive
behavior. Notably, in a study of malignant PET-detected thyroid lesions not selected for PTEN loss by
[110]
Kim et al. , there was overall a low degree of GLUT-1 and GLUT-3 expression but a high level of VEGF
expression. Consistent results were reported by Ohba et al. in a study of benign PET-detected thyroid
[111]
incidentalomas that were found to have a higher degree of vascularity than benign thyroid nodules not
exhibiting FDG uptake.

Mutations in the p53 tumor suppressor gene are exhibited in nearly 50% of all cancers yet are identified in
only 10% of thyroid cancers . In a retrospective study of patients with PET-detected thyroid cancers, 86%
[112]
of those that underwent operation were found to express p53 mutations, and this was not related to
SUV max [42] . The significance of this finding is not yet known.

Fine needle aspiration yields indeterminate results in 15%-30% of patients , which may persist after repeat
[113]
FNAC. Molecular diagnostic tests such as Afirma , ThyroSeq [115,116] , and ThyGeNEXT/ThyraMIR have
[114]
[117]
been developed to differentiate this indeterminate category, yet the utility of these tests is unclear in a
population selected for FDG avidity. In a study utilizing Afirma Gene Expression Classifier (GEC) or
Genome Sequence Classifier (GSC) profiling in thyroid PETomas with indeterminate cytology,
Endo et al. found that 28.6% of these nodules were predicted malignant per Afirma GEC/GSC compared
[118]
to a 36.4% rate of malignancy in histologically proven nodules. The benign call rate (BCR) was significantly
higher in patients with low-risk ultrasound features (83.3%) vs. 29% in intermediate- or high-risk ultrasound
features (P = 0.026). The higher BCR with Afirma GSC (64%) may indicate that surgical intervention can be
safely avoided or delayed in these patients.

MANAGEMENT RECOMMENDATIONS
Clinical guidelines for the management of thyroid nodules in the general population are well
established [119,120] . Given that most PET/CT imaging is pursued to evaluate another malignancy that may
limit life expectancy, it is difficult to determine if these guidelines should apply to this population. Thyroid
cancer is associated with an excellent prognosis, with overall 10-year survival rates of differentiated thyroid
cancers exceeding 90%-95% . For example, in patients that underwent cytologic diagnosis of an incidental
[121]
thyroid cancer, the risk of death from thyroid cancer was < 1% . Studies of active surveillance of low-risk
[32]
papillary microcarcinomas (cytologically confirmed PTC with nodule diameter ≤ 1 cm without high-risk
features) have shown safety with this approach. In this review, only 7%-8% of observed nodules increased in
[122]
size, and there were no instances of recurrence or death following salvage surgery . Contrary to this,
Are et al. suggested that incidentalomas are associated with a poorer prognosis due to a higher rate of
[55]
unfavorable pathologic features such as tall cell variant, poor differentiation, and extrathyroidal extension.
Data from our institution identified a 30% rate of poor prognostic features in these patients .
[18]

Although most thyroid carcinomas are associated with an excellent prognosis, it does seem prudent that
each incidentally discovered thyroid lesion be carefully evaluated for risk factors that may elucidate the
relevance of such lesions. Review of prior images should be conducted to evaluate the evolution of the noted
lesion over time . In addition to the previously mentioned features, PET scans may reveal signs of lateral
[123]
lymph node metastases , which is associated with a poorer prognosis [124-126] and is key for developing
[24]
adequate surgical plans should this route be pursued . Other features contributing to malignancy risk
[127]
include younger age [19,128] , male gender [128,129] , childhood radiation exposure [130,131] , and family history of
[132]
thyroid cancer .