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Page 10 of 19 Corn et al. J Cancer Metastasis Treat 2021;7:41 https://dx.doi.org/10.20517/2394-4722.2021.63

68 Ga-DOTA PET/CT imaging is evolving as a method to evaluate and monitor neuroendocrine tumors
expressing somatostatin receptors with a sensitivity and specificity as high as 96% and 100%,
68
respectively [77,78] . Multiple Ga-DOTA peptides have been studied that have a variable affinity for
[79] 68
64
somatostatin receptor subtypes . Ga- and Cu-DOTATATE are currently the only peptides clinically
approved by the FDA in the USA for PET imaging. Physiologic uptake has been noted in the pituitary,
[80]
thyroid, spleen, liver, adrenal glands, head of the pancreas, and urinary tract . Normal thyroid tissue
expressed somatostatin transmembrane receptors (SSTR), typically resulting in very low, diffuse uptake .
[78]
High SSTR2 expression has been noted in differentiated thyroid cancers and benign thyroid conditions ,
[81]
but it is unclear if this uptake pattern varies from baseline physiologic uptake. Furthermore, activated
lymphocytes are known to express SSTR. Thus benign inflammatory conditions such as thyroiditis, trauma,
[80]
or surgery may induce abnormal uptake . Importantly, medullary thyroid cancers would be expected to be
highlighted on Ga-DOTATATE PET/CTs. However low or variable SSTR expression may give false-
68
[80]
negative results . These scans are also subject to spatial resolution limitations. Studies have shown a 4.1%-
11% rate of detection of thyroid incidentalomas on this imaging [47,82] , with an average of 2.6% (0.5%-2.9%)
showing diffuse uptake. A study by Nockel et al. evaluated 237 Ga-DOTATATE scans to assess the
[47]
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uptake patterns in the thyroid gland. Abnormal thyroid uptake was noted in 11% (26 of 237), with 14
displaying focal uptake and 12 with a diffuse pattern. Three of the focal lesions were found to be
differentiated thyroid cancers (21.4% of focal incidentalomas). No significant difference was noted in
SUV values between benign and malignant lesions.
max

A recent study by Kohlenberg et al. assessed thyroid lesions with focal Ga-DOTATATE PET/CT uptake,
[83]
68
which was detected in 4.9% of scans (94 of 1927). Notably, four patients were imaged for the staging of a
known medullary thyroid cancer. Five patients (one multifocal) were diagnosed with medullary thyroid
cancer, one of which was discovered incidentally due to this imaging. As expected, the baseline calcitonin
levels were quite elevated in MTC patients (median 1156 pg/mL), while this data was limited in other
patients. The 2015 American Thyroid Association guidelines do not recommend assessment of calcitonin in
68
patients with thyroid nodules; however it certainly seems reasonable to consider it in patients with Ga-
DOTATATE avidity. In addition to commonly reported semiquantitative measures of PET avidity such as
SUV , focal thyroid lesions were also graded relative to normal tissues as internal controls. Two-thirds of
max
68
MTC nodules were found to have relative Ga-DOTATATE avidity greater than that of the liver, which has
previously been proposed as a favorable target for peptide receptor radionuclide therapy .
[84]
68 Ga-PSMA imaging is a promising tool increasingly used to stage and monitor prostate cancer by binding
prostate-specific membrane antigen (PSMA) . PSMA is expressed in normal prostate epithelium and
[48]
highly expressed in prostate carcinoma. Expression of PSMA has been identified in the neovasculature of
several other solid tumor types, including thyroid carcinomas, with strong staining noted in classical PTC,
follicular thyroid carcinoma, and iodine-refractory cancers. All evaluated metastatic lesions exhibited PSMA
[85]
expression compared to only 67% of lymph node metastases . Furthermore, in a study of 10 patients with
metastatic differentiated thyroid cancer, Ga-PSMA PET/CT identified 30 of 32 metastatic lesions . These
68
[86]
findings may advocate for use of this imaging for evaluation of suspected metastatic disease, particularly in
radioiodine-refractory tumors.
68
Incidental Ga-PSMA thyroidal uptake is rare, the literature being punctuated mostly by single case reports.
In a systematic review published in June 2019, Bertagna et al. collected a total of 23 cases of PSMA thyroid
[87]
incidentaloma from 12 papers. Among these 23 patients, malignancy was documented in 6:5 primary
thyroid (4 papillary thyroid carcinoma, one follicular thyroid carcinoma) and one metastasis from renal cell
carcinoma.