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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 13 of 19

Current clinical guidelines recommend further investigation, including FNAC, to evaluate all PET-
[119]
identified thyroid incidentalomas greater than 1 cm in diameter . However, a study utilizing SEER data
[133]
found that only tumor size > 2.5 cm was associated with an increased mortality . Another population-
based study found size > 2 cm, microcalcifications, and solid composition related to increased malignancy
risk . The risk of cancer in solid lesions has been reported at 13% compared to 4% for mixed solid/cystic
[134]
lesions .
[135]
Ultrasound has been the mainstay of imaging thyroid nodules. Several risk stratification systems (ACR-,
EU-, and K-TIRADS) have been developed, however, it is open for debate if these systems are applicable to
PET-detected thyroid incidentalomas. Previous investigators have proposed that these lesions have a greater
likelihood of high-risk features [18,55] , which may make these stratifications schemes unreliable. However, a
reliable stratification schema is essential as it is impractical to require FNAC of all PET-detected thyroid
incidentalomas. Trimboli et al. examined the ability of EU-TIRADS to appropriately stratify focal PET-
[136]
detected thyroid incidentalomas with histologic diagnoses or scintigraphic confirmation of an
autonomously functioning thyroid nodule. Of the 13 confirmed malignancies included in this study, 11
were categorized as EU-TIRADS 5, 1 as EU-TIRADS 4, and 1 as EU-TIRADS 3. SUV and SUV ratio
max
max
were also found to be significantly higher in the cancer population, with the most accurate cut-off values
determined as > 7.1 and > 3.65, respectively. The presence of one of these risk factors (SUV > 7.1, SUV
max
max
ratio > 3.65, or EU-TIRADS 5) detected 12 of 13 cancers (92% sensitivity) while the absence of these features
detected 34 or 35 benign lesions (97% specificity). This data was recently expanded to evaluate ACR-
TIRADS and K-TIRADS systems in addition to EU-TIRADS . EU-TIRADS and K-TIRADS both showed
[137]
100% specificity and NPV, while the sensitivity of ACR-TIRADS was 81%. This resulted in
recommendations to obtain FNAC in 48% of patients according to ACR-TIRADS, 61% per EU-TIRADS,
and 75% per K-TIRADS. Given the higher likelihood of cancer in this population, EU-TIRADS and K-
TIRADS were advocated as the preferred stratification tools due to the greater number of FNAC
recommended.

In debating the issues of appropriate management, those with a known or suspected underlying cancer or
life-limiting comorbidity must be considered separately from an asymptomatic, healthy patient. An
otherwise healthy patient should receive the full measure of workup and treatment as indicated by current
guidelines. In patients with life-limiting malignancies or comorbidities should be approached with further
judiciousness. Thoughtful consideration of patient factors (age, comorbidities, quality of life), underlying
malignancy (prognosis, required treatment), and local radiologic features are mandatory . The risk of
[32]
intervention must be weighed against the potential benefits. Further evaluation with dedicated ultrasound
imaging incites little risk, and FNAC should be considered if appropriate per TIRADS recommendations.
Given the diversity of cancers diagnosed in these patients (see Table 2), it does seem prudent to biopsy these
lesions where possible. Confirmation of metastasis or thyroid lymphoma would be expected to drive a
change in treatment approach. Diagnosis of a papillary thyroid cancer may prompt consideration of active
surveillance due to the generally indolent nature of this condition, or surgical management if the patient’s
condition permits. Patient status should be continually assessed with re-evaluation of the management plan,
and it is certainly plausible to consider surveillance of a thyroid nodule during treatment of the index cancer
with conversion to active management as the status improves.

Summary of recommendations
1. Assess the patient’s clinical condition, considering the index cancer, comorbidities, and frailty.