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Page 2 of 13 Quartuccio et al. J Cancer Metastasis Treat 2021;7:14 I http://dx.doi.org/10.20517/2394-4722.2020.118

Keywords: PET/CT, hematogenous metastases, lung, bone, thyroid cancer, FDG, meta-analysis

INTRODUCTION
Primitive thyroid cancers can be divided into 2 main pathological entities: tumors originating from
follicular cells and medullary cancer (arising from para-follicular C cells). The first group of cancers
include differentiated (follicular and papillary carcinoma and their variants), poorly differentiated, and
[1]
undifferentiated tumors (anaplastic carcinoma) .

After surgical removal of the tumor, due to the risk of disease recurrence, differentiated thyroid cancer
(DTC) is followed-up by assessing serum thyroglobulin (Tg), whereas calcitonin and carcinoembryonic
[2,3]
antigen are biochemical markers for postoperative surveillance in medullary thyroid cancer . Overall,
lymph node is the most frequent metastatic site for thyroid cancer. Nevertheless, patients with thyroid
cancer may present also distant metastases in other organs due to hematogenous dissemination, especially
to bone and lung. Patients with extranodal metastases usually present a worse prognosis compared to
[4,5]
patients with metastases limited to lymph nodes . It follows that it is extremely important to identify
hematogenous metastases in these patients to better address clinical management.

Patients with history of DTC, who no longer respond to radioactive iodine (RAI) therapy, have developed
[6]
RAI-Refractory DTC. The majority of these cases with advanced disease have a worse prognosis . The
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use of 2-deoxy-2-[18F]fluoro-D-glucose ( F-FDG) positron emission tomography/computed tomography
(PET/CT) has proved beneficial in assessing recurrence of thyroid cancer in the case of a rise of Tg but
[7,8]
131
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no evidence of disease at Iodium ( I) whole-body scan . This clinical scenario has been related to
the so-called flip-flop phenomenon and appears to be associated with worse prognosis; thyroid cells,
indeed, demonstrate an upregulation of glucose transporters (GLUT1) and a reduction of sodium-iodide
[9]
symporters (NIS) when a dedifferentiation process occurs (from DTC towards a more aggressive histotype) .
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In the literature, there are systematic reviews and meta-analyses documenting the accuracy of F-FDG
18
PET/CT or F-FDG PET in assessing in patients with thyroid cancer with suspected recurrence, although
these studies did not differentiate between lymph node and hematogenous metastases [10-12] .

Due to the widespread availability of hybrid PET/CT scanners in current nuclear medicine facilities
worldwide, we excluded from our systematic review studies involving the use of stand-alone PET scanners.
Lee and coworkers recently demonstrated in a network meta-analysis the superiority of L-6-[18F]fluoro-
18
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3,4-dihydroxyphenylalnine) ( F-DOPA) over F-FDG in medullary thyroid cancer. We, therefore, decided
[13]
to focus on thyroid cancer histotypes other than medullary .
The primary aim of this systematic review and meta-analysis was to collect the evidence on the detection
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rate (DR) and accuracy (AC) of F-FDG PET/CT in identifying hematogenous metastatic lesions in
patients with advanced differentiated thyroid cancer on a per-patient and per-lesion basis. The secondary
18
goal was the comparison of the diagnostic performance of F-FDG PET/CT with other imaging techniques.

METHODS
The systematic review was conducted in accordance with the PRISMA guideline (Preferred Reporting
[14]
Items for Systematic Reviews and Meta-Analyses) .
Literature search
A comprehensive PubMed/MEDLINE database research was carried out by a researcher (N.Q.) to
retrieve prospective or retrospective studies, aiming the identification of distant metastases in patients