Clinical role of ¹⁸F-FDG PET/CT for detection of radioactive iodine refractory differentiated thyroid cancer

Abstract

In clinical settings, an estimated 10% differentiated thyroid cancer (DTC) cases become radioactive iodide refractory (RAIR), which lack a molecular marker and have fewer treatment selections. A higher uptake of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) might indicate poor prognosis for DTC. This study aimed to evaluate the clinical value of ¹⁸F-FDG psitron emission tomography/computed tomography (PET/CT) for the early diagnosis of RAIR-DTC and high-risk DTC. A total of 68 DTC patients were enrolled and underwent ¹⁸F-FDG PET/CT for the detection of recurrence and/or metastasis. ¹⁸F-FDG uptake was evaluated in patients with different postoperative recurrence risks or TNM stages and compared between RAIR and non-RAIR-DTC based on its maximum standardized uptake value and tumor/liver (T/L) ratio. The final diagnosis was judged by histopathology and follow-up data. Of 68 DTC cases, 42 were RAIR and 24 non-RAIR, with 2 not determined. A total of 263 of 293 lesions detected on ¹⁸F-FDG PET/CT were confirmed to be locoregional or metastatic after follow-up. The T/L ratio was significantly higher for RAIR than for non-RAIR (median 5.18 vs 1.44; P < .01) and also significantly higher in postoperative patients at high-risk of recurrence than at low to medium risk (median 4.90 vs 2.16; P < .01). ¹⁸F-FDG PET/CT exhibited a sensitivity of 83.3% and specificity of 87.5% for identifying RAIR, with a cutoff T/L value of 2.98. ¹⁸F-FDG PET/CT has the potential to diagnose RAIR-DTC early and identify the high-risk DTC. The T/L ratio is a useful parameter for the detection of RAIR-DTC patients.

1. Introduction

Thyroid cancer is the most common malignant endocrine carcinoma with an increasing incidence over time.^[1] Differentiated thyroid cancer (DTC), including papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), originates from thyroid follicular cells^[2] and accounts for the most of thyroid cancer.^[3] DTC is characterized by highly intra- and inter-tumoral heterogeneity, as manifested with its diverse clinical characteristics and phenotyping, ranging from indolent to rapidly progressively lethal disease. With the widespread use of ultrasound in physical examinations, the incidence of DTC has significantly increased in China. However, active screening has not been widely used in rural areas, and therefore, many patients are at an advanced stage at diagnosis, with regional invasion or distant metastasis.

The great spatial and temporal heterogeneity of DTC hinders the appropriate management. When DTC has become the radioactive iodine refractory (also known as radioactive iodine refractory [RAIR]) status, the treatment modalities of RAIR are limited due to lack of a molecular biomarker.^[3] Furthermore, fewer studies focus on risk stratification of preoperative DTC. Currently, approximately 10% of DTC patients have suffered from a highly aggressive disease, characterized by excessive lymph node metastasis and distant metastasis. Clearly, appropriate staging is of great importance for precision management. Current studies demonstrated that the molecular characteristics of DTC may drive the clinical presentations.^[4] Nuclear medicine and molecular imaging are of great value for the differentiation of RAIR behavior and highly aggressive risk from other DTC cases of favorable curability and prognosis.

Generally, about 23% of DTC cases have distant metastases, of which 33% might gradually dedifferentiate to RAIR status.^[5,6] RAIR-DTC is more malignant and aggressive than non-RAIR-DTC. Dedifferentiated DTC may lose its capacity to take up iodine because of oncogene activation via signaling pathways. RAIR-DTC benefits little from ¹³¹I therapy. RAIR-DTC could not be identified timely, which might lead to unnecessary ¹³¹I therapy and hamper active treatment such as multi-kinase inhibitors.^[7] Thus, there is an urgent need for a feasible technique to distinguish RAIR from non-RAIR cases with DTC.

DTC patients have good prognosis and usually only need surgery, but high-risk DTC patients have a relatively worse prognosis and require more active screening and treatment. However, traditional radiology techniques, such as CT, have a limited value to identify RAI-refractory status.^[3] According to the definition of high-risk and low-risk DTC from the American thyroid association (ATA) guideline 2015, a study observed that ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) psitron emission tomography/computed tomography (PET/CT) could differentiate low and high-risk through detection of the metabolism levels of glycol in the lesions.^[8] It has been reported that a higher maximum standardized uptake value (SUV_max) value of thyroid cancer from ¹⁸F-FDG PET/CT indicated higher aggressiveness and poorer outcome.^[9] To date, there have been few studies showing the value of ¹⁸F-fluorodeoxyglucose (FDG) PET/CT for identifying RAIR-DTC. ¹⁸F-FDG PET/CT has been used to detect recurrence and metastasis in thyroid cancer, with FDG-avid lesions indicating rapid progression and poor outcomes.^[3,10] This study aimed to evaluate the clinical value of ¹⁸F-FDG PET/CT for the early identification of RAIR and high-risk DTC.

2. Materials and methods

2.1. Patients

The study scheme is shown in Figure 1. A total of 68 patients (23 males and 45 females; with a mean age of 54 years old) diagnosed with DTC at Nanjing First Hospital between January 2017 and December 2021 were retrospectively enrolled in this study. All patients who underwent ¹⁸F-FDG PET/CT were pathologically diagnosed as DTC after surgery, with clinical characteristics shown in Table S1, Supplemental Digital Content, http://links.lww.com/MD/J27, and followed-up for at least 2 years. Patients with medullary thyroid cancer, anaplastic cancer, or specific rare types of thyroid cancer, such as squamous carcinoma and lymphoma, were excluded from this study.

Figure 1.

Scheme of study design.

Of 68 recruited patients, 50 were diagnosed as PTC, 16 as FTC, and 2 as both PTC and FTC. A total of 64 patients received ¹³¹I treatment. The clinical characteristics were recorded, including TNM stage and thyroglobulin (Tg) and anti-Tg antibody (TgAb) levels. The upper limit of normal values in our hospital was 4.11 IU/mL for TgAb, which was measured by a test kit provided by Abbott Laboratory, Singapore. According to the 2015 ATA guidelines, a Tg level < 0.20 ng/mL indicated no recurrence or metastasis of thyroid cancer after total thyroidectomy and thyroid hormone replacement therapy.^[3] In this study, 5 patients had significantly elevated TgAb levels and 4 had Tg < 0.04 ng/mL. The clinical characteristics of the patients are summarized in Table S1, Supplemental Digital Content, http://links.lww.com/MD/J27. The study protocol was approved by the Ethics Committee of Nanjing First Hospital, and informed consent was obtained from all the patients. Permission was obtained from relatives of patients who died.

2.2. Imaging acquisition

All patients fasted for 6 to 8 hours before PET/CT and their plasma glucose levels were measured (nondiabetic patients had a fasting blood glucose level < 8 mmol/L, whereas diabetic cases < 11 mmol/L). ¹⁸F-FDG was injected intravenously at a dose of 0.05 to 0.1 mCi/kg. PET/CT was performed from the top of the head to the middle thigh for an emission time of 3 minutes at 1 to 1.5 hours after injection of ¹⁸F-FDG (uMI780, United Imaging Healthcare, Shanghai, China) with the following parameters: tube potential of 120 kVp, tube current 200 mAs with tube current modulation, pitch 0.9875, rotation time 0.5 seconds, slice thickness 3-mm, and slice interval 1.50 mm, respectively. PET images were reconstructed using an ordered subset expectation maximization algorithm with 2 iterations, 20 subsets, and 3-mm Gaussian post-filtering. The volume of interest of the lesion was delineated on axial images using a semiautomatic segmentation tool with a commercial medical image post-processing workstation (uWS-MI R2.0; United Imaging Healthcare). The SUV_max of the volume of interest was obtained.

2.3. ¹⁸F-FDG PET/CT image interpretation

¹⁸F-FDG PET/CT images were interpreted by 2 certificated nuclear medicine physicians with more than 5 years of professional experience. Diagnosis was made according to ¹⁸F-FDG metabolic characteristics, position, morphology, size, density, and ultrasonic display of the lesions (Table S2, Supplemental Digital Content, http://links.lww.com/MD/J28), as well as chief complaints, sex, age, Tg, and TgAb. When the SUV_max value of the lesion > 2.5 or nonphysiological radioactive uptake in the lesion was significantly higher than that of the surrounding tissue, uptake was considered as abnormal except for physiological FDG uptake in the brain, heart, muscles, kidney, and bladder, as described previously.^[11] Lesions were classified into the following sites: thyroid bed (remnants/recurrent), nodules (cervical and mediastinal), lung, and skeletal muscle. The number of lesions at each site was also noted, except in the lungs, where more than 5 lesions were labeled as multiple lesions.

The diagnostic criteria for true-positive lesions were either histopathology or follow-up showing that the original lesions became larger or new lesions occurred, or ¹³¹I-Whole-body scan (WBS) revealed significant RAI uptake by lesions. The diagnostic criteria for false-positive lesions were: histopathological evidence and lesion(s) that disappeared in the period of follow-up. The diagnostic criteria for true-negative lesions were as follows: Tg < 0.20 ng/mL at the follow-up for thyroid hormone assay; no obvious metastasis during the period of follow-up; original negative lesions found by PET/CT disappeared spontaneously in the follow-up imaging; and no significant changes in lesions during 12 months of follow-up. The diagnostic criteria for false-negative lesions were as follows: histopathology; ¹³¹I-WBS revealing significant RAI uptake; disease progression during the period of follow-up; and Tg elevation with no other suspicious true-positive lesions.^[11]

2.4. Diagnostic criteria for RAIR-DTC

Appropriate thyroid-stimulating hormone stimulation and iodine preparation generally allowed RAIR-DTC to be diagnosed if any one of the following criteria was met: No RAI uptake in metastatic foci in the first therapeutic WBS (Rx-WBS); Original iodine-avid metastatic lesions gradually lost the ability to take up RAI after ¹³¹I therapy; Some metastases took up iodine, while others did not; and Metastatic lesions remained iodine-avid after multiple ¹³¹I therapies, but progressed within 1 year after the last ¹³¹I therapy (e.g., enlargement of lesion, occurrence of new lesions, and continuous increase in serum Tg).^[3,6,12]

2.5. Classification of RAI uptake in recurrent or metastatic DTC lesions

RAI uptake in recurrent or metastatic lesions was classified into 4 grades by visual assessment: 0 for no uptake; For faint uptake; For moderate uptake; and For intense uptake.^[13]

SUV_max and its ratio of tumor to liver (SUV_max/SUV_liver, or tumor/liver [T/L]), were calculated to evaluate tumor RAI uptake, respectively, where the term SUV_max was defined as the highest value of all the SUV values of true-positive and false negative lesions, whereas SUV_liver was defined as the average of the 3 SUV_mean values on 3 continuous layers of the liver for a patient.

2.6. Statistical analysis

Data with a non-normal distribution were described as median and interquartile range. The T/L ratio was compared between the 2 groups (RAIR vs non-RAIR) in DTC cases using Wilcoxon rank sum test, and data across multiple groups were compared using Kruskal–Wallis test. If the Kruskal–Wallis test showed a significant difference among groups, pairwise comparisons were performed using Bonferroni correction. The correlation between ¹³¹I and FDG uptake in recurrent or metastatic lesions was assessed using the Spearman correlation analysis. The diagnostic efficacy of T/L was estimated using the receiver operating characteristic curve. The area under the curve (AUC), sensitivity, and specificity were calculated. Statistical significance was set at a 2-tailed P value < .05. Data were analyzed using Stata 11.0 (Statacorp, Texas, USA) and GraphPad Prism 8 (GraphPad Software, California, USA).

3. Results

3.1. Comparison of FDG uptake between RAIR and non-RAIR in DTC patients

A total of 66 patients with DTC were enrolled in the study, including 42 for RAIR and 24 for non-RAIR (Fig. 2). The remaining 2 cases could not be determined because of lack of Rx-WBS data. The T/L ratio was significantly higher in the RAIR group than in the non-RAIR group [5.18 (3.15, 7.42) vs 1.44 (0.79, 2.40); z = 5.36, P < .01] (Fig. 3A, Table 1). The receiver operating characteristic curve of ¹⁸F-FDG PET/CT for RAIR is shown in Figure 4A. The diagnostic efficacy of ¹⁸F-FDG PET/CT was best when the T/L ratio was 2.98, with a sensitivity of 83.3%, a specificity of 87.5%, and an AUC of 0.90, respectively.

Figure 2.

¹⁸F-FDG PET/CT and Rx-WBS images of a 59-year-old man. The patient had RAIR-DTC and underwent a right radical thyroidectomy. Tg was 8.92 μg/L. (A) PET/CT image showing the right cricoid cartilage (arrow) with high fluorodeoxyglucose (FDG) uptake. (B) Rx-WBS showing that the lesion (indicated by the arrow) was ¹³¹I-negative. ¹⁸F-FDG = ¹⁸F-fluorodeoxyglucose, DTC = differentiated thyroid carcinoma, PET/CT = psitron emission tomography/computed tomography, RAIR = radioactive iodine refractory, Tg = thyroglobulin, WBS = Whole-body scan.

Figure 3.

¹⁸F-FDG uptake in patients with DTC in relation to differentiation and risk of recurrence ¹⁸F-FDG uptake in lesions in (A) patients with RAIR-DTC and non-RAIR-DTC, and (B) patients with high and medium-low postoperative recurrence risk. ¹⁸F-FDG = ¹⁸F-fluorodeoxyglucose, DTC = differentiated thyroid carcinoma, RAIR = radioactive iodine refractory.

Table 1.

Comparison of the T/L ratio between patients. The patients were divided into 2 groups according to iodine refractory status, postoperative recurrence risk, TNM stage, or size of lung metastases using Wilcoxon rank sum test.

Factors	T/L*		P value
	Median	Interquartile range
Iodine refractory
RAIR-DTC†	5.18	3.15–7.42	<.01
Non-RAIR-DTC	1.44	0.79–2.40
Postoperative recurrence risk
High-risk	4.90	2.87–7.27	<.01
Medium-low-risk	2.16	1.07–3.05
TNM stage
III–IV	4.29	2.87–7.27	.03
I–II	2.92	1.25–5.69
Size of lung metastases
>8 mm	2.59	1.66–6.36	<.01
≤8 mm	0.66	0.37–0.97

DTC = differentiated thyroid carcinoma, RAIR = radioactive iodine refractory, T/L = tumor/liver.

^*T/L tumor/liver ratio (SUV_max/SUV_liver).

^†RAIR-DTC radioactive iodine refractory differentiated thyroid carcinoma.

Figure 4.

ROC curves of ¹⁸F-FDG PET/CT in patients with RAIR-DTC (A) and high-risk of postoperative recurrence (B). DTC = differentiated thyroid carcinoma, PET/CT = psitron emission tomography/computed tomography, RAIR = radioactive iodine refractory, ROC = receiver operating characteristic curve.

3.2. FDG uptake among patients with different postoperative recurrence risks

All 66 patients were stratified into 4 groups according to the ATA guideline^[3]: 4 for low-risk, 18 intermediate-risk, 41 high-risk (Fig. 5), with 5 not determined because surgery was performed a long time ago and related data was not available. The T/L ratio was significantly higher in high-risk group than in medium- and low-risk group [4.90 (2.87, 7.27) vs 2.16 (1.07, 3.05); z = 3.50, P < .01] (Fig. 3B, Table 1). The diagnostic efficacy of ¹⁸F-FDG PET/CT was best when the T/L ratio was 3.11, with a sensitivity of 68.3%, a specificity of 81.8%, and an AUC of 0.77, respectively (Fig. 4B).

Figure 5.

¹⁸F-FDG PET/CT images of a 44-year-old woman. The patient was at high-risk of postoperative recurrence and underwent radical thyroidectomy. Axial (A) and coronal (B) images showing pulmonary nodules (indicated by the arrow) with high FDG avidity (SUV_max 26.49), whereas Rx-WBS showing pulmonary metastases (indicated by the arrow) were ¹³¹I-negative. ¹⁸F-FDG = ¹⁸F-fluorodeoxyglucose, PET/CT = psitron emission tomography/computed tomography, SUV_max = maximum standardized uptake value, WBS = Whole-body scan.

3.3. FDG uptake in relation to TNM stage

These patients were stratified into 5 groups according to the 8^th edition of the AJCC/TNM staging system for thyroid cancer:^[14] 15 for stage I, 25 stage II, 1 stage III, 25 stage IV (Fig. 6), with 2 not determined (1 case due to the presence of TxN0M0, and the other due to insufficient pathological data). Patients at stages I to II were classified as low-risk, and those at stages III to IV as high-risk. T/L was significantly higher at stage III to IV than at stage I to II [4.29 (2.87, 7.27) vs 2.92 (1.25, 5.69); z = 2.17, P = .03] (Table 1). We evaluated the efficacy of ¹⁸F-FDG PET/CT in screening high-risk DTC patients at the stages III-IV). The diagnostic efficacy of ¹⁸F-FDG PET/CT was best at a cutoff value of 3.44 for T/L ratio, with a sensitivity of 65.4%, a specificity of 70.0%, and an AUC of 0.69, respectively.

Figure 6.

¹⁸F-FDG PET/CT images of a 75-year-old man. The patient was diagnosed with TNM stage IV disease and underwent a bilateral total thyroidectomy. Tg was 588.40 μg/L at the time of PET/CT). Axial (A) and coronal (B) images showing pulmonary nodules (as indicated by the arrow) with high FDG avidity (SUV_max 37.89) and Rx-WBS showing pulmonary metastases (as indicated by the arrow) were ¹³¹I-negative. ¹⁸F-FDG = ¹⁸F-fluorodeoxyglucose, PET/CT = psitron emission tomography/computed tomography, SUV_max = maximum standardized uptake value, Tg = thyroglobulin, WBS = Whole-body scan.

3.4. Correlation between ¹³¹I and FDG uptake by recurrent or metastatic lesions

Of 68 patients with true-positive or false-negative lesions, 33 cases (75 lesions) received ¹⁸F-FDG PET/CT within 3 months before ¹³¹I therapy. The ¹³¹I uptake levels were shown as follows: 0 grade for 31 lesions, 1^st for 5 lesions, 2^nd for 15 lesions, and 3^rd for 24 lesions (Table 2). The T/L ratio of recurrent or metastatic lesions was negatively correlated with the ¹³¹I uptake levels of the lesions (Fig. 7), with higher ¹³¹I uptake in lesions with lower T/L values (r= −0.39, P < .01).

Table 2.

Correlation between ¹³¹I uptake and FDG uptake of the patients.

131I uptake levels	T/L		Spearman correlation analysis
	Median	Interquartile rang
0 grade	3.01	2.19–4.30	r=−0.39, P < .01
1st grade	3.15	2.75–4.74
2nd grade	0.70	0.53–1.88
3rd grade	1.71	1.06–2.08

T/L tumor/liver ratio (SUV_max/SUV_liver).

T/L = tumor/liver.

Figure 7.

Pictures showing tumor dedifferentiation lead to decreased uptake of ¹³¹I and increased ¹⁸F-FDG avidity in Patient A to Patient B. (A) Tumor cells showed classical papillary structure associated with increased ¹³¹I uptake and decreased ¹⁸F-FDG. (The lesion is indicated by the arrow) (B) Tumor cells with tall cell variant of papillary thyroid carcinoma and follicular structure associated with increased ¹⁸F-FDG uptake and decreased ¹³¹I uptake in the tumor. (The lesion is indicated by the arrow). ¹⁸F-FDG = ¹⁸F-fluorodeoxyglucose.

3.5. ¹⁸F-FDG uptake by recurrent or metastatic lesions

A total of 263 lesions in 68 DTC patients were confirmed as metastatic lesions by histopathology, imaging, and clinical follow-up. Up to 5 lesions per patient and up to 2 lesions per organ were chosen. A total of 141 lesions were analyzed. These lesions included 7 in the thyroid bed, 35 in the cervical lymph nodes, 41 in the lungs, 17 in the mediastinal lymph nodes, 36 in bone metastases, and 5 in visceral metastases. The T/L values of the lesions differed significantly across 4 groups (cervical lymph nodes, lungs, mediastinal lymph nodes, vs bone metastasis) (χ² = 10.20, P = .02), with a marked difference between the bone and lung nodules [2.83 (1.72, 5.53) vs 1.55 (0.69, 4.20), P < .01]. Among the 41 lung metastases, 24 lesions were > 8 mm and 17 lesions were ≤ 8 mm, with T/L values of 2.59 (1.66, 6.36) and 0.66 (0.37, 0.97), respectively (z = 4.82, P < .01) (Table 1).

4. Discussion

In this study, ¹⁸F-FDG uptake in the tumor was evaluated in the differentiation of RAIR and non-RAIR behavior, different TNM stages, and different risks for postoperative recurrence in Chinese patients with DTC. Further, we assessed those recurrent or metastatic lesions on ¹⁸F-FDG uptake and correlated with ¹³¹I uptake. We observed that ¹⁸F-FDG PET/CT presented with better performance in the differentiation of RAIR from non-RAIR behavior, and risk stratification of postoperative recurrent or metastatic events according to a prespecified T/L ratio. This study provided some evidence that would help for the early identification of RAIR status and risk stratification.

Early diagnosis of RAIR-DTC is a great challenge in clinical settings and ultimately affects the outcome and quality of life. However, the appropriate definition of RAIR-DTC remains controversial, and the mechanism responsible for the RAIR status is not fully understood. Tyrosine kinase inhibitors are classically prescribed to patients with RAIR-DTC; however, the optimal window needs to be explored because identifying the optimal treatment window would improve the response of high-risk patients with metastatic DTC to tyrosine kinase inhibitors. Our latest study showed that TKI apatinib combined with RAI had beneficial synergistic or complementary antitumor effects in progressive metastatic DTC.^{[11] 18}F-FDG and ⁶⁸Ga-NOTA-PRGD2 PET/CT was effective in evaluating apatinib-treated RAIR-DTC.^[15]

It is well documented that ¹⁸F-FDG PET/CT is a valuable tool in the diagnosis of DTC, especially in patients at intermediate-risk and above, leading to a change in management of up to 38% of patients. Patients with a negative ¹⁸F-FDG PET/CT show higher response to RAI. In ¹⁸F-FDG PET, SUVmax value > 4 has been identified as a cutoff in identifying non-avid ¹³¹I lesions.^[16] In the current study, we retrospectively evaluated the ability of ¹⁸F-FDG PET/CT to distinguish RAIR from and high-risk metastasis in DTC patients. RAIR-DTC is often diagnosed after use of ¹³¹I therapy achieving a cumulative dose of >600 mCi, which is undesirable and impairs clinical outcomes. In addition, the diagnosis requires several cycles of ¹³¹I treatment, with an interval of more than 6 months between 2 cycles, thus delaying the diagnosis of RAIR-DTC.^[17] A primary tumor size > 40 mm, extrathyroidal extension, and aged > 55 years were significant risk factors for RAIR-DTC.^{[18] 18}F-FDG PET/CT can be used to identify lesions and patients with rapid disease progression or a high-risk of disease-specific death. The latest study comprising 53 patients with suspected RAIR-DTC further demonstrated that the use of ¹⁸F-FDG PET/CT led to a significant reduction in the blinded RAI administration, and patients with hypermetabolic lesions would benefit more from the integration of multiple therapies.^[19] A previous study found that at a cutoff value of 4.0 SUV_max, ¹⁸F-FDG PET/CT could differentiate ¹³¹I-non-avid from ¹³¹I-avid metastatic DTC lesions.^[18] However, SUVmax showed great variability due to different instrument systems and acquisition times, and the T/L ratio showed relatively little variation. Furthermore, RAIR-DTC had significant intra- and inter-tumoral heterogeneity, and some RAIR-DTC patients had both ¹³¹I-avid and non-avid metastatic lesions, and the T/L ratio might avoid deviation. The current study showed that ¹⁸F-FDG PET/CT is a valuable tool for the early identification of RAIR-DTC, with an optimal cutoff T/L value of 2.98.

High-risk DTC confers a high-risk of postoperative recurrence or worsen TNM stage III to IV.^[3,14] Among patients with FDG-avid DTC with a metabolic volume of the primary tumor > 10 cm³, the concomitant use of SUV, volumetric, and textural parameters could predict high-risk of recurrence in DTC patients.^[20] Extrathyroidal extension, number of positive lymph nodes, and low lymph node yield were also independent clinicopathological risk factors for postoperative recurrence of well-differentiated thyroid cancer.^[21] The current study included 4 low-risk, 18 intermediate-risk, and 41 high-risk patients. ¹⁸F-FDG PET is valuable for predicting DTC with high postoperative risk. A T/L cutoff value of 3.11 efficiently predicted high recurrence risk for patients. The T/L ratio was significantly higher in patients with stage III or IV disease than in those with stage I or II disease, consistent with the results of a previous study.^[22]

In this study, ¹³¹I uptake in 75 recurrent or metastatic lesions negatively correlated to the T/L ratio in ¹⁸F-FDG PET images. The “flip-flop” phenomenon has been observed in thyroid cancer, in which metastases trapping ¹³¹I show no uptake of ¹⁸F-FDG, whereas the metastases not trapping ¹³¹I exhibit high ¹⁸F-FDG uptake.^[23] Patients with higher ¹³¹I uptake were recommended for RAI, whereas those with higher FDG uptake might select targeted therapy, and those with both moderate ¹³¹I and FDG uptake might choose ¹³¹I therapy in combination with a TKI. Drugs that can enhance RAI uptake, such as selpercatinib and larotrectinib, have also been developed.^[24,25] The 2015 ATA guideline strongly recommend the use of RAI therapy to treat pulmonary micro metastases, because the highest rates of complete remission have been reported in this subgroup.^[3] The guidelines suggest that patients with RAI-avid pulmonary macronodular metastases can receive RAI therapy; however, complete remission is unlikely. RAI therapy may improve survival but is rarely curative in patients with iodine-avid bone metastases. In summary, RAI therapy is more effective in patients with pulmonary micro metastases than with pulmonary macronodular or bone metastases. Notably, the current study found that the T/L ratio was significantly lower in patients with pulmonary micro metastases than with pulmonary macronodular or bone metastases. In this study, 5 patients with significantly increased TgAb (Tg < 0.04 μg/L) had multiple FDG-avid lesion. Significantly increased postoperative TgAb levels in DTC patients may indicate a higher risk of recurrence or metastasis.

However, this study still had some limitations. The number of patients was relatively small, which might lead to bias in the identification of RAIR-DTC or high-risk DTC. In addition, the microenvironment of thyroid cancer, including glucose deprivation, lactic acid accumulation, and acidification, may affect ¹⁸F-FDG uptake in tumors.^[26] However, few studies focused on ¹⁸F-FDG PET/CT guided precision therapy and tumor response evaluation in RAIR-DTC. Further studies are needed to explore tumor glycolysis and immune inflammatory infiltration in thyroid cancer, elucidate the mechanisms underlying RAIR-DTC, and identify eligible molecular biomarkers.

5. Conclusion

¹⁸F-FDG PET/CT is a clinically valuable tool for the early identification of RAIR behavior and risk stratification in DTC patients, assisting the selection of a more appropriate treatment strategy.

Acknowledgments

The authors would like to thank all the participants and staff from Nanjing First Hospital, Nanjing Medical University, China, for their contributions to the study (in particular, Ms. Fei Yu for her biostatistical consultation). We also thank Dr Susan Furness from Liwen Bianji (Edanz) (www.liwenbianji.cn) for her language editing of the draft of the manuscript.

Author contributions

Data curation: Xiaowei Tang, Liang Shi, Jun Wang, Rui Yang, Yue Huang, Jun Tang, Zhengguo Chen.

Investigation: Xiaowei Tang, Zhenyu Zhao, Feng Wang.

Methodology: Xiaowei Tang, Zhenyu Zhao, Feng Wang.

Writing – original draft: Xiaowei Tang.

Writing – review & editing: Liang Shi, Jun Tang, Feng Wang.

Supplementary Material

medi-102-e33878-s001.pdf ^{(349.8KB, pdf)}

medi-102-e33878-s002.pdf ^{(250.9KB, pdf)}