Archives in Cancer Research

Keywords

Differentiated thyroid carcinoma; Lung metastasis; 131I therapy; Refractoriness; 18F- FDG; PET/CT

Introduction

The most common disease of malignant endocrine tumors is thyroid cancer, which is still increasing in incidence [1,2]. Differentiated thyroid carcinoma (DTC) including papillary and follicular thyroid carcinoma accounts for more than 90% of all thyroid cancers. DTC generally has a favorable prognosis, with 10-year overall and cause-specific survival rates of 76.8% and 84.9%, respectively [3]. However, in DTC patients with distant metastasis, the 10-year overall and cause-specific survival rates decrease to 24% and 27%, respectively [4]. The presence or absence of distant metastases in DTC is one of the most important factors for determining the prognosis.

Radioiodine therapy with 131I (131I therapy) after a near-total or total thyroidectomy has been an established treatment for patients with DTC [5,6]. Previous studies have reported that 131I therapy improves the clinical prognosis of patients [7,8], while DTC patients who have recurrent or metastatic lesions without 131I accumulation have a poor prognosis [9,10]. However, according to some recent articles, molecular-targeted therapy with sorafenib significantly improved progression-free survival in patients with progressive radioactive iodine-refractory DTC [11,12]. Therefore, establishment of the indications for the molecular-targeted therapy would be of great clinical benefit, especially in DTC patients with distant metastasis.

Positron emission tomography/computed tomography using 2-[F-18]-fluoro-2-deoxy-D-glucose (18F-FDG PET/CT) is known to be a useful modality for the detection of iodine-negative DTC lesions [10,13,14], since Feine et al. first formally proposed the “flip-flop pattern”, an inverse correlation between 18F-FDG and 131I uptake in the metastatic lesions from DTC patients [15]. As the mechanism, it has been reported that DTC cells show glucose transporter 1 (GLUT1) upregulation and reduced expression of the sodium-iodide symporter during the dedifferentiation process [16]. Although it has been reported that residual lymph node metastasis from DTC showed significantly higher 18F-FDG uptake in lesions without 131I uptake than those with 131I uptake [17,18], among DTC patients with lung metastasis (LM), the relationship between the resistance to 131I therapy and 18F-FDG accumulation in LM remains unclear. The purpose of this study was to retrospectively clarify the association between 18F-FDG accumulation in LM before 131I therapy and resistance to 131I therapy among DTC patients.

Materials and Methods

Patients

This retrospective study was approved by our institutional review board, and the written informed consent was from all patients.

Two-hundred sixty-three consecutive patients with DTC who were treated with 131I therapy between October 2012 and September 2016 at Kyushu University Hospital after near-total or total thyroidectomy were retrospectively analyzed. DTC patients with LM histopathologically diagnosed as either papillary or follicular carcinoma were included. The definition of LM was determined by at least one of the following criteria: (1) 131I accumulation in the lung field higher than the surrounding tissue identified on 131I SPECT/CT (32 patients), and (2) multiple pulmonary nodules in the bilateral lung, which showed progressive increase in size on follow-up CT (observation period 35 ± 9 months: 29 patients). Patients who had a past history of any other malignant disease, who had distant metastasis in organs other than the lung, who had a low thyroid-stimulating hormone (TSH) level (< 30 U/mL), or who had a high blood glucose level (> 150 mg/dL) were excluded from this study. Consequently, a total of 61 patients (41 females and 20 males) were included in our study. All patients underwent thyroid hormone withdrawal for at least 4 weeks before 131I therapy for the purpose of TSH stimulation, and all patients were prescribed a low-iodine diet for 2 weeks in preparation for 131I administration. The patient characteristics are indicated in Table 1.

Age	18 to 78 years (Median: 60)
Men/Women	20/41
Papillary/Follicular	57/4
TSH level	35.7 – 330.7 U/mL (Median: 135)
TG level before 131I therapy *	15.2 – 2590 U/mL (Median: 317)
TG level after 131I therapy *	0.9 – 1850 U/mL (Median: 183)
131I administration dose	4.0 – 5.5 GBq (Median: 4.5)

TSH: Thyroid-stimulating hormone; TG: Thyroglobulin.
*Twelve of 61 patients with a high level of serum anti-thyroglobulin antibody (> 45 IU/mL) were excluded.

Table 1: Baseline characteristics of the patients.

131I Scintigraphy

Post-therapy 131I scintigraphy was performed at 4–7 days (median: 5 days) after 131I administration (4.0–5.5 GBq, median: 4.5 GBq).

All patients underwent a whole-body 131I scan (WBS) and SPECT/ CT with a hybrid camera combining a dual-head c-camera with a 6-slice spiral CT within the same gantry (Symbia T6: Siemens, Hoffman Estates, IL). On WBS, anterior images were acquired at a speed of 10 cm/min with high-energy parallel-hole collimators, a 256 × 1024 matrix, and a 364-keV photopeak with 15% windows. SPECT images were acquired in a step-and-shoot mode, with 40 projections (a duration of 45 s at each projection), a noncircular orbit over 360°, high-energy parallel-hole collimators, a 128 × 128 matrix, and a 364-keV photopeak with 15% windows. Then, 3D ordered-subset expectation–maximization iterative reconstruction was performed, with 4 iterations and 8 subsets. SPECT images were subjected to CT-based attenuation correction without scattered correction. The CT scan parameters were 130 keV, 30 mAs or less (for minimization of radiation exposure), a 512 × 512 matrix, and a 2 × 2.5 mm collimation.

18F-FDG PET/CT

Each 18F-FDG PET/CT acquisition was performed under the TSH-stimulated state. In each patient, 185 MBq of 18F-FDG was intravenously administered after at least 4 hr of fasting. Scans were conducted from the middle of the thigh to the top of the skull 60 min after 18F-FDG administration. 18F-FDG PET/ CT images were obtained using an integrated PET/CT scanner Discovery STE (GE Medical Systems, Milwaukee, WI). The PET scanner comprises 24 ring detectors consisting of 560 BGO crystals (4.7 × 6.3 × 30 mm). All emission scans were performed in 3-dimensional mode with 128 × 128 matrices (5.47 × 5.47 × 3.27 mm), and the acquisition time per bed position was 3 min. The PET images were reconstructed using the ordered-subset expectation–maximization method (VUE Point Plus) with 2 full iterations of 28 subsets, and the full-width at half maximum was 5.2 mm. A low-dose 16-slice CT (tube voltage, 120 kV; effective tube current, 30–250 mA) from the vertex to the proximal thigh was performed for attenuation correction, and for determining the precise anatomic location before acquisition of the PET image. The CT scan was reconstructed by filtered back-projection into 512 × 512 pixel images with a slice thickness of 5 mm to match the PET scan. The PET/CT fusion images were made by GENIE–Xeleris software using a dedicated work station, Xeleris (GE Medical Systems, Milwaukee, WI).

Diagnostic CT protocol

A diagnostic chest CT covering the upper mediastinum to the upper abdomen was performed with a 64-MDCT (multi detector-row CT) scanner (Aquilion 64; Toshiba Medical Systems, Tokyo, Japan) after 131I scintigraphy, using the following parameters: tube voltage 120 kV, effective tube current 300 mA, collimation 0.5 mm, pitch 27.0. The MDCT scan was reconstructed by filtered back projection into 512 × 512 pixel images with a slice thickness of 3 mm. In all patients, 18F-FDG PET/CT, diagnostic CT, and 131I scintigraphy were performed within one week.

Data Analysis

All patients in this study underwent patient-based analysis by LM. After determination of the LM with highest 18F-FDG accumulation in PET images, the highest pixel value in the LM on 18F-FDG PET/ CT was determined as the maximum standardized uptake value (SUVmax). On 131I scintigraphy, 131I accumulation higher than the background in at least one LM was defined as 131I-positive LM and that as low as background in all LMs as 131I-negative LM by visual evaluation. SUVmax was compared between patients with and without 131I-positive LMs, and between those with and without an increased thyroglobulin (TG) level 12 ± 2 months after initial 131I therapy. The predictability for 131I accumulation in LM or an increased level of TG after 131I therapy and the correlation of SUVmax in LM with a TG level before or after 131I therapy were also analyzed.

Statistical Analysis

Comparisons of SUVmax between patients with and without 131I-positive LM, and between those with and without an increased level of TG after 131I therapy were analyzed by the Wilcoxon test. Analysis of the predictability for 131I accumulation in LM or an increased TG level after 131I therapy was performed by receiveroperating- characteristic (ROC) analysis. The correlation of SUVmax in LM with TG level before or after 131I therapy was analyzed by Pearson’s correlation analysis. The tests were performed using JMP® (version 9.0.2; SAS Institute, Cary, North Carolina) statistical software. A p value less than 0.05 was considered statistically significant.

Results

Comparison of 18FDG accumulation between patients with 131I-positive and 131I-negative LM

The SUVmax in LMs of all 61 patients ranged from 0.5 to 26 (mean ± SD; 3.8 ± 4.8). In 3 of 61 patients, LMs were detected only with 131I scintigraphy, not with CT images. For the other 58 patients, the greatest short-axis diameters in the largest LM nodules ranged from 3 to 21 mm (mean ± SD; 7 ± 4 mm). Of the 61 patients, 32 patients had 131I-positive LM and 29 had no 31I-positive LM. 18F-FDG accumulation as indicated by SUVmax was significantly higher in patients without 131I-positive LM than in those with 131I-positive LM [5.9 ± 6.0 vs. 1.9 ± 2.0 (mean ± SD), p<0.01] shown in Figure 1. All 8 patients with SUVmax higher than 7.3 had 131I-negative findings in all LM.

Figure 1: Box-and-whisker plot of SUVmax in LM for patients with and without 131I-positive LM after 131I therapy. The boxes represent the 25?75% range with bisecting lines showing the median values, and the horizontal lines represent the 10?90% range. Of 61 DTC patients with LM, the SUVmax of the LM was significantly greater for patients with 131I-positive LM than for those without 131I-positive LM.

Predictability of 18F-FDG PET/CT for 131I accumulation in LM

Use of an optimal cutoff threshold for SUVmax of 0.8 differentiated patients without 131I-positive LM from patients with 131I-positive LM at a sensitivity of 59.4% (19/32), a specificity of 82.8% (24/29), an accuracy of 70.5% (43/61), and an area under the curve (AUC) of 0.78.

Comparison of 18FDG accumulation between patients with and without an increased level of TG after 131I therapy

Forty-nine of 61 patients without a high level of anti-TG antibody (> 45 IU/mL) were analyzed. The TG levels before and after 131I therapy of the 49 patients ranged from 15.2 to 2590 (mean ± SD; 461 ± 531) and from 0.9 to 1850 (mean ± SD; 379 ± 450), respectively. Of the 49 patients, 18 patients had an increased TG level and 31 patients did not. 18F-FDG accumulation in LM as indicated by SUVmax was significantly higher in patients whose TG levels increased than in those whose TG levels didn’t increase [7.0 ± 4.9 vs. 1.2 ± 1.0 (mean ± SD), p<0.01] shown in Figure 2. All 11 patients with SUVmax greater than 3.8 showed an increased TG level after 131I therapy.

Figure 2: Box-and-whisker plot of SUVmax in LM in patients with and without an increased level of TG after 131I therapy. The boxes represent the 25?75% range with bisecting lines showing the median value, and the horizontal lines represent the 10?90% range. Of 49 DTC patients without a high level of anti-TG antibody (upper left), SUVmax of LM was significantly greater for patients whose TG levels after 131I therapy did not increase than for those whose levels did increase. Of 27 patients with 131I-positive LM (lower left), there was no significant difference in SUVmax of LM between patients with and without an increased level of TG after 131I therapy. Of 22 patients without 131I-positive LM (lower right), SUVmax of LM was significantly greater for patients whose TG levels after 131I therapy did not increase than for those whose levels did increase.

The 49 patients were divided into 27 patients with 131I-positive LM and 22 patients without 131I-positive LM. The 27 patients with 131I-positive LM consisted of 4 patients with an increased TG level and 23 patients without, and there was no significant difference between patients with and without an increased TG level (3.0 ± 2.1 vs. 1.1 ± 0.9, p=0.08). On the other hand, of the 22 patients without 131I-positive LM, 14 patients whose TG levels increased showed significantly higher SUVmax than 8 patients whose TG levels did not increase (8.2 ± 4.9 vs. 1.7 ± 1.4, p<0.01) (Figure 2).

Representative 18F-FDG PET/CT images for good responders and poor responders to 131I therapy are presented in Figures 3 and 4.

Figure 3: A representative case of good response to 131I therapy in a 30-year-old woman with LM from DTC. A pulmonary nodule in the right lower lobe without 18F-FDG accumulation before the initial 131I therapy showed 131I accumulation in post-therapy 131I scintigraphy. The nodule decreased in size and the TG level of the patient also decreased 12 months after 131I therapy (28.5 to 0.9 ng/mL). a) 18F-FDG PET/CT image (arrow lesion), b) 131I SPECT/CT image (arrow lesion), c) CT image at an initial 131I therapy (arrow lesion), d) CT image after 131I therapy (arrow lesion).

Figure 4: A representative case of poor response to 131I therapy in a 47-year-old man with LM from DTC. A pulmonary nodule in the right upper lobe showed the highest 18F-FDG accumulation (SUVmax 12.7) of multiple LM in bilateral lung before initial 131I therapy. LM in the patient showed the absence of 131I accumulation in post-therapy 131I scintigraphy. The nodule increased in size and the TG level of the patient also increased 11 months after 131I therapy (317 to 601 ng/mL). a) 18F-FDG PET/CT image (arrow lesion), b) 131I SPECT/CT image (arrow lesion), c) CT image at an initial 131I therapy (arrow lesion), d) CT image after 131I therapy (arrow lesion).

Predictability of 18F-FDG PET/CT for poor response to 131I therapy

Among the 49 patients, use of the optimal cutoff threshold for SUVmax of 1.6 differentiated patients with an increased level of TG from those without at a sensitivity of 74.2% (23/31), a specificity of 94.4% (17/18), an accuracy of 81.6% (40/49), and an AUC of 0.91.

Correlation of 18F-FDG accumulation in LM with the TG levels before or after 131I therapy

Among the 49 patients, there was no significant correlation between the SUVmax in LM and the TG levels before 131I therapy (r =0.21, p=0.14). On the other hand, the TG levels after 131I therapy showed a significant correlation with the SUVmax in LM (r =0.69, p<0.01) represented by Figure 5.

Figure 5: Scatterplots of SUVmax in LM and pre-therapeutic TG levels (left) and of SUVmax in LM and post-therapeutic TG levels (right) in the 49 patients without a high level of anti-thyroglobulin antibody. Best-fit lines are shown. There was no significant correlation between SUVmax in LM and the TG level before 131I therapy (r = 0.21, p = 0.14). The TG level 12 ± 2 months after 131I therapy had a significant correlation with SUVmax in LM (r = 0.69, p<0.01).

Discussion

Our results demonstrated that SUVmax of LM on 18F-FDG PET/CT had a high predictive value for 131I accumulation in LM from DTC and the response to 131I therapy. That suggests that high 18F-FDG accumulation in LM is associated with a shift to dedifferentiation of LM and poor clinical outcome in DTC patients with LM. Hong et al previously reported that SUVmax greater than 3.6 in distant metastases from DTC was significantly predictive of reduced disease-specific survival in multivariate analysis [19]. All of the patients with SUVmax greater than 3.8 for LM in our study showed an increased TG level after 131I therapy. The previous article and our study indicate that SUVmax of LM in DTC patients is an important index to predict a therapeutic effect for 131I therapy.

Especially in patients without 131I-positive LM, SUVmax of LM in DTC patients with an increased level of TG after 131I therapy was significantly higher than those without. Therefore, we hypothesize that 131I-negative LM includes two types of clinically aggressive and unaggressive features. For DTC patients with an aggressive type of LM, alternative treatment such as moleculartargeted therapy is needed instead of 131I therapy. It is proposed that 18F-FDG -PET/CT is effective in the selection of DTC patients with the aggressive type of 131I-negative LM and can determine the indications for molecular-targeted therapy, which has a beneficial effect on tumor progression in patients with radioactive iodine-refractory metastatic DTC.

Additionally, SUVmax of LM in DTC patients before 131I therapy had a significant correlation not with the TG levels before 131I therapy, but with that after 131I therapy. These data show that 18F-FDG accumulation in LM before 131I therapy expresses post-therapeutic resistance to 131I therapy, although, interestingly, it had no significant relation to the progression of DTC before 131I therapy. Recently, an association has been found histopathologically between high expression of GLUT1 in thyroid cancer stem cells and high resistance to 131I therapy [20]. Therefore, 18F-FDG PET/ CT can be a helpful tool to assess the potential of DTC patients with LM to benefit from 131I therapy and can contribute to the clinical management and determination of the best therapeutic strategy post-resection.

In our study, 18F-FDG PET/CT was performed on the condition of sufficient TSH stimulation, because 18F-FDG PET under TSH stimulation improves the detection of DTC metastases [21]. Moreover, our judgment of 131I accumulation in LM was performed using 131I SPECT/CT as post-therapy 131I scintigraphy in all patients based on the findings of recent articles, reporting that SPECT/ CT improves detection and localization of 131I accumulation in distant metastases in comparison with whole-body scintigraphy [22,23]. Thus, the present study has shown that the evaluation of 18F-FDG and 131I accumulation in LM from DTC is feasible and effective.

Our study had several limitations. First, diagnoses of LM were not always made using a histopathologic procedure but were also sometimes made at clinical follow-up. Although 131I-avid LM uptake usually indicates a metastatic lesion from DTC, 131I-nonavid LM judged at the time of clinical follow-up might be revealed not to be a metastatic lesion at a later date. Because DTC is a slowgrowing neoplasm, a long follow-up period is needed to make a more accurate clinical diagnosis. Second, we lack sufficient data to prove that the outcomes of patients without increased TG level were better than those of patients with increased TG level. Further studies are needed to evaluate the outcomes of DTC patients, who generally having long disease courses.

Conclusion

In conclusion, 18F-FDG accumulation in LM was related to the lack of 131I accumulation and also associated with poor response to 131I therapy especially in patients without 131I accumulation. High 18F-FDG accumulation in LM from DTC was associated with poor treatment outcome after 131I therapy. By contrast, even though low 18F-FDG accumulation in the LM indicates the poor likelihood of 131I accumulation, it also indicates a more stable status of DTC tumor activity. 18F-FDG PET/CT can predict refractoriness to 131I therapy and determine the indication of molecular-targeted therapy in DTC patients with LM.

Conflict of Interest

The authors declare that they have no conflict of interest that competes with any of the contents of the manuscript.

Authors' Contributions

Yasuhiro Maruoka mainly designed and conducted experiments, performed analysis and wrote the manuscript; Takuro Isoda and Yoshiyuki Kitamura performed analysis; Koichiro Abe, Masayuki Sasaki and Hiroshi Honda wrote the manuscript and supervised the project; and Shingo Baba planned and initiated the project, designed and conducted experiments, wrote the manuscript, and supervised the entire project.

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