Value of Diagnostic Radioiodine Whole-Body Scanning After Initial Therapy in Patients with Differentiated Thyroid Cancer at Intermediate and High Risk for Recurrence

Abstract

Background:

Diagnostic radioiodine whole-body scanning (DxWBS) in combination with stimulated thyroglobulin (Tg) (i.e., measurement after levothyroxine [L-T4] withdrawal or recombinant human TSH administration) continues to be recommended for patients with differentiated thyroid carcinoma (DTC) at high or intermediate risk for recurrence with negative basal Tg and ultrasonography (US) after ablation. However, the value of DxWBS has been questioned, even in these cases. The objective of this prospective study was to evaluate the value of DxWBS in these patients.

Methods:

The study consisted of 318 patients who had total thyroidectomy with apparent complete tumor resection for DTC. Further, per inclusion criteria, they had the following characteristics (i) a post-therapy radioiodine whole-body scan (RxWBS) showing no metastases and uptake in the thyroid bed of ≤2%, (ii) classification as high or intermediate risk for recurrence based on the large tumor size, tumor extension beyond the thyroid capsule, and lymph node metastases, (iii) Tg during L-T4 therapy (TgT4) of <1 ng/mL, (iv) negative anti-Tg antibodies (TgAb), and (v) normal US performed 8–12 months after ablation. Tg stimulation combined with DxWBS was performed in all patients. Patients without apparent disease in the initial assessment were followed up for 24 to 96 months.

Results:

In the initial assessment, stimulated Tg continued to be <1 ng/mL in 253 (79.5%) patients and converted to levels >1 ng/mL in 65 (20.4%). None of the patients had metastases on DxWBS, and 46 (14.4%) had discrete uptake (<0.5%) only in the thyroid bed. ¹⁸F-fluorodeoxyglucose positron-emission tomography and computed tomography (FDG-PET/CT) revealed metastases in three patients with elevated stimulated Tg. Fourteen (4.4%) patients without initially apparent disease relapsed during follow-up, including five (2%) with initial stimulated Tg < 1 ng/mL. There was no disease-related death. Thyroid bed uptake on DxWBS had no prognostic value for recurrence, irrespective of stimulated Tg levels.

Conclusions:

DxWBS can be avoided in patients with large tumors or extensions beyond the thyroid capsule or lymph node metastases, but who show no apparent disease upon initial RxWBS and US and whose serum TgT4 of <1 ng/mL and negative TgAb after thyroidectomy and ablation.

Introduction

I n patients with differentiated thyroid carcinoma (DTC), who initially have total thyroidectomy followed by remnant ablation with ¹³¹I and who have no ectopic uptake on post-therapy radioiodine whole-body scans (RxWBS), the success of initial therapy is evaluated 6 to 9 months after ablation (1 –3). For this evaluation, thyroglobulin (Tg) levels during levothyroxine (L-T4) therapy (hereafter referred to as TgT4), anti-Tg antibodies (TgAb), and ultrasonography (US) are obtained (1 –3). It is recommended that, in patients in whom all of these parameters are negative, stimulated Tg measurement (i.e., Tg measurement after L-T4 withdrawal or recombinant human TSH [rhTSH] administration) be obtained (1 –3). Diagnostic radioiodine whole-body scanning (DxWBS) in combination with stimulated Tg measurement continues to be recommended for high- or intermediate-risk patients with negative basal Tg and US after ablation (1 –3). In this setting, high (1,2)- or intermediate-risk (3) patients are defined as those who have the following features: large tumors, tumor extension beyond the thyroid capsule, or lymph node metastases. However, even in these cases, some have questioned the value of DxWBS (4).

The objective of this prospective study was to determine whether DxWBS in combination with stimulated Tg is necessary for patients who have no apparent metastases on RxWBS and who have a negative neck US, TgT4, and TgAb after ablation, but who are considered to be at high or intermediate risk for recurrence.

Materials and Methods

The study patients were those with DTC who had been treated with total thyroidectomy and, when preoperative US or perioperative evaluation suggested lymph node metastases, cervical lymph node dissection. Furthermore, the study was restricted to those with apparently complete tumor resection and who had the following characteristics: RxWBS after 3.7 or 5.5 GBq ¹³¹I showing no metastases and uptake in the thyroid bed ≤2% (5)—classified as high risk by the Latin American Thyroid Society (LATS) (1) and European Thyroid Association (ETA) (2) and as intermediate risk by the American Thyroid Association (ATA) (3) (Table 1), negative TgT4, negative TgAb, and normal neck US 8–12 months after radioiodine ablation.

Table 1.

Patients Classified as High Risk by the LATS and the ETA and as Intermediate or High Risk by the ATA

LATS

High risk: Large tumors or tumor extension beyond the thyroid capsule (T3 and T4); lymph node (N1) or distant (M1) metastases; aggressive histology; residual cancer after surgery

ETA

High risk: Large tumors or tumor extension beyond the thyroid capsule (T3 and T4); lymph node (N1) or distant metastases (M1); incomplete tumor resection

ATA

Intermediate risk: Microscopic tumor invasion into perithyroidal soft tissues; cervical lymph node metastases or ¹³¹I uptake outside the thyroid bed on RxWBS; aggressive histology or vascular invasion

High risk: Macroscopic tumor invasion; incomplete tumor resection; distant metastases; possibly thyroglobulinemia out of proportion to what is seen on the RxWBS

Sources: Latin American Thyroid Society (LATS) (1), European Thyroid Association (ETA) (2), American Thyroid Association (ATA) (3).

RxWBS, radioiodine whole-body scan.

Tg stimulation combined with DxWBS was performed in all study patients. Patients with a stimulated Tg of <1 ng/mL and a negative DxWBS did not have any additional imaging procedures. Patients with Tg ranging from 1 to 10 ng/mL after L-T4 withdrawal or from 1 to 5 ng/mL after rhTSH administration had chest and mediastinum computed tomography (CT). In addition, ¹⁸F-fluorodeoxyglucose positron-emission tomography (FDG-PET) was performed on patients with Tg >10 ng/mL after thyroid hormone withdrawal or >5 ng/mL after rhTSH administration (1,3,6). None of the patients without apparent disease received new treatment with ¹³¹I, irrespective of Tg levels or the presence of uptake in the thyroid bed on DxWBS.

The study was approved by the Research Ethics Committee of our Institution.

Late follow-up

Patients without apparent disease in the initial assessment were followed up by annual TgT4, TgAb, and neck US. Imaging studies other than US (first, chest and mediastinum CT; if negative, FDG-PET/CT; if negative, administration of an empirical activity of ¹³¹I [3.7 GBq]) were performed when TgT4 converted from negative to positive or when TgAb became positive. Patients without apparent disease, who initially had stimulated Tg of >1 ng/mL, were submitted to new Tg stimulation at an interval of 2 years (6), until the stimulated Tg became <1 ng/mL. Additional imaging methods were performed when there was an increase in the stimulated Tg levels (6).

Patients without apparent disease who had stimulated Tg <1 ng/mL were maintained on a dose of L-T4 sufficient to obtain a serum TSH of 0.1 to 0.5 mIU/L. Patients with elevated Tg were maintained on a dose of L-T4 sufficient to obtain a serum TSH of <0.1 mIU/L as long as serum Tg continued to be elevated. In the case of patients lost to follow-up (n=4) or those who died of a cause not related to thyroid cancer (n=10), the last evaluation available was considered. Apparent disease was defined based on the results of the imaging methods, cytology or histology, and/or unequivocal ectopic uptake (excluding false-positive results) on RxWBS or FDG-PET.

Imaging methods

US was performed with a linear multifrequency 10-MHz transducer. All suspected lesions apparent on the scans (7) were evaluated by ultrasound-guided fine-needle aspiration biopsy. Chest and mediastinum CT was performed on 5–10-mm sequential sections. Whole-body scanning was performed with a tracer (185 MBq, DxWBS) or therapeutic (3.7–5.5 GBq, RxWBS) activity of ¹³¹I after L-T4 withdrawal for 4 weeks or stimulation with rhTSH (1 –3). The patients received instructions regarding limiting exposure to environmental iodine and using a low-iodine diet for 10 days before ¹³¹I administration. Anterior and posterior whole-body images were obtained 3 (DxWBS) or 7 (RxWBS) days after iodine administration and the scans were analyzed by three experienced nuclear medicine professionals. FDG-PET/CT was carried out after stimulation with rhTSH.

Assays

Tg was measured by a radioimmunometric assay with a functional sensitivity of 1 ng/mL. Stimulated Tg was measured after L-T4 withdrawal for 4 weeks or stimulation with rhTSH (1 –3). TgAb were determined by a chemiluminescent assay (Nichols Institute Diagnostics [a detection limit of 1 IU/mL and a reference value of up to 2 IU/mL] or Immulite 2000 [a detection limit of 20 IU/mL and a reference value of up to 40 IU/mL]). Patients with TgAb were excluded.

Statistical analysis

Means were compared between groups by the Student's t-test or the nonparametric Mann–Whitney U test. The Fisher's exact test or the χ ² test was used to detect differences in the proportion of cases. A p-value <0.05 was considered to be significant.

Results

The characteristics of the patients are shown in Table 2. For DxWBS and measurement of stimulated Tg in the initial assessment (8–12 months after ablation), 218 patients were prepared by L-T4 withdrawal and 100 by the administration of rhTSH. These patients were similar in terms of gender, age, histology, and tumor stage.

Table 2.

Characteristics of the Patients Studied

Gender
Female	212 (66.6%)
Male	106 (33.3%)
Age (years)	9–80 (mean: 49.6)
Histological type
Papillary	280 (88%)
Follicular	38 (12%)
Aggressive histological subtype
All	28 (8.8%)
Tall-cell	4
Columnar-cell	4
Diffuse sclerosing	8
Invasive follicular	8
Hürthle-cell	4
Vascular invasion	12 (3.7%)
Tumor size
Range (mean)	0.5–7 cm (2.9 cm)
≤2 cm	82 (25.8%)
2–4 cm	169 (53.1%)
>4 cm	67 (21%)
Extrathyroid invasion	168 (52.8%)
Lymph node metastases
All	220 (69.1%)
Central cervical	198
Lateral cervical	106
Superior mediastinal	37
Multicentricity of the tumor	102 (32%)
TNM classification (3)
T1 N1a M0	14
T1 N1b M0	18
T2 N1a M0	42
T2 N1b M0	46
T3 N0 M0	90
T3 N1a M0	17
T3 N1b M0	79
T4 N0 M0	8
T4 N1a M0	0
T4 N1b M0	4

Initial assessment: stimulated Tg and DxWBS

Stimulated Tg continued to be <1 ng/mL in 253 (79.5%) patients and converted to levels >1 ng/mL in 65 (20.4%). None of the patients had ectopic uptake (metastases) on DxWBS. The frequency of discrete uptake only in the thyroid bed according to stimulated Tg levels is shown in Table 3 and was less than 0.5% in all patients.

Table 3.

Results of Stimulated Thyroglobulin Measurement and DxWBS in Patients with Tg/T4 < 1 ng/mL, Negative Tg Antibodies, and Normal Neck Ultrasonography 8–12 Months After Ablation

	Tg measured after L-T4 withdrawal (number of patients)
DxWBS	<1 ng/mL	1–10 ng/mL	>10 ng/mL	Total
Negative	146	31	6	183
Uptake only in thyroid bed^a	25	8	2	35
Ectopic uptake	0	0	0	0
Total	171	39	8	218

	Tg measured after rhTSH (number of patients)
DxWBS	<1 ng/mL	1–5 ng/mL	>5 ng/mL	Total
Negative	74	13	2	89
Uptake only in thyroid bed^a	8	3	0	11
Ectopic uptake	0	0	0	0
Total	82	16	2	100

Uptake <0.5% in all patients.

DxWBS, diagnostic ¹³¹I whole-body scanning; L-T4, levothyroxine; rhTSH, recombinant human TSH; Tg, thyroglobulin.

Initial assessment: other imaging methods

Chest and mediastinum CT, performed on 39 patients with Tg ranging from 1 to 10 ng/mL after L-T4 withdrawal and on 16 with post-rhTSH Tg ranging from 1 to 5 ng/mL, revealed no metastases. FDG-PET and CT showed lymph node metastases (posterior cervical metastases in one and mediastinal metastases in another) in 2/8 patients with Tg after L-T4 withdrawal >10 ng/mL, and pulmonary micrometastases in one of two patients with post-rhTSH Tg > 5 ng/mL.

Long-term follow-up: recurrence rate and mortality

The recurrence rates after 24–96 months (mean: 60 months) according to initial stimulated Tg are shown in Table 4. There were no disease-related deaths.

Table 4.

Long-Term Recurrence Rate in Patients Without Apparent Disease in the Initial Assessment According to Stimulated Thyroglobulin Levels

Preparation	Tg measured after preparation [recurrence rate (percent)]
	<1 ng/mL	1–10 ng/mL	>10 ng/mL
L-T4 withdrawal (n = 216)	3/171 (1.75%)	4/39 (10.2%)	2/6 (33.3%)
	<1 ng/mL	1–5 ng/mL	>5 ng/mL
rhTSH (n = 99)	2/82 (2.4%)	2/16 (12.5%)	1/1 (100%)
Total (n = 315)	5^a/253 (2%)	6^b/55 (10.9%)	3^c/7 (42.8%)

Site recurrence: cervical lymph nodes, 5.

Site recurrence: cervical lymph nodes, 4; mediastinum, 1; lung, 1.

Site recurrence: cervical lymph nodes, 1; bone, 1; lung, 1.

Prognostic value of DxWBS

Among 253 patients with stimulated Tg < 1 ng/mL, a recurrence was detected in 4/220 (1.8%) with a negative DxWBS versus 1/33 (3%), with uptake in the thyroid bed. In contrast, among the 55 patients with Tg >1 ng/mL, but <10 ng/mL after L-T4 withdrawal or <5 ng/mL after rhTSH, recurrence was detected in 5/44 (11.3%) with a negative DxWBS versus 1/11 (9%) with uptake in the thyroid bed. Finally, among the seven patients with Tg >10 ng/mL after L-T4 withdrawal or >5 ng/mL after rhTSH, recurrence was detected in 2/5 (40%) with a negative DxWBS and 1/2 (50%) with uptake in the thyroid bed.

Discussion

In the present study, patients classified as high risk by the Latin American Thyroid Society (1) and European Thyroid Association (2) and as intermediate risk by the American Thyroid Association (3) were evaluated. The American Thyroid Association (3) defines patients with persistent and apparent disease after thyroidectomy (i.e., incomplete tumor resection and/or distant metastases) as high risk (Table 1).

Our target population were patients without known (on RxWBS) or apparent metastases detected by neck US. It is possible that the inclusion of patients with known disease on RxWBS and treated for metastases with ¹³¹I may have contributed to the higher value of DxWBS reported in previous studies (8,9). In addition, many of the metastases detected by DxWBS would be seen by US, which was not a routine method some years ago.

Another important fact is that large thyroid remnants showing intense cervical uptake may obscure the visualization of lymph node metastases by planar RxWBS, which would subsequently be detected by DxWBS (5). This would not occur with discrete uptake in the thyroid bed (5), which can be obtained in all patients submitted to total thyroidectomy by an experienced surgeon (10). The inclusion of these inadequately operated cases may also overestimate the value of DxWBS, in patients, in whom initial RxWBS revealed no metastases (5). Since rapid progression (<1 year), especially if not accompanied by an increase of basal Tg, is exceptional in well-differentiated thyroid carcinoma, it is likely that the metastases eventually detected by DxWBS some months after ablation already were present at the time of ablation. It is therefore difficult to explain why an activity of 185 MBq reveals disease that is not detected with 3.7 GBq.

A recent study showed that DxWBS does not add information in the case of high-risk patients when stimulated Tg is negative and proposed that this method is not necessary in these cases (4). These data do not seem to be sufficient, since in clinical practice DxWBS is obtained concomitantly with stimulated Tg and not in sequence. We therefore selected patients with negative basal Tg. Since DxWBS did not add information, even in patients having conversion of Tg to levels >1 ng/mL, we propose the measurement of stimulated Tg without DxWBS. This set of factors (RxWBS showing no ectopic uptake and discrete uptake in the thyroid bed in combination with Tg/T4 < 1 ng/mL, negative TgAb, clinical examination and neck US showing no anomalies 8–12 months after ablation) seems to be the best explanation for the present findings (DxWBS showing no ectopic uptake in all 318 patients) and can be used as a criterion to avoid this imaging method after initial therapy, even in patients who are at high (1,2) or intermediate (3) risk for recurrence.

In the present study, the finding of discrete uptake in the thyroid bed had no prognostic significance and does not justify additional treatment with ¹³¹I. This is in agreement with previous studies involving unselected patients with stimulated Tg <1 ng/mL after ablation (10,11). Uptake in the thyroid bed alone also had no prognostic value of recurrence in patients with stimulated Tg >1 ng/mL.

After initial assessment, patients without apparent disease were followed for an average period of 5 years. Although late recurrence may be observed, it is known that two-thirds of recurrences occur within these first years after initial therapy (12 –14). The recurrence rate was only 2% in the subgroup of patients with stimulated Tg < 1 ng/mL, negative TgAb, and normal US. Similar rates have been reported in previous studies involving unselected or low-risk patients (10,11,15,16), confirming that histological data have a minor impact on patient evolution when an initial assessment shows complete remission (including negative stimulated Tg and imaging methods) (16,17). On the basis of these considerations, it is reasonable to propose that even patients initially classified as high or intermediate risk for recurrence can be followed using a less extensive, but regular work-up and that strict TSH suppression is not necessary if the patient meets the criteria of complete remission.

Despite unfavorable histological characteristics, only a minority of our patients with stimulated Tg > 1 ng/mL and negative US after initial therapy had or developed metastases. This is in agreement with previous studies (6,10,15,16). Among these patients, those with stimulated Tg > 10 ng/mL after L-T4 withdrawal or >5 ng/mL after rhTSH were at a higher risk of presenting or developing metastases than those with lower Tg levels (60% vs. 10%), confirming the results of other series (6,10,15,16). For this reason, these patients require additional work-up with other imaging methods, should be maintained on a dose of L-T4 sufficient to obtain TSH suppression, and should be followed more closely.

In conclusion, DxWBS can be avoided in patients with DTC whose histological features indicate a higher risk for recurrence (large tumors, tumor extension beyond the thyroid capsule, or lymph node metastases), but who have no apparent disease on initial RxWBS and neck US and who have basal Tg < 1 ng/mL and negative TgAb after ablation. The recurrence risk is low even in these patients when stimulated Tg continues to be <1 ng/mL. In contrast, additional imaging methods are recommended when there is a significant increase of Tg (>10 ng/mL after L-T4 withdrawal or >5 ng/mL after rhTSH) and the long-term recurrence rate is high in this case. It is possible that in the future highly sensitive assays will make the use of Tg stimulation unnecessary (18,19), but studies involving this group of patients (high or intermediate risk for recurrence) are still needed.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

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