A Low Postoperative Nonstimulated Serum Thyroglobulin Level Does Not Exclude the Presence of Radioactive Iodine Avid Metastatic Foci in Intermediate-Risk Differentiated Thyroid Cancer Patients

Abstract

Background:

Postsurgical thyrotropin (TSH)-stimulated serum thyroglobulin (Tg) level can be used to predict the likelihood of finding radioactive iodine (RAI) avid metastatic foci on postablation scanning. However, there is little data regarding the predictive value of a nonstimulated postoperative Tg obtained on levothyroxine therapy in patients being considered for recombinant human TSH (rhTSH)-assisted remnant ablation.

Methods:

The study included 290 intermediate-risk differentiated thyroid cancer (DTC) patients with a postsurgical nonstimulated Tg<10 ng/mL prior to rhTSH-assisted remnant ablation. Patients were stratified into four groups based on the postsurgical nonstimulated Tg value: Tg<0.6 ng/mL (n=146), Tg 0.6–0.9 ng/mL (n=76), Tg 1–5 ng/mL (n=51), and Tg>5–10 ng/mL (n=17). RAI avid metastatic foci were identified using post-therapy scanning with SPECT/CT (single photon emission computed tomography).

Results:

RAI avid metastases were identified in 16% (46/290) of patients, including 12% (17/146) with Tg<0.6 ng/mL, 14% (11/76) with Tg 0.6–0.9 ng/mL, 25% (13/51) with Tg 1–5 ng/mL, and 29% (5/17) with Tg>5–10 ng/mL (p=0.02). While 99% of the RAI avid foci were located in the neck, lung uptake was seen in one patient with Tg<0.6 ng/mL (0.7%, 1/146), one patient with Tg 0.6–0.9 ng/mL (1.3%, 1/76), and 2 patients with Tg>5–10 ng/mL (11%, 2/17 patients).

Conclusions:

A postoperative nonstimulated Tg<0.6 ng/mL does not exclude identification of RAI avid metastatic foci on postablation SPECT/CT scanning in intermediate-risk DTC patients. Therefore, patient selection for RAI ablation in the intermediate-risk group must be based on an integration of multiple risk factors rather than any single clinicopathologic risk factor.

Introduction

T he revised American Thyroid Association (ATA) management guidelines for patients with thyroid nodules and differentiated thyroid cancer (DTC) call for selective use of radioactive iodine (RAI) in DTC when “the combination of age, tumor size, lymph node status, and individual histology predicts an intermediate to high risk of recurrence or death from thyroid cancer”(1). This risk-adapted management approach has been validated in studies demonstrating excellent clinical outcomes in properly selected intermediate-risk patients followed without RAI remnant ablation (2 –5). As noted in the ATA guidelines, “clinical judgment must prevail in the decision making process”(1) since no single model has been developed that can adequately integrate all of the various clinicopathological risk factors (patient age, tumor size, number of metastatic lymph nodes, size of metastatic lymph nodes, presence of extranodal extension, histological subtypes, vascular invasion, postoperative stimulated serum thyroglobulin [Tg] level, RAI avidity, presence of extrathyroidal extension, or gross multifocal disease) into an individualized risk of recurrence estimate.

Recently, we were faced with several patients with well-differentiated thyroid cancer who were classified as ATA intermediate-risk on the basis of minor extrathyroidal extension, documented lymph node metastases, or intrathyroidal vascular invasion, who already had an undetectable postoperative nonstimulated Tg prior to planned recombinant human thyrotropin (rhTSH)–assisted RAI remnant ablation. Since a nonstimulated Tg value is less sensitive for the detection of persistent/recurrent disease, it is unclear whether or not a Tg obtained postoperatively without TSH stimulation has adequate negative or positive predictive value to accurately guide the selective use of RAI for ablation. This is further complicated because stimulated Tg measurements are not recommended in conjunction with rhTSH-stimulated RAI ablation as the Tg value obtained 72 hours after the second rhTSH injection (48 hours after administration of RAI for ablation) can be artificially elevated secondary to the leakage of Tg from thyroid cells damaged by the radiation (6). Therefore, it is important to understand the clinical implication of an undetectable nonstimulated postoperative Tg value obtained in patients who have other possible indications for RAI remnant ablation.

In previous studies, RAI avid metastatic foci outside the thyroid bed on post-therapy planar imaging were identified in up to 6% of thyroid cancer patients with stimulated Tg values <1.5 ng/mL at the time of remnant ablation (7 –9). Conversely, Giovanella et al. recently reported that none of the 63 DTC patients that had a postsurgical nonstimulated Tg of <0.2 ng/mL (<0.4 ng/mL normalized to CRM 457) had detectable uptake outside the thyroid bed on post-therapy planar scanning (10). However, we have previously demonstrated that post-therapy imaging with SPECT/CT provides better characterization of metastatic foci than routine planar imaging and often identifies discrete locoregional or distant metastatic foci that are not easily appreciated on planar imaging (11).

Therefore, the goal of our study was to determine how often RAI avid locoregional or distant metastases were identified on postablation SPECT/CT imaging in patients with low level nonstimulated postoperative Tg levels who had been selected for RAI remnant ablation on the basis of other clinicopathological risk factors (ATA intermediate-risk). We hypothesized that ATA intermediate-risk patients selected for ablation despite very low postoperative Tg values would be very unlikely to have RAI avid locoregional or distant metastases, and that the likelihood of identifying RAI avid metastatic foci would be positively correlated with the postoperative nonstimulated Tg level.

Methods

Subjects

After obtaining approval from our institutional review board, we retrospectively reviewed the charts of patients who had RAI remnant ablation in our hospital between January 2008 and March 2012. During this time period, SPECT/CT postablation scans were routinely employed at our center in all patients undergoing RAI remnant ablation. Inclusion criteria for the study were as follows: (i) RAI ablation within 6 months of initial surgery, (ii) postoperative nonstimulated Tg≤10 ng/mL with a concurrent TSH<10 mIU/mL, and (iii) intermediate risk for disease recurrence according to the ATA classification (Table 1) selected for RAI ablation (1).

Table 1.

Initial American Thyroid Association Risk of Recurrence Classification

Low risk	Intermediate risk	High risk
All the following are present: • No local or distant metastases • All macroscopic tumor has been resected • No invasion of locoregional tissues • Tumor does not have aggressive histology (e.g., tall cell, insular, columnar cell carcinoma, Hürthle cell carcinoma, follicular thyroid cancer). • No vascular invasion • No RAI uptake outside the thyroid bed on the post-treatment scan, if done	Any of the following is present: • Microscopic invasion into the perithyroidal soft tissues • Cervical lymph node metastases or RAI uptake outside the thyroid bed on the post-treatment scan done after thyroid remnant ablation • Tumor with aggressive histology (e.g., tall cell, insular, columnar cell carcinoma, Hürthle cell carcinoma, follicular thyroid cancer) • Vascular invasion	Any of the following is present: • Macroscopic tumor invasion • Incomplete tumor resection with gross residual disease • Distant metastases

RAI, radioactive iodine.

It is important to note that not all ATA intermediate-risk patients are routinely selected for RAI remnant ablation at our center. For example, patients classified as ATA intermediate-risk on the basis of minimal lymph node involvement are routinely given the option of following without RAI remnant ablation. Therefore, the patients included in this study represent a subset of ATA intermediate-risk patients selected for RAI ablation by an experienced disease management team because RAI remnant ablation was expected to improve initial staging or decrease recurrence. Exclusion criteria included medullary thyroid carcinoma, anaplastic thyroid carcinoma, and the presence of interfering anti-Tg antibodies.

Laboratory studies

Tg levels were measured 2–6 months after surgery, together with anti-Tg antibodies and TSH. All Tg values were measured using the Dynotest-TgS immunoradiometric assay (Brahms, Inc., Berlin, Germany; functional sensitivity 0.6 ng/mL normalized to Certified Reference Material [CRM] 457) (12). TSH was measured using Advia Centaur two-site sandwich immunoassay (Bayer Corp., Tarrytown, NY). Anti-Tg antibodies were measured using Siemens Immulite 2500 Chemistry Analyzer (Siemens Healthcare Medical Diagnostics, Bad Nauheim, Germany).

Radioactive iodine ablation

The activity of ¹³¹I selected for ablation was based on the recommendations of our thyroid cancer tumor board, consisting of endocrinologists, nuclear medicine physicians, thyroid surgeons, and oncologists (5). The clinical features of the patient, histologic and intraoperative findings, risk of recurrence, and the results of the diagnostic scan were all considered in selecting the RAI administered activity for each individual patient. Following preparation with rhTSH, 1.5 mCi of ¹²³I was orally administered 2 hours after the second rhTSH injection. Approximately 24 hours later, pretherapy whole-body images were obtained and the therapeutic activity of ¹³¹I was administered. Five to seven days after RAI administration, post-therapy scan of whole-body images, spot views of the neck, and SPECT/CT images of the base of skull down to the diaphragm were acquired.

Outcomes

The primary outcome was RAI uptake outside the thyroid bed detected on the post-therapy SPECT/CT whole-body scan. Data were collected on both the location of uptake and whether or not a structural correlate was visualized in the corresponding CT image. Secondary outcomes included the correlation between Tg levels and the risk of locoregional metastases and predictive clinical and/or histological features. For categorical analysis, patients were divided into four cohorts based on the postsurgical nonstimulated Tg value as follows: Tg<0.6 ng/mL (below the detection limit of the Tg assay used in the patients in this study), Tg 0.6–0.9 ng/mL (detectable, but <1 ng/mL, which reflects the limit of detection in Tg assays still in common use), Tg 1–5 ng/mL, or Tg>5–10 ng/mL.

Statistical methods

Continuous data are presented as mean and standard deviations or median and ranges, as appropriate for each variable. Categorical comparisons were performed with Fisher's exact or chi-square test, and continuous variables were compared using Student's t-test, Mann–Whitney U-test, or one-way ANOVA, as appropriate. Correlation analyses were performed using Pearson's linear correlation test. Analysis was performed using SPSS software (Version 18.0.1; SPSS, Inc., Chicago, IL). A p-value of ≤0.05 was considered statistically significant.

Results

Initial clinicopathological characteristics of the entire cohort

A total of 290 ATA intermediate-risk DTC patients selected for RAI remnant ablation who demonstrated a nonstimulated postoperative serum Tg level of ≤10 ng/mL prior to routine rhTSH-assisted RAI ablation were included in this study. The median postoperative nonstimulated Tg was 0.6 ng/mL (mean±SD: 1.3±1.6) with a corresponding median serum TSH of 0.56 mIU/L (1.3±1.8). The nonstimulated Tg was below the assay detection limit (<0.6 ng/mL) in 146 patients (50%), between 0.6 and 0.9 ng/mL in 76 patients (26%), between 1 and 5 ng/mL in 51 patients (18%), and between 5 and 10 ng/mL in 17 patients (6%).

Since only ATA intermediate-risk patients were eligible for the study, each patient had at least one clinical feature associated with an increased risk of recurrence, which included 66% with T3 disease, 57% with extrathyroidal extension, 40% with vascular invasion, 36% having central neck lymph node metastases, 29% with lateral neck lymph node metastases, 33% classified as AJCC stage III, and 11% as AJCC stage IVa (Table 2) (13). A mean of 4.3±6 metastatic lymph nodes were surgically removed with a mean size of the metastatic lymph node being 1.6±0.5 cm.

Table 2.

Baseline Characteristics

	Entire cohort
	(n=290)
Female	201 (69%)
Age (years)	46±14
Median	46
Histology
Classic PTC	169 (58%)
Tall cell	54 (19%)
FVPTC	23 (8%)
Follicular cancer	14 (5%)
Hürthle cell	12 (4%)
Poorly differentiated	12 (4%)
Other variants	6 (2%)
Tumor size (cm)	2.3±1.7
ETE	165 (57%)
VI	115 (40%)
Pre-RAI AJCC staging
Stage I	147 (51%)
Stage II	15 (5%)
Stage III	95 (33%)
Stage IV	33 (11%)
Tumor classification
T1	55 (19%)
T2	44 (15%)
T3	191 (66%)
Lymph node classification
N0 or Nx	102 (35%)
N1a	103 (36%)
N1b	85 (29%)
TSH (mU/L)	1.3±1.8 (median: 0.56)
Tg (ng/mL)	1.3±1.6 (median: 0.6)
RAI activity (mCi)	125±30
24 h uptake (%)	0.71±1.3 (median: 0.24)

Data are presented as number (percentage) or mean±SD.

PTC, papillary thyroid cancer; FVPTC, follicular variant PTC; ETE, extrathyroidal extension; VI, vascular invasion; AJCC, American Joint Committee on Cancer; TSH, thyrotropin; Tg, thyroglobulin.

With regard to initial surgical therapy, 50% had total thyroidectomy without neck dissection, 20% had total thyroidectomy with therapeutic central neck dissection, and 30% total thyroidectomy with therapeutic central and lateral neck dissection. Routine prophylactic neck dissection is not performed at our center.

RAI avid metastases detected on SPECT/CT

Radioiodine avid metastatic foci outside the thyroid bed were identified on post-therapy SPECT/CT imaging in 16% (46/290) of patients with a nonstimulated postoperative Tg<10 ng/mL who were selected for RAI remnant ablation (Table 3 and Fig. 1). Uptake outside the thyroid bed was seen on the postablation SPECT/CT scan in 12% (17/146) of patients with Tg<0.6 ng/mL, in 14% (11/76) of patients with Tg 0.6–0.9 ng/mL, in 25% (13/51) of patients with Tg 1–5 ng/mL, and in 29% (5/17) of patients with Tg>5–10 ng/mL.

FIG. 1.

Two patients with undetectable postoperative serum thyroglobulin level with radioactive iodine (RAI) uptake in metastases seen on SPECT/CT. (A) Case 1: 46-year-old female with a 0.9 cm papillary thyroid cancer (PTC) with extrathyroidal extension demonstrating RAI uptake in a structurally identifiable right supraclavicular lymph node. (B) Case 2: 27-year-old female with a 1.1 cm PTC with vascular invasion demonstrating a discrete focus of RAI uptake in the lung without a structural correlate.

Table 3.

Identification of Radioactive Iodine Avid Metastases on Postablation SPECT/CT Based on Nonstimulated Postoperative Serum Thyroglobulin Level

	Entire cohort (n=290)	Tg<0.6 ng/mL (n=146)	Tg 0.6–0.9 ng/mL (n=76)	Tg 1–5 ng/mL (n=51)	Tg>5–10 ng/mL (n=17)
Lymph node uptake	16% (46/290)	12% (17/146)	14% (11/76)	25% (13/51)	29% (5/17)
Pulmonary uptake	1.4% (4/290)	0.7% (1/146)	1.3% (1/76)	0% (0/51)	6% (2/17)

In most cases one abnormal focus of uptake was identified in the neck (76%), while two foci were detected in 11% and three or more foci in 13% of cases. Overall, 57 neck metastases were detected in 46 patients, with the following distribution: 33% in level II, 30% in level III, 28% in level IV, 2% in level 5, and 7% in the retrosternal area.

RAI avid distant metastases were identified in 1.4% (4/290) of patients. This included one patient (1/146, 0.7%) with Tg<0.6 ng/mL who demonstrated a focus of uptake in a cervical lymph node and a solitary focus of uptake in the right lung, and one patient (1/76, 1.3%) with a Tg of 0.8 ng/mL who demonstrated a focus of uptake in a cervical lymph node and diffuse uptake in the lungs without a structural correlate. Two patients (2/17, 11%) in the Tg 5–10 ng/mL group had focal RAI uptake in the lungs without a structural correlate.

RAI avidity outside the thyroid bed was associated with structurally identifiable disease on the SPECT/CT images in 11% (31/290) of the patients. This included 8% (12/146) of patients with Tg<0.6 ng/mL, in 11% (8/76) of patients with Tg 0.6–0.9 ng/mL, in 16% (8/51) of patients with Tg 1–5 ng/mL, and in 18% (3/17) of patients with Tg>5–10 ng/mL.

RAI avid metastases detected on SPECT/CT with nonstimulated postoperative Tg <0.6 ng/mL

Additional analysis of the cohort of patients with a nonstimulated postoperative Tg value<0.6 ng/mL demonstrated that none of the metastatic foci seen on the post-therapy SPECT/CT imaging were identified on preablation planar RAI imaging. Further, the Tg antibody assay and the Tg recovery assay failed to identify the presence of anti-Tg antibodies in any of the 17 patients with RAI avid foci identified in the setting of a nonstimulated Tg<0.6 ng/mL.

A comparison of clinicopathologic risk factors between those patients that either did or did not have RAI avid metastatic foci identified on post-therapy SPECT/CT scanning revealed that the 17 patients that had RAI avid metastatic foci identified on post-therapy SPECT/CT scanning were significantly more likely to have tall cell variant papillary thyroid cancer (PTC) and less likely to have classic PTC than the 129 patients without RAI avid metastases (p<0.01; Table 4). Further, patients with RAI avid metastases identified outside the thyroid bed also presented with larger lymph nodes than patients without RAI avid metastastic foci (1.9±1.3 cm vs. 1.0±0.7 cm, p<0.01). However, no significant differences between the cohorts were identified with respect to age at diagnosis, sex, TSH, tumor size, AJCC stage, location of lymph node metastases, number of lymph node metastases, the presence of vascular invasion, or extrathyroidal extension (Table 4).

Table 4.

Clinicopathologic Characteristics of Patients with Serum Thyroglobulin Below 0.6 ng/ml

	Uptake outside TB (n=17)	No abnormal uptake (n=129)	p-Value
Female	11 (65%)	99 (77%)	NS
Age (years)	50±16	47±15	NS
TSH (mU/L)	0.9±1.4	1.3±1.7	NS
Pathology			<0.01
Classic	8 (47%)	71 (55%)
Tall cell	5 (29%)	26 (20%)
FVPTC	0	10 (8%)
Follicular carcinoma	0	10 (8%)
Hürthle cell	1 (6%)	7 (5%)
Poorly differentiated	1 (6%)	4 (3%)
Other variants	2 (12%)	1 (0.8%)
Tumor size (cm)	1.9±1.2	2.2±1.5	NS
<1 cm	5 (29%)	15 (12%)	NS
1–4 cm	11 (65%)	100 (78%)
>4 cm	1 (6%)	14 (11%)
ETE	9 (53%)	66 (51%)	NS
VI	6 (35%)	54 (42%)	NS
AJCC staging^a			NS
Stage I	7 (41%)	65 (50%)
Stage II	0	9 (7%)
Stage III	7 (41%)	44 (34%)
Stage IV A	3 (18%)	11 (9%)
Tumor classification			NS
T1	7 (41%)	28 (22%)
T2	0	22 (17%)
T3	10 (59%)	79 (61%)
Lymph node classification			NS
N0 or Nx	9 (53%)	53 (41%)
N1a	3 (18%)	46 (36%)
N1b	5 (29%)	30 (23%)
LN size (cm)	1.9±1.3	1±0.7	<0.01
<1 cm	3 (18%)	37 (29%)	NS
≥1 cm	5 (29%)	34 (26%)
Metastatic LN (number)	2.7±4	3.3±5	NS
<5 LNs	5 (29%)	46 (36%)	NS
≥5 LNs	3 (18%)	30 (23%)
Central	3 (18%)	46 (36%)	NS
Lateral	5 (29%)	30 (23%)

Data are presented as number (percentage) or mean±SD.

According to data available before RAI administration

NS, not significant; LN, lymph node.

Review of the clinicopathologic features in the 17 patients who demonstrated RAI uptake outside the thyroid bed despite having a nonstimulated postoperative Tg of <0.6 ng/mL shows that the majority of these patients have other clinical features that are associated with an increased risk of recurrence (Table 5). These include nine patients with higher risk histologies (Table 5, cases 9–17: five with tall cell variant PTC, two with solid variant PTC, one with Hürthle cell carcinoma, and one with poorly-differentiated thyroid cancer), often with vascular invasion (cases 10 and 14–17). Further, out of the eight patients with classic PTC, four had large volume lymph node metastases (cases 1, 5, 6, and 8), and one had vascular invasion (case 4). The remaining three cases (cases 2, 3, and 7) did not appear to have major risk factors for recurrence, with two patients demonstrating only minor extrathyroidal extension (cases 3 and 7), and one patient (case 2) demonstrating only small volume lymph node metastases (three metastatic lymph nodes, all subcentimeter).

Table 5.

Clinicopathologic Characteristics of 17 Patients with Radioactive Iodine Avid Metastatic Disease and Nonstimulated Postoperative Serum Thyroglobulin Level Below 0.6 ng/mL

	Initial pathology and staging								RAI remnant ablation
Case	Histology	Age at surgery (years)	Size of primary tumor (cm)	VI	ETE	Metastatic LN (number)	Size of largest LN (cm)	AJCC stage	Tg (ng/mL)	TSH (mIU/L)	TB uptake (%)	Uptake site outside TB
1	PTC	46	0.5	N	N	3	3.5	4A	<0.6	0.2	0.3	LN
2	PTC	32	0.7	N	N	3	0.9	1	<0.6	5.7	0.2	LN
3	PTC	46	0.9	N	Y	0		3	<0.6	0.2	0.3	LN
4	PTC	27	1.1	Y	N	2	0.7	1	<0.6	<0.02	0.2	LN & lung
5	PTC	45	1.2	N	N	12	3.5	4A	<0.6	1.4	0.1	LN
6	PTC	36	1.5	N	N	12	1.1	1	<0.6	1.6	0.2	LN
7	PTC	56	1.9	N	Y	0		3	<0.6	0.6	0.1	LN
8	PTC	48	3.9	N	Y	10	2.6	4A	<0.6	1.9	0.1	LN
9	TCV	68	0.9	N	Y	1	0.3	3	<0.6	0.02	0.4	LN
10	TCV	69	0.9	Y	Y	0		3	<0.6	0.8	0.3	LN
11	TCV	53	1.8	N	Y	0		3	<0.6	<0.02	0.2	LN
12	TCV	64	2.2	N	Y	0		3	<0.6	<0.02	0.1	LN
13	TCV	64	3.7	N	Y	0		3	<0.6	0.02	0.6	LN
14	SV-PTC	67	1.7	Y	N	0		1	<0.6	0.8	0.1	LN
15	SV-PTC	22	3	Y	Y	5	2.5	1	<0.6	0.5	0.8	LN
16	HCC	73	1.8	Y	N	0		1	<0.6	0.2	0.4	LN
17	PDTC	34	4.1	Y	N	0		1	<0.6	1.5	0.6	LN

TCV, tall cell variant PTC; SV-PTC, solid variant PTC; HCC, Hürthle cell carcinoma; PDTC, poorly-differentiated thyroid carcinoma; TB, thyroid bed.

Discussion

Our data demonstrate that a nonstimulated postoperative serum Tg value<0.6 ng/mL does not rule out the presence of RAI avid metastases in DTC patients selected for RAI ablation on the basis of having other clinicopathologic risk factors for recurrence. While the RAI avid disease was nearly always located in the locoregional lymph nodes, 0.7% (1/146) of patients with a postoperative nonstimulated Tg value<0.6 ng/mL demonstrated a focus of uptake in the lung. Our findings are in contrast to the study by Giovanella et al. from 2008 (10) in which planar postablation scanning demonstrated no RAI avid metastases in 63 DTC patients who had a nonstimulated postoperative Tg<0.2 mg/mL. However, a direct comparison of these two studies is complicated by significant differences in study design that included the observation that our cohort had significantly more higher-risk patients (66% T3 vs. 10% in the Giovanella cohort, 29% N1b vs. 9% in the Giovanella cohort, and 29% tall cell or other aggressive variants in our cohort), and that we used a more sensitive detection method for identifying RAI avid metastases (SPECT/CT). It is likely that these methodological differences explain the 12% detection rate of RAI avid metastases in our cohort in contrast to the 0% rate seen in the study by Giovanella et al. (10)

Our data are consistent with previous studies that demonstrate that RAI avid foci can be detected on postablation scanning in patients with very low postoperative stimulated Tg levels. As with our study, the likelihood of finding RAI avid metastases appear to be related both to the selection of patients for study and the stimulated Tg level (14). Rosario et al. (8) found no uptake outside the thyroid bed in 132 low-risk thyroid cancer patients with a stimulated postoperative Tg<1 ng/mL. However, in consecutive series of patients undergoing RAI ablation (not risk-stratified), Giovanella et al. (15) detected RAI avid metastases in 11/36 (30%) patients with a stimulated Tg<0.4 ng/mL (10 locoregional disease, one with lung metastases). Similarly, in an unselected consecutive cohort of 824 DTC patients undergoing routine RAI remnant ablation, nonphysiological uptake outside the thyroid bed was identified in 6.3% (52/824) of the patients who had a postsurgical stimulated Tg<2 ng/mL (16).

Therefore, it is clear that RAI avid locoregional (and rare distant metastases) can be identified in intermediate and high-risk patients with nonstimulated or stimulated postoperative serum Tg levels<0.4–0.6 ng/mL. It is likely that a wide variety of methodological issues in the measurement of serum Tg (including interference by anti-Tg antibodies, heterophile antibodies, hook-effects, and significant differences in results obtained from various antibody immunoassays) account for the discrepancy between undetectable stimulated Tg values and the presence of RAI avid disease (15,17).

Within the cohort of patients who demonstrated a postsurgical nonstimulated Tg<0.6 ng/mL, uptake outside the thyroid bed was associated with more aggressive histologies (tall cell and poorly differentiated variants), and larger size of the metastatic lymph nodes. As previously described, Tg levels are affected by tumor histology, and may be lower in more aggressive histologies or in tumors harboring a BRAF mutation (18,19). Other clinicopathological risk factors for recurrence (such as sex, age, tumor size, extrathyroidal extension, vascular invasion, and AJCC stage) were not significantly associated with the presence of RAI avid metastases. However, 14/17 patients who have RAI avid metastases associated with a postsurgical nonstimulated Tg<0.6 ng/mL had other major risk factors for recurrence including higher risk histologies in nine patients, large volume lymph node metastases in five patients, and vascular invasion in six patients. The remaining 3/17 patients with RAI avid metastases also demonstrated minor risk factors for recurrence including small volume lymph node metastases and microscopic extrathyroidal extension. These findings demonstrate that a postsurgical nonstimulated Tg<0.6 ng/mL does not completely exclude the possibility of having RAI avid metastatic disease in patients with other higher-risk features.

Even though an undetectable postsurgical nonstimulated Tg in our cohort did not rule out RAI avid metastatic disease in patients with other high-risk features, the risk of identifying RAI metastases was related to the nonstimulated postoperative Tg levels. The likelihood of finding RAI avid metastases increased from 14% in patients with Tg 0.6–0.9 ng/mL, to 25% in patients with Tg 1–5 ng/mL, and 29% in patients with Tg>5–10 ng/mL (including two patients with pulmonary metastases). Since postoperative Tg values can be significantly influenced by the volume of residual normal thyroid tissue remaining after a “total thyroidectomy,” it is important to note that the median 24-hour thyroid bed uptake in our cohort was very low (0.24%). Therefore, the rates of RAI avid metastases within the Tg cohorts described in this article are likely to be applicable only to patients who have had meticulous total thyroidectomy with very little residual normal tissue. If significant normal thyroid tissue remains after total thyroidectomy, the risk of finding RAI avid metastases will be significantly lower as the Tg from the normal tissue is detected in a higher percentage of patients.

For the majority of patients in this study, RAI ablation was given not only to facilitate initial staging and improve the sensitivity of follow-up evaluations, but also as adjuvant therapy. The adjuvant therapy function of RAI was best demonstrated in the 16% of patients that demonstrated RAI avid metastatic disease on postablation scanning that had not been identified prior to ablation. However, it is unlikely that destruction of relatively small volume lymph node metastases in patients at intermediate risk of recurrence, but low risk of disease specific mortality, would have any measurable effect on overall mortality. Further, it is unclear whether destruction of small volume RAI avid lymph node metastases will have any significant impact on subsequent locoregional recurrences rates since (i) biopsy proven metastatic disease in the thyroid bed and in locoregional lymph nodes can remain stable for years (20,21), and (ii) additional metastatic foci that were not RAI avid could remain in cervical lymph nodes and become clinically apparent in the future. Therefore, controversy will continue with regard to the potential benefit of routine (or selective) use of RAI ablation in intermediate-risk patients.

Our study had several limitations. First, we included a selected group of intermediate-risk patients who underwent RAI ablation in our hospital. This group represents our approach of not routinely treating patients with only minimal extrathyroidal extension or with minimal central neck LN involvement, who have a very low risk of recurrence without ablation (2). Second, the retrospective design has inherent limitations that we tried to compensate for by including only patients who were treated and followed up in our institute to ensure a similar therapeutic approach, laboratory evaluation and imaging studies. Third, the functional sensitivity of our Tg assay was 0.6 ng/mL, which is higher than the available assays with a 0.2 ng/mL threshold. While it is possible that when using a more sensitive assay fewer patients would have an abnormal uptake outside the thyroid bed, it is unlikely to solve the problem of the discrepancy between the Tg levels and the presence of RAI avid metastatic disease in intermediate-risk patients.

In conclusion, our data demonstrate that a nonstimulated, postsurgical Tg of <0.6 ng/mL does not rule out the presence of RAI avid metastases in ATA intermediate-risk patients selected for RAI remnant ablation. However, the risk of identifying RAI avid metastases is higher in patients with nonstimulated postsurgical Tg in the 5–10 ng/mL range than in the <1 ng/mL range when a complete thyroidectomy is done by experienced surgeons. Therefore, patient selection for RAI ablation in the intermediate-risk group must be based on an integration of multiple risk factors rather than any single clinicopathologic risk factor.

Footnotes

Disclosure Statement

R.M.T. has been a consultant to and received research support from Genzyme. E.R. was supported by the Davidoff Foundation clinical fellowship grant, 2011–2012. R.K.G., S.F., and M.S. have no competing financial interests.

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