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Department of Internal Medicine, University of Florida (E.L.M.), Gainesville, Florida 32608-4653; and Center for Health Outcome Policy Evaluation Studies (E.L.M.) and Department of Internal Medicine and Radiology, Divisions of Endocrinology, Diabetes, and Metabolism, and Nuclear Medicine (R.T.K.), Ohio State University, Columbus, Ohio 43210-1228
Address all correspondence and requests for reprints to: Dr. Ernest L. Mazzaferri, 4020 SW 93rd Drive, Gainesville, Florida 32608-4653. E-mail: . mazz01{at}bellsouth.net
Abstract
Measuring serum Tg and performing a diagnostic whole body scan (DxWBS) has become the standard for follow-up of patients with differentiated thyroid carcinoma. The primary aim of this study was to determine whether recombinant human TSH (rhTSH)-stimulated Tg alone is sufficiently sensitive to identify residual cancer in patients with no clinical evidence of disease and undetectable or very low serum Tg levels during thyroid hormone (TH) therapy. A secondary aim was to investigate the frequency of tumor in such patients.
One hundred and seven consecutive patients, aged 10.9–85.3 yr (median, 36.3), at the time of initial surgery who had Tg levels on TH therapy that were undetectable (95% 
0.5 ng/ml) or low (4% 0.6 ng/ml, 1% 1.0 ng/ml) and who underwent rhTSH-stimulated testing 10 months to 35 yr (median, 3.5 yr) after initial thyroidectomy and 131I ablation were retrospectively studied. Many (50%) were at high risk of tumor recurrence, and 5 had distant metastases during the course of their disease. In response to rhTSH, Tg ranged from 0.5 or less to 17.9 ng/ml, remaining at 0.5 ng/ml or less in 68 (64%) patients and increasing to levels between 0.6 and 2 ng/ml in 19 (18%) others and to levels higher than 2 ng/ml in 20 (19%) patients.
Eleven patients (10%), all of whom had rhTSH-stimulated serum Tg levels above 2 ng/ml, were found to have persistent tumor in lung (4 patients), lymph nodes (5 patients, 3 with cervical central compartment, 1 bilateral cervical, and 1 with mediastinal nodes) identified by fine needle cytology, surgical pathology, posttherapy whole body scans, or computed tomography and, in two patients, with high serum Tg values alone (4.6 and 7.0 ng/ml after rhTSH and, respectively, 28.5 and 70.6 ng/ml after TH withdrawal), although in neither could the tumor site be identified. Thirteen patients (12%) were treated with surgery or 131I, and in some cases both, as a result of the rhTSH studies; 10 had tumor, 1 had residual uptake in the thyroid bed visible on rhTSH-stimulated diagnostic whole body scan (DxWBS), and 2 had high serum Tg levels, presumably originating from a tumor site that could not be identified. A patient’s tumor status, even in retrospect, usually was not predictable on the basis of Tg during TH therapy or tumor node metastasis status: among patients found to have tumor after rhTSH, serum Tg during TH therapy was 0.5 ng/ml or less in 55% and 0.6 ng/ml in 36%, and tumor node metastasis status was T2N1 or less in 82%.
In no case did the rhTSH-stimulated DxWBS show the site of persistent tumor. There were correlations between visible thyroid bed uptake on DxWBS and quantitated 131I uptake (r2 = 0.11; P = 0.001), between DxWBS and rhTSH-stimulated Tg (r2 = 0.54; P = 0.001), and between rhTSH-stimulated Tg and 131I uptake (r2 = 0.66; P = 0.0001). There was no statistically significant difference (P = 0.4) in bed 131I uptake in patients with rhTSH-stimulated serum Tg levels of 0.5 ng/ml or less compared with that in subjects with higher rhTSH-Tg levels.
An rhTSH-stimulated Tg level greater than 2 ng/ml had a sensitivity of 100%, a negative predictive value of 100%, and a false positive rate of 9%. The rhTSH Tg had a substantially better performance than the other studies; the false negative rates were 64% for Tg higher than 0.5 ng/ml on TH therapy, 73% for rhTSH-stimulated DxWBS showing uptake, and zero for an rhTSH-stimulated Tg more than 2 ng/ml.
In conclusion, of 107 patients who were clinically free of disease, 10% had persistent tumor (4 with pulmonary metastases and 5 with regional disease) that was only identified with an rhTSH-stimulated serum Tg level greater than 2 ng/ml. This study shows that tumor amenable to early therapy may be found when rhTSH-stimulated serum Tg rises above 2 ng/ml without performing a DxWBS, which merely provides data concerning the completeness of thyroid ablation, but not persistent tumor. An elevated rhTSH-stimulated Tg greater than 2 ng/ml warrants further study.
ALTHOUGH THE long-term prognosis for survival with papillary and follicular (differentiated) thyroid cancer is generally quite good, tumor recurrence is common, affecting at least 20% of patients with the disease, sometimes decades after initial therapy (1). However, what is perceived as recurrent thyroid cancer often is persistent tumor that has fallen below the detection limits of the tests used to identify it, particularly diagnostic 131I scans performed in the presence of large thyroid remnants or inadequate serum Tg assays and Tg measurements made during TSH suppression.
Complete thyroid ablation should be performed in all patients undergoing surgery for thyroid carcinoma (2, 3) not only to remove tumor in the contralateral lobe and normal thyroid tissue with a predilection for becoming malignant (4), but also to facilitate follow-up with diagnostic 131I scans and Tg measurements stimulated by TSH, which substantially improves the sensitivity of Tg testing (5, 6).
The application of highly sensitive tests is likely to reduce the late recurrence of tumor; however, applying such sensitive testing may also increase the rate of false positive results or raise the potential of uncovering minimal tumor that may be of little clinical significance. On the other hand, therapy is most likely to be successful and to have the greatest bearing on long-term prognosis when the tumor burden is small and discovered early, particularly in the case of lung metastases (7).
Performing a whole body scan (WBS) and measuring serum Tg is the standard of care in the initial phases of follow-up of patients with differentiated thyroid cancer (3, 8), but whether it is best to perform a diagnostic WBS (DxWBS) before 131I therapy is uncertain. For example, the panel of experts that formulated the National Cancer Center Network guidelines for the diagnosis and treatment of thyroid cancer could not reach a consensus on recommending a 131I DxWBS in lieu of a posttherapy scan (RxWBS) during postsurgical evaluation (9). One retrospective study (10) of 76 patients undergoing follow-up after initial thyroid ablation found that 2 consecutive negative 131I DxWBSs had a greater likelihood of predicting relapse-free survival than did 1 such study; however, serum Tg was not measured under TSH stimulation, which is a considerably more sensitive test than DxWBS (5, 6). Another study (11) of 256 patients found that a 2- to 5-mCi 131I (74–185 MBq) DxWBS performed 6 months to 1 yr after thyroid ablation did not correlate with the serum Tg, but only confirmed the completeness of thyroid ablation, suggesting that DxWBS is unnecessary in this setting; patients with a Tg level exceeding 10 ng/ml after thyroid hormone (TH) withdrawal were given 100 mCi 131I, followed by RxWBS. The paradigm of using recombinant human TSH (rhTSH)-stimulated Tg alone during follow-up might be successful, but the main conclusions of 2 large studies showing that rhTSH stimulation and TH withdrawal are comparable in identifying papillary and follicular thyroid cancer during follow-up are mainly drawn from data using DxWBS alone (5) or with Tg (6).
The primary purpose of the present study was to determine whether rhTSH-stimulated serum Tg measurement alone is sufficiently sensitive to identify residual tumor in patients who are clinically free of disease after thyroid ablation and have undetectable or low serum Tg levels on TH therapy. A secondary aim was to investigate the frequency of persistent disease identified by rhTSH studies in these patients.
Subjects and Methods
Patients
Patients with papillary or follicular thyroid cancer without anti-Tg antibodies who had undergone rhTSH testing between January 8, 1999, and March 23, 2001, were studied if, before rhTSH testing, they had been free of disease on the basis of clinical examination and had one or more undetectable or low serum Tg measurements taken while receiving TH therapy. All had previously undergone 131I DxWBS and RxWBS after initial ablation, chest x-ray, and, in some cases, ultrasonography, 131I RxWBS, computed tomography (CT), magnetic resonance imaging, or positron emission tomography (PET).
rhTSH studies
rhTSH (0.9 mg, im) was given on 2 consecutive days, followed by approximately 4 mCi 131I on the third day and serum Tg and 131I neck uptake (RAIU) measurement and DxWBS on the fifth day (72 h after rhTSH), as previously described (5).
DxWBS and RAIU
After adhering to a low iodine diet (12) for 1 wk before study, patients underwent rhTSH-stimulated 131I imaging (13) and quantitative RAIU measurement at our institution. DxWBS 131I imaging was performed with 3.8–5.1 mCi (141–189 MBq) 131I [4.1 ± 0.03 mCi (±SD); 152 ± 1.11 MBq], orally (14). Thyroid bed uptake was diagnosed on whole body or spot view images that showed only visible uptake between the suprasternal notch and thyroid cartilage; faint midline uptake superior to the thyroid cartilage was considered to be in a thyroglossal duct remnant.
Images were obtained using a Picker Prism 2000XP camera (Philips Electronics/Marconi Medical Systems/Picker Health Care Products, Cleveland, OH) using a 3/8-in. thick crystal and a high energy, general all-purpose collimator. WBS with anterior and posterior views were performed at a scan speed of 5.23 cm/min. Anterior neck/chest spot views with and without markers (technitium-99m) on the suprasternal notch and chin, and pinhole collimator images with and without thyroid cartilage and suprasternal notch markers were obtained for 10 min each using dual isotope photopeak windowing. RAIU measurements were made using 1/1000th of the tracer 131I activity as the standard. Using the Atomlab 930 Thyroid Uptake System (Sun Nuclear Corp., Melbourne, FL) with the maximum count time in the automatic mode set at 60 sec, the coefficient of variation (CV) for a RAIU of 0.008% is 31.7%; for an RAIU ranging from 0.03–0.1%, CVs are 2.7–18.4%, respectively; for an RAIU of 0.7%, CV is 11.1%; and for 1.6–13.6%, the CVs are 1.0–5.1%, respectively.
Tg measurement
The average serum Tg value is reported from duplicate measurements made in our laboratories using the Nichols chemiluminescence immunoradiometric assay (catalog no. 60-4240, Nichols Institute Diagnostics, San Juan Capistrano, CA; sensitivity, 0.5 ng/ml). The CVs for three controls [1.49–2.29, 18.10–21.90 (kit controls), and 3.93–6.01 (serum pool control) ng/ml] were 10.6%, 4.8%, and 10.5%, respectively, and 24.8% for a Tg level of 0.44 ng/ml in a pooled serum control. Because some samples with Tg levels as low as 35 ng/ml were previously found to have a hook effect after dilution, all samples with Tg values above 20 ng/ml and some below this level were redetermined at a dilution of 1:10. Serum samples are frozen and reassayed with the latest Tg sample if deemed necessary.
Anti-Tg antibody measurement
Anti-Tg antibodies were quantitated with each Tg measurement using the Nichols chemiluminescence Tg antibody kit (catalog no. 60-4185, Nichols Institute Diagnostics; sensitivity, 2.0 U/ml). Using local pooled control standards, the CV for an anti-Tg antibody level of 1.23 U/ml (below the assay sensitivity) is 16.7%; for antibody levels ranging from 3.5–34.5 ng/dl, the CV ranges from 10.5–13.4%. A negative test is an antibody level less than 2 U/ml.
Statistics
All results are reported as the mean ± SE. Percentages are rounded to the nearest integer. Tg levels clinically reported as below 0.5 ng/ml are considered 0.5 ng/ml for statistical purposes. Wilcoxon rank-sum test or ANOVA was applied to detect differences among means. A two-tailed P < 5% was considered statistically significant. The Ohio State institutional review board approved our ongoing follow-up study of patients with thyroid cancer.
Results
Patient characteristics
One hundred and seven patients, 88 (82%) females and 19 (18%) males, aged 10.9–85.3 yr (median, 36.3) at the time of thyroidectomy, were given rhTSH 10 months to 35 yr (median, 3.5 yr) after thyroidectomy. The median follow-up from initial surgery was 4.2 yr.
Tumor characteristics
Patients had histologically typical papillary carcinoma (71%); follicular variant (9%), tall cell (2%), or Hurtle cell variant (1%) papillary carcinomas; or typical follicular (11%) or Hurtle cell (6%) carcinoma. Fifty percent were at high risk of recurrence (T3, T4, or N1 or M1; Table 1
). Two patients had distant metastases when thyroid cancer was initially diagnosed: a 41-yr-old woman with diffuse papillary lung metastases seen only on 131I RxWBS (patient 89) and a 12-yr-old boy with a solitary frontal bone metastasis from follicular carcinoma; both had a good response to therapy and were thought to be free of disease at the time of study.
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Total or near-total thyroidectomy was performed on all patients, although this was achieved by completion thyroidectomy in 39 (36%) patients. Lymph node surgery comprised simple excision in 19 (18%) patients, ipsilateral modified neck dissection in 7 (7%) patients, bilateral modified neck dissection in 3 (3%) patients, and no lymph node surgery in 78 (72%) patients. After surgery, all patients were given 131I in doses ranging from 26–228 mCi 131I (median, 96); total 131I administered ranged from 26–800 mCi (median, 105).
Tumor recurrence before rhTSH study
Three patients had tumor identified after initial thyroid ablation but were thought to be free of disease at the time of this study. One was a man with papillary carcinoma who, 12 yr after initial therapy, developed a solitary brain metastasis at age 48 yr that was surgically resected; 3 yr later he was free of disease and had a negative 100 mCi 131I RxWBS and undetectable serum Tg before and after TH withdrawal, and 12 months later he had undetectable serum Tg before and after rhTSH treatment. The second patient, a woman who first underwent thyroid surgery at age 11 yr for papillary carcinoma, had a thyroid bed tumor diagnosed at age 31 yr and a mediastinal nodal metastasis found at age 39 yr that were treated with surgery and 131I; 7 yr later her Tg levels were undetectable before and after rhTSH. The third was a woman (patient 90) who first underwent surgery and 131I therapy for papillary carcinoma with multiple bilateral lymph node metastases at age 31 yr; 20 yr later she underwent excision of peritracheal tumor followed by 100 mCi 131I; 3 yr later she underwent partial tracheal resection for invasive peritracheal tumor with negative surgical margins, followed by 208 mCi 131I with a negative RxWBS. One year later, at age 55 yr, her Tg was 0.5 ng/ml during TH treatment, but increased to 6.2 ng/ml after rhTSH treatment, and pulmonary metastases that did not concentrate 131I were found on CT scan and were confirmed by open lung biopsy.
Baseline Tg during TH therapy
Serum Tg during TH therapy was 0.5 ng/ml or less in 102 (95%) patients (Fig. 1A), 0.6 ng/ml in 4 patients, and 1.0 ng/ml in patient 89, who had presented with diffuse lung metastases seen only on RxWBS that had been treated with 467 mCi 131I.
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Tg less than 0.5 ng/ml.
The rhTSH-stimulated serum Tg failed to rise above 0.5 ng/ml in 68 (64%) patients (Fig. 1A
, Table 2). Neck 131I uptake in these patients ranged from none to 0.3% (mean 0.07 ± 0.01), and faint DxWBS uptake was visible in the thyroid bed or thyroglossal duct remnant in 5 (7%) patients. None of the patients had evidence of disease on physical examination, chest x-ray or DxWBS, and further studies were not pursued except for neck ultrasonography in some patients.
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and Table 2). Neck 131I uptake in these patients ranged from 0–0.5% (mean, 0.09 ± 0.03), and DxWBS showed bed or thyroglossal duct uptake in 3 (16%) patients that was clinically insignificant. None of the patients had evidence of disease on physical examination, chest x-ray, or DxWBS and, in some cases, neck ultrasonography, and further studies were not performed.
Tg more than 2 ng/ml.
The rhTSH-stimulated serum Tg increased from baseline levels ranging from 0.5 or less to 1.0 ng/ml to above 2 ng/ml in 20 patients (Fig. 1, C and D, and Table 2). Neck 131I uptake in these patients ranged from 0–0.6% (mean, 0.15 ± 0.04), and uptake on DxWBS was faintly visible in the thyroid bed or thyroglossal duct remnant in 4 (20%) patients.
Eleven patients (10%) had persistent tumor (Fig. 1D and Tables 2 and 3) identified in lung (four patients) and lymph nodes (five patients: three cervical central compartment, one bilateral cervical, and one mediastinal) identified by fine needle cytology, surgical pathology, 131I RxWBS, or CT and in two patients with high serum Tg values alone (4.6 and 7.0 ng/ml after rhTSH and, respectively, 28.5 and 70.6 ng/ml after TH withdrawal), although in neither could the tumor site be identified on the RxWBS or other studies (Table 3). DxWBS failed to show the site of persistent disease in all patients with persistent tumor.
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), but tumor could not be found on physical examination, chest x-ray, and, in most cases, ultrasonography. One patient had significant thyroid bed uptake visible on rhTSH-stimulated DxWBS. Final tumor status according to duration of follow-up
The rhTSH-stimulated Tg level was 1.8 ± 0.4 ng/ml in 53 patients followed fewer than 3.5 yr (median follow-up) and 1.2 ± 0.2 ng/ml in 54 patients followed 3.5 yr or longer (P = 0.34, by Wilcoxon rank sum). Six of the new cases of persistent tumor had been followed less than 3.5 yr, and 5 patients had been followed 3.5 yr or longer. There were no differences in disease status according to years of follow-up, viewed as a dichotomous variable before and after 3.5 yr (P = 0.7) or as a continuous variable (P = 0.5).
Patients treated
Thirteen patients (12%) were treated as a result of the rhTSH studies (Fig. 1, C and D, and Table 3). Ten patients with persistent tumor were treated with either 131I (n = 6), surgery (n = 2), or 131I followed by surgery (n = 2). The two patients treated with both 131I and surgery displayed similar clinical characteristics. One was a 29-yr-old woman (patient 60) who underwent total thyroidectomy for a 2.5-cm papillary carcinoma followed by ablation of the thyroid bed uptake with 150 mCi 131I who subsequently had two negative TH withdrawal DxWBSs. At age 39 yr her rhTSH-stimulated Tg was 2.2 ng/ml, DxWBS remained negative, TH withdrawal Tg was 14.9 ng/ml, and RxWBS was negative. This prompted neck ultrasonography and biopsy of a suspicious 6 x 6 x 5-mm right central lymph node that was posterior to the carotid and difficult to reach, yielding no malignant cytology. Neck and chest CT and whole body PET imaging were negative, but because the lymph node seen on ultrasonography appeared malignant, surgical exploration was performed, and a single metastatic lymph node was removed. A repeat rhTSH-stimulated Tg performed without 131I imaging 27 months later was 0.5 ng/ml.
The second patient treated with both 131I and surgery was a 30-yr-old woman (patient 87) who had a multifocal bilateral papillary carcinoma, the largest focus of which measured 1.5 cm, with bilateral cervical lymph node metastases. Postoperatively she received 150 mCi 131I and subsequently had two negative DxWBSs. Neck ultrasound also revealed a suspicious 6 x 6 x 5-mm lymph node that was also in a challenging position to biopsy behind the carotid artery and jugular vein. Neck and chest CT were normal, but PET revealed suspicious foci in the prevascular space [standard uptake value (SUV) = 2.1], right submandibular area (SUV = 1.7), liver (SUV = 2.7), and possibly lung (SUV = 0.7–0.9). Because of the possibility of distant metastases, the patient’s occupation as a singer, and a Tg of 15.1 ng/ml after TH withdrawal, she was given lithium and was treated with 131I, after which the RxWBS showed uptake only in a breast cyst (false positive). However, examination during hypothyroidism revealed a previously unappreciated palpable lymph node in the neck, and ultrasonography revealed four suspicious bilateral cervical lymph nodes that were positive on ultrasound-guided fine needle aspiration. Bilateral modified neck dissections were performed, yielding tumor on both sides (Table 2). A subsequent rhTSH-stimulated Tg measurement performed without imaging was 1.1 ng/ml. The patient with disease who was not treated (patient 89) after rhTSH study had already received 467 mCi for lung metastases.
The patient with persistent thyroid bed uptake on DxWBS was a 60-yr-old man who had a T3N0M0 follicular thyroid carcinoma treated with lobectomy and completion thyroidectomy. After surgery and off TH therapy his TSH rose to only 4.9 µIU/ml, and neck ultrasonography revealed a large amount of left thyroid bed tissue that was treated with 29 mCi 131I. In response to rhTSH, his serum Tg level rose to 2.8 ng/ml (Fig. 1C), and he had clearly visible left thyroid bed uptake with an RAIU of 0.2%. In response to TH withdrawal, his Tg rose to 7.3 ng/ml, and the DxWBS showed 0.5% uptake in the left thyroid bed that was also seen on RxWBS. Ten months later while he was hypothyroid his Tg was 3.3 ng/ml, and his DxWBS was negative.
Two other patients had rhTSH-stimulated Tg levels of 2.5 and 5.8 ng/ml (Fig. 1C), prompting 131I treatment in one and lymph node resection in the other. Neck ultrasonography was negative in both patients, as it was in all others in whom tumor could not be found who had Tg levels higher than 2.0 ng/ml after rhTSH treatment. The patient treated with 131I had a serum Tg level of 7.1 ng/ml after TH withdrawal and showed only diffuse hepatic uptake on RxWBS without tumor elsewhere. In the other patient the histopathology was negative after surgery performed for suspicious lymph nodes on PET with an SUV of 4.5.
We intended to perform TH withdrawal studies and possibly treat a third patient categorized here as no clinical evidence of disease (NED; Fig. 1C), who we thought had disease on the basis of a Tg that increased from 0.5 to 4.5 ng/ml after rhTSH treatment. However, the patient elected not to undergo TH withdrawal. Eight months later his baseline Tg increased to 1.7 ng/ml, but he again elected to be followed without further study, although we were reasonably certain he had persistent disease.
Correlation of neck 131I uptake with DxWBS and rhTSH-stimulated Tg levels
Thyroid bed uptake on DxWBS was seen in 7% (5 of 68) and 18% (7 of 39) of patients with, respectively, an rhTSH-stimulated Tg level of 0.5 ng/ml or less and more than 0.5 ng/ml (Fig. 2A); however, DxWBS in these patients did not show any evidence of persistent disease. Small, but clinically unimportant, differences were seen in RAIU among patients with incrementally higher serum Tg levels (Fig. 2B). Nonetheless, there were correlations between visible bed uptake on DxWBS and 131I RAIU (r2 = 0.11; P = 0.001), between visible bed uptake on DxWBS and rhTSH-stimulated Tg (r2 = 0.54; P = 0.001), and between rhTSH-stimulated Tg and 131I RAIU (r2 = 0.66; P = 0.0001). There were no differences in mean 131I uptake in patients with rhTSH-Tg levels of 0.5 ng/ml or less and those with higher levels (Fig. 2A; P = 0.4, by Wilcoxon rank-sum test).
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For the purposes of this analysis, tumor was considered present if it was found on fine needle aspiration cytology, surgical histopathology, with 131I uptake clearly outside the thyroid bed, on CT scan of lung, and in two patients with Tg levels of 28.5 and 70.6 ng/ml after TH withdrawal. All others were categorized as negative for disease, including those with thyroid bed uptake on DxWBS. We tested the hypothesis that tumor could be identified with a positive test defined as 1) a Tg level greater than 0.5 ng/ml during TH therapy, 2) any visible metastatic or thyroid bed 131I uptake on DxWBS, or 3) a Tg level greater than 2 after rhTSH (Fig. 3). The false negative test rates were 64% for Tg level above 0.5 ng/ml on TH therapy, 73% for rhTSH-stimulated DxWBS (Fig. 2C), and zero for rhTSH-stimulated Tg level more than 2 ng/ml. An rhTSH-stimulated Tglevel greater than 2 ng/ml had a negative predictive value of 100%, a positive predictive value of 55%, and a false positive rate of 9%.
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Two main points emerge from this study. First, a large number of patients who were considered free of disease on the basis of very low or undetectable serum Tg levels had persistent tumor (10%) or faint thyroid bed uptake when studied with rhTSH an average of about 6 yr after initial surgery. Second, DxWBS and RAIU added almost no diagnostic information to that provided by rhTSH-stimulated serum Tg.
Persistent disease, which was found from 1–24 yr after initial therapy, often occurred in patients with low TNM tumor status and serum Tg levels of 0.5 ng/ml or less during TH therapy. Among the patients found to have disease after rhTSH treatment, the serum Tg level during TH therapy was 0.5 ng/ml or less in 55% and 0.6 ng/ml in 36%. Detailed analysis of the cases showed that a patient’s disease status, even in retrospect, was often not predictable. For example, patients with an initial tumor status of T2N1 or less, who comprise 64% of our study cohort, accounted for 82% of the cases of persistent tumor, including two with undiagnosed pulmonary metastases (no. 20 and 90). We did not suspect lung metastases in three of the four patients in whom they were found after rhTSH testing who, on TH therapy, had serum Tg levels of 0.6 ng/ml or less, whereas the fourth patient (no. 89) with a serum Tg level during TH therapy of 1.0 ng/ml had lung metastases that had previously responded well to therapy.
On the other hand, three patients with advanced disease that had already been treated, two with distant metastases and one with grossly invasive tumor, showed no evidence of persistent disease. An 11-yr-old boy with a skull metastasis from follicular carcinoma treated surgically and with 131I and a 48-yr-old man with a solitary brain metastasis from papillary carcinoma treated surgically, respectively, 2 and 4 yr before study, had no metastatic tumor on previous RxWBS, DxWBS, bone scan, CT, or magnetic resonance imaging and had Tg levels after treatment that were persistently 0.5 ng/ml or less that failed to increase with rhTSH. The other was a woman who had received four treatments of 200 mCi 131I between ages 27 and 33 yr for grossly invasive, incompletely resected (T4N1M0) tumor. Several neck ultrasonograms and DxWBS and RxWBS studies were negative before she was studied at age 52 yr when her Tg level of 0.5 ng/ml or less did not increase in response to rhTSH.
Only one patient had visible thyroid bed uptake that we believed warranted therapy, although it is possible that more patients might have had it had they undergone TH withdrawal DxWBS. Haugen et al. (5) found that an rhTSH-stimulated Tg level greater than 2 ng/ml identified only 52% of the patients with visible thyroid bed uptake on withdrawal DxWBS, although quantitative RAIU was not performed, and any uptake in the neck was viewed as a positive test. We regarded faint thyroid bed uptake as clinically unimportant in three patients with an rhTSH-stimulated Tg level of 0.5 ng/ml or less and an RAIU less than 0.5%, and in six others with faint uptake seen only in a thyroglossal remnant, who we categorized as NED. It is highly unlikely that any of these patients would have been found to have more significant neck uptake or persistent disease when studied with TH withdrawal, given the low rhTSH-simulated Tg and correlations we found between it and RAIU or visible uptake on DxWBS. Furthermore, there is no evidence that faint bed uptake increases the risk of persistent or recurrent disease or requires further therapy.
All 87 patients (81%) with no evidence of disease had Tg levels of 0.5 ng/ml or less during TH therapy; Tg did not rise after rhTSH stimulation in 68 patients, but did so in 19 others, rising to levels ranging from 0.6–2.0 ng/ml. No tumor was seen on chest x-ray or on previous TH withdrawal DxWBS, although most had thyroid bed 131I uptake on RxWBS in the past. Among the 19 patients with rhTSH-stimulated serum Tg values between 0.5 and 2 ng/ml, all had RAIU less than 0.5%, and only 3 had faintly visible thyroglossal remnant uptake on DxWBS. When Tg increased in response to rhTSH, patients were usually studied with neck ultrasonography.
We suspect that some, if not all, of the eight patients with rhTSH-stimulated Tg levels between 2.1 and 5.8 ng/ml in whom no disease was found might manifest clinically apparent disease over time. Indeed, any rise in Tg whatsoever after rhTSH treatment might portend clinical problems with tumor.
The diagnostic accuracy of serum Tg during TH therapy was very poor; Tg levels of 0.5 ng/ml or more had a sensitivity of 36% and a false negative rate of 64%. Likewise, rhTSH-stimulated DxWBS had a sensitivity of only 27% and a false negative rate of 73%. However, rhTSH-stimulated serum Tg levels greater than 2 ng/ml had a sensitivity of 100%, yielding a negative predictive value of 100% and a 9% false positive rate, all within an acceptable range for detecting persistent cancer. The stringent criteria used to define a positive test produced the highest likelihood of false positive test results, which we believe over time might be shown to be true positive tests.
The greatest potential for error during follow-up occurs when a patient with cancer has a false negative test, because, as a practical matter, negative tests ordinarily prompt less frequent and less aggressive follow-up, creating a scenario for delaying the diagnosis until the tumor reaches an advanced stage. Tests to detect cancer should have a very high negative predictive value, which was not true for undetectable or low serum Tg levels determined while our patients were taking TH. Because of this, patients with no clinical evidence of disease and undetectable Tg levels should periodically undergo serum Tg measurements under TSH stimulation, which is most conveniently done with rhTSH (5, 8). The present study shows that performing a DxWBS in this setting adds little to diagnostic accuracy, and its omission could reduce cost and expedite management with little likelihood of doing harm. Similar observations about forgoing DxWBS in lieu of serum Tg measurements after TH withdrawal in patients who are clinically free of disease have been made by Cailleux et al. (11); a withdrawal Tg greater than 10 ng/ml prompted selection of patients for 131I therapy and RxWBS.
It is always necessary to question whether diagnostic paradigms that detect carcinoma early in its course offer patients enhanced survival. Delaying the initial diagnosis of thyroid cancer longer than 1 yr increases mortality rates significantly, worsening as the delay becomes longer, and eventually imparting a risk comparable with that of advanced age (3). There are compelling reasons to believe that this same risk exists when persistent thyroid cancer has gone unrecognized for years after treatment. For example, respiratory insufficiency due to pulmonary metastases is the most common cause of death from thyroid cancer (15), and their early diagnosis and treatment substantially enhance survival. Schlumberger (7) reported that complete remission and 10-yr survival rates were, respectively, 96% and 100% when the metastases were detected by high Tg and positive RxWBS alone, 83% and 91% when the diagnosis was apparent on 131I DxWBS, and 53% and 63% when micronodules were seen on chest x-ray. Discovering lung metastases only by high Tg and positive RxWBS is not uncommon; 3 cases were found in this study of 107 patients. In another study (3) we found that among 12 patients with lung metastases and normal chest x-rays, elevated serum Tg levels identified 11 (92%), and 9 (75%) were seen only on RxWBS.
The tumor bulk of distant metastases ranks second only to patient age as a predictor of death from thyroid cancer (16), suggesting that a strong argument can be made for early detection and treatment. Whether the removal of residual cervical lymph node metastases diminishes the risk of subsequent distant metastases remains speculative; however, all current therapeutic modalities are more effective when tumor bulk is smallest. There is also evidence that earlier detection of tumor increases the likelihood that it will concentrate 131I. One study (16) found that uptake was seen in 95% of patients with pulmonary metastases and a normal chest x-ray; uptake occurred in 88% of those with micronodular disease and 37% of those with macronodular disease (16). In short, the larger the tumor mass, the less likely it will be successfully ablated with 131I therapy and the higher the mortality rate. This even seems to occur with multiple metastatic sites; complete responses occur in 82% of patients with pulmonary or bone metastases and a normal radiograph compared with 15% of patients with an abnormal radiograph (16).
Late clinical recurrences, including lung metastases, are a matter of record for papillary and follicular cancer (3). We believe that most are simply cases of persistent disease that have fallen below the detection limits of our tests in patients who seem clinically free of disease, sometimes for many years. This study suggests that such tumors can be detected early when periodic rhTSH testing increases serum Tg above 2 ng/ml.
Acknowledgments
Footnotes
E.L.M. is Senior Research Scholar at the Center for Health Outcome Policy Evaluation Studies, Ohio State University.
Abbreviations: CT, Computed tomography; CV, coefficient of variation; DxWBS, diagnostic whole body scan; NED, no clinical evidence of disease; PET, positron emission tomography; RAIU, 131I neck uptake; rhTSH, recombinant human TSH; RxWBS, posttherapy whole body scans; SUV, standard uptake value; TH, thyroid hormone; WBS, whole body scan.
Received August 23, 2001.
Accepted November 28, 2001.
References
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), another was given 131I (*) after rhTSH, and another (
) received 131I to treat residual 131I uptake in the thyroid bed. D, Patients with persistent tumor (n = 11; 
, pulmonary metastases), and 10 were treated with 131I and/or surgery after rhTSH, one (
