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Section of Endocrinology, Department of Endocrinology and Metabolism, University of Pisa (E.M., M.G.C., L.A., R.E., C.C., F.L., D.T., L.G., A.P.), 56124 Pisa, Italy; and Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism, and Biochemistry, University of Siena (F.P.), 53100 Siena, Italy
Address all correspondence and requests for reprints to: F. Pacini, M.D., Department of Endocrinology, Via Paradisa, 2, 56124 Pisa, Italy. E-mail: fpacini{at}endoc.med.unipi.it.
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Abstract |
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Introduction |
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Recently, three large clinical studies have demonstrated the safety and efficacy of rhTSH in stimulating the uptake of diagnostic doses of radioiodine as well as the release of Tg by thyroid remnants and metastatic lesions of well differentiated thyroid carcinoma (3, 4, 5). In particular, in a phase III study (5), rhTSH-stimulated Tg alone predicted the presence of local or distant metastases in 100% of the cases. This finding was confirmed by a prospective study by our group (6) and by two additional studies (7, 8), suggesting that an rhTSH-stimulated Tg approach without diagnostic WBS is all that we need to identify patients with unsuspected residual or recurrent disease. At variance with these data, Robbins et al. (9), found that when using the rhTSH-based follow-up approach, the combination of diagnostic WBS and serum Tg was superior to serum Tg testing alone.
The aim of this study was to evaluate the diagnostic accuracy of rhTSH-stimulated WBS and serum Tg alone or in combination in a large retrospective series of differentiated thyroid cancer patients. An additional end point of the study was to assess the diagnostic utility of routine neck ultrasonography.
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Subjects and Methods |
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The reason for testing was to control for thyroid ablation after surgery and radioiodine in 191 patients, a second control after 1 negative test in 52 patients, and to control for disease remission in the remaining 97 patients, who at the previous evaluation off L-T4 had evidence of residual or metastatic thyroid tissue (local or distant metastases in 42, persistence of thyroid bed uptake in 37, and positive Tg with negative diagnostic WBS in 18). The time interval between initial radioactive iodine ablation and this follow-up study was 21.5 ± 14.1 months (range, 10–82).
Study design
The study design consisted of serum Tg measurements and 131I WBS under rhTSH stimulation during L-T4 suppressive therapy. Patients received one injection of rhTSH (0.9 mg, im; Thyrogen, Genzyme Corp., Cambridge, MA) for 2 consecutive days, followed by a 4-mCi tracer dose of 131I on the third day. WBS was obtained 48 h after 131I administration. Serum samples for TSH and Tg measurements were collected before the first rhTSH injection and during the following days, up to d 5.
All patients underwent neck ultrasonography. Suspicious neck masses or lymph nodes were submitted to fine needle aspiration cytology (FNAC). We defined as suspicious those lymph nodes with particular echographic features: clear hypoechoic and disomogeneous pattern and rounded or bulging shape without evidence of central halo.
Additional imaging procedures [posttherapy 131I WBS, computed tomography (CT), and magnetic resonance imaging] were scheduled when indicated. In the absence of a gold standard defining metastatic disease, the final evaluation of diagnostic accuracy took into account the results of these tests and those of neck ultrasound plus FNAC as well as the previous history.
Methods
Sequential serum Tg and TSH determinations were run in the same assay. Serum Tg was measured using a commercial immunometric assay (Diagnostic Products, Los Angeles, CA) with a lower detection limit of 0.2 ng/ml and a functional sensitivity of 0.9 ng/ml. The assay is standardized against the certified reference material for human Tg (CRM 457) of the Community Bureau of Reference of the European Commission (10). In our laboratory the intra- and interassay coefficients of variation of the method are 4.3% and 7.0%, respectively. Based on the functional sensitivity of the assay (0.9 ng/ml), we selected 1 ng/ml as the cut-off value discriminating undetectable from detectable Tg levels.
Anti-Tg autoantibodies (TgAb) were measured in all sera by an immunoradiometric assay method (ICN Pharmaceuticals, Inc., Beerse, Belgium). A concentration of AbTg less than 5 U/ml was considered negative. Twenty-five patients had concentration of circulating anti-Tg antibodies greater than 5 U/ml, which was considered to possibly interfere with the Tg assay. Serum TSH was measured using an ultrasensitive commercial immunometric assay (Diagnostic Products). WBS was performed using a one-head 
-camera (Apex SPX 4000, Elscint Italia, Milano, Italy) with a high energy collimator and a sensitivity of 160 cpm/µCi. The scan speed was 10 cm/min with total counts of at least 100,000 cpm. Neck ultrasound was performed using a color Doppler apparatus (AU 590 Asynchronous, Esaote Biomedica, Firenze, Italy) with a 7.5-MHz linear transducer.
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Results |
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As shown in Fig. 1
, after rhTSH treatment, serum Tg remained undetectable in 250 patients (85.0%). The diagnostic 131I WBS was negative in 225 (90.0%) patients, positive for residual uptake in the thyroid bed in 23 (9.2%), positive for lymph node metastases in one (0.4%), and positive for an isolated bone metastasis, confirmed by CT scan, in one patient (0.4%). By neck ultrasound lymph node metastases were suspected in three (1.2%) patients, the one with positive WBS mentioned above and two with negative WBS. The metastatic origin of the lymph nodes in these cases was confirmed by FNAC. In summary, an undetectable stimulated serum Tg was falsely negative in four patients (1.6%) with documented metastatic disease, two of whom were also missed by the diagnostic WBS (0.8%)
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Patients with undetectable (<1 ng/ml) basal serum Tg and positive TgAb (n = 25; Fig. 2)
Despite the presence of circulating TgAb, serum Tg converted from undetectable to detectable in four (16.0%) patients, all with negative diagnostic WBS. A therapeutic dose of radioiodine was administered in two patients. The posttherapy WBS showed thyroid bed uptake in one patient and lymph node metastases, confirmed by neck ultrasound and FNAC, in the other. The other two patients are scheduled for the same therapy.
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Patients with detectable basal serum Tg and negative TgAb (n = 21; Fig. 3)
In this group basal serum Tg was indicative of the presence of residual or metastatic thyroid tissue. After rhTSH treatment, serum Tg increased further (mean basal Tg, 9.7 ± 20.6 ng/ml; mean peak Tg after rhTSH, 43.6 ± 112.2 ng/ml). WBS was positive in four of 21 (19.1%) patients who had thyroid bed uptake (n = 3) or bone metastases (n = 1) and was negative in 17 of 21 (80.9%). A therapeutic dose of radioiodine was given to 13 patients, and the posttherapy WBS showed thyroid bed uptake in five, lymph node metastases in three, lung metastases in two, and no uptake in three patients. Lymph node metastases were documented in two patients by neck ultrasound and FNAC. In summary, the diagnostic WBS was informative of metastatic disease in only one of eight patients with documented metastatic disease.
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)For this analysis we considered all patients with metastatic disease documented by any diagnostic procedure (neck ultrasound, FNAC, CT scan, diagnostic or posttherapy 131I WBS) and those with no evidence of disease. Patients with 131I uptake limited to the thyroid bed by diagnostic or posttherapy WBS without any evidence of metastatic disease were not considered. Patients with positive serum TgAb were considered only in the analysis of diagnostic WBS accuracy. In the absence of a gold standard defining a patient with or without disease, diagnostic accuracy was calculated based on our ability to detect disease with the above- mentioned imaging procedures.
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). The addition of neck ultrasound to rhTSH-stimulated Tg, increased the sensitivity to 96.2% and the negative predictive value (NPV) to 99.5% and decreased the false negative rate to 3.7% (Fig. 4B). An rhTSH-stimulated 131I WBS positive outside the thyroid bed had a sensitivity of only 20.5%, with a false negative rate of 79% and a negative predictive value of 89% (Fig. 4C). The combination of both tests (Tg and WBS) had a sensitivity of 92.7%, a false negative rate of 7.4%, and a negative predictive value of 99% (Fig. 4D). These values were only marginally superior to those in rhTSH-stimulated serum Tg alone, but were inferior to those with the combination of rhTSH-stimulated serum Tg plus neck ultrasound.
Finally, Table 1 reports the diagnostic accuracy of rhTSH-stimulated Tg, diagnostic WBS, and neck ultrasonography as a single test in excluding or predicting the presence of loco-regional disease, excluding distant metastases. As can be seen, even as a single test, neck ultrasound and stimulated serum Tg had much better results than diagnostic WBS.
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Serum Tg remained unchanged (<1 ng/ml) after rhTSH treatment in 223 patients with no evidence of disease, in 23 patients with evidence of thyroid bed uptake (considered as normal thyroid residues), in three patients with lymph node metastases, and in one patient with a single bone lesion. In the remaining 44 patients serum Tg became greater than 1 ng/ml after rhTSH treatment. As shown in Fig. 5, individual stimulated Tg values in this group peaked between 1.6–39 ng/ml, with a significant overlap between patients with different clinical status. In particular, any detectable level of serum Tg, even as low as 1.6–5.0 ng/ml, might be associated with significant local or distant metastatic disease requiring treatment.
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As shown in Table 2, stimulated Tg alone and stimulated Tg plus neck ultrasound had better sensitivity than diagnostic WBS alone or combined with stimulated Tg in low risk patients. However, in high risk patients, stimulated Tg plus diagnostic WBS had a better sensitivity (100%). This finding may suggest an important role of diagnostic WBS in the high risk patients.
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Discussion |
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In recent years, the validation of rhTSH as an effective alternative to L-T4 withdrawal for the stimulation of 131I uptake and Tg secretion (4, 5) has changed the strategy of follow-up while preserving the patient’s quality of life. Follow-up strategies based on rhTSH stimulation pose the problem of ascertaining whether the same criteria used when studying the hypothyroid patient also apply to the euthyroid patient treated with rhTSH.
The present retrospective study, aimed at ascertaining the diagnostic accuracy of rhTSH-stimulated serum Tg and 131I WBS in daily practice, allows us to draw three main conclusions: 1) the high sensitivity of rhTSH-stimulated serum Tg alone in predicting the presence or absence of active disease, 2) the very low sensitivity of the diagnostic WBS, and 3) the crucial importance of routine neck ultrasound for detecting small local disease not seen by both Tg and WBS.
The large majority of patients with undetectable basal and rhTSH-stimulated serum Tg were in apparent remission. Falsely negative Tg tests were limited to four patients, three of whom had tiny lymph node metastases discovered by neck ultrasound and one who had the very exceptional finding of a single vertebral bone metastasis visible in the diagnostic WBS, but not producing Tg (also during hypothyroidism). The association of neck ultrasound and serum Tg measurement increased diagnostic sensitivity from 85.0% (stimulated Tg alone) to 96.3%. With this combination, the only metastatic patient left undiagnosed was the one with the single vertebral metastasis. On the other hand, the diagnostic sensitivity of WBS was as low as 20.5%, similar to that reported when the test is performed in the hypothyroid state. The diagnostic WBS failed to detect 31 of 39 metastatic patients. Many of these cases were detected when the WBS was performed after therapeutic doses of 131I, confirming previous studies indicating that posttherapy scans are much more sensitive than diagnostic scans (13, 14, 15, 16). In patients with negative Tg tests apparently in remission, WBS may add the information of minimal residual uptake in the thyroid bed, which is clinically not relevant. The combination of diagnostic WBS and Tg test had a sensitivity of 92.7%, only marginally higher than that of the Tg test alone (85.0%), but lower than that of the Tg test and neck ultrasound combined (96.3%).
Our results are in agreement with the most relevant series published in recent years on the same subject (6, 7, 8, 9, 17, 18). In a prospective study carried out by our group (6) in patients with undetectable (<1 ng/ml) basal serum Tg, a positive response of Tg to rhTSH injection was able to identify 100% of the metastatic patients. In a recent retrospective study by Mazzaferri and Kloos (7) including 107 patients, the diagnostic WBS never added any valuable information other than evidence of residual thyroid bed uptake. In particular, all 11 patients with persistent disease had positive rhTSH-stimulated serum Tg levels, but no evidence of disease by scan.
In a phase III rhTSH study (5), serum Tg was 2 ng/ml or higher after rhTSH in all patients with documented distant metastases. Diagnostic WBS performed during hypothyroidism or after rhTSH stimulation failed to detect 17 and 29% of these metastatic patients, respectively.
In a recent multicentric study (19) based on 300 patients, the researchers found that rhTSH-stimulated Tg testing without WBS was able to identify 18% of patients with evidence of disease, previously thought to be free of disease on the basis of undetectable serum Tg during thyroid hormone suppression. Of particular importance in this study is that this finding applied even to patients studied 5–10 yr after the initial surgery.
The results reported by Robbins et al. (9) seem to differ from the above studies. These researchers found that using a cut-off of 2 ng/ml, rhTSH Tg testing alone failed to detect a significant proportion of metastatic patients (13%). The diagnostic WBS was informative in nearly half of these cases. Based on this finding, the researchers concluded that Tg testing alone was not sufficient to screen unselected cases, but might be sufficient in low risk patients, especially when they have had a previous negative diagnostic WBS. A possible explanation for the different results of Robbins et al. (9) may derive from the different selection of patients. Indeed, the disproportionate number of high risk and metastatic patients present in their series may be ascribed to the selective inclusion of particular patients. As a matter of fact, when our analysis was limited to high risk patients (more similar to those of the Robbins study) we also noticed that the diagnostic accuracy of the diagnostic WBS combined with the results of rhTSH-stimulated Tg was very high, reaching a sensitivity of 100%.
It is also worth noting that in the Robbins study, neck ultrasound was not routinely employed, and false negative Tg due to interference of anti-Tg antibodies was not ruled out by direct measurement of anti-Tg antibodies by a sensitive immunoradiometric assay, but simply by a recovery test, which is considered less informative for the presence of interference (20).
Recently, an editorial by Wartofsky (8) concluded that an rhTSH-stimulated Tg approach without a diagnostic scan can be used in low risk patients and will serve to identify 10–20% of patients with unsuspected residual or recurrent disease. Our experience fully agrees with this statement. The large majority of patients with thyroid carcinoma have well differentiated tumors that are completely cured by surgery and thyroid ablation. These patients may avoid the diagnostic WBS at their first follow-up after initial treatment (surgery and radioiodine ablation) in favor of the much more simple approach represented by the rhTSH-stimulated Tg test and neck ultrasound. A rise in serum Tg above the cut-off identified in each center (1 ng/ml in our laboratory, 2 ng/ml in others) and/or a suspicious finding at ultrasound will allow identification of the few patients requiring further diagnostic and therapeutic procedures. The sequence of screening tests that may be proposed according to our results is schematically reported in Fig. 6.
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Footnotes |
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M.C.G. is the recipient of a fellowship from Federazione Italiana Ricerca sul Cancro.
Abbreviations: CT, Computed tomography; FNAC, fine needle aspiration cytology; NPV, negative predictive value; rhTSH, recombinant human TSH; Tg, thyroglobulin; TgAb, Tg autoantibodies; WBS, whole body scan.
Received December 9, 2002.
Accepted May 6, 2003.
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