Is diagnostic iodine-131 scanning with recombinant human TSH useful in the follow-up of differentiated thyroid cancer after thyroid ablation?

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% < or =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 (131)I 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 (131)I, 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 (131)I uptake (r(2) = 0.11; P = 0.001), between DxWBS and rhTSH-stimulated Tg (r(2) = 0.54; P = 0.001), and between rhTSH-stimulated Tg and (131)I uptake (r(2) = 0.66; P = 0.0001). There was no statistically significant difference (P = 0.4) in bed (131)I 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.     

Serum thyroglobulin and 131I whole body scan after recombinant human TSH stimulation in the follow-up of low-risk patients with differentiated thyroid cancer

OBJECTIVE: The 'standard' postoperative follow-up of patients with differentiated thyroid cancer (DTC) has been based upon serum thyroglobulin (Tg) measurement and (131)I whole body scan ((131)I-WBS) after thyroid hormone (T(4)) treatment withdrawal. However, (131)I-WBS sensitivity has been reported to be low. Thyroid hormone withdrawal, often associated with hypothyroidism-related side effects, may now be replaced by recombinant human thyroid stimulating hormone (rhTSH). The aim of our study was to evaluate the diagnostic accuracy of (131)I-WBS and serum Tg measurement obtained after rhTSH stimulation and of neck ultrasonography in the first follow-up of DTC patients. DESIGN: Ninety-nine consecutive patients previously treated with total thyroidectomy and (131)I ablation, with no uptake outside the thyroid bed on the post-ablative (131)I-WBS (low-risk patients) were enrolled. METHODS: Measurement of serum Tg and (131)I-WBS after rhTSH stimulation, and ultrasound examination (US) of the neck. RESULTS: rhTSH-stimulated Tg was 1 ng/ml (Tg+) in 21 patients, including 6 patients with Tg levels >5 ng/ml. (131)I-WBS was negative for persistent or recurrent disease in all patients (i.e. sensitivity = 0%). US identified lymph-node metastases (confirmed at surgery) in 4/6 (67%) patients with stimulated Tg levels >5 ng/ml, in 2/15 (13%) with Tg >1<5 ng/ml, and in 2/78 (3%) who were Tg-negative. CONCLUSIONS: (i) diagnostic (131)I-WBS performed after rhTSH stimulation is useless in the first follow-up of DTC patients; (ii) US may identify lymph node metastases even in patients with low or undetectable serum Tg levels.     

A comparison of the effectiveness of 131I whole body scans and plasma Tg determinations in the diagnosis of metastatic differentiated carcinoma of the thyroid: a retrospective study

In 68 patients with proved metastases of differentiated thyroid carcinoma the comparative value of the 131I whole body scan and plasma Tg measurements in establishing the diagnosis of metastasis or recurrence was analyzed retrospectively. At the time of primary therapy most metastases were diagnosed by the post-therapy scan (78%). Eight of 9 scintigraphic negative metastases in the post-therapy scan were indicated by elevated Tg levels (greater than 10 ng/ml). Twenty-four of 28 recurrences after a disease free interval were negative in the 2 mCi 131I scan, 18 of these patients were Tg positive. Of the 4 recurrences with positive 131I uptake all were Tg positive; two of them only during endogenous TSH stimulation. It is concluded that the routine 2 mCi whole body scan is less efficient in follow-up than is generally assumed. The most important follow-up parameter for these patients is the plasma Tg which can be obtained under suppressive therapy if a sensitive assay is used. In patients with a negative post-therapy scan and a negative Tg (less than 5 ng/ml) it seems justified to omit further 131I whole body control scans as long as Tg remains negative.     

Is stimulation of thyroglobulin (Tg) useful in low‐risk patients with thyroid carcinoma and undetectable Tg on thyroxin and negative neck ultrasound?

OBJECTIVE: To determine the usefulness of thyroglobulin (Tg) stimulation in low-risk patients with undetectable Tg on T4 and negative neck ultrasound (US) after initial therapy of thyroid carcinoma. METHODS: We evaluated 122 consecutive patients classified as low risk 6 months to 1 year after total thyroidectomy and remnant ablation. All patients had a normal clinical exam, Tg < or = 1 ng/ml during suppressive therapy (TSH < 0.1 mIU/l), and undetectable antithyroglobulin antibodies. RESULTS: After T4 withdrawal and elevation of TSH to values > 30 mIU/l, 26 patients (21.3%) converted Tg to levels > 1 ng/ml. Metastases were detected in 10 patients, nine showing stimulated Tg levels > 1 ng/ml. Cervical metastases were observed in 9/10 patients and lung metastases in one patient. Neck US identified all cervical metastases. Seventeen patients with stimulated Tg levels > 1 ng/ml initially showed no apparent disease, with a reduction in Tg being observed upon subsequent measurements, and 13 patients presented undetectable Tg off T4 at the end of the study. Undetectable Tg on T4 showed a high negative predictive value (NPV; 91.8%), which increased to 99.1% when combined with neck US. Stimulated Tg levels < 1 ng/ml presented a 98.9% NPV. A total of 113 patients with undetectable Tg on T4 and negative US had to be exposed to hypothyroidism in order to diagnose one further case of metastases. CONCLUSION: Undetectable Tg on T4 combined with negative neck US presented a high NPV in low-risk patients and Tg stimulation might be avoided in these patients.     

Long-term course and predictive factors of elevated serum thyroglobulin and negative diagnostic radioiodine whole body scan in differentiated thyroid cancer

Following the initial management, some patients with differentiated thyroid cancer (DTC) develop a state of high thyroglobulin (Tg) and negative diagnostic radioactive iodine (RAI) whole body scan (DxWBS). The predisposing factors and outcome of this condition are unclear. In this study, our objectives were to determine the predictive factors for the development of high Tg and negative DxWBS (Tg+/scan-) and to study the long-term course of the disease in patients with this condition. METHODS: We, retrospectively, reviewed the medical records of a cohort of 105 non-selected DTC patients (26 males and 79 females; median age 37.7 yr, range 7-72). None of these patients had positive Tg antibodies or distant metastases. All Tg levels were obtained off thyroid hormone therapy. At the first follow-up visit after RAI ablation (13 +/- 7.6 months), patients were classified into those with low Tg (<2 ng/ml off L-T4) and negative DxWBS (control group) and those with high Tg ( > or = 22 ng/ ml off L-T4) and negative DxWBS (Tg+/scan- group). Using univariate and multivariate logistic regression analyses, we evaluated a number of parameters (see results) for their association with the development of Tg+/scan-. In addition, the long-term course of the disease in Tg+/scan- group was analyzed. RESULTS: In univariate analysis, the following factors were found to be significantly associated with Tg+/scan-: perithyroidal tumor extension (p=0.025), soft tissue invasion (p=0.001), cervical lymph node metastases (p=0.014) and Tg level before RAI ablation (p=0.015). In multivariate analysis, only soft tissue invasion remained significantly associated with Tg+/scan- [p 0.001, odds ratio, 15.6 (95% Cl, 2.96-82.06)]. Age, sex, duration of goiter before surgery, pressure symptoms, tumor size, tumor multifocality, lymph nodedissection at initial surgery, tumor-node-metastasis (TNM) stage, and RAI ablative dose were not associated with Tg+/ scan-. In 53 patients with Tg+/scan-, 42 cases were followed without any therapeutic intervention; over a median follow-up of 71.6 months (range, 13-144.7), 31 cases had a spontaneous remission and 11 cases continued to have a persistent disease (Tg > or = 2 ng/ml, negative DxWBS, and no palpable disease or distant metastases); Tg declined from 9.32 +/- 9.91 ng/ml at first visit after RAI ablation to 1.59 +/- 5.39 ng/ml at last visit (p<0.0001). In the other 11 cases of Tg+/scan- group, one or more therapeutic interventions (RAI, surgery, or external radiotherapy) were undertaken. Over a median follow-up of 98.4 months (range, 6-147), Tg decreased from 110.2 +/- 147.5 to 23.5 +/- 41.2 ng/ml (p 0.026); 4 cases achieved remission, 5 cases continued to have persistent disease, and 2 cases had progression of their disease, which led to their death. CONCLUSION: Soft tissue invasion on original surgery strongly predicts the development of Tg+/scan- in DTC patients. The long-term course of the disease is mostly favorable especially when the Tg level is only modestly elevated.     

Revisiting serum thyroglobulin in the follow-up of patients with differentiated thyroid carcinoma

This study analyzed serum thyroglobulin (Tg) during hypothyroidism in 207 patients with differentiated thyroid carcinoma treated with total thyroidectomy and radioiodine ablation and undetectable anti-Tg antibodies. Disease staging was defined by clinical examination, stimulated Tg, pre- and post-ablative radioiodine scanning, and other imaging methods (X-Ray, US, CT and MIBI-scan). The average interval from initial therapy was 2.3 years. 153 patients (74%) had no evident disease, 34 (16.4%) presented neck/mediastinal disease, and 20 (9.6%) had distant metastases (Mt). The best cut-off for Tg was 1 ng/ml, showing 100% sensitivity for distant Mt and 88.2% for local recurrence or lymph node Mt, and 88.8% specificity for any Mt and 74.8% for distant Mt. In patients with Tg <1 ng/ml, 2.8% showed cervical lymph nodes Mt. Cervical or mediastinal disease were 26% of cases with Tg between 1 and 5 ng/ml. Tg from 5 to 10 ng/ml was associated to distant Mt in 14.2% of the cases and others showed lymph nodes Mt. In patients with Tg >10 ng/ml, 51.3% presented distant Mt. We suggest the need for neck US even in cases with Tg <1 ng/ml. In addition, patients with Tg levels <5 ng/ml should be investigated by neck US and mediastinal CT only, and empirical therapy should be limited to patients with a minimum Tg level >5 ng/ml.     

Does a highly sensitive thyroglobulin (Tg) assay change the clinical management of low‐risk patients with thyroid cancer with Tg on T4 < 1 ng/ml determined by traditional assays?

Objective To evaluate a highly sensitive thyroglobulin (Tg) assay [functional sensitivity (FS): 0·1 ng/ml] (Tg‐ICMA) in low‐risk patients with known Tg on T4 ≤ 1 ng/ml measured by a traditional assay (FS: 1 ng/ml) (Tg‐IRMA). Methods Tg‐ICMA was measured in serum samples stored at –70 °C. Samples were obtained 6 months or more after total thyroidectomy and remnant ablation with ¹³¹I, during L‐T4 therapy (TSH < 0·4 mIU/l). All patients had well‐differentiated and completely resected tumours, no ectopic uptake on post‐therapy whole‐body scans and were considered to be at low risk for recurrence. On the occasion of collection and retesting for this study, Tg‐IRMA was ≤ 1 ng/ml in all samples and no antibody interference was observed. Results Tg‐ICMA ≤ 0·1 ng/ml was observed in 130/178 (73%) patients and recurrence was diagnosed in only 1/130 (0·8%). Tg‐IRMA measured after L‐T4 withdrawal was > 1 ng/ml in 5/130 (3·8%) patients. Forty‐eight (27%) patients had Tg‐ICMA > 0·1 ng/ml (0·12–1·6 ng/ml) and recurrence was diagnosed in 5/48 (10·5%). Tg‐IRMA measured after L‐T4 withdrawal was > 1 ng/ml in 20/48 (41·6%) patients. A negative predictive value of 100% was achieved with Tg‐ICMA on T4 ≤ 0·1 ng/ml combined with neck ultrasonography (US) or with stimulated Tg‐IRMA ≤ 1 ng/ml. Conclusions Patients at low risk for recurrence with undetectable Tg on T4 measured by a highly sensitive assay (FS: 0·1 ng/ml) in the absence of antibody interference and with a negative sensitive neck US do not need to be submitted to Tg stimulation. Recurrence is rare in these cases and only a minority of patients convert to stimulated Tg > 1–2 ng/ml.     

Contribution of computed tomography in patients with lung metastases of differentiated thyroid carcinoma not apparent on plain radiography who were treated with radioiodine

Computed tomography (CT or CAT Scan) of the chest is more sensitive than radiography in the detection of lung metastases of differentiated thyroid cancer (DTC), but little information is available regarding the aggregated value of this method. The present study evaluated the response of patients with lung metastases of DTC not apparent on radiography to treatment with 131I and the value of CT in these cases. Twenty-five patients with lung metastases not apparent on radiography, who initially received 100-200 mCi I151, were evaluated and those presenting pulmonary uptake on post-therapy WBS were submitted to a new treatment after 6 to 12 months, and so on. The chance of detection of pulmonary uptake on post-therapy WBS did not differ between patients with negative and positive CT (100% versus 91.5%). Mean serum Tg levels were higher in patients with positive CT (108 ng/ml versus 52 ng/ml). Negative post-therapy WBS was achieved in 82% of patients with positive CT and in 92.3% with negative CT and the cumulative I131 activity necessary to achieve this outcome did not differ between the two groups (mean=300 mCi). Stimulated Tg was undetectable in 47% of patients with negative CT at the end of treatment, but in none of the patients whose CT continued to be positive. In patients with elevated Tg, the CT result apparently did not change the indication of therapy or the I131 activity to be administered. In cases with lung metastases, the persistence of micronodules on CT was associated with the persistence of detectable Tg in patients presenting negative post-therapy WBS.     

Usefulness of radioiodine scanning in patients with moderate/high risk differentiated thyroid carcinoma in whom thyroglobulin after thyroxin withdrawal is undetectable after initial treatment

We selected 92 patients without antithyroglobulin antibodies (TgAb), in whom thyroglobulin (Tg) after L-thyroxin withdrawal was undetectable (<1 ng/ml) 6-12 months after initial therapy and who were considered to be at moderate / high risk for recurrence by this criteria: age >45 years; tumor size >1.5 cm; and lymph nodes metastases in 43 (46.7%), local invasion in 26 (28.2%) or distant metastases in 23 (25%). Control whole-body scanning was negative in 78.2% of the cases and showed cervical uptake in the others. Cases presenting thyroid bed uptake in the absence of tumor recurrence did not receive radioiodine and Tg remained undetectable one year after the initial evaluation in all. Cervical uptake was not observed in 4/13 cases on repeated scan. In contrast, even in the absence of uptake and with undetectable Tg, 7 patients with recurrence confirmed by ultrasound (US) received surgical treatment. US showed 92.8% sensitivity for the detection of local-regional disease. The present study suggests that even moderate/high-risk patients without TgAb and with undetectable Tg levels (off T4) do not require radioiodine scanning after initial treatment and can be evaluated by cervical US.     

Effects of therapeutic doses of 131I in thyroid papillary carcinoma patients with elevated thyroglobulin level and negative 131I whole-body scan: comparative study

OBJECTIVE: Previous studies have shown a high rate of visualization of uptake and a decrease in serum thyroglobulin (Tg) after therapeutic doses of 131I in well-differentiated thyroid cancer patients with elevated thyroglobulinaemia but negative diagnostic 131I whole-body scan (DxWBS), but its therapeutic effect remains controversial. We evaluate the effect of therapeutic doses of 131I in patients with elevated thyroglobulin level but negative DxWBS. DESIGN: Among papillary thyroid carcinoma patients who underwent total or near-total thyroidectomy and remnant ablation with radioiodine during 1996 to 2000 in our hospital, the patients who showed elevated serum Tg levels and no abnormal uptake in DxWBS were selected. The selection for treatment or no treatment was decided according to the preference of the patients, considering side-effects of therapeutic doses of 131I, and the patients were thereafter studied retrospectively. PATIENTS: Sixty papillary thyroid carcinoma patients with elevated thyroglobulinaemia but negative DxWBS were included. Twenty-eight patients were treated, and 32 were untreated. MEASUREMENTS: We compared serum Tg levels measured at less than 3 months before the administration of therapeutic doses of 131I or DxWBS with the levels at 6-12 months after administration between two groups. Comparable data on changes in serum Tg levels during TSH suppression (Tg-on) and those in hypothyroid phase (Tg-off) were available in 25 and 49 patients, respectively. RESULTS: Percentage decreases in both Tg-on and Tg-off levels of the treated group [41.2 (10.1-94.1)% and 37.0 (-176.6-88.4)%, respectively] were significantly higher than those of the untreated group [-43.6 (-180.1-7.3)% and -66.6 (-10644.2-39.1)%, respectively] (P < 0.001). The treated patients were followed-up for 23.8 +/- 19.6 months after the administration of therapeutic doses of 131I. In four cases, serum Tg levels converted to negative (< 1.0 ng/ml) both on and off T4 15-22 months after the administration of therapeutic doses of 131I, and negative serum Tg levels persisted for 24-70 months. However, negative conversion of elevated serum Tg levels was not observed in any of the untreated group. Post-treatment WBS revealed pathologic uptake in 12 of 28 cases (42.9%). CONCLUSIONS: This study revealed that the administration of therapeutic doses of 131I has a therapeutic effect, at least for palliation in short-term observation, considering the serum Tg level as an index of tumour burden, and that it can disclose previously undiagnosed lesion in some patients with differentiated thyroid cancer who show elevated thyroglobulin level but negative diagnostic 131I whole-body scan.     

Clinical manifestations and diagnosis of distant metastases of differentiated thyroid carcinoma after initial therapy

We studied 58 patients with distant metastases of differentiated thyroid carcinoma diagnosed after initial therapy. Lymph node metastases were observed in 65% of the patients on initial presentation. All lymph node metastases, ninety percent of the lung metastases and only 25% of the bone metastases were asymptomatic. Radiography revealed lytic metastases in cases of bone involvement, was normal in 39.6% of the patients, and showed micrometastases in 34.5% and macrometastases in 25.8% of the patients with lung disease. Thyroglobulin (Tg) under thyroxine use was detectable in all patients without antibodies at a cut-off > 1 ng/ml, in 90% at > 5 ng/ml and in 80% at > 10 ng/ml, and after thyroxine withdrawal in 100% at a cut-off > 5 ng/ml and in 94% at > 10 ng/ml. In the case of patients with antibodies (13.8%), Tg was undetectable in half of them. Diagnostic scanning was positive in 83 and 77.6% of the patients with bone and lung metastases, respectively. After ablative therapy, the sensitivity was 100 and 93%, respectively. Eighty-five percent of patients with a negative diagnostic scan had lung metastases visible on radiographs. The determination of serum Tg is the best method in the follow-up of patients with differentiated thyroid cancer. Elevated Tg levels suggest the presence of metastases, indicating the need for ablative therapy with posttreatment scanning, which might reveal non-apparent metastases.     

Follow-up of low risk patients with papillary thyroid cancer: role of neck ultrasonography in detecting lymph node metastases

Persistent or recurrent disease is rare in low risk patients with papillary thyroid cancer, and follow-up of these patients is a matter of debate. Neck ultrasonography (US), serum thyroglobulin (Tg), and whole body scan (WBS) after T(4) withdrawal were performed in 456 patients, followed up to 5 yr. At the end of the first year, 335 patients were Tg negative, and 121 were Tg positive; 65 of 96 patients with Tg levels between 1 and 10 ng/ml became spontaneously Tg negative after 2 yr. During follow-up, WBS discovered node metastases in 13 subjects, and US discovered node metastases in 38 subjects (31 Tg positive and 7 Tg negative). WBS did not add any information, because all WBS-positive patients were also US and Tg positive. Fifty percent of metastases were less than 1 cm and not palpable. Finally, the negative predictive value of both negative Tg and US at first follow-up was 98.8%. We suggest a first follow-up based upon US assessment and stimulated (after T(4) withdrawal or recombinant human TSH) serum Tg determination; subsequently, 1) US should not be mandatory at each examination in initially Tg- and US-negative subjects, but is strongly suggested in all other cases; 2) Tg determination should be repeated 1 yr later, after exogenous or endogenous TSH stimulation only in initially Tg-positive patients without any other evidence of residual disease; and 3) Tg measurement during therapy should be sufficient in all other cases.     

Positive predictive value of detectable stimulated tg during the first year after therapy of thyroid cancer and the value of comparison with Tg-ablation and Tg measured after 24 months.

This study evaluated the positive predictive value (PPV) of detectable stimulated thyroglobulin during the first year after treatment of thyroid carcinoma (Tg-1) and the value of comparison with Tg-ablation and measured after 24 months (Tg-2). Forty-two consecutive patients undergoing total thyroidectomy and ablation with detectable Tg-1 (>1ng/mL) were selected. The patients had well-differentiated tumors, which were completely resected, and there was no ectopic uptake on whole body scan after 3.7-5.5GBq I(131). Imaging methods during follow-up revealed metastases in 10 patients (24%) (15% if Tg-1 10 ng=mL). Tg-ablation (cutoff of 10 ng/mL) presented a negative predictive value (NPV) of 91% and PPV of 42%. Comparing Tg-ablation with Tg-1, the PPV of an increase was 100%, whereas the NPV of a decrease was 88%. Thirty-six patients presented negative imaging results upon first assessment and Tg-1 was compared to Tg-2. Metastases were detected in all patients who presented an increase in Tg (n=4), whereas patients without variation (n=4) or with a decrease (n=28) showed no apparent disease. Among disease-free patients (n=32), 50% presented undetectable Tg and 40% showed a >50% decrease after 2 years. In conclusion, most patients with detectable stimulated Tg during the first year after therapy had no metastases, and evaluation of the slope of Tg helped discriminate cases with apparent disease.     

Investigating patients with differentiated thyroid carcinoma and elevated serum thyroglobulin but negative whole-body scan

Findings of elevated thyroglobulin (Tg) and a negative whole-body scan (WBS) are not uncommon during the follow-up of differentiated thyroid carcinoma. In 12% of our patients submitted to thyroidectomy and radioiodine with Tg >10 ng/ml during hypothyroidism had a negative diagnostic WBS. This finding generally corresponds to a false-negative WBS. Inadequate preparation in terms of iodine exposure and insufficient elevation of TSH should be excluded. Micrometastases which do not accumulate sufficient iodine to be detected by low radioiodine activity and the loss of the capacity to express the sodium/iodine symporter explain many cases. In patients with elevated Tg, metastases can be identified after the administration of a therapeutic radioiodine dose, with this procedure being indicated in cases with Tg >10 ng/ml during hypothyroidism or >5 ng/ml after recombinant TSH, after exclusion of lung and cervical macrometastases. In the present study, 5 of 7 patients with these criteria showed ectopic uptake on post-therapy WBS. If the post-therapy scan is negative or reveals discrete uptake in the thyroid bed, other methods (e.g. FDG PET) can be performed, and the physician should not insist on radioiodine therapy. If WBS detect lymph node metastases, surgery is indicated, while in cases of diffuse lung metastases radioiodine is indicated until the occurrence of a negative WBS or normalization of stimulated Tg levels. Patients with a positive post-therapy scan may show a significant reduction in Tg, with even complete remission in some cases after radioiodine, but the impact of this treatment on mortality remains controversial.     

The use of recombinant human TSH in the follow-up of differentiated thyroid cancer: experience from a large patient cohort in a single centre

BACKGROUND: Periodic evaluation of serum thyroglobulin (Tg) and whole body 131I imaging (131I-WBS) are essential in the follow-up of differentiated thyroid carcinoma (DTC); both diagnostic modalities require stimulation by high levels of TSH. Administration of recombinant human TSH (rhTSH) is an alternative to the withdrawal of thyroid hormone therapy. OBJECTIVE: The aim of this study was to report our experience in the use of rhTSH for the management of patients with DTC. PATIENTS: One hundred and four patients were enrolled in the study. A dose of 10 U of rhTSH therapy was injected intramuscularly for 2 consecutive days; 24 h after the second dose of rhTSH the patients were administered 4--5 mCi of 131I and, 48 h later, WBS was performed. RESULTS: In all patients, baseline mean serum Tg and TSH levels were 2.4 +/- 1.9 ng/ml and 0.0153 +/- 0.0232 mIU/l, respectively. Basal Tg levels were detectable in 58 out of 104 patients. After rhTSH injection, mean serum TSH levels rose to 122.67 +/- 47.36 mIU/l. Stimulated serum Tg levels increased to greater-than-or-equal 5 ng/ml and the 131I-WBS showed an uptake in 18 patients (17.4%). Among them there were three with bone metastases and one with brain metastases, who reported violent skeletal pain and a severe headache, respectively. These were caused by the growth of tumour mass of metastases induced by rhTSH administration. CONCLUSIONS: The use of rhTSH avoids the debilitating effects of hypothyroidism and its use successfully promotes iodine uptake and increases the sensitivity of serum Tg testing. The risk of causing serious side-effects recommends performing skull magnetic resonance and radionuclide bone scan in cases of suspected brain or skeletal metastases.     

Is diagnostic iodine-131 scanning useful after total thyroid ablation for differentiated thyroid cancer?

A diagnostic iodine-131 (131I) total body scan (TBS) is usually recommended 6 to 12 months after thyroid ablation for differentiated thyroid carcinoma. Its usefulness was evaluated in 256 consecutive patients treated and followed up at the Institut Gustave Roussy for papillary (n = 200), well differentiated (n = 27), or poorly differentiated (n = 29) follicular thyroid carcinomas. All patients underwent a near-total or total thyroidectomy and 131I ablation with 3.7 GBq (100 mCi). No TBS was performed before 131I ablation. The TBS performed after the administration of 131I to destroy the thyroid remnants showed uptake (<2%) limited to the thyroid bed. A diagnostic 131I-TBS was obtained after withdrawal of T4 treatment, with either 74 MBq (2 mCi; n = 82) or 185 MBq (5 mCi; n = 174), 6 to 12 months after initial treatment, with serum thyroglobulin (Tg) determination. No interference in the Tg assay was found in these 256 patients. Uptake in the thyroid bed was not detected (total ablation) in 236 patients, was visible but too low to be measured in 19 patients, and attained 1% in only 1 patient. No uptake was found outside the thyroid bed. The serum Tg level, once thyroid hormone treatment had been withdrawn, was below 1 ng/mL in 210 patients, ranged from 1-10 ng/mL in 31 patients, and was above 10 ng/mL in 15 patients. A 131I-TBS performed with 3.7 GBq in nine patients with a Tg level above 10 ng/mL, showed foci of uptake outside the thyroid bed in three patients; lung metastases were demonstrated by a CT scan in another patient, and palpable lymph node metastases were found in one patient. In conclusion, a diagnostic 131I-TBS with 74-185 MBq performed 1 yr after thyroid ablation demonstrated no abnormal uptake; it did not correlate with results of Tg determination and only confirmed the completeness of thyroid ablation. The serum Tg level obtained after withdrawal of T4 treatment permits the selection of patients with a Tg level exceeding 10 ng/mL, for scanning with 3.7 GBq (100 mCi).     

Lobectomy versus total thyroidectomy in children with post-Chernobyl thyroid cancer: a 15 year follow-up

In 1994, 21 Belarus children presenting papillary thyroid cancer (PTC) diagnosed after the Chernobyl disaster, and already submitted to subtotal surgery, underwent thyroid re-operation and post-operative radioiodine (131(I)) therapy. All were re-evaluated after a 15-year follow-up, to evaluate the results of partial versus total thyroidectomy. Nineteen out of 21 children (mean age 9.2?years) had previously undergone a lobectomy. All cases underwent re-operation in 1994. Histology revealed a PTC in the residual lobe in three cases, three had lymph node metastases. After surgery, 20 patients underwent 131(I) therapy. The post-131(I) whole body scan was negative in seven cases, showed neck node metastases in five, lung metastases in three, multiple associated metastases in six. The follow-up was performed with rhTSH-stimulated serum thyroglobulin (Tg) evaluation and ultrasonography. Twenty patients showed Tg <1?ng/ml and negative ultrasonography; the patient who refused 131(I) therapy showed a thyroid remnant and a Tg of 32?ng/ml. Chi-square analysis showed significantly higher prevalences of residual cancer in the neck or lung, lymph node metastases, and re-operations (before completion) in patients who had undergone lobectomy than in those who had undergone completion thyroidectomy and 131(I) therapy. The surgical complications after lobectomy were similar to those after completion thyroidectomy. A less-than-total thyroidectomy should not be indicated in patients with radiation-induced PTC, due to the high risk of residual cancer in the thyroid left in situ. The results of this study favor total thyroidectomy as the initial treatment for thyroid cancer in children exposed to fallout radiation.     

Are there disadvantages in administering 131I ablation therapy in patients with differentiated thyroid carcinoma without a preablative diagnostic 131I whole‐body scan?

OBJECTIVE: To evaluate the risk of performing inappropriate (131)I ablative therapies for thyroid carcinoma in patients lacking thyroid remnants or metastases, using a strategy of treatment without a preliminary iodine-131 diagnostic whole-body scan (DxWBS). DESIGN: Retrospective evaluation of post-therapy whole-body scans to assess the prevalence of thyroid remnants or metastases after total thyroidectomy. Comparison of (131)I uptake test and thyroglobulin (Tg) off levothyroxine (L-T4) performed before therapy with post-therapy scans, in order to evaluate the ability to predict inappropriate treatments. PATIENTS: A group of 875 consecutive patients with previous total or near-total thyroidectomy for differentiated thyroid carcinoma underwent (131)I ablative therapy without a preliminary (131)I-DxWBS. All patients were clinically free of distant metastases and macroscopic residual tumour. MEASUREMENTS: Whole-body scans were performed 2-5 days after the treatment as gold standard for thyroid remnants and metastases; 24-h (131)I quantitative neck uptake test and Tg off L-T4 were performed before (131)I therapy. RESULTS: The majority of patients (94%) were found to have thyroid remnants or metastases at post-therapy scans, in most cases (91.2%) with detectable Tg off L-T4 and positive 24-h neck uptake. 14 patients (1.6%) with tiny lymph-node metastases positive at post-therapy scans showed undetectable Tg off L-T4. In 30 patients (3.6%) faint positive post-therapy images for thyroid remnants have been classified as false-positive results on the basis of both negative 24-h neck uptake and undetectable Tg off L-T4. CONCLUSIONS: This study confirms that most patients have residual thyroid tissue after total thyroidectomy and that it seems reasonable to omit routine diagnostic whole-body scans before (131)I treatment with clinical, managerial and economic advantages.     

Does undetectable basal Tg measured with a highly sensitive assay in the absence of antibodies and combined with normal ultrasonography ensure the absence of disease in patients treated for thyroid carcinoma?

It has been proposed that, in patients treated for well-differentiated thyroid carcinoma, undetectable basal thyroglobulin (Tg) levels measured with a highly sensitive assay in the absence of anti-thyroglobulin antibodies (TgAb) and combined with negative neck ultrasonography (US) ensured the absence of disease. We report a series of five patients with well-differentiated (papillary) carcinoma submitted to total thyroidectomy with apparently complete tumor resection, followed by remnant ablation with (131)I (100-150 mCi), who had no distant metastases upon initial post-therapy whole-body scanning. When tumor recurrence or persistence was detected, these patients presented undetectable basal Tg (0.1 ng/mL) in the absence of TgAb, and US showed no anomalies. Two patients had lymph node metastases, one had mediastinal metastases, bone involvement was observed in one patient, and local recurrence in one. We conclude that further studies are needed to define in which patients undetectable basal Tg (negative TgAb) combined with negative US is sufficient, and no additional tests are required.     

Prediction of disease status by recombinant human TSH-stimulated serum Tg in the postsurgical follow-up of differentiated thyroid carcinoma.

Stimulation with recombinant human TSH (rhTSH) has been introduced in clinical practice as an effective alternative to thyroid hormone withdrawal for the diagnostic follow-up (Tg measurement and 131-iodine whole-body scan) of patients with differentiated thyroid cancer. The present study was specifically aimed to evaluate the utility of rhTSH-stimulated serum Tg measurements in patients with undetectable serum Tg values, on L-T(4) therapy, as the only test to differentiate patients with persistent disease from patients who are disease-free. We studied 72 consecutive patients with differentiated thyroid cancer, previously treated with near-total thyroidectomy and 131-I thyroid ablation. Admission criteria were: an undetectable (<1 ng/ml) serum Tg, on L-T(4) therapy, and negative anti-Tg antibodies. The study design consisted of a Tg-stimulation test after rhTSH, during L-T(4), followed by diagnostic WBS and serum Tg measurement off L-T(4). After rhTSH, serum Tg remained undetectable in 41 of 72 patients (56.9%). A negative rhTSH Tg test agreed with an undetectable hypo-Tg in 36 of 41 cases (87.8%), all without evidence of metastatic disease at hypo-WBS. In 5 of 41 cases (12.2%), hypo-Tg was detectable (1.1-7.8 ng/ml), in association with negative hypo-WBS or faint uptake in the thyroid bed. Serum Tg converted from undetectable to detectable after rhTSH in 31 of 72 patients (43.1%), with a peak Tg ranging between 1.2 and 23.0 ng/ml. Hypo-Tg was always detectable in these patients (100% concordance), and it was significantly higher than rhTSH-stimulated Tg (P < 0.0002). Hypo-WBS was positive in 23 of 31 patients (74.2%), showing thyroid residues in 12, cervical lymph nodes in 7, and lung metastases in 4 cases. In 8 of 31 cases, hypo-WBS was negative, despite detectable serum Tg. Thus, rhTSH-stimulated Tg was able to detect all cases of documented local or distant metastases. In conclusion, our data indicate that, in patients with undetectable basal levels of serum Tg, rhTSH-stimulated Tg represents an informative test to distinguish disease-free patients (not requiring WBS) from diseased patients (requiring further diagnostic and/or therapeutic procedures).