Follow-up of differentiated thyroid carcinoma

Thyroid cancer is the most common endocrine malignancy. More than 90% of primary thyroid cancers are differentiated papillary or follicular types. The treatment of differentiated thyroid carcinoma (DTC) consists of total thyroidectomy and radioactive iodine ablation therapy, followed by L-thyroxine therapy. The extent of initial surgery, the indication for radioiodine ablation therapy and the degree of TSH-suppression are all issues that are still being debated cancers are in relation to the risk of recurrence. Total thyroidectomy reduces the risk of recurrence and facilitates (131)I ablation of thyroid remnants. The aim of radioiodine ablation is to destroy any normal or neoplastic residuals of thyroid tissue. These procedures also improve the sensitivity of thyroglobulin (Tg) as a marker of disease, and increase the sensitivity of (131)I total body scan (TBS) for the detection of persistent or recurrent disease. The aim of TSH-suppressive therapy is to restore euthyroidism and to decrease serum TSH levels, in order to reduce the growth and progression of thyroid cancer. After initial treatment, the objectives of the follow-up of DTC is to maintain adequate thyroxine therapy and to detect persistent or recurrent disease through the combined use of neck ultrasound (US) and serum Tg and (131)I TBS after TSH stimulation. The follow-up protocol should be adapted to the risk of recurrence. Recent advances in the follow-up of DTC are related to the use of recombinant human TSH (rhTSH) in order to stimulate Tg production and the ultrasensitive methods for Tg measurement. Undetectable serum Tg during TSH suppressive therapy with L-T4 does not exclude persistent disease, therefore serum Tg should be measured after TSH stimulation. The results of rhTSH administration and L-thyroxine therapy withdrawal are equivalent in detecting recurrent thyroid cancer, but the use of rhTSH helps to avoid the onset of hypothyroid symptoms and the negative effects of acute hypothyroidism on cardiovascular, hepatic, renal and neurological function. In low-risk DTC patients serum Tg after TSH stimulation, together with ultrasound of the neck, should be used to monitor persistent disease, avoiding diagnostic TBS which has a poor sensitivity. These recommendations do not apply when Tg antibodies are present in the serum, in patients with persistent or recurrent disease or limited thyroid surgery. Low-risk patients may be considered to be in remission when undetectable Tg after TSH stimulation and negative US evaluation of the neck are present. On the contrary, detectable Tg after TSH stimulation is an indicator in selecting patients who are candidates for further diagnostic procedures.     

Recombinant human thyrotropin is helpful in the follow-up and 131I therapy of patients with thyroid cancer: a report of the results and benefits using recombinant human thyrotropin in clinical routine.

There is no doubt that the availability of recombinant human thyrotropin (rhTSH) is one of the milestones in the management of patients with differentiated thyroid cancer (DTC). It offers the opportunity to obtain representative serum thyroglobulin (Tg) levels and diagnostic whole-body scanning (Dx WBS) with 131I under adequate TSH elevation, while the patient continues to receive thyroid hormone. But rhTSH is also used with success in the treatment of local recurrences and distant metastases. In this retrospective analysis we were able to show that our excellent clinical experiences with the use of rhTSH (rare side effects and high compliance) could also be demonstrated by sufficiently elevated TSH levels and representative stimulated Tg measurements. Since April 2001 most of the patients with thyroid cancer in our hospital have undergone diagnostic examination (205 patients underwent 319 examinations) and 131I therapy (a total of 68 treatments) with rhTSH stimulation excluding the first radioiodine ablation of remnants after initial thyroidectomy. Our results show that under rhTSH stimulation 83.5% (diagnostic group) and 88% (therapy group) of our patients with DTC obtained a TSH level of greater than 80 mU/L after two injections of rhTSH (Thyrogen, Genzyme Corp., Cambridge, MA) 0.9 mg intramuscularly 24 hours and 48 hours before the administration of 131I. Only 2.3% (diagnostic group) and 0% (therapy group) demonstrated TSH levels less than 50 mU/L. Serum Tg levels under rhTSH-stimulated conditions showed that in 81.2% the serum Tg maximum was obtained on day 5. Because of the costs associated with periodically rhTSH-assisted Tg testing and based on the data of other studies we are now testing mainly on day 5 to identify residual tumor mass and to compare these Tg levels in the follow-up. Our experience demonstrates that the administration of rhTSH is a safe, effective, and-from an economic point of view- valuable tool in the management of patients with DTC.     

Thyroid-stimulating hormone-stimulated fused positron emission tomography/computed tomography in the evaluation of recurrence in 131I-negative papillary thyroid carcinoma.

Fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) detects recurrence of papillary thyroid carcinoma (PTC) in thyroidectomized patients with elevated thyroglobulin (Tg) levels and negative (131)I-whole-body scans. This paper describes the utility of thyroid-stimulating hormone (TSH)-stimulated fused FDG-PET/computed tomography (CT) scanning on our first 15 patients of this population. METHODS: Patients were prepared for PET/CT imaging with thyroid hormone withdrawal (n = 7) or recombinant human TSH (n = 8). All other imaging before the PET/CT did not demonstrate evidence of recurrence. RESULTS: PET/CT scans revealed active foci in 9 patients, 4 prepared with hypothyroidism, and 5 with exogenous TSH. Positive results were demonstrated even in those with relatively low stimulated-TSH Tg values (13 and 14 microg/L). Six patients with positive PET/CT scans were treated surgically, yielding malignant tissue for 5 of those patients. CONCLUSION: PET/CT scans performed under TSH stimulation are an effective method of detecting of recurrence of PTC and direct surgical interventions, even in those with persistently elevated but relatively low Tg levels.     

Pyramidal lobe decreases endogenous TSH stimulation without impact on radio-iodine therapy outcome in patients with differentiated thyroid cancer

Objectives

The aim of the study was to assess the frequency of pyramidal lobe (PL) detected in iodine-131 (I-131) scans of thyroid bed in patients after thyroidectomy for differentiated thyroid cancer (DTC) and to investigate influence of PL on endogenous thyrotropin (TSH) stimulation as well as on the effects of the radio-iodine ablation in one-year follow-up.

Patients and methods

This study was designed as a retrospective analysis of 302 radio-iodine neck scans of patients thyroidectomized due to DTC. The study population was selected from patients with PL detected in thyroid bed scintigraphy. Patients without PL were included to the control group. The study and the control groups did not differ in age, sex of patients, histological type and stage of the DTC.

Results

Pyramidal lobes were found in 30.5% of all patients. Patients in the study group underwent repeat surgery more often than controls without PL. Preablative TSH level in patients with PL was statistically lower than in the control group, in contrast to free thyroid hormones, which were higher in patients with PL. Preablative and postablative TSH-stimulated thyroglobulin (Tg) and antibodies against thyroglobulin (TgAbs) were measured in both groups, and comparison did not reveal differences. Moreover, for the per-patient analysis, sites of uptake in whole body scintigraphy performed 1 year after radio-iodine remnant ablation (RRA) did not differ between the study and the control groups.

Conclusion

Pyramidal lobe decreases endogenous TSH stimulation without impact on radio-iodine therapy outcome in patients with DTC.     

The diagnostic use of the rhTSH/thyroglobulin test in differentiated thyroid cancer patients with persistent disease and low thyroglobulin levels

BACKGROUND: Serum thyroglobulin (Tg) measurement after TSH stimulation, by either thyroid hormone withdrawal or recombinant human TSH (rhTSH) administration, is the most sensitive method for early detection of patients with persistent or recurrent differentiated thyroid cancer (DTC) after total thyroidectomy and 131I ablation. The use of rhTSH is now increasing because it avoids thyroid hormone suppressive therapy (THST) withdrawal and the consequent symptoms of severe hypothyroidism. Current guidelines suggest measurement of serum Tg 4 days after starting a 2-day course of rhTSH injections, and assumes that Tg reaches maximum serum levels at that time. OBJECTIVE: The present study was carried out to evaluate the accuracy of rhTSH/thyroglobulin test in DTC patients with persistent disease and low thyroglobulin levels. PATIENTS AND MEASUREMENTS: A series of 13 DTC patients was selected because they had proven persistent disease associated with low Tg levels (< 2.0 micro g/l) under l-thyroxine treatment. In all of them, serum Tg was > 5.0 micro g/l at the last THST withdrawal. We measured serum Tg and TSH levels on days 0.5, 1, 1.5, 2, 4, 7, 10 and 15 after the first of a 2-day course of intramuscular rhTSH injections. RESULTS: Serum Tg values were variable in terms of both peak and time-course. Detectable serum Tg levels were recorded on day 4 in all patients. However, among these 13 patients, the peak Tg value was reached earlier than day 4 in three patients and later in two others. In one patient, Tg level at day 2 was higher (3.0 micro g/l) than at day 4 (1.8 micro g/l). In six of the 13 patients studied we compared Tg values after rhTSH to those subsequently obtained after THST withdrawal: in five of them Tg values were two to three times higher after the latter stimulation. Serum Tg value variability after rhTSH was partially accounted for by variability of serum TSH levels, which were inversely related to patient body surface. CONCLUSIONS: In DTC patients with persistent disease and low Tg levels, optimization of the diagnostic use of Tg measurement after rhTSH may require rhTSH dose adjustment to the patient body surface area and repeated blood sampling, in order to improve diagnostic accuracy. In these patients not even a TSH-stimulated serum Tg cut-off of 2.0 micro g/l on day 4 provides 100% accuracy, whereas a cut-off of 1.0 micro g/l seems more appropriate. Therefore, in this subset of patients, if any detectable Tg level >or= 1.0 micro g/l is found after rhTSH, re-evaluation after THST should be advised.     

A new functional parameter measured at the time of ablation that can be used to predict differentiated thyroid cancer recurrence during follow-up

BACKGROUND: This study addresses the questions whether patients with a high risk for recurrent thyroid cancer can be identified at initial stage, i.e. at the time of ablation. METHODS: We evaluated tumor recurrence in consecutive patients treated for differentiated thyroid cancer (DTC). Prognostic factors were statistically analyzed. We defined prognostic parameters based on thyroglobulin (Tg) levels, 24-h I-131 uptake rates and TSH values: (a) Tg/TSH, (b) Tg/24-h I-131 uptake value, and (c) Tg/(TSHx24-h I-131 uptake). RESULTS: We included 190 patients (50 male, 140 female; mean age 47 years) with DTC for analysis, 146 without distant metastases and 44 with M1 tumor stage at initial presentation. The mean period of follow-up was 10.4 years (s.d. +/- 3.7 years). In 18 out of the 146 DTC patients with M0 disease (12.4%), tumor recurrence was found during follow-up. Although tumor stage, age, and standard biochemical values significantly differ between patients with and without recurrent disease or between patients with M0 and M1 tumor stage, the newly defined parameter Tg/(TSHx24-h I-131 uptake) was the best independent significant prognostic parameter in the assessment whether patients will develop a tumor recurrence during follow-up or not. CONCLUSION: High Tg/(TSHx24-h I-131 uptake) ratios justify an adjustment of the I-131 activity for ablation therapy. To assess the optimal cut-off value for a dose adjustment, however, further studies are required in more patients, but the initial results are encouraging with respect to improving outcome in DTC patients.     

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.     

Postradioiodine treatment whole-body scan in the era of 18-fluorodeoxyglucose positron emission tomography for differentiated thyroid carcinoma with elevated serum thyroglobulin levels

Background: Patients with differentiated thyroid cancer (DTC) who have a suspicious recurrent or persistent disease based on an elevated serum thyroglobulin (Tg) or Tg antibodies (TgAb) are usually referred for empiric radioiodine ((131)I) administration to localize and treat the disease. The aim of this retrospective monocentric study was to assess the sensitivity of postempiric (131)I whole-body scan (WBS) compared to 18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in such patients who had an initial normal postablation WBS. Methods: Among 47 consecutive patients with DTC who had a normal postablation WBS and were referred for empiric (131)I administration, 34 patients (12M, 22F; mean age 53 years) underwent FDG PET/CT and form the basis of this report: 23 patients had persistently elevated serum Tg levels, 10 had elevated Tg levels observed during follow-up after they initially became under 1?ng/mL, and 1 had appearance of TgAb during follow-up. Postempiric (131)I WBS and FDG PET/CT were analyzed by independent readers. Results: A total of 75 lesions were found in 23 patients, distributed in 36 organs. Lesions were located in the neck (30), lungs (28), mediastinum (11), and bones (6). The sensitivities for the detection of individual lesions and for the diagnosis of metastatic organs were 88% and 97% for PET/CT and 16% and 22% for WBS, respectively (p<0.01). PET/CT was abnormal in 22 patients, among which 5 also had an abnormal postempiric (131)I WBS. There was only one patient with an abnormal postempiric (131)I WBS and a normal FDG PET/CT. This patient underwent two further (131)I administrations, with the last WBS being normal and the last stimulated Tg level being undetectable. Other patients were either treated with surgery, or classified as radioactive iodine refractory and treated with levothyroxine suppressive therapy or tyrosine kinase inhibitors. Conclusion: In patients with suspicious recurrence based on the Tg level after a normal postablation WBS, FDG PET/CT is the preferred scintigraphic method to localize disease rather than postempiric (131)I WBS. Empiric (131)I administration may be used only in patients who do not have a significant FDG uptake.     

Recombinant human TSH use in differentiated thyroid cancer

Traditionally, the immediate treatment of patients with differentiated thyroid carcinoma (DTC) after total thyroidectomy (TT) is thyroid remnant ablation (TRA) with 131I, during hypothyroidism. Late follow-up of DCT includes suppressive doses of T4, serial measurements of thyroglobulin (Tg), whole body scan (WBS) with 131I and cervical ultrasound (US). In the last years, TRA with the aid of recombinant human TSH (rhTSH) has shown not only to avoid symptoms of hypothyroidism and a lower quality of life, but also to have the same efficacy as TRA during endogenous TSH elevation. Stimulated Tg with endogenous or exogenous TSH, 9 to 12 months after the initial treatment of DTC, associated with cervical US, is able to identify low-risk patients virtually cured of their disease, in whom TSH suppression does not need to be so strict, avoiding the heart and bone complications of prolonged exogenous thyrotoxicosis. Finally, in spite of the absence of randomized studies designed to evaluate the role of rhTSH in metastatic DTC disease, results of the combined treatment of rhTSH and 131I show a clinical benefit in the majority of treated patients.     

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 consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma

Recent studies have provided new information regarding the optimal surveillance protocols for low-risk patients with differentiated thyroid cancer (DTC). This article summarizes the main issues brought out in a consensus conference of thyroid cancer specialists who analyzed and discussed this new data. There is growing recognition of the value of serum thyroglobulin (Tg) as part of routine surveillance. An undetectable serum Tg measured during thyroid hormone suppression of TSH (THST) is often misleading. Eight studies show that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels usually below 1 micro g/liter during THST had, in response to recombinant human TSH (rhTSH), a rise in serum Tg to more than 2 micro g/liter. When this happened, 36% of the patients were found to have metastases (36% at distant sites) that were identified in 91% by an rhTSH-stimulated Tg above 2 micro g/liter. Diagnostic whole body scanning, after either rhTSH or thyroid hormone withdrawal, identified only 19% of the cases of metastases. Ten studies comprising 1599 patients demonstrate that a TSH-stimulated Tg test using a Tg cutoff of 2 micro g/liter (either after thyroid hormone withdrawal or 72 h after rhTSH) is sufficiently sensitive to be used as the principal test in the follow-up management of low-risk patients with DTC and that the routine use of diagnostic whole body scanning in follow-up should be discouraged. On the basis of the foregoing, we propose a surveillance guideline using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and (131)I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 micro g/liter during THST.     

Evaluation of the diagnostic value of the first thyroglobulin determination in detecting metastases after differentiated thyroid carcinoma surgery.

AIM: Evaluation of the diagnostic value of the first thyroglobulin (Tg) level measurement, performed after thyroidectomy, before another treatment, as an early marker of either metastases or local recurrence of differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: Data of 178 patients (160 women, 18 men, 14-79 years) with DTC and without known interference in Tg assay were evaluated retrospectively. In all patients, neck radioiodine uptake (Tup (24)), thyroid remnants volume (V), TSH and Tg were measured. The Tg/V and Tg/Tup (24) ratios were calculated to correct Tg concentration with regard to V and Tup (24). Six months after initial evaluation and routine therapy all patients underwent control examinations under endogenous TSH stimulation. RESULTS: During follow-up metastases or local recurrence were found in 32 patients. The groups of patients with no diagnosed metastases (M0) and with detected metastases (M1), did not differ with regard to V, serum TSH or Tup (24); difference between the two groups was found in Tg concentration (4.3 ng/ml VS 97.4 ng/ml; p=0.000001). The ratios of Tg/Tup (24) (p=0.000000) and Tg/V (p=0.004) were lower in the group M0 than M1. The areas under receiver operating characteristic curves (ROC) for Tg concentrations, Tg/Tup (24), and Tg/V ratios were 0.773 (95% CI - 0.655-0.892), 0.817 (0.709-0.925) and 0.712 (0.541-0.884), respectively. CONCLUSIONS: Both the absolute Tg concentration and Tg/V and Tg/Tup (24) ratios, determined after thyroidectomy but before another treatment in patients with metastases of DTC, diagnosed within 6 months after (131)I administration, are higher than those in patients without such metastases. This indicates that the mentioned parameters may be applied as early markers of either local recurrence or metastases of DTC. The highest discriminative value demonstrates Tg/Tup (24) ratio, Tg concentration has a lower value and Tg/V ratio has the lowest one.     

Clinical value of different responses of serum thyroglobulin to recombinant human thyrotropin in the follow-up of patients with differentiated thyroid carcinoma.

In the present study, we examined the clinical value of a differential response of thyroglobulin (Tg) concentration after recombinant human thyrotropin (rhTSH) stimulation (rhTSH Tg testing) and its correlation with (131)I uptake and whole body scanning (rhTSH-WBS) in 104 patients who had previously undergone near total thyroidectomy and (131)I ablation for differentiated thyroid carcinoma (DTC). RhTSH Tg testing was considered negative for rhTSH-Tg < 0.9 ng/mL, low positive for rhTSH-Tg of 1-5 ng/mL and high positive for rhTSHTg > 5 ng/mL. RhTSH Tg testing was negative in 70 patients, one of whom had a lymph-node metastasis, but no (131)I uptake. Seven patients had low positive rhTSH Tg testing and no (131)I uptake, but two of these patients had cervical lymph-node metastases. Twenty-seven patients had high positive rhTSH Tg testing and (131)I uptake was detected in lung, bone, or mediastinum in 11. Imaging techniques (CT, MRI, FDG-PET) documented metastatic disease in 22. In conclusion, our results suggest that any rise in rhTSH-Tg, even at low level, should raise the suspicion of persistent or recurrent DTC. Patients with rhTSH-Tg at high level should be carefully evaluated, since DTC persistence is highly probable. TSH-WBS provides little adjunctive information.     

Management of papillary and follicular (differentiated) thyroid cancer: new paradigms using recombinant human thyrotropin

The incidence of differentiated thyroid cancer (DTC) has increased in many places around the world over the past three decades, yet this has been associated with a significant decrease in DTC mortality rates in some countries. While the best 10-year DTC survival rates are about 90%, long-term relapse rates remain high, in the order of 20-40%, depending upon the patient's age and tumor stage at the time of initial treatment. About 80% of patients appear to be rendered disease-free by initial treatment, but the others have persistent tumor, sometimes found decades later. Optimal treatment for tumors that are likely to relapse or cause death is total thyroidectomy and ablation by iodine-131 ((131)I), followed by long-term levothyroxine suppression of thyrotropin (TSH). On the basis of regression modeling of 1510 patients without distant metastases at the time of initial treatment and including surgical and (131)I treatment, the likelihood of death from DTC is increased by several factors, including age >45 years, tumor size >1.0 cm, local tumor invasion or regional lymph-node metastases, follicular histology, and delay of treatment >12 months. Cancer mortality is favorably and independently affected by female sex, total or near-total thyroidectomy, (131)I treatment and levothyroxine suppression of TSH. Treatments with (131)I to ablate thyroid remnants and residual disease are independent prognostic variables favorably influencing distant tumor relapse and cancer death rates. Delay in treatment of persistent disease has a profound impact on outcome. Optimal long-term follow-up using serum thyroglobulin (Tg) measurements and diagnostic whole-body scans (DxWBS) require high concentrations of TSH, which until recently were possible to achieve only by withdrawing levothyroxine treatment, producing symptomatic hypothyroidism. New paradigms, however, provide alternative pathways to prepare patients for (131)I treatment and to optimize follow-up. Patients with undetectable or low Tg concentrations and persistent occult disease can now be identified within the first year after initial treatment by recombinant human (rh)TSH-stimulated serum Tg concentrations greater than 2 microg/l, without performing DxWBS. These new follow-up paradigms promptly identify patients with lung metastases that are not evident on routine imaging, but which respond to (131)I treatment. In addition, rhTSH can be given to prepare patients for (131)I remnant ablation or (131)I treatment for metastases, especially those who are unable to withstand hypothyroidism because of concurrent illness or advanced age, or whose hypothyroid TSH fails to increase.     

PET imaging in differentiated thyroid cancer: where does it fit and how do we use it?

Positron emission tomography (PET) is a rapidly evolving imaging modality that has gained widespread acceptance in oncology, with several radionuclides applicable to thyroid cancer. Thyroid cancer patients have been studied most commonly using 18F-Fluorodeoxyglucose (FDG)-PET, with perhaps the greatest utility being the potential localization of tumor in differentiated thyroid cancer (DTC) patients who are radioiodine whole body scan (WBS) negative and thyroglobulin (Tg) positive. Also of value is the identification of patients unlikely to benefit from additional 131I therapy and identification of patients at highest risk of disease-specific mortality, which may prompt more aggressive therapy or enrollment in clinical trials. Emerging data suggest that PET/CT fusion studies provide increased accuracy and modify the treatment plan in a significant number of DTC cases when compared to PET images alone. However, studies documenting improvements in survival and tumor recurrence attributable to FDG-PET imaging in thyroid cancer patients are lacking. Specific case examples of thyroid cancer patients who appear to have benefited from FDG-PET imaging do exist, while less data are available in the setting of anaplastic or medullary thyroid carcinoma. This article reviews the utility and limitations of FDG-PET in DTC management, and offers practical recommendations.     

Use of recombinant human thyrotropin before radioiodine therapy in patients with advanced differentiated thyroid carcinoma

The use of 131I for radioablative therapy in patients with differentiated thyroid cancer (DTC) requires a sufficient serum concentration of TSH for efficient thyroid tissue uptake of iodine. We describe the use of recombinant human TSH (rhTSH) in conjunction with ablative radioiodine therapy (RIT) in 11 patients (16 total treatments) with advanced and/or recurrent DTC (5 papillary, 6 follicular) for whom withdrawal of thyroid hormone suppression therapy (THST), the standard method to increase serum TSH, was not an option. Indications for rhTSH use in these patients included inability to tolerate withdrawal of thyroid hormones due to very poor physical condition or inability to achieve sufficient serum TSH levels after THST withdrawal. Ten patients had undergone thyroidectomy, and most (9 of 11) had received prior ablative RIT after THST withdrawal. Baseline thyroglobulin levels ranged from 25 to nearly 30,000 ng/mL, reflecting the heterogeneity of the patient population. In 7 cases (5 patients), posttherapy thyroglobulin levels assessed at a mean of 4.3 months (range, 2-10 months) after 131I therapy were decreased by at least 30% compared to pretherapy levels. In follow-up visits, an additional 3 patients showed marked clinical improvement or decreased or stabilized tumor burden in whole body scans compared to pretherapy scans. Three patients died of progressive disease within 2 months of therapy before follow-up assessments occurred. No adverse events were reported among the 8 surviving patients. The results suggest that rhTSH offers a promising alternative to THST withdrawal to allow ablative RIT after effective TSH stimulation in patients with advanced recurrent DTC who would not otherwise be able to receive this treatment. This therapeutic indication extends the clinical potential of this new agent, already demonstrated to be effective for use with 131I for diagnostic purposes.     

Thyroglobulin measurement before rhTSH-aided 131I ablation in detecting metastases from differentiated thyroid carcinoma

Aim Thyroidectomy followed by administration of large activities of 131‐iodine (¹³¹I) is the treatment of choice for differentiated thyroid carcinoma (DTC). The serum thyroglobulin (Tg) measurement during hypothyroidism (offT4‐Tg), just before radioiodine thyroid ablation, has proved to be effective for predicting persistent/recurrent disease. However, the Tg measurement cannot be used as a corresponding value for pre‐ablative offT4‐Tg when recombinant human TSH (rhTSH) is used as stimulus before treatment. The present study was undertaken to evaluate if post‐thyroidectomy Tg values, measured before rhTSH‐stimulated radioiodine ablation is of prognostic value in patients affected by DTC. Methods We enrolled 126 patients with DTC submitted to total thyroidectomy. T4 treatment was started just after surgery to suppress TSH levels and Tg levels (onT4‐Tg) were measured just before rhTSH‐aided thyroid ablation by ¹³¹I (3700 MBq). Neck radioiodine uptake (RAIU) was measured just before ablation and a post‐treatment whole body scan (PT‐WBS) was performed. Results A significant relationship was found between thyroid remnants’ RAIU and onT4‐Tg levels (P < 0·001). The 1·10 ng/ml onT4‐Tg threshold selected by ROC curve analysis identifies patients with positive PT‐WBS with 83·3% sensitivity, 65·7% specificity, 44·5% positive predictive value (PPV) and 93·6% negative predictive value (NPV). The 0·65 ng/ml cut‐off level recognizes metastatic patients with 82·9% sensitivity, 55·2% specificity, 43·3% PPV and 97·8% NPV when compared with 12 months restaging results. Among 63 patients with initially undetectable onT4‐Tg (i.e. ≤ 0·2 ng/ml) none had positive PT‐WBS nor DTC relapse at 12‐month restaging (NPV 100%). Conclusions Based on our data we conclude that pre‐ablative onT4‐Tg is a prognostic marker and should be used instead of pre‐ablative TSH‐stimulated Tg measurement when rhTSH‐aided radioiodine ablation is done.     

Clinical value of different responses of serum thyroglobulin to recombinant human thyrotropin in the follow-up of patients with differentiated thyroid carcinoma.

In the present study we examined the clinical value of a differential response of thyroglobulin (Tg) concentration after recombinant human thyrotropin (rhTSH) stimulation (rhTSH Tg testing) and its correlation with (131)I uptake and whole-body scanning (rhTSH-WBS) in 104 patients who had previously undergone near-total thyroidectomy and (131)I ablation for differentiated thyroid carcinoma (DTC). rhTSH Tg testing was considered negative for rhTSH-Tg less than 0.9 ng/mL, low positive for rhTSH-Tg of 1-5 ng/mL and high positive for rhTSHTg greater than 5 ng/mL. rhTSH Tg testing was negative in 70 patients, 1 of whom had a lymph-node metastasis, but no (131)I uptake. Seven patients had low positive rhTSH Tg testing and no (131)I uptake, but 2 of these patients had cervical lymph node metastases. Twenty-seven patients had high positive rhTSH Tg testing and (131)I uptake was detected in lung, bone, or mediastinum in 11. Imaging techniques (computed tomography [CT], magnetic resonance imaging [MRI], fluorine-18 2-fluoro-2-deoxy-D-glucose-positron emission tomography [FDGPET]) documented metastatic disease in 22. In conclusion, our results suggest that any rise in rhTSH-Tg, even at low level, should raise the suspicion of persistent or recurrent DTC. Patients with rhTSH-Tg at high level should be carefully evaluated, because DTC persistence is highly probable. TSH-WBS provides little adjunctive information.     

Serum thyroglobulin measurements in thyroid cancer: evaluation of''false'' positive results

OBJECTIVE: Serum thyroglobulin (Tg) should be undetectable in patients successfully treated for thyroid carcinoma. We have examined the course of disease in 19 patients with raised serum Tg (greater than 5 micrograms/l) on initial measurement but no other evidence of residual, recurrent or metastatic cancer. DESIGN: 416 patients from several centres were followed for periods between 1 and 9 years. Serum Tg was measured at 6-12-month intervals. PATIENTS: All had differentiated thyroid cancer, treated by partial or total thyroidectomy and/or 131I ablation, and were receiving suppressive thyroxine therapy. MEASUREMENT: Serum Tg was measured and clinical, X-ray and scan assessment made of presence or absence of residual, recurrent or metastatic cancer. RESULTS: Of 416 patients initially assessed, only 19 had Tg greater than 5 micrograms/l but no clinical or radiological evidence of disease. At follow-up, 11 patients had developed overt signs of malignancy; one had been treated with 131I with a subsequent fall in Tg; five had Tg between 5 and 20 micrograms/l with incompletely suppressed TSH levels; two subjects remained with slightly elevated Tg and undetectable TSH. CONCLUSION: Patients with elevated Tg require careful follow-up even in the apparent absence of disease. Moderate elevation of serum Tg may be due to inadequate thyroxine suppression therapy, assessed by detectable TSH values measured in a sensitive assay.