Outcomes of patients with differentiated thyroid carcinoma following initial therapy.

This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid cancer patients. The study setting was a prospectively followed multi-institutional registry. Patients were stratified as low risk (stages I and II) or high risk (stages III and IV). Treatments employed included near-total thyroidectomy, administration of radioactive iodine, and thyroid hormone suppression therapy. Outcome measures were overall survival, disease-specific survival, and disease-free survival. Near-total thyroidectomy, radioactive iodine, and aggressive thyroid hormone suppression therapy were each independently associated with longer overall survival in high-risk patients. Near-total thyroidectomy followed by radioactive iodine therapy, and moderate thyroid hormone suppression therapy, both predicted improved overall survival in stage II patients. No treatment modality, including lack of radioactive iodine, was associated with altered survival in stage I patients. Based on our overall survival data, we confirm that near-total thyroidectomy is indicated in high-risk patients. We also conclude that radioactive iodine therapy is beneficial for stage II, III, and IV patients. Importantly, we show for the first time that superior outcomes are associated with aggressive thyroid hormone suppression therapy in high-risk patients, but are achieved with modest suppression in stage II patients. We were unable to show any impact, positive or negative, of specific therapies in stage I patients.     

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.     

Long-term clinical outcome of differentiated thyroid cancer patients with undetectable stimulated thyroglobulin level one year after initial treatment

Background: Measurement of the serum thyroglobulin (Tg) level with TSH stimulation (sTg) is the cornerstone of monitoring for the recurrence or persistence of differentiated thyroid cancer (DTC) in patients who have undergone surgery and remnant ablation. However, there have been several reports that an undetectable sTg could not predict the absence of future recurrence. The aim of this study was to evaluate the long-term outcome of DTC patients who achieved biochemical remission (BR, defined as sTg<1?ng/mL) after initial treatment, and to determine the role of repeated sTg measurement in detecting a clinical recurrence. Methods: This is a retrospective observational cohort study in a tertiary referral hospital. There were 1010 DTC patients who achieved BR at 12 months after the initial treatment (surgery and ablation), and they were eligible for analysis. Among them, 787 patients had values of repeated sTg. Results: Thirteen out of 1010 (1.3%) patients had clinical recurrences during a median 84 months of follow-up. All of the clinical recurrences were limited to the cervical lymph nodes without clinical evidence of distant metastasis. Among 787 patients with available repeated sTg, 10 had clinical recurrences (5 out of 750 patients with repeated sTg<1?ng/mL and 5 out of 37 patients with repeated sTg≥1?ng/mL). Patients with repeated sTg ≥1?ng/mL had a much greater chance of disease recurrence (log-rank statistics=43.7, df=1, p<0.001). Conclusions: About 1% of DTC patients who had sTg<1?ng/mL 12 months after initial treatment had a clinical recurrence. All of clinical recurrences were loco-regional recurrences. Although repeated sTg measurement can be helpful to predict recurrence, we could not recommend it for surveillance in patients with BR due to its very low yield.     

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.     

Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective

OBJECTIVE: Because differentiated (follicular and papillary) thyroid cancer (DTC) may recur years after initial treatment, the follow-up of patients with DTC is long term. However, this population has changed, with more individuals being discovered at an earlier stage of the disease, so that previous follow-up protocols based mostly on data from high-risk patients no longer apply. We sought to develop an improved protocol for the follow-up of low-risk patients with DTC based on the findings of recent studies. METHODS: We analysed recent literature on the follow-up of DTC. RESULTS: Recent large studies have produced three important findings: (i) in patients with low-risk DTC with no evidence of disease up to the 6- to 12-month follow-up, diagnostic whole-body scan adds no information when serum thyroglobulin (Tg) is undetectable and interference from anti-Tg antibodies is absent; (ii) use of recombinant human thyroid-stimulating hormone to aid Tg measurement is effective and provides greater safety, quality-of-life and work productivity than does levothyroxine withdrawal with its attendant hypothyroidism; and (iii) ultrasonography performed by an experienced operator is the most sensitive means of detecting neck recurrences of DTC. CONCLUSIONS: We present a revised follow-up protocol for low-risk patients taking into account the above findings. This protocol should help clinicians enter a new era of monitoring characterized by greater safety, simplicity, convenience and cost savings.     

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.     

低危已分化甲状腺癌患者在给予重组人促甲状腺激素或停用甲状腺激素后用放射性碘清除甲状腺残余组织的疗效观察

在已分化甲状腺卜皮癌(DTC)的治疗中,术后甲状腺残余组织的清除是一关键因素.非随机化试验的结果显示,高危患者加用放射性碘治疗后,肿瘤复发率降低.     

Approach to the patient with a positive serum thyroglobulin and a negative radioiodine scan after initial therapy for differentiated thyroid cancer

The 10-yr survival of differentiated thyroid cancer is about 76-93%, and at least 10% of patients manifest tumor persistence or recurrence, depending on their disease stage, after initial therapy, which typically includes total thyroidectomy and (131)I ablation. Previously the realization of their residual/recurrent cancer often presented simultaneously with the additional surprise that they lacked pathological uptake on their diagnostic whole-body radioiodine image despite their elevated stimulated serum thyroglobulin (Tg) level, a scenario referred to as the scan-negative, Tg-positive patient. Now that serum Tg and neck ultrasonography have supplanted the diagnostic whole-body scan because of its inferior sensitivity, patients are often recognized to harbor residual disease without radioiodine imaging, and a new challenging scenario has emerged: the ultrasonography-negative, Tg-positive patient. Similarities and differences of these two patient populations aside, these Tg-positive patients are frequently encountered, and some are considered for additional (131)I therapy, although now typically after negative anatomic +/- (18)F-fluorodeoxyglucose positron emission tomography imaging or in the setting of known or suspected distant metastases already localized by anatomic imaging. Thus, the scan-negative, Tg-positive patient of today differs from those of the past, but the term still has relevance to current practice. The optimal evaluation and treatment of these patients remain controversial, partly because many of these patients will not die from thyroid cancer, and there are no randomized trials to demonstrate that intervention could have prevented the deaths that do occur. Here a case is presented that adds the complexity of advanced age, and one approach to these challenging patients is offered.     

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.     

Effects of L-thyroxine suppressive therapy on cardiac mass in patients with differentiated thyroid cancer

Patients with differentiated thyroid carcinoma (DTC) receive a life time l-thyroxine therapy in suppressive doses and may exhibit signs of cardiac hypertrophy. The aim of the study was to analyze the left ventricle mass parameters by echocardiography in patients treated with suppressive doses of thyroxine and to relate them to the possible occurrence of cardiac arrhythmias. Ninety four patients aged 19-70 years treated chronically with l-thyroxine were randomly chosen from the population of patients with DTC without concomitant diseases of circulatory system. They were divided into two subgroups according to the length of thyroxine therapy (< 60 months and > or = 60 months). Control group consisted of 41 healthy volunteers, aged 22-73 years. Heart muscle dimensions were measured by echocardiography. Left ventricle mass (LVM) and mass index (LVMI) was calculated. Electrocardiography according to Holter was carried out in 57 patients. The results of echocardiography in the whole group of patients did not differ significantly from the control group, although a tendency towards higher dimensions of the left ventricle was observed. No correlation of hormonal parameters, or thyroxine dose, with LVM or results of Holters ecg was noted. When patients were subdivided into two groups, according to the duration of therapy, significantly higher values of LVM (215 +/- 64 g versus 186 +/- 55; p < 0.05) and LVMI (114 +/- 31 g/m versus 102 +/- 23 g/m; p < 0.05) were observed in patients treated > or = 60 months in comparison to the control group. When results of Holter's ecg in patients with increased LVMI were analyzed, cardiac rhythm disturbances were stated in 50% of them, but most were of minor clinical relevance. Suppressive l-thyroxine therapy does not induce significant left heart hypertrophy during the first 5 years of treatment. Patients treated through a longer period of time should be controlled by echocardiography because of the increasing risk of the left ventricle hypertrophy and arrhythmia.     

Even without additional therapy, serum thyroglobulin concentrations often decline for years after total thyroidectomy and radioactive remnant ablation in patients with differentiated thyroid cancer

Background: Current management guidelines suggest that 6-12 months after total thyroidectomy and radioactive iodine remnant ablation (RAI-RA), patients with differentiated thyroid cancer should be re-evaluated with serum thyroglobulin (Tg) and neck ultrasonography to assess the efficacy of initial treatment and to guide subsequent management. However, if serum Tg levels can continue to decline for many years after RAI-RA, then an early assessment of response to therapy could lead to excessive evaluations and treatments in patients with low-level Tg values that are likely to resolve over time without additional therapies. Methods: Serum Tg concentrations in patients with differentiated thyroid cancer, who had been thyroidectomized (Tx), received RAI-RA, and who were receiving levothyroxine to suppress serum thyrotropin (suppressed serum Tg), were retrospectively analyzed. The study included 299 patients, 69% of whom were women with an overall median age of 46 years and who had a median follow-up of 7 years. The study was limited to patients who received no additional treatments beyond total Tx, RAI-RA, and levothyroxine therapy to suppress thyrotropin. The primary endpoints were the time required to achieve the lowest Tg (nadir Tg) and the time required to achieve a suppressed serum Tg<1?ng/mL. Results: The nadir -suppressed serum Tg was achieved by 6 months in 58% of the patients and by 12 months in 75% of the patients. The remaining 25% of patients required 18 months or longer to reach the nadir Tg. However, in the subgroup of patients that eventually reached a nadir suppressed serum Tg<1?ng/mL (n=223 patients), this goal was achieved by 6 months in 81%, by no more than 12 months in 91%, and by no more than 18 months in 94%. In patients with a 6-month suppressed serum Tg of 1-5?ng/mL, 54% eventually developed a suppressed serum Tg of <1?ng/mL without additional therapy. Conclusions: In patients selected for continued observation, serum Tg levels often continue to decline for several years after total Tx and RAI-RA. While a 6-12-month assessment of the response to initial therapy is useful in patient management, strong consideration should be given to continued observation without additional therapy in patients with well-differentiated thyroid cancer who have 6-month suppressed serum Tg values of 1-5?ng/mL without a structurally identifiable disease.     

Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer

Objective To describe the risk of structural disease recurrence in a cohort of patients with differentiated thyroid cancer selected for treatment with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation (RRA). Design Retrospective review. Patients A total of 289 patients were selected for either thyroid lobectomy (n = 72) or total thyroidectomy (n = 217) without RRA and followed with modern disease detection tools in a tertiary referral centre. Most patients had papillary thyroid cancer (89%) without clinically evident lymph node metastases (91%). However, 55% (156/289) of patients had primary tumours that were >1 cm and 10% (28/289) had minor extrathyroidal extension. Measurements The primary endpoint was detection of recurrent/persistent structural disease. Results After a 5‐year median follow‐up, structural disease recurrence was detected in 2·3% (5/217) of patients treated with total thyroidectomy without RRA, and in 4·2% (3/72) of patients treated with thyroid lobectomy. Size of the primary tumour, the presence of cervical lymph node metastases and American Thyroid Association risk category were all statistically significant predictors of recurrence. Changes in serum thyroglobulin were not helpful in identifying the presence of persistent/recurrent structural disease. Importantly, 88% (7/8) of the patients that had recurrent disease were rendered clinically disease free with additional therapies. Conclusions Initial risk stratification is able to identify a cohort of patients with differentiated thyroid cancer with a very low risk of structural disease recurrence following treatment with either thyroid lobectomy or total thyroidectomy without RRA. Our data strongly support a selective approach to the initial management of thyroid cancer.     

Recurrent differentiated thyroid cancer without elevation of serum thyroglobulin.

Thyroglobulin (Tg) is a reliable tumor marker in patients with well-differentiated thyroid cancer (WDTC). We identified 11 patients who had undetectable serum Tg and no thyroglobulin antibody (TgAb) in the presence of clinical disease. Three had residual disease after ablation of the thyroid by surgery plus radioiodine and 8 relapsed after a disease-free interval. Histologic review confirmed that 7 of the tumors were papillary carcinomas and 4 were follicular carcinomas. Immunohistochemical staining for Tg was positive in 6 of 7 papillary and in 3 of 4 follicular carcinomas. There were no identifiable histologic or clinical features that could be used to predict further patients who may relapse with absence of this serum marker. Negative serum Tg did not appear to be an adverse prognostic feature. During follow-up, measurement of Tg and TgAb should be supplemented by radioiodine scanning and radiological imaging in patients in whom recurrence is likely or suspected.     

Early detection of isolated left ventricular diastolic dysfunction in high-risk differentiated thyroid carcinoma patients on TSH-suppressive therapy

Objective L‐Thyroxine‐suppressive therapy benefits high‐risk differentiated thyroid cancer patients by decreasing recurrence rates and cancer‐related mortality. However, fully suppressed serum thyroid‐stimulating hormone (TSH) implies a state of subclinical hyperthyroidism (SCH) with associated adverse cardiac effects. Because left ventricular (LV) diastolic dysfunction may be the first manifestation of more severe LV failure, and to balance the risks from thyroid cancer recurrence with risks of cardiac failure, the purpose of this study was to analyse new parameters of LV function in asymptomatic patients with exogenous SCH. Design Case–control study with 24 patients on TSH‐suppressive therapy of short duration (≤4 years) after thyroid ablative therapy for differentiated thyroid carcinoma and 20 age‐ and sex‐matched subjects. Measurements LV function [LV global strain and strain rate (SR) curves] was assessed by speckle tracking imaging echocardiography in each subject. Results Patients and controls do not differ in body mass index, systolic blood pressure and heart rate. No significant differences were observed in LV morphology (LV mass and relative wall thickness), cardiac output and parameters of LV systolic function between patients on suppressive therapy and controls. When compared with controls, patients with exogenous SCH had a significantly impaired longitudinal protodiastolic strain, SR and strain diastolic index but preserved radial strain and SR function. Conclusions In subjects with SCH at the early phase of TSH‐suppressive therapy, evidence of isolated longitudinal LV diastolic dysfunction was observed, despite a normal LV morphology. Further prospective studies to clarify the prognosis of picking‐up early diastolic dysfunction in asymptomatic patients are needed before serial measurements could be recommended.     

Clinical significance of elevated level of serum antithyroglobulin antibody in patients with differentiated thyroid cancer after thyroid ablation

OBJECTIVE: Inhibin B in males is produced principally by Sertoli cells under the influence of FSH and is thought to have a role in feedback regulation of FSH. The aims of our study were to investigate how inhibin B changes from birth to late adolescence in boys, to derive reference data and to explore its relation with pubertal stage, FSH and testosterone. DESIGN AND SUBJECTS: Blood samples were collected from (i) 366 boys aged 0--18 years to obtain age-related reference data; (ii) 195 boys who had full pubertal staging; and (iii) a cohort of 15 boys studied longitudinally as they approached and entered early puberty. MEASUREMENTS: Dimeric inhibin B was measured by double antibody enzyme-linked immunosorbent assay (ELISA), FSH by immunoradiometric assay (IRA) and testosterone by an extraction radioimmunoassay. RESULTS: Inhibin B was high in infant boys, decreased gradually to a nadir at 6--10 years of age, then increased rapidly in early adolescence to reach a new plateau at 12--17 years. It was detectable in all samples. Age-related reference ranges and data for calculation of SD scores are presented. In prepubertal boys, inhibin B correlated positively with age (P < 0.001), but not with FSH. Inhibin B increased progressively from pubertal stages G1 to G3 but then decreased slightly at stages G4 to G5 (P less-than-or-equal 0.01). At stage G2, inhibin B correlated positively with testosterone (P < 0.01) but not with FSH. From stage G3 onwards, inhibin B correlated inversely with FSH (P < 0.01) but lost its relationship with testosterone. In the cohort of boys studied longitudinally, inhibin B increased progressively prior to pubertal onset and further on entry into early clinical puberty (P < 0.05). Testosterone also increased over this period (P < 0.05) but FSH showed no significant change. CONCLUSIONS: The two peaks of inhibin B during infancy and early puberty appear to reflect the two periods of Sertoli cell proliferation in normal human males. During mid-childhood, a relatively constant amount of inhibin B is secreted constitutively. The early FSH-independent increase in inhibin B that precedes clinical puberty and continues to stage G2 may be stimulated by testosterone or other factors from Leydig cells. The inverse relationship between inhibin B and FSH that subsequently develops from mid-puberty onwards is consistent with the establishment of a negative feedback loop at this time.