Pulmonary metastases in differentiated thyroid cancer: efficacy of radioiodine therapy and prognostic factors

in European Journal of Endocrinology
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  • Department of Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233, People's Republic of China

Correspondence should be addressed to Q-Y Luo; Email: lqyn@sh163.net

Context

Data from a large cohort of patients with pulmonary metastases from differentiated thyroid cancer (DTC) were retrospectively analyzed.

Objective

To assess the effect of radioiodine therapy and investigate the prognostic factors of survival for patients with pulmonary metastasis secondary to DTC.

Methods

A total of 372 patients with pulmonary metastasis from DTC treated with 131I entered the study. According to the results of 131I whole-body scan (WBS), pulmonary metastases were classified as 131I-avid and non-131I-avid. For patients with 131I-avid lung metastases, treatment response was measured by three parameters: serum thyroglobulin (Tg) levels, chest computed tomography (CT) and post-therapeutic 131I-WBS. Overall survival was calculated by the Kaplan–Meier method. Factors predictive of the outcome were determined by multivariate analyses.

Results

Among patients demonstrating 131I-avid pulmonary metastases (256/372, 68.8%), 156 cases (156/256, 60.9%) showed a significant decrease in serum Tg levels after 131I therapy and 138 cases (138/229, 60.3%) showed a reduction in pulmonary metastases on follow-up CT. A complete cure, however, was only achieved in 62 cases (62/256, 24.2%). Multivariate analysis showed that only age, the presence of multiple distant metastases and pulmonary metastatic node size were significant independent variables between the groups of 131I-avid and non-131I-avid.

Conclusion

This study indicated that, most 131I-avid pulmonary metastases from DTC can obtain partial or complete remission after 131I therapy. Younger patients (<40 years old) with only pulmonary metastases and small (‘fine miliaric’ or micronodular) metastases appear to have relative favorite outcomes. Patients who do not respond to 131I treatment have a worse prognosis.

Abstract

Context

Data from a large cohort of patients with pulmonary metastases from differentiated thyroid cancer (DTC) were retrospectively analyzed.

Objective

To assess the effect of radioiodine therapy and investigate the prognostic factors of survival for patients with pulmonary metastasis secondary to DTC.

Methods

A total of 372 patients with pulmonary metastasis from DTC treated with 131I entered the study. According to the results of 131I whole-body scan (WBS), pulmonary metastases were classified as 131I-avid and non-131I-avid. For patients with 131I-avid lung metastases, treatment response was measured by three parameters: serum thyroglobulin (Tg) levels, chest computed tomography (CT) and post-therapeutic 131I-WBS. Overall survival was calculated by the Kaplan–Meier method. Factors predictive of the outcome were determined by multivariate analyses.

Results

Among patients demonstrating 131I-avid pulmonary metastases (256/372, 68.8%), 156 cases (156/256, 60.9%) showed a significant decrease in serum Tg levels after 131I therapy and 138 cases (138/229, 60.3%) showed a reduction in pulmonary metastases on follow-up CT. A complete cure, however, was only achieved in 62 cases (62/256, 24.2%). Multivariate analysis showed that only age, the presence of multiple distant metastases and pulmonary metastatic node size were significant independent variables between the groups of 131I-avid and non-131I-avid.

Conclusion

This study indicated that, most 131I-avid pulmonary metastases from DTC can obtain partial or complete remission after 131I therapy. Younger patients (<40 years old) with only pulmonary metastases and small (‘fine miliaric’ or micronodular) metastases appear to have relative favorite outcomes. Patients who do not respond to 131I treatment have a worse prognosis.

Introduction

Differentiated thyroid cancer (DTC) is most commonly confined to the thyroid gland with or without involvement of regional lymph nodes because of its typical slow-growing pattern. Distant metastases are an uncommon event in DTC and a wide range in prevalence (4–23%) has been reported (1, 2, 3, 4, 5, 6). Lungs are the most frequent site of distant metastasis in DTC and the resulting respiratory failure may be the most common cause of death. About 50% of patients with such metastases die within 10 years (7). Postoperative ablation therapy with 131I is a mainstay of treatment in such cases, in conjunction with complete surgical resection of the thyroid and thyrotropin (TSH) suppression with thyroxine (T4). According to iodine-concentrating capacity (8), pulmonary metastases are classified as 131I-avid and non-131I-avid. 131I therapy is only recommended for patients with 131I-avid lung metastases, and there is no obvious benefit for those with non-131I-avid metastases. Thus, the characteristics and prognosis differ between the two groups. However, few previous investigations have discussed the efficacy of radioiodine therapy and prognostic factors of 131I-avid and non-131I-avid lung metastases separately.

Serum thyroglobulin (Tg) level is a useful prognostic factor after radioactive iodine ablation and its measurement is included in the follow-up DTC patients according to the guidelines of the British Thyroid Association and the American Thyroid Association (9, 10). Conventional chest X-ray is routinely used for diagnosis and follow-up of DTC patients with pulmonary metastases. However, pulmonary metastases are more often encountered in patients with papillary carcinoma and their radiological size is usually <1 cm and frequently below the spatial resolution of the chest X-ray. Chest computed tomography (CT) is preferred over chest X-rays and it enhances the diagnostic accuracy in most patients with normal chest X-ray findings (11). Thus, it is useful for the detection of pulmonary metastases of DTC and is able to measure the node size of metastases accurately.

In this study, data from a large cohort of patients with pulmonary metastasis from DTC treated and managed at the same institution were retrospectively analyzed. We aimed to: i) asses the therapeutic effects of radioiodine treatment on 131I-avid pulmonary metastases by the change of Tg level and node size; ii) investigate the prognostic factors related to 131I-avid pulmonary metastases; iii) compare the significant factors that affect the ability of 131I uptake between patients with 131I-avid and non-131I-avid pulmonary metastases and iv) evaluate the overall survival (OS) and the variables influencing survival.

Subjects and methods

Patients

From January 1997 to December 2013, 4681 patients with DTC were treated at our institution and 372 (372/4681, 7.95%) who had lung metastases yielded the final cohort with the average age of 54.25±16.08 years (range, 12–86 years). Primary thyroid cancers were papillary in 288 patients and follicular in 84. Only pulmonary metastases were involved in 298 patients while 74 patients also had distant metastases to other organs.

Diagnostic criteria for DTC pulmonary metastases

Definitive cytological or pathologic confirmation was not possible in all patients; therefore, diagnosis of pulmonary metastases was based on clinical and postoperative or follow-up chest CT findings, diagnostic or therapeutic 131I whole-body scan (WBS) and serum Tg levels. A patient satisfying the following criteria was considered to have pulmonary metastases: i) pathological results confirmed; ii) pulmonary 131I uptake on 131I-WBS+pulmonary node(s) on chest CT+elevated serum Tg level; iii) pulmonary 131I uptake on 131I-WBS+normal chest CT+elevated serum Tg level or iv) no pulmonary 131I uptake on 131I-WBS+pulmonary nodes on chest CT+elevated serum Tg level.

According to the results of 131I-WBS, pulmonary metastases were classified as 131I-avid (functioning pulmonary metastases) and non-131I-avid (non-functioning pulmonary metastases). According to the chest CT results, patients were divided into three categories: i) included patients with negative chest CT but 131I uptake on 131I-WBS, defined as ‘fine miliaric’; ii) included patients with micronodular pulmonary metastases, defined radiologically as ≤1 cm in diameter and iii) included patients who had macronodular pulmonary metastases, defined radiologically as >1 cm in diameter. According to the discovery time, pulmonary metastases were defined as initial (found at the time of or within 6 months after thyroidectomy) and developed (found 6 months or more after thyroidectomy).

Procedures for radioiodine therapy

Two hundred and seven (55.65%) patients received unilateral total and contralateral subtotal thyroidectomy and total thyroidectomy was performed in 165 (44.35%) cases. The patients achieved a sufficient hypothyroid state clinically with a serum TSH level >30 μIU/ml. All patients were instructed to follow a low-iodine diet for at least 2 weeks. The dose of 131I was 3.7–7.4 GBq (100–200 mCi). Conventional measurements, including free tri-iodothyronine, free T4, TSH, Tg, Tg antibody (TgAb), neck ultrasonography and chest CT scan were performed before 131I administration. Tg and TgAb were measured by RIA (from 1997 to 1999) and chemiluminescence (from 1999 to 2013). All patients underwent conventional CT for examination of metastatic lesions without the use of contrast media in order not to affect the radioiodine therapy. The CT images were obtained with 7 mm slice thickness starting from the apex of the lungs. All CT images were obtained with the patient in the supine position. Patients were evaluated in terms of metastatic pulmonary lesions and the lesions were classified according to size. Levothyroxine (l-T4) therapy was replaced 48 h later and post-therapeutic 131I-WBS was carried out 5 days after 131I administration. Post-treatment 131I-WBS was obtained in the anterior and posterior projections with a large field-of-view gamma camera equipped with a high-energy (peak energy centred on 360 keV with a 20% energy window), parallel-hole collimator (Hawkeye Millennium VG, GE Medical Systems, Milwaukee, WI, USA). In patients with 131I-avid metastases on 131I-WBS, additional treatments with 131I were given 4–12 months later. In cases with considerable residual thyroid tissue, even post-therapeutic WBS may fail to show 131I concentration in the lungs owing to significant neck uptake (12), therefore, 131I therapy was discontinued in patients with non-131I-avid lung metastases after residual thyroid tissue was completely ablated.

Evaluation of changes in serum Tg level

After at least two courses of 131I therapy, changes in Tg level were classified into three types: effectiveness (biochemical relief (BR)), stabilization and ineffectiveness according to our previously study (13). i) Effectiveness: compared with pretreatment, the serum Tg levels exhibited a reduction of ≥25%; ii) stabilization: compared with pretreatment, the serum Tg decreased or increased by <25% and iii) ineffectiveness: compared with pretreatment, the serum Tg increased by ≥25%.

Evaluation of changes in chest CT images

Chest CT responses were assessed using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) as follows: i) complete response (CR), disappearance of all lesions; ii) partial response (PR), ≥30% decrease in the sum of lesions diameters, taking as reference the baseline sum diameters; iii) progressive disease (PD), ≥20% increase in the sum of lesion diameters or appearance of greater than or equal to one new lesions is also considered progression and iv) stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Criteria for complete cure

Complete cure was defined by all the following criteria: no evidence or minimal visual evidence of 131I concentration on 131I-WBS in the chest region; no evidence of residual disease on chest CT; and undetectable serum Tg or ≤10 ng/ml in the hypothyroid status and in the absence of TgAb.

Statistical analysis

SPSS version 17.0 and SAS version 13.0 were used for statistical analyses. All data are expressed as mean±s.d., proportions or absolute numbers. All the factors that may have affected serum Tg and anatomical imaging in the pulmonary metastases were analyzed by univariate analysis and confirmed by the χ2 test. Binary logistic regression analysis was used to determine which factors contributed to the outcome of 131I therapy response. Kaplan–Meier survival analysis was applied to evaluate the effect of different variables on survival and the differences between the groups were compared using the log-rank test. Multivariate analysis was performed to assess the relationship between survival time and several variables simultaneously. For analyses of this type, Cox proportional hazards model was used. A P value <0.05 was considered to indicate statistical significance.

Results

Characteristics of patients with pulmonary metastases

There were 372 enrolled patients with a predominance of females (male=134, female=238 and male:female ratio=1:1.78). The ratio was lower than that observed in the general series of DTC patients, which means that pulmonary metastases are relatively more frequent in male patients. The mean age at diagnosis was 54.25±16.08 years (range, 12–86 years) and the mean follow-up period was 59.48±40.41 months. The initial pulmonary metastases were detected in 43 patients and the remaining 329 patients were diagnosed at follow-up (developed pulmonary metastases). Chest CT showed that pulmonary metastases were negative in 28 (28/372, 7.53%) patients, micronodular (≤1 cm) in 313 (313/372, 84.14%) patients and macronodular (>1 cm) in 31 (31/372, 8.33%) patients. 131I-avid pulmonary metastases was observed in 256 (256/372, 68.82%) patients and non-131I-avid pulmonary metastases was found in 116 (116/372, 31.18%) patients. The median cumulative radioiodine dose was 18.315 GBq (495 mCi) with a range of 3.7–86.95 GBq (100–2350 mCi). A single dose was given to 37 patients, two doses to 61 patients and greater than or equal to three doses to the remaining 274 patients.

Changes in serum Tg level after 131I therapy

Changes in serum Tg in 256 DTC patients with 131I-avid pulmonary metastases after radioiodine therapy are shown in Table 1. 131I therapy was effective in 156 patients (BR, effective rate, 60.9%) and the average serum Tg varied from 683 (range, 17–6957) to 311 (range, 0–1407) ng/ml. Stabilization of Tg was seen in 55 patients (stable rate, 21.5%) after 131I therapy and the average serum Tg varied from 791 (range, 27–8027) to 692 (range, 15–8395) ng/ml. Treatment was ineffective in 45 patients (ineffective rate, 17.6%) and the average serum Tg increased from 847 (range, 19–15 955) to 1301 (range, 26–20 475) ng/ml.

Table 1

Changes of serum Tg for 256 DTC patients with 131I-avid lung metastases after 131I therapy: univariate statistical analysis.

FactorsNo. of patientsEffectiveStableIneffectiveχ2P
Agea4.5950.032
 0–1918 (7.03%)1062
 20–39112 (43.75%)712615
 40–5986 (33.59%)571613
 ≥6040 (15.63)18715
Gender5.3230.021
 Male95 (37.11%)652010
 Female161 (62.89%)913535
Pathological type1.6680.434
 Papillary193 (75.39%)1144534
 Follicular63 (24.61%)421011
Operation method2.4750.115
 Lobectomy or subtotal thyroidectomy140 (54.69%)812930
 Total thyroidectomy116 (45.31%)752615
Time of lung metastasis0.0590.806
 Initial39 (15.23%)23115
 Developed217 (84.77%)1334440
Tg levelb99.860<0.0001
 <10041 (16.02%)3029
 100–1000141 (55.08%)872826
 >100074 (28.90%)392510
Metastatic site14.0880.0002
 Lung and lung+lymph node197 (76.95%)1265021
 Lung+bone and lung+other organsc59 (23.05%)30524
CT results4.7490.029
 Positive229 (89.45%)1364845
 Negative27 (10.55%)2070
Total2561565545

Tg, thyroglobulin.

Age at discovery of lung metastases.

Tg level following l-T4 withdrawal (ng/ml).

Brain in one patient, parapharyneal in eight patients, liver in one patient, kidney in two patients and soft tissue in two patients.

Univariate analysis showed that changes in serum Tg were influenced by age, sex, the initial Tg level, combination with other distant metastases and pulmonary node size (P valves 0.0321, 0.0210, <0.0001, 0.0002 and 0.0293 respectively). Multivariate analyses revealed that age, combination with other distant metastases and pulmonary node size had a significant impacts on Tg changes (P values 0.0270, 0.0013 and 0.0272 respectively; shown in Table 2). Significantly decreased serum Tg (BR) and favorable efficacy were observed in patients who were aged <40 years, only had pulmonary metastases and ‘fine miliaric’ nodes (negative chest CT).

Table 2

Multivariate analysis of response factors of 131I therapy.

FactorsChanges in serum TgImaging changes of lung metastases
Adjusted odds ratios95% CIP valueAdjusted odds ratios95% CIP value
Age (≥40/<40)1.4141.040–1.9340.0271.4221.051–1.9230.022
Gender (females/males)0.7420.446–1.2330.2481.4830.890–2.4700.130
Time of lung metastasis (initial/developed)0.7660.468–1.2550.290
Tg levela1.2640.856–1.8670.2391.3750.948–1.9950.093
Site (lung combined with other organsb metastases/only lung)2.5621.443–4.5490.0011.5750.890–2.7850.118
Node sizec2.5531.111–5.8650.0274.4641.863–10.6970.0008

Tg level following l-T4 withdrawal (ng/ml).

Brain in one patient, parapharyneal in eight patients, liver in one patient, kidney in two patients and soft tissue in two patients.

Node size: for serum Tg group, CT was positive/negative; for anatomical imaging group, CT was nodule >1/≤1 cm.

Changes in chest CT after 131I therapy

Of the 229 pulmonary metastases patients with positive chest CT findings, only 38 achieved CR (16.6%), 100 PR (43.7%), 76 SD (33.2%) and 15 had PD (6.5%). Univariate analyses of the factors influencing the changes of CT are shown in Table 3. Age, sex, time of lung metastases, initial Tg level, combination with other distant metastases and pulmonary node size were significantly associated with CT changes (P values 0.0134, 0.0245, 0.0003, 0.0425, 0.0046 and <0.0001 respectively). Multivariate analyses revealed that age <40 years and node size <1 cm had favorable effect on CT changes (P values 0.0223 and 0.0008; Table 2).

Table 3

Changes of anatomical imaging for 229 DTC patients with 131I-avid lung metastases after 131I therapy: univariate statistical analysis.

FactorsNo. of patientsCRPRSDPDχ2P
Agea6.1090.013
 0–1914 (6.11%)3470
 20–3999 (43.23%)2043315
 40–5976 (33.19%)1436242
 ≥6040 (17.47%)117148
Gender5.0580.024
 Male86 (37.55%)1449203
 Female143 (62.45%)24515612
Pathological type0.9930.802
 Papillary175 (76.42%)30765910
 Follicular54 (23.58%)824175
Operation method0.0380.845
 Lobectomy or subtotal thyroidectomy132 (57.64%)2357439
 Total thyroidectomy97 (42.36%)1543336
Time of lung metastasis13.1000.0003
 Initial33 (14.41%)151152
 Developed196 (85.59%)23897113
Tg levelb4.1140.042
 1–10037 (16.16%)111394
 100–1000121 (52.84%)2551369
 >100071 (31.00%)236312
Metastatic site8.0440.004
 Lung and lung+lymph node175 (76.42%)28934311
 Lung+bone and lung+other organsc54 (23.58%)107334
Node size (cm)15.801<0.0001
 ≤1212 (92.58%)3696746
 >117 (7.42%)2429
Total229381007615

CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

Age at discovery of lung metastases.

Tg level following l-T4 withdrawal (ng/ml).

Brain in one patient, parapharyneal in eight patients, liver in one patient, kidney in two patients and soft tissue in two patients.

Patients who achieved complete cure

Sixty-two patients achieved complete cure after radioiodine therapy for pulmonary metastases. Mean age was 30 years old (range, 12–56 years). Fifty-eight patients had pulmonary metastases only and the remaining four patients had single bone metastases, which were treated with surgery and external radiotherapy. Serum Tg level measured after withdrawal of l-T4 treatment were undetectable in 39 patients and <10 ng/ml in the remaining 23 patients. Complete cure occurred in 24 patients with a negative chest CT examination at discovery of pulmonary metastases, 36 with micronodular metastases and two with macronodular metastases. The mean cumulative dose of 131I administered to the 62 patients was 11.248 GBq (304 mCi), six with <7.4 GBq (200 mCi), 40 with 7.4–14.8 GBq (200–400 mCi), 13 with 14.8–22.2 GBq (400–600 mCi) and only three with a cumulative activity >22.2 GBq (600 mCi). Three of these 62 patients have relapsed during follow-up period.

Patients with no 131I uptake

A total of 116 patients had non-functioning pulmonary metastases. Fifteen of these patients had multiple organ involvement. The non-functioning lung metastases occurred late (found 6 months or more after thyroidectomy) in 112 patients. The proportion of patients older than 40 years was much higher (non-131I-avid vs 131I-avid=84.5% vs 49.2%).

After univariate analysis between the patients with 131I-avid and non-131I-avid pulmonary metastases (Table 4), the significant factors related to the ability of 131I uptake were age, pathological type, time of discovery lung metastases, combination with other distant metastases and node size. After multivariate analysis (Table 5), only age, combination with other distant metastases and node size remained significant for 131I uptake.

Table 4

Comparison by univariate statistical analysis between the groups of DTC patients with 131I-avid and non-131I-avid lung metastases.

FactorsNo. of patients131I-avidNon-131I-avidχ2P
Agea43.639<0.0001
 0–1919 (5.11%)181
 20–39129 (34.68%)11217
 40–59141 (37.90%)8655
 ≥6083 (22.31%)4043
Gender0.4200.516
 Male134 (36.02%)9539
 Female238 (63.98%)16177
Pathological type1.9270.165
 Papillary288 (77.42%)19395
 Foliicular84 (22.58%)6321
Operation method0.3040.581
 Lobectomy or subtotal thyroidectomy207 (55.65%)14067
 Total thyroidectomy165 (44.35%)11649
Time of lung metastasis9.7240.002
 Initial43 (11.56%)394
 Developed329 (88.44%)217112
Metastatic site5.1120.024
 Lung and lung+lymph node298 (80.11%)197101
 Lung+bone and lung+other organsb74 (19.89%)5915
Node size (cm)11.5010.0003
 CT-negative28 (7.53%)271
 ≤1313 (84.14%)212101
 >131 (8.33%)1714
Total372256116

Age at discovery of lung metastases.

For 131I-avid group: brain in one patient, parapharyneal in eight patients, liver in one patient, kidney in two patients and soft tissue in two patients; for non-131I-avid group: brain in two patient, parapharyneal in two patients, liver in one patient, kidney in one patient and soft tissue in one patient.

Table 5

Multivariate analysis between the groups of DTC patients with 131I-avid and non-131I-avid lung metastases.

FactorsAdjusted odds ratios95% CIP value
Age (≥40/<40)2.4941.865–3.350<0.0001
Time of lung metastasis (initial/developed)1.0280.644–1.6410.909
Site (lung combined with other organs metastasesa/only lung)2.2031.260–3.8500.005
Nodule size (>1/≤1 cm)6.3353.269–12.278<0.0001

For 131I-avid group: brain in one patient, parapharyneal in eight patients, liver in one patient, kidney in two patients and soft tissue in two patients; for non-131I-avid group: brain in two patient, parapharyneal in two patients, liver in one patient, kidney in one patient and soft tissue in one patient.

Survival rate and prognostic survival factors

The survival rate and prognostic survival factors are listed in Table 6. Survival rate in 131I-avid patients was 87.0% at 5 years, 69.2% at 10 years and 56.2% at 15 years. In non-131I-avid patients, survival rate was 69.7% at 5 years, 38.1% at 10 years and 20.9% at 15 years (Fig. 1). For 131I-avid patients, the univariate analysis showed that survival rate was affected by age, combination with other distant metastases and pulmonary node size (P value <0.0001 for all the factors). Prognostic variables were strongly inter-related. After adjusting for other significant factors, Cox's regression analyses showed that the three variables remained significant for survival (P valves 0.00015, <0.0001 and <0.0001 respectively).

Table 6

Survival for patients with lung metastatic differentiated thyroid cancer.

FactorNo. of patients5-year survival rate (%)10-year survival rate (%)15-year survival rate (%)Univariate P valueMultivariate P valueHazard ratio (95% CI)
Age (years)<0.00010.00015
 <40130 (50.78%)90.779.566.91
 ≥40126 (49.22%)77.659.232.71.7 (1.2–2.6)
GenderNS
 Males95 (37.11%)81.767.655.8
 Females161 (62.89%)85.372.262.9
Pathological typeNS
 Papillary193 (75.39%)88.073.660.4
 Follicular63 (24.61%)80.569.258.8
Time of lung metastasisNS
 Initial39 (15.23%)86.973.364.8
 Developed217 (84.77%)89.575.462.3
Metastatic site<0.0001<0.0001
 Lung and lung+lymph node197 (76.95%)90.073.660.91
 Lung+bone and lung+other organs59 (23.05%)45.934.317.22.3 (1.7–3.6)
Node size (cm)<0.0001<0.0001
 Negative27 (10.55%)100.090.975.81
 ≤1212 (82.81%)88.568.950.11.9 (1.1–3.4)
 >117 (6.64%)59.230.603.5 (2.1–5.8)
 131I<0.0001<0.0001
 Yes256 (68.82%)87.069.256.21
 No116 (31.18)69.738.120.92.1 (1.3–3.2)

CI from multivariate analysis; NS, not significant.

Figure 1
Figure 1

Overall survival for patients with lung metastases by 131I-avid and non-131I-avid.

Citation: European Journal of Endocrinology 173, 3; 10.1530/EJE-15-0296

The survival rate at 10 years was 79.5% in patients aged <40 years and 59.2% in patients older than 40 years (Fig. 2). For patients with only lung metastases, the survival rate at 10 years was 73.6%, which was significantly higher than patients with multiple organ metastases (for whom the 10-year survival rate was 34.3%; Fig. 3). The 10-year survival rate of 90.9% in patients with negative chest CT was higher than the 68.9% survival rate observed in patients with micronodular metastases (≤1cm) and the 30.6% observed in those with macronodular metastases (>1cm) (Fig. 4).

Figure 2
Figure 2

Overall survival for patients with lung metastases by age at diagnosis.

Citation: European Journal of Endocrinology 173, 3; 10.1530/EJE-15-0296

Figure 3
Figure 3

Overall survival for patients with lung metastases by sites of metastasis.

Citation: European Journal of Endocrinology 173, 3; 10.1530/EJE-15-0296

Figure 4
Figure 4

Overall survival for patients with lung metastases by pulmonary node size.

Citation: European Journal of Endocrinology 173, 3; 10.1530/EJE-15-0296

Discussion

We studied a large number of DTC patients with pulmonary metastases. We assessed the effect of radioiodine therapy and investigated the prognostic factors for survival for DTC patients with pulmonary metastases. A few studies have looked primarily at the clinical management and outcome of patients with DTC presenting with lung metastases (1, 2, 3, 4, 8, 11, 12, 14, 15). Our study differed from earlier investigations in three regards: i) we included a larger patient sample; ii) when evaluating the effect of radioiodine therapy, we explored only the patients with 131I-avid pulmonary metastases and the factors that affected 131I uptake were discussed for non-131I-avid lung metastases and iii) the parameters of Tg level and chest CT were selected as an evaluation index and discussed.

For patients with non-131I-avid (radioiodine-refractory) pulmonary disease, the benefit of radioiodine therapy was very limited. It was not appropriate for evaluation of the efficacy of 131I therapy in these patients. Loss of radioiodine avidity is associated with a poor outcome. Several studies have reported that DTC patients with 131I-avidity have longer survival rates than those with non-131I-avid pulmonary metastasis (15, 16, 17, 18). In agreement with the previous studies, our patients with non-131I-avid disease had a 10-year OS rate of 38.1% compared to 69.2% for 131I-avid metastases (P<0.0001). We further investigated the factors related to 131I uptake. After univariate and multivariate analyses, age >40 years (P<0.0001), combination with other distant metastases (P=0.0056) and macronodular lesions (P<0.0001) were independently significant predictors for non-131I-avid pulmonary metastases.

Numerous studies have been performed on the diagnostic value of serum Tg measurement and have found that it is a highly sensitive means of detecting metastases (19). Moreover, Tg level was an independent prognostic indicator for disease-free remission and death (20, 21). It was thought that the serum Tg level under TSH elevation (>30 mU/l) was the most reliable indicator for persistent or recurrent disease. Therefore, the change in serum Tg levels (after the withdrawal of L-T4 over the course of 3–4 weeks) was considered to be a prognostic indicator to assess the efficacy of 131I therapy for pulmonary metastases. We found a significant decrease in serum Tg (BR) in 156 patients (60.9% effective rate). Multivariate analyses revealed that age ≤40 years, only lung metastases and ‘fine miliaric’ nodes (negative chest CT) were the favorable factors. These corresponded well with the favorable prognostic factors of OS and suggested that decreased serum Tg indicates the effectiveness of radioiodine therapy. However, serum Tg was only reliable if TgAb was undetectable, otherwise serum Tg level could have been falsely lowered (21). Thus, patients with positive antibodies were excluded from the study. The size of pulmonary metastases was usually <1 cm, which was below the spatial resolution of chest X-ray. Chest CT could enhance the diagnostic accuracy in most patients with normal chest X-ray and had an additive effect to 131I-WBS and Tg level (11). According to nodule size on chest CT, pulmonary metastases were divided into three categories: i) normal (n=27); ii) micronodular (≤1 cm, n=212) and iii) macronodular (>1 cm, n=17). The significance of this classification was that it was related to radioiodine efficacy. Micronodular pattern of lung metastases was invariably related to good 131I uptake, while macronodular metastases frequently showed poor 131I uptake (14). In our study, multivariate analyses revealed that patients with node size <1 cm had a favorable response on changes in CT imaging (P=0.0008, OR=4.464, 95% CI, 1.863–10.697). Complete remission following 131I therapy always occurred in patients with micronodular metastases, especially for ‘fine miliaric’ nodes. The 10-year survival rate was significantly higher in category 1 (90.9%) patients, lower in category 2 (68.9%) and only 30.6% in category 3 patients.

In our cohort, for patients with 131I-avid pulmonary metastases, the 5-, 10- and 15-year OS rates were 87.0, 69.2 and 56.2% respectively. This corresponded with the result of those reported in the previous studies (8, 15, 22, 23, 24). Cox's regression analysis showed that the three variables, including age, combination with other distant metastases and pulmonary node size, were significant predictor for survival (P valves 0.00015, <0.0001 and <0.0001 respectively). Age is known to be an independent prognostic factor for mortality in DTC (14, 25, 26), and the mortality risk increases with age. In our series, survival rate at 10 years was 79.5% in the patients younger than 40 years of age, while it was only 59.2% in the patients older than 40 years. Although pulmonary metastases with 131I uptake may be stable for several years or decades, all metastases should be treated at an early stage. Favorable responses have been observed in patients with small metastases. Previously, Casara et al. (14) showed that micronodular metastasis susceptible to 131I therapy had a good prognosis, whereas macronodular metastasis of non-131I- avid lesions had a poor prognosis. As in our study, patients with normal chest CT can achieve a CR with radioiodine alone for long periods of time. Macronodular metastases frequently show poor 131I uptake (14/31, 45.2%) and poor survival rate (10-year, OS=30.6%).

Limitations

First, our study was retrospective. During the long study period, a few clinical data were missing, which might have caused bias in the data selection. Second, in the diagnosis of lung metastasis in non-131I-avid patients, the histopathological confirmation was not always possible, particularly in patients with small (‘fine miliaric’ or micronodular) lesions. Therefore, they were clinically diagnosed based on their CT images and elevated Tg levels. However, we cannot completely rule out the possibility of other conditions, such as incidental primary lung cancers or benign lung diseases such as inflammation.

Summary

In conclusion, our study indicated that most 131I-avid pulmonary metastases from DTC can obtain partial or complete remission after 131I therapy. Younger patients (<40 years old) with only pulmonary metastases and small (‘fine miliaric’ or micronodular) metastases appear to have relative favorable outcomes. In contrast, patients with non 131I-avid pulmonary metastases who do not respond to radioiodine treatment have a worse prognosis, and 131I treatment should be abandoned and other treatment modalities used when tumour progression has been documented.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was sponsored by the National Natural Science Foundation of China (No. 81271611 and 81201115).

Author contribution statement

H-J Song, Z-L Qiu and Q-Y Luo conceived and designed the paper. H-J Song, C-T Shen and W-J Wei collected the data. H-J Song and Z-L Qiu analyzed the data. H-J Song wrote the paper.

References

  • 1

    Massin JP, Savoie JC, Garnier H, Guiraudon G, Leger FA, Bacourt F. Pulmonary metastases in differentiated thyroid carcinoma. Study of 58 cases with implications for the primary tumor treatment. Cancer 1984 53 982992. (doi:10.1002/1097-0142(19840215)53:4<982::AID-CNCR2820530427>3.0.CO;2-E).

    • Search Google Scholar
    • Export Citation
  • 2

    Ruegemer JJ, Hay ID, Bergstralh EJ, Ryan JJ, Offord KP, Gorman CA. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. Journal of Clinical Endocrinology and Metabolism 1988 67 501508. (doi:10.1210/jcem-67-3-501).

    • Search Google Scholar
    • Export Citation
  • 3

    Casara D, Rubello D, Saladini G, Gallo V, Masarotto G, Busnardo B. Distant metastases in differentiated thyroid cancer: long-term results of radioiodine treatment and statistical analysis of prognostic factors in 214 patients. Tumori 1991 77 432436.

    • Search Google Scholar
    • Export Citation
  • 4

    Samaan NA, Schultz PN, Haynie TP, Ordonez NG. Pulmonary metastasis of differentiated thyroid carcinoma: treatment results in 101 patients. Journal of Clinical Endocrinology and Metabolism 1985 60 376380. (doi:10.1210/jcem-60-2-376).

    • Search Google Scholar
    • Export Citation
  • 5

    Jonklaas J, Sarlis NJ, Litofsky D, Ain KB, Bigos ST, Brierley JD, Cooper DS, Haugen BR, Ladenson PW, Magner J et al. . Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 2006 16 12291242. (doi:10.1089/thy.2006.16.1229).

    • Search Google Scholar
    • Export Citation
  • 6

    Lang BH, Wong KP, Cheung CY, Wan KY, Lo CY. Evaluating the prognostic factors associated with cancer specific survival of differentiated thyroid carcinoma presenting with distant metastasis. Annals of Surgical Oncology 2013 20 13291335. (doi:10.1245/s10434-012-2711-x).

    • Search Google Scholar
    • Export Citation
  • 7

    Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2001 86 14471463. (doi:10.1210/jcem.86.4.7407).

    • Search Google Scholar
    • Export Citation
  • 8

    Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, Caillou B, Ricard M, Lumbroso JD, De Vathaire F et al. . Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. Journal of Clinical Endocrinology and Metabolism 2006 91 28922899. (doi:10.1210/jc.2005-2838).

    • Search Google Scholar
    • Export Citation
  • 9

    Watkinson JC. The British Thyroid Association guidelines for the management of thyroid cancer in adults. Nuclear Medicine Communications 2004 25 897900. (doi:10.1097/00006231-200409000-00006).

    • Search Google Scholar
    • Export Citation
  • 10

    Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M et al. . American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009 19 11671214. (doi:10.1089/thy.2009.0110).

    • Search Google Scholar
    • Export Citation
  • 11

    Ilgan S, Karacalioglu AO, Pabuscu Y, Atac GK, Arslan N, Ozturk E, Gunalp B, Ozguven MA. Iodine-131 treatment and high-resolution CT: results in patients with lung metastases from differentiated thyroid carcinoma. European Journal of Nuclear Medicine and Molecular Imaging 2004 31 825830. (doi:10.1007/s00259-004-1460-x).

    • Search Google Scholar
    • Export Citation
  • 12

    Samuel AM, Rajashekharrao B, Shah DH. Pulmonary metastases in children and adolescent with well-differentiated thyroid cancer. Journal of Nuclear Medicine 1998 39 15311536.

    • Search Google Scholar
    • Export Citation
  • 13

    Qiu ZL, Song HJ, Xu YH, Luo QY. Efficacy and survival analysis of 131I therapy for bone metastases form differentiated thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2011 96 30783086. (doi:10.1210/jc.2011-0093).

    • Search Google Scholar
    • Export Citation
  • 14

    Casara D, Rubello D, Saladini G, Masarotto G, Favero A, Girelli ME, Busnardo B. Different features of pulmonary metastases in differentiated thyroid cancer: natural history and multivariate statistical analysis of prognostic variables. Journal of Nuclear Medicine 1993 34 16261631.

    • Search Google Scholar
    • Export Citation
  • 15

    Cho SW, Choi HS, Yeom GJ, Lim JA, Moon JH, Park do J, Chung JK, Cho BY, Yi KH, Park YJ. Long-term prognosis of differentiated thyroid cancer with lung metastasis in Korea and its prognostic factors. Thyroid 2014 24 277286. (doi:10.1089/thy.2012.0654).

    • Search Google Scholar
    • Export Citation
  • 16

    Pelizzo MR, Boschin IM, Toniato A, Piotto A, Pagetta C, Gross MD, Al-Nahhas A, Rubello D. Papillary thyroid carcinoma: 35-year outcome and prognostic factors in 1858 patients. Clinical Nuclear Medicine 2007 32 440444. (doi:10.1097/RLU.0b013e31805375ca).

    • Search Google Scholar
    • Export Citation
  • 17

    Sisson JC, Giordano TJ, Jamadar DA, Kazerooni EA, Shapiro B, Gross MD, Zempel SA, Spaulding SA. 131-I treatment of micronodular pulmonary metastases from papillary thyroid carcinoma. Cancer 1996 78 21842192. (doi:10.1002/(SICI)1097-0142(19961115)78:10<2184::AID-CNCR21>3.0.CO;2-U).

    • Search Google Scholar
    • Export Citation
  • 18

    Dinneen SF, Valimaki MJ, Bergstralh EJ, Goellner JR, Gorman CA, Hay ID. Distant metastases in papillary thyroid carcinoma: 100 cases observed at one institution during 5 decades. Journal of Clinical Endocrinology and Metabolism 1995 80 20412045.

    • Search Google Scholar
    • Export Citation
  • 19

    Lind P, Kohlfürst S. Respective roles of thyroglobulin, radioiodine imaging, and positron emission tomography in the assessment of thyroid cancer. Seminars in Nuclear Medicine 2006 36 194205. (doi:10.1053/j.semnuclmed.2006.03.002).

    • Search Google Scholar
    • Export Citation
  • 20

    Heemstra KA, Liu YY, Stokkel M, Kievit J, Corssmit E, Pereira AM, Romijn JA, Smit JW. Serum thyroglobulin concentrations predict disease-free remission and death in differentiated thyroid carcinoma. Clinical Endocrinology 2007 66 5864.

    • Search Google Scholar
    • Export Citation
  • 21

    Brassard M, Borget I, Edet-Sanson A, Giraudet AL, Mundler O, Toubeau M, Bonichon F, Borson-Chazot F, Leenhardt L, Schvartz C et al. . Long-term follow-up of patients with papillary and follicular thyroid cancer: a prospective study on 715 patients. Journal of Clinical Endocrinology and Metabolism 2011 96 13521359. (doi:10.1210/jc.2010-2708).

    • Search Google Scholar
    • Export Citation
  • 22

    Mihailovic J, Stefanovic L, Malesevic M, Markoski B. The importance of age over radioiodine avidity as a prognostic factor in differentiated thyroid carcinoma with distant metastases. Thyroid 2009 19 227232. (doi:10.1089/thy.2008.0186).

    • Search Google Scholar
    • Export Citation
  • 23

    Huang IC, Chou FF, Liu RT, Tung SC, Chen JF, Kuo MC, Hsieh CJ, Wang PW. Long-term outcomes of distant metastasis from differentiated thyroid carcinoma. Clinical Endocrinology 2012 76 439447. (doi:10.1111/j.1365-2265.2011.04231.x).

    • Search Google Scholar
    • Export Citation
  • 24

    Sampson E, Brierley JD, Le LW, Rotstein L, Tsang RW. Clinical management and outcome of papillary and follicular (differentiated) thyroid cancer presenting with distant metastasis at diagnosis. Cancer 2007 110 14511456. (doi:10.1002/cncr.22956).

    • Search Google Scholar
    • Export Citation
  • 25

    Ronga G, Filesi M, Montesano T, Di Nicola AD, Pace C, Travascio L, Ventroni G, Antonaci A, Vestri AR. Lung metastases from differentiated thyroid carcinoma. A 40 years' experience. Quarterly Journal of Nuclear Medicine and Molecular Imaging 2004 48 1219.

    • Search Google Scholar
    • Export Citation
  • 26

    Brierley J, Tsang R, Panzarella T, Bana N. Prognostic factors and the effect of treatment with radioactive iodine and external beam radiation on patients with differentiated thyroid cancer seen at a single institution over 40 years. Clinical Endocrinology 2005 63 418427. (doi:10.1111/j.1365-2265.2005.02358.x).

    • Search Google Scholar
    • Export Citation

 

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    Overall survival for patients with lung metastases by 131I-avid and non-131I-avid.

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    Overall survival for patients with lung metastases by age at diagnosis.

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    Overall survival for patients with lung metastases by sites of metastasis.

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    Overall survival for patients with lung metastases by pulmonary node size.

  • 1

    Massin JP, Savoie JC, Garnier H, Guiraudon G, Leger FA, Bacourt F. Pulmonary metastases in differentiated thyroid carcinoma. Study of 58 cases with implications for the primary tumor treatment. Cancer 1984 53 982992. (doi:10.1002/1097-0142(19840215)53:4<982::AID-CNCR2820530427>3.0.CO;2-E).

    • Search Google Scholar
    • Export Citation
  • 2

    Ruegemer JJ, Hay ID, Bergstralh EJ, Ryan JJ, Offord KP, Gorman CA. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. Journal of Clinical Endocrinology and Metabolism 1988 67 501508. (doi:10.1210/jcem-67-3-501).

    • Search Google Scholar
    • Export Citation
  • 3

    Casara D, Rubello D, Saladini G, Gallo V, Masarotto G, Busnardo B. Distant metastases in differentiated thyroid cancer: long-term results of radioiodine treatment and statistical analysis of prognostic factors in 214 patients. Tumori 1991 77 432436.

    • Search Google Scholar
    • Export Citation
  • 4

    Samaan NA, Schultz PN, Haynie TP, Ordonez NG. Pulmonary metastasis of differentiated thyroid carcinoma: treatment results in 101 patients. Journal of Clinical Endocrinology and Metabolism 1985 60 376380. (doi:10.1210/jcem-60-2-376).

    • Search Google Scholar
    • Export Citation
  • 5

    Jonklaas J, Sarlis NJ, Litofsky D, Ain KB, Bigos ST, Brierley JD, Cooper DS, Haugen BR, Ladenson PW, Magner J et al. . Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 2006 16 12291242. (doi:10.1089/thy.2006.16.1229).

    • Search Google Scholar
    • Export Citation
  • 6

    Lang BH, Wong KP, Cheung CY, Wan KY, Lo CY. Evaluating the prognostic factors associated with cancer specific survival of differentiated thyroid carcinoma presenting with distant metastasis. Annals of Surgical Oncology 2013 20 13291335. (doi:10.1245/s10434-012-2711-x).

    • Search Google Scholar
    • Export Citation
  • 7

    Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2001 86 14471463. (doi:10.1210/jcem.86.4.7407).

    • Search Google Scholar
    • Export Citation
  • 8

    Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, Caillou B, Ricard M, Lumbroso JD, De Vathaire F et al. . Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. Journal of Clinical Endocrinology and Metabolism 2006 91 28922899. (doi:10.1210/jc.2005-2838).

    • Search Google Scholar
    • Export Citation
  • 9

    Watkinson JC. The British Thyroid Association guidelines for the management of thyroid cancer in adults. Nuclear Medicine Communications 2004 25 897900. (doi:10.1097/00006231-200409000-00006).

    • Search Google Scholar
    • Export Citation
  • 10

    Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M et al. . American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009 19 11671214. (doi:10.1089/thy.2009.0110).

    • Search Google Scholar
    • Export Citation
  • 11

    Ilgan S, Karacalioglu AO, Pabuscu Y, Atac GK, Arslan N, Ozturk E, Gunalp B, Ozguven MA. Iodine-131 treatment and high-resolution CT: results in patients with lung metastases from differentiated thyroid carcinoma. European Journal of Nuclear Medicine and Molecular Imaging 2004 31 825830. (doi:10.1007/s00259-004-1460-x).

    • Search Google Scholar
    • Export Citation
  • 12

    Samuel AM, Rajashekharrao B, Shah DH. Pulmonary metastases in children and adolescent with well-differentiated thyroid cancer. Journal of Nuclear Medicine 1998 39 15311536.

    • Search Google Scholar
    • Export Citation
  • 13

    Qiu ZL, Song HJ, Xu YH, Luo QY. Efficacy and survival analysis of 131I therapy for bone metastases form differentiated thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2011 96 30783086. (doi:10.1210/jc.2011-0093).

    • Search Google Scholar
    • Export Citation
  • 14

    Casara D, Rubello D, Saladini G, Masarotto G, Favero A, Girelli ME, Busnardo B. Different features of pulmonary metastases in differentiated thyroid cancer: natural history and multivariate statistical analysis of prognostic variables. Journal of Nuclear Medicine 1993 34 16261631.

    • Search Google Scholar
    • Export Citation
  • 15

    Cho SW, Choi HS, Yeom GJ, Lim JA, Moon JH, Park do J, Chung JK, Cho BY, Yi KH, Park YJ. Long-term prognosis of differentiated thyroid cancer with lung metastasis in Korea and its prognostic factors. Thyroid 2014 24 277286. (doi:10.1089/thy.2012.0654).

    • Search Google Scholar
    • Export Citation
  • 16

    Pelizzo MR, Boschin IM, Toniato A, Piotto A, Pagetta C, Gross MD, Al-Nahhas A, Rubello D. Papillary thyroid carcinoma: 35-year outcome and prognostic factors in 1858 patients. Clinical Nuclear Medicine 2007 32 440444. (doi:10.1097/RLU.0b013e31805375ca).

    • Search Google Scholar
    • Export Citation
  • 17

    Sisson JC, Giordano TJ, Jamadar DA, Kazerooni EA, Shapiro B, Gross MD, Zempel SA, Spaulding SA. 131-I treatment of micronodular pulmonary metastases from papillary thyroid carcinoma. Cancer 1996 78 21842192. (doi:10.1002/(SICI)1097-0142(19961115)78:10<2184::AID-CNCR21>3.0.CO;2-U).

    • Search Google Scholar
    • Export Citation
  • 18

    Dinneen SF, Valimaki MJ, Bergstralh EJ, Goellner JR, Gorman CA, Hay ID. Distant metastases in papillary thyroid carcinoma: 100 cases observed at one institution during 5 decades. Journal of Clinical Endocrinology and Metabolism 1995 80 20412045.

    • Search Google Scholar
    • Export Citation
  • 19

    Lind P, Kohlfürst S. Respective roles of thyroglobulin, radioiodine imaging, and positron emission tomography in the assessment of thyroid cancer. Seminars in Nuclear Medicine 2006 36 194205. (doi:10.1053/j.semnuclmed.2006.03.002).

    • Search Google Scholar
    • Export Citation
  • 20

    Heemstra KA, Liu YY, Stokkel M, Kievit J, Corssmit E, Pereira AM, Romijn JA, Smit JW. Serum thyroglobulin concentrations predict disease-free remission and death in differentiated thyroid carcinoma. Clinical Endocrinology 2007 66 5864.

    • Search Google Scholar
    • Export Citation
  • 21

    Brassard M, Borget I, Edet-Sanson A, Giraudet AL, Mundler O, Toubeau M, Bonichon F, Borson-Chazot F, Leenhardt L, Schvartz C et al. . Long-term follow-up of patients with papillary and follicular thyroid cancer: a prospective study on 715 patients. Journal of Clinical Endocrinology and Metabolism 2011 96 13521359. (doi:10.1210/jc.2010-2708).

    • Search Google Scholar
    • Export Citation
  • 22

    Mihailovic J, Stefanovic L, Malesevic M, Markoski B. The importance of age over radioiodine avidity as a prognostic factor in differentiated thyroid carcinoma with distant metastases. Thyroid 2009 19 227232. (doi:10.1089/thy.2008.0186).

    • Search Google Scholar
    • Export Citation
  • 23

    Huang IC, Chou FF, Liu RT, Tung SC, Chen JF, Kuo MC, Hsieh CJ, Wang PW. Long-term outcomes of distant metastasis from differentiated thyroid carcinoma. Clinical Endocrinology 2012 76 439447. (doi:10.1111/j.1365-2265.2011.04231.x).

    • Search Google Scholar
    • Export Citation
  • 24

    Sampson E, Brierley JD, Le LW, Rotstein L, Tsang RW. Clinical management and outcome of papillary and follicular (differentiated) thyroid cancer presenting with distant metastasis at diagnosis. Cancer 2007 110 14511456. (doi:10.1002/cncr.22956).

    • Search Google Scholar
    • Export Citation
  • 25

    Ronga G, Filesi M, Montesano T, Di Nicola AD, Pace C, Travascio L, Ventroni G, Antonaci A, Vestri AR. Lung metastases from differentiated thyroid carcinoma. A 40 years' experience. Quarterly Journal of Nuclear Medicine and Molecular Imaging 2004 48 1219.

    • Search Google Scholar
    • Export Citation
  • 26

    Brierley J, Tsang R, Panzarella T, Bana N. Prognostic factors and the effect of treatment with radioactive iodine and external beam radiation on patients with differentiated thyroid cancer seen at a single institution over 40 years. Clinical Endocrinology 2005 63 418427. (doi:10.1111/j.1365-2265.2005.02358.x).

    • Search Google Scholar
    • Export Citation