Warning: fopen(/home/virtual/enm-kes/journal/upload/ip_log/ip_log_2024-03.txt): failed to open stream: Permission denied in /home/virtual/lib/view_data.php on line 88 Warning: fwrite() expects parameter 1 to be resource, boolean given in /home/virtual/lib/view_data.php on line 89 Prognosis of Differentiated Thyroid Carcinoma with Initial Distant Metastasis: A Multicenter Study in Korea
Skip Navigation
Skip to contents

Endocrinol Metab : Endocrinology and Metabolism

clarivate
OPEN ACCESS
SEARCH
Search

Articles

Page Path
HOME > Endocrinol Metab > Volume 33(2); 2018 > Article
Original Article
Prognosis of Differentiated Thyroid Carcinoma with Initial Distant Metastasis: A Multicenter Study in Korea
Hosu Kim1,2orcid, Hye In Kim1*orcid, Sun Wook Kim1orcid, Jaehoon Jung2orcid, Min Ji Jeon3orcid, Won Gu Kim3orcid, Tae Yong Kim3orcid, Hee Kyung Kim4orcid, Ho-Cheol Kang4orcid, Ji Min Han5orcid, Yoon Young Cho6orcid, Tae Hyuk Kim1orcid, Jae Hoon Chung1orcid
Endocrinology and Metabolism 2018;33(2):287-295.
DOI: https://doi.org/10.3803/EnM.2018.33.2.287
Published online: June 21, 2018

1Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

2Division of Endocrinology, Department of Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University School of Medicine, Changwon, Korea.

3Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

4Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.

5Division of Endocrinology and Metabolism, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea.

6Division of Endocrinology and Metabolism, Department of Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea.

Corresponding author: Jae Hoon Chung. Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. Tel: +82-2-3410-3434, Fax: +82-2-3410-3849, thyroid@skku.edu
Corresponding author: Tae Hyuk Kim. Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. Tel: +82-2-3410-6049, Fax: +82-2-3410-3849, taehyukmd.kim@samsung.com
*Current affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea.
• Received: January 30, 2018   • Revised: May 3, 2018   • Accepted: May 10, 2018

Copyright © 2018 Korean Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • 5,206 Views
  • 57 Download
  • 30 Web of Science
  • 27 Crossref
  • 28 Scopus
  • Background
    Most patients with differentiated thyroid cancer (DTC) have a favorable prognosis. However, patients with DTC and initial distant metastasis have not been commonly found, and their clinical characteristics have seldom been reported. In this study, we analyzed the clinical features and prognosis of patients with DTC and initial distant metastasis in Korea.
  • Methods
    We retrospectively reviewed the clinical data of 242 patients with DTC and initial distant metastasis treated from 1994 to 2013, collected from five tertiary hospitals in Korea.
  • Results
    The patients' median age was 51 years, and 65% were women. They were followed for a median of 7 years. Lung was the most common site of distant metastasis: only lung 149 patients (62%), only bone 49 (20%), other single site one (pleura), and combined sites 43 (40 were lung and bone, two were bone and other site, and one was lung and other site). At the time of diagnosis, 50 patients (21%) had non-radioactive iodine (RAI) avidity. Five-year disease-specific survival (DSS) was 85% and 10-year DSS was 68%, which were better than those in previous studies. After multivariate analysis, old age, male sex, metastatic site, and histologic type (follicular type) were significant factors for poor prognosis. However, negative RAI avidity status was not a significant prognostic factor after adjusting for other variables.
  • Conclusion
    The prognosis of Korean patients with DTC and initial distant metastasis was better than in previous studies. Old age, male sex, metastasis site, and histologic type were significant prognostic factors.
Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are often referred to together as differentiated thyroid cancer (DTC). Recently, the incidence of DTC has been increasing worldwide [123]. Despite the increase in incidence, most patients with DTC have a favorable prognosis [45]. However, 1% to 9% of patients with DTC present with distant metastasis at the time of diagnosis, and the mortality rate is significantly higher when initial distant metastasis is present [6789].
Previous studies of DTC with distant metastasis show inconsistent results. Long-term survival rates range from 13% to 100% [9101112]. This difference is thought to be due to heterogeneity among patients. Because of the rarity of the disease, most of the previous studies did not distinguish distant metastasis at initial diagnosis from distant metastasis found during follow-up. However, these two groups had different disease entities, disease characteristics, and prognoses [10]. Furthermore, primary tumor histology and site of distant metastasis are associated with different disease characteristics and prognosis [891314]. Therefore, enrollment of a homogenous group is necessary to evaluate the disease characteristics more clearly.
The epidemiology of thyroid cancer has recently been changing [1516]. Earlier diagnoses of thyroid cancer have increased since the introduction of high-resolution ultrasound sonography. New therapeutic modalities, such as tyrosine kinase inhibitors (TKIs), have been developed for the treatment of radioactive iodine (RAI)-refractory DTC [1718]. Therefore, the current prognosis of DTC with distant metastasis might be different from the past. In this study, we analyzed the clinical characteristics and long-term prognoses of Korean patients with DTC and initial distant metastasis.
We reviewed the clinical data of 242 patients with DTC and initial distant metastasis at the time of diagnosis that had been treated between 1994 and 2013 at Samsung Medical Center, Asan Medical Center, Chonnam National University Hwasun Hospital, Samsung Changwon Hospital, and Gyeongsang National University Hospital. Duplicated patients were identified by chart review and were treated as one person at the time of analysis. The Institutional Review Board at each participating hospital approved this study (IRB number: SMC 2017-02-058, IRB 2017-0601, CNUHH-2017-069, SCMC2017-11-001, 2017-10-009). Informed consent was waived due to retrospective design.
Initial distant metastasis was defined as distant metastasis detected before or within 6 months after initial treatment. Distant metastasis was found by pathological confirmation or imaging studies such as whole-body scan (WBS), computed tomography (CT), magnetic resonance imaging, bone scan, or positron emission tomography (PET) scans [19]. Distant metastasis was classified according to the metastatic site: (1) only lung, (2) only bone, (3) combined, and (4) other site metastasis. Lung metastasis included micronodular (smaller than 1 cm), macronodular (larger than 1 cm), and miliary lung metastasis. Bone metastasis included solitary or multiple bone metastases. The combined group included cases where two or more different metastatic sites were found. Iodine avidity was determined by visual uptake in the known site of metastatic disease by WBS after RAI therapy [8].
Various factors that influence distant metastasis were reviewed for analysis. Age at initial diagnosis, gender, histologic finding of thyroid cancer after surgery, data on additional therapy for distant metastasis, and RAI avidity of the metastatic site were included for analysis. Histologic findings of thyroid cancer included primary tumor histology (PTC, FTC, Hürthle cell carcinoma [HTC]), tumor size, lymph node metastasis, extrathyroidal extension, involvement of resection margin, and lymphovascular invasion. Additional therapy included RAI therapy, TKI, external radiotherapy, and systemic chemotherapy. Disease-specific death and survival were used for prognostic analysis.
Statistical analysis
Continuous data were expressed as mean±standard deviation. Data on categorical characteristics were expressed as percent values or absolute numbers. For comparisons of clinical and pathological characteristics between the initial distant metastasis groups, a chi-sqaure test was used for categorical data and t test was used for continuous data. A multivariate Cox proportional hazard model applying the backward elimination method was used to identify factors associated with disease-specific death. P<0.05 was considered significant. Statistical analysis was performed using SPSS software version 23 (IBM Co., Armonk, NY, USA).
Baseline characteristics
We studied 242 Korean patients with DTC and initial distant metastasis. The incidence of initial distant metastasis was 0.7% during the study period. The baseline characteristics of enrolled patients are shown in Table 1. Their median age was 51.0±17.1 years with a range from 13 to 79 years, and 65% were women. They were followed for a median of 7 years (interquartile range, 4.1 to 10.1). PTC was diagnosed in 175 patients (72%), FTC in 62 (26%), and HTC in five (2%). Among PTC subtypes, classic PTC was 147, follicular variant PTC was six, and other type of PTC was six. The median primary tumor size representing initial distant metastasis was 2.8 cm (interquartile range, 0.1 to 11.5). Gross extrathyroidal extension was found in 87 patients (36%), and positive resection margin was detected in 69 patients (29%). Nearly all patients had undergone total thyroidectomy (97%) and RAI therapy (99%), respectively.
Characteristics of initial distant metastasis
Of the 242 enrolled patients, 149 (62%) were classified as only lung metastasis, 49 patients (20%) were classified as only bone metastasis, and 43 patients (18%) were classified as combined metastasis. One patient presented with only pleural metastasis. Among other site metastasis except lung and bone, three patients showed pleural metastasis and one patient showed brain metastasis. Pleural metastasis was found in CT and brain metastasis was found in PET CT.
Among the only lung metastasis group, 87 patients (58%) were classified with micronodular lung metastasis, 24 (16%) with macronodular lung metastasis, and 38 (26%) with miliary metastasis. Among the only bone metastasis group, 17 patients (35%) were classified with single bone metastasis and 32 (65%) with multiple bone metastases (Fig. 1). The combined metastasis group included 40 patients with lung and bone, two with bone and other site, and one with lung and other site metastasis. Only lung metastasis was more frequent in PTC than in FTC (79% vs. 13%, P<0.001), and only bone metastasis was more frequent in FTC than in PTC (50% vs. 8%, P<0.001).
Among 242 patients, 50 (21%) had non-RAI avidity. According to the metastatic site, 25 of the patients (17%) with only lung metastasis, six of the patients (12%) with only bone metastasis, 18 of the patients (42%) with combined metastasis, and one of the patients with pleural metastasis had non-RAI avidity, respectively. The combined metastasis group (42%) had a higher rate of non-RAI avidity than the other lung and bone only groups.
Treatment response and survival characteristics
A total of 240 patients (99%) had undergone initial RAI therapy. Two patients were not treated with RAI for personal reasons. TKI was used in 20 patients (8%) and systemic chemotherapy in 10 patients (4%). External radiotherapy was performed on 54 patients (22%) with bone metastasis.
Sixty-three patients (26%) died of thyroid cancer after a median of 5 years (interquartile range, 0.5 to 15.1) after initial surgery. The 5-year survival rate was 84.8%, the 10-year survival rate was 68.1%, and the 15-year survival rate was 59.4%. Kaplan-Meier analysis and a log-rank test were used to evaluate the risk factors for disease-specific death. Age (>55 years), male sex, tumor histology (FTC), site of distant metastasis (combined metastasis), and non-RAI avidity were significant risk factors for disease-specific death (Fig. 2). After adjustment for all other variables using a Cox proportional hazard model, old age, male sex, tumor histology (FTC), and site of distant metastasis were independent risk factors for disease-specific death (Table 2). Combined metastasis had a worse prognosis than single-organ metastasis by univariate log-rank test, but there was no statistical significance according to the multivariate Cox proportional hazard model (hazard ratio, 1.63; 95% confidence interval, 0.78 to 3.41; P=0.195). The following prognostic factors were stratified according to age: site of metastasis, tumor histology, and RAI avidity. After this stratification, bone and combined metastasis, FTC, and non-RAI avidity were increased with age (Fig. 3).
We analyzed 242 patients with DTC and initial distant metastasis. To the best of our knowledge, this study was the largest study investigating DTC and initial distant metastasis, specifically regarding long-term prognosis and recent treatment status. The 10-year survival rate associated with DTC and initial distant metastasis was 68.1%, which was higher than in previous reports. Age, gender, histology, and site of distant metastasis were revealed to be the prognostic factors.
Survival rates in this study were higher than in other studies. Ruegemer et al. [20] reported that the 5- and 10-year survival rates of DTC with distant metastasis were 35% and 25%, respectively. Recently, Nixon et al. [14] reported that the 5-year disease-specific survival rate was 68% in 52 patients with DTC and initial distant metastasis at the Memorial Sloan-Kettering Cancer Center. In our study, the 5- and 10-year disease-specific survival rates were 84.8% and 68.1%, respectively. These discrepancies could be explained by a few differences. First, the study population is different. In a study by Shaha et al. [21], 43% (19/44) of the patients had PTC, 41% (18/44) had FTC, and 16% (7/44) had HTC, respectively. However, in our study, patients with PTC were predominant (PTC 72% [175/242] vs. FTC/HTC 28% [67/242]). In another study in Korea, patients with PTC were also predominant (72%) [22]. The survival rate of patients with DTC with distant metastasis in our study should be better than that in the Western studies, because of good prognosis associated with PTC compared to FTC and HTC [891314]. Second, some patients with early diagnosis of DTC, such as those with papillary thyroid microcarcinomas (PTMC) less than 1 cm in diameter, were enrolled in our study [1516]. Patients with PTMC accounted for 11% (19/174) of total PTC patients. Therefore, early detection of metastatic cancer may affect better prognosis than previous studies. Third, new therapeutic modalities such as TKI were available in our study and they might have increased the survival rate, although a limited number of patients had undergone additional therapy (TKI 8%, chemotherapy 4%) [1718].
In the previous study, the prognostic factors associated with initial distant metastasis were age, number of involved organs, RAI avidity, extent of metastasis, and symptoms [1012142023]. In our study, older age, male sex, FTC, combined metastasis, and non-RAI avidity were associated with poor prognosis in a univariate log-rank test (Fig. 2). The non-RAI avidity and combined metastasis groups had poor prognosis (P<0.001). However, when the multivariate Cox proportional hazard model was used to adjust for the other variables, RAI avidity and combined metastasis were no longer significant (Table 2). As age increased, the ratio of FTC, combined metastasis, and non-RAI avidity were increased, which had a negative impact on prognosis (Fig. 3). This likely reflects that older patients tended to present with more aggressive clinical behaviors of metastatic DTC. When the patients were divided into PTC and FTC (including HTC) to analyze the factors affecting the prognosis, significant factors which affecting prognosis were different (Table 3). The factors affecting disease specific death of PTC were old age, site of metastasis (combined>lung metastasis), positive resection margin, and non-RAI avidity. However, only old age and site of metastasis (lung only>bone only) were significant prognostic factor for FTC. Because the numbers of FTC patients were relatively small, reassignment of a few cases might have changed the results.
In our study, there were two noteworthy features. One was that the youngest patient diagnosed with initial distant metastasis was 13 years old. This finding indicates that distant metastasis can occur even in children. The other was that initial distant metastasis was found in a patient whose primary tumor size was 0.1 cm in diameter, although this was an extremely rare finding. Distant metastases have usually been observed in DTC patients with tumors ≥0.8 cm [24]. Therefore, careful evaluation should be necessary even in young patients or patients with very small tumors.
Our study has several limitations. First, it was a retrospective multicenter study, and therefore some data were missing during the long-term follow-up. Also, the centers did not use the same guidelines for evaluation and treatment. Second, the proportion of patients with initial distant metastasis might have been overestimated because patients were selected from the institutional databases of tertiary care centers. Third, molecular markers such as BRAFV600E or telomerase reverse transcriptase (TERT) promoter mutations could not be used for prognostic analysis. Fourth, despite the relatively large number of DTC patients with initial distant metastasis, the numbers in some subgroups were small. Additional nationwide studies will be needed for detailed subgroup analyses. Nevertheless, this study has strength as the first large cohort study in patients with DTC and initial distant metastasis in Korea. This study presented a prevalence of initial distant metastasis in DTC patients, and also showed the distribution of initial metastasis sites, rate of initial RAI refractoriness in initial distant metastasis patients. Also it showed recent trend in treatment for advanced metastatic DTC patients and mortality. These results may be helpful in further clinical research and patient management.
In conclusion, this study showed the clinical characteristics and long-term prognosis of Korean patients with DTC and initial distant metastasis. Age, gender, tumor histology, and metastatic site were the prognostic factors for patients with DTC and initial distant metastasis, and their survival rates were better compared to those in other reports.
Acknowledgements
This work was supported by the Korean Endocrine Society of EnM Research Award 2017.

CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS: Conception or design: T.H.K., J.H.C. Acquisition, analysis, or interpretation of data: H.K., H.I.K., S.W.K., J.J., M.J.J., W.G.K., T.Y.K., H.K.K., H.C.K., J.M.H., Y.Y.C. Drafting the work or revising: H.K., T.H.K. Final approval of the manuscript: T.H.K., J.H.C.

  • 1. Durante C, Montesano T, Torlontano M, Attard M, Monzani F, Tumino S, et al. Papillary thyroid cancer: time course of recurrences during postsurgery surveillance. J Clin Endocrinol Metab 2013;98:636–642. ArticlePubMed
  • 2. Olaleye O, Ekrikpo U, Moorthy R, Lyne O, Wiseberg J, Black M, et al. Increasing incidence of differentiated thyroid cancer in South East England: 1987–2006. Eur Arch Otorhinolaryngol 2011;268:899–906. ArticlePubMedPDF
  • 3. Pires BP, Alves PA Jr, Bordallo MA, Bulzico DA, Lopes FP, Farias T, et al. Prognostic factors for early and long-term remission in pediatric differentiated thyroid carcinoma: the role of sex, age, clinical presentation, and the newly proposed American Thyroid Association risk stratification system. Thyroid 2016;26:1480–1487. ArticlePubMed
  • 4. Cho BY, Choi HS, Park YJ, Lim JA, Ahn HY, Lee EK, et al. Changes in the clinicopathological characteristics and outcomes of thyroid cancer in Korea over the past four decades. Thyroid 2013;23:797–804. ArticlePubMedPMC
  • 5. Kim H, Kim TH, Choe JH, Kim JH, Kim JS, Oh YL, et al. Patterns of initial recurrence in completely resected papillary thyroid carcinoma. Thyroid 2017;27:908–914. ArticlePubMed
  • 6. 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;53:982–992. ArticlePubMed
  • 7. Pittas AG, Adler M, Fazzari M, Tickoo S, Rosai J, Larson SM, et al. Bone metastases from thyroid carcinoma: clinical characteristics and prognostic variables in one hundred forty-six patients. Thyroid 2000;10:261–268. ArticlePubMed
  • 8. 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;110:1451–1456. ArticlePubMed
  • 9. Schlumberger M, Tubiana M, De Vathaire F, Hill C, Gardet P, Travagli JP, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 1986;63:960–967. ArticlePubMedPDF
  • 10. Lee J, Soh EY. Differentiated thyroid carcinoma presenting with distant metastasis at initial diagnosis clinical outcomes and prognostic factors. Ann Surg 2010;251:114–119. ArticlePubMed
  • 11. Shaha AR, Ferlito A, Rinaldo A. Distant metastases from thyroid and parathyroid cancer. ORL J Otorhinolaryngol Relat Spec 2001;63:243–249. ArticlePubMed
  • 12. Shoup M, Stojadinovic A, Nissan A, Ghossein RA, Freedman S, Brennan MF, et al. Prognostic indicators of outcomes in patients with distant metastases from differentiated thyroid carcinoma. J Am Coll Surg 2003;197:191–197. ArticlePubMed
  • 13. 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. Ann Surg Oncol 2013;20:1329–1335. ArticlePubMed
  • 14. Nixon IJ, Whitcher MM, Palmer FL, Tuttle RM, Shaha AR, Shah JP, et al. The impact of distant metastases at presentation on prognosis in patients with differentiated carcinoma of the thyroid gland. Thyroid 2012;22:884–889. ArticlePubMedPMC
  • 15. Ahn HS, Kim HJ, Kim KH, Lee YS, Han SJ, Kim Y, et al. Thyroid cancer screening in South Korea increases detection of papillary cancers with no impact on other subtypes or thyroid cancer mortality. Thyroid 2016;26:1535–1540. ArticlePubMed
  • 16. Lubitz CC, Sosa JA. The changing landscape of papillary thyroid cancer: epidemiology, management, and the implications for patients. Cancer 2016;122:3754–3759. ArticlePubMed
  • 17. Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 2014;384:319–328. ArticlePubMedPMC
  • 18. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621–630. ArticlePubMed
  • 19. Haugen BR. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: what is new and what has changed? Cancer 2017;123:372–381. ArticlePubMed
  • 20. Ruegemer JJ, Hay ID, Bergstralh EJ, Ryan JJ, Offord KP, Gorman CA. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab 1988;67:501–508. ArticlePubMedPDF
  • 21. Shaha AR, Shah JP, Loree TR. Differentiated thyroid cancer presenting initially with distant metastasis. Am J Surg 1997;174:474–476. ArticlePubMed
  • 22. Jeon MJ, Kim WG, Kim TH, Kim HK, Kim BH, Yi HS, et al. Disease-specific mortality of differentiated thyroid cancer patients in Korea: a multicenter cohort study. Endocrinol Metab (Seoul) 2017;32:434–441. ArticlePubMedPMC
  • 23. Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91:2892–2899. ArticlePubMedPDF
  • 24. Roti E, Rossi R, Trasforini G, Bertelli F, Ambrosio MR, Busutti L, et al. Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients. J Clin Endocrinol Metab 2006;91:2171–2178. ArticlePubMedPDF
Fig. 1

Classification of initial distant metastasis in this study. A total of 242 patients were diagnosed with initial distant metastasis. Patients were classified according to site of distant metastasis. Diagnoses were as follows: 149 with lung only, 49 with bone only, and 43 with combined metastasis. One patient was diagnosed with other site only metastasis. Lung metastasis was subdivided into micronodular, macronodular, and miliary metastasis. Bone metastasis was subdivided into solitary and multiple metastases.

enm-33-287-g001.jpg
Fig. 2

Survival analysis according to risk factors in patients with differentiated thyroid carcinoma and initial distant metastasis. A Kaplan-Meier analysis and log-rank test were used to evaluate the risk factors for disease-specific death (DSD). (A) Age (>55 years), (B) male sex, (C) tumor histology (follicular thyroid carcinoma [FTC] rather than papillary thyroid carcinoma [PTC]), (D) radioactive iodine (RAI) avidity (non-RAI avidity), and (E) metastatic site were significant risk factors for DSD. HTC, Hürthle cell carcinoma.

enm-33-287-g002.jpg
Fig. 3

Prognostic factors according to change of age. When the prognostic factors site of distant metastasis, tumor histology, and radioactive iodine (RAI) avidity were stratified according to age, (A) the bone only/combined metastasis group, (B) follicular thyroid carcinoma (FTC), and (C) non-RAI avidity were increased with age. However, lung only group, papillary thyroid carcinoma (PTC), and RAI avidity decreased according to age. HTC, Hürthle cell carcinoma.

enm-33-287-g003.jpg
Table 1

Baseline Characteristics of Differentiated Thyroid Cancer Patients with Initial Distant Metastasis

enm-33-287-i001.jpg
Characteristic Total enrolled patients
Age, yr 51.0±17.1
Female sex 157 (64.9)
Type of thyroid surgery
 Total thyroidectomy 234 (96.7)
 Lobectomy 8 (3.3)
RAI treatment
 Yes 240 (99.2)
 No 2 (0.8)
Initial neck dissection
 No 37 (15.3)
 Yes 205 (84.7)
Tumor histology
 PTC 175 (72.3)
 FTC 62 (25.6)
 HTC 5 (2.1)
Tumor size, cm 2.8±2.0
ETE
 No 61 (25.1)
 Microscopic ETE 94 (38.9)
 Gross ETE 87 (36.0)
Resection margin
 Positive 69 (28.5)
 Negative 173 (71.5)
No. of resected LN 17.5±25.8
No. of initial LN metastasis 6.0±11.2
Lymphatic invasion
 Yes 70 (28.9)
 No 172 (71.1)
Vascular invasion
 Yes 45 (18.6)
 No 197 (81.4)
T stage
 T1 64 (26.4)
 T2 79 (32.6)
 T3a 50 (20.7)
 T3b 33 (13.6)
 T4a 11 (4.5)
 T4b 4 (1.7)
N stage
 N0 77 (31.8)
 N1a 38 (15.7)
 N1b 126 (52.1)

Values are expressed as mean±SD or number (%).

RAI, radioactive iodine; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; HTC, Hürthle cell carcinoma; ETE, extrathyroidal extension; LN, lymph node.

Table 2

Prognostic Factors for Disease Specific Death in Patients with Differentiated Thyroid Cancer and Initial Distant Metastasis

enm-33-287-i002.jpg
Characteristic Unadjusted Adjusted
OR (95% CI) P value OR (95% CI) P value
Age at diagnosis, yr 1.08 (1.05–1.10) <0.001 1.07 (1.05–1.10) <0.001
Male sex 2.19 (1.33–3.61) 0.002 2.60 (1.49–4.53) 0.001
LN dissection
 No Reference 0.126 - -
 CND 1.96 (1.03–3.73) 0.042 - -
 LND 1.27 (0.72–2.23) 0.408 - -
Distant metastasis
 Lung only Reference <0.001 Reference 0.003
 Bone only 1.14 (0.56–2.34) 0.852 0.43 (0.16–1.13) 0.088
 Combined 3.36 (1.95–5.81) <0.001 1.63 (0.78–3.41) 0.195
 Other site 0.00 (0.00–0.00) 0.974 0.00 (0.00–0.00) 0.977
Tumor histology
 PTC Reference <0.001 Reference 0.007
 FTC 3.00 (1.81–4.97) <0.001 3.25 (1.51–7.01) 0.003
 HTC 1.04 (0.14–7.63) 0.968 0.95 (0.12–7.53) 0.964
Tumor size 1.22 (1.11–1.35) <0.001 - -
No. of initial LN metastases 0.97 (0.95–1.00) 0.047 - -
Positive lymphatic invasion 2.36 (1.41–3.95) 0.001 - -
Positive blood vessel invasion 1.45 (0.80–2.64) 0.221 - -
Positive resection margin 0.97 (0.57–1.65) 0.899 - -
ETE
 No Reference 0.363 - -
 Microscopic ETE 0.63 (0.33–1.19) 0.156 - -
 Gross ETE 0.81 (0.44–1.48) 0.490 - -
Non-RAI avidity 3.69 (2.19–6.23) <0.001 - -

Cox proportional hazard regression model was performed.

OR, odds ratio; CI, confidence interval; LN, lymph node; CND, central neck dissection; LND, lateral neck dissection; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; HTC, Hürthle cell carcinoma; ETE, extrathyroidal extension; RAI, radioactive iodine.

Table 3

Prognostic Factors for Disease Specific Death in Patients with Differentiated Thyroid Cancer and Initial Distant Metastasis According to Pathologic Subtype

enm-33-287-i003.jpg
Characteristic PTC FTC (including HTC)
OR (95% CI) P value OR (95% CI) P value
Age at diagnosis, yr 1.09 (1.05–1.13) <0.001 1.06 (1.01–1.11) 0.025
Male sex 5.88 (2.10–16.44) 0.001 0.93 (0.30–2.88) 0.906
LN dissection
 No Reference 0.048 Reference 0.552
 CND 0.15 (0.03–0.87) 0.035 1.71 (0.61–4.81) 0.303
 LND 0.11 (0.02–0.67) 0.017 1.51 (0.36–6.43) 0.568
Distant metastasis
 Lung only Reference 0.114 Reference 0.004
 Bone only 0.66 (0.07–5.80) 0.704 0.18 (0.04–0.79) 0.023
 Combined 3.45 (1.24–9.57) 0.017 1.30 (0.36–4.72) 0.692
 Other site 0.00 (0.00–0.00) 0.978 0.00 (0.00–0.00) -
Tumor size 1.22 (1.11–1.35) 0.103 1.23 (0.94–1.60) 0.134
No. of initial LN metastases 0.97 (0.95–1.00) 0.539 0.98 (0.88–1.10) 0.765
Positive lymphatic invasion 2.36 (1.41–3.95) 0.265 2.41 (0.76–7.64) 0.135
Positive blood vessel invasion 1.45 (0.80–2.64) 0.807 1.10 (0.37–3.25) 0.866
Positive resection margin 3.73 (1.42–9.84) 0.008 0.33 (0.07–1.53) 0.158
ETE
 No Reference 0.761 Reference 0.455
 Microscopic ETE 1.22 (0.23–6.44) 0.815 0.53 (0.15–1.80) 0.303
 Gross ETE 0.86 (0.20–3.62) 0.837 0.41 (0.10–1.73) 0.226
Non-RAI avidity 3.04 (1.24–7.35) 0.014 1.12 (0.41–3.05) 0.827

Multivariate Cox proportional hazard regression model was performed.

PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; HTC, Hürthle cell carcinoma; OR, odds ratio; CI, confidence interval; LN, lymph node; CND, central neck dissection; LND, lateral neck dissection; ETE, extrathyroidal extension; RAI, radioactive iodine.

Figure & Data

References

    Citations

    Citations to this article as recorded by  
    • Case report: A case of hyperthyroidism secondary to bone metastasis of differentiated thyroid cancer
      Tingyu Gu, Zhihong Zhao, Yuanyuan Shi, Zhenhua Sun, Yao Wang, Zhiyuan He, Kun Wang
      Frontiers in Oncology.2024;[Epub]     CrossRef
    • Thyroid Hormone Withdrawal versus Recombinant Human TSH as Preparation for I-131 Therapy in Patients with Metastatic Thyroid Cancer: A Systematic Review and Meta-Analysis
      Luca Giovanella, Maria Luisa Garo, Alfredo Campenní, Petra Petranović Ovčariček, Rainer Görges
      Cancers.2023; 15(9): 2510.     CrossRef
    • Molecular Theranostics in Radioiodine-Refractory Differentiated Thyroid Cancer
      Petra Petranović Ovčariček, Alfredo Campenni, Bart de Keizer, Desiree Deandreis, Michael C. Kreissl, Alexis Vrachimis, Murat Tuncel, Luca Giovanella
      Cancers.2023; 15(17): 4290.     CrossRef
    • Differentiating pulmonary metastasis from benign lung nodules in thyroid cancer patients using dual-energy CT parameters
      Taeho Ha, Wooil Kim, Jaehyung Cha, Young Hen Lee, Hyung Suk Seo, So Young Park, Nan Hee Kim, Sung Ho Hwang, Hwan Seok Yong, Yu-Whan Oh, Eun-Young Kang, Cherry Kim
      European Radiology.2022; 32(3): 1902.     CrossRef
    • Feasibility of Recombinant Human TSH as a Preparation for Radioiodine Therapy in Patients with Distant Metastases from Papillary Thyroid Cancer: Comparison of Long-Term Survival Outcomes with Thyroid Hormone Withdrawal
      Hsi-Chen Tsai, Kung-Chu Ho, Shih-Hsin Chen, Jing-Ren Tseng, Lan-Yan Yang, Kun-Ju Lin, Ju-Chin Cheng, Miaw-Jene Liou
      Diagnostics.2022; 12(1): 221.     CrossRef
    • Long-Term Quality of Life (5-15 Years Post-Thyroidectomy) of Thyroid Carcinoma Patients in Two Tertiary Care Hospitals
      Mohammed Yousef Alyousef, Mohammed Khaled Ghandour, Mohammed Al-Mohawes, Mosaad Alnwaisir, Tahera Islam, Khalid Al Qahtani
      Cureus.2022;[Epub]     CrossRef
    • Evaluation of Lipocalin-2 and Twist expression in thyroid cancers and its relationship with epithelial mesenchymal transition
      Pınar Celepli, İrem Bigat, Sefika Karabulut, Salih Celepli, Sema Hücümenoğlu
      Annals of Diagnostic Pathology.2022; 59: 151973.     CrossRef
    • Clinical study of ultrasonic evaluation of T/N staging of differentiated thyroid carcinoma using AJCC 8th staging criteria
      Yu Liang, Xingxiang Huang, Zhe Song, Yang Yang, Ju Lei, Mei Ren, Li Tan, Hui Zhang, Francis Moore
      PLOS ONE.2022; 17(6): e0269994.     CrossRef
    • Therapeutic challenges in metastatic follicular thyroid cancer occurring in pregnancy: A case report
      Claudio Spinelli, Beatrice Sanna, Marco Ghionzoli, Elisabetta Micelli
      World Journal of Obstetrics and Gynecology.2022; 11(3): 33.     CrossRef
    • Initial clinical and treatment patterns of advanced differentiated thyroid cancer: ERUDIT study
      Juan Antonio Vallejo Casas, Marcel Sambo, Carlos López López, Manuel Durán-Poveda, Julio Rodríguez-Villanueva García, Rita Joana Santos, Marta Llanos, Elena Navarro-González, Javier Aller, Virginia Pubul, Sonsoles Guadalix, Guillermo Crespo, Cintia Gonzál
      European Thyroid Journal.2022;[Epub]     CrossRef
    • Male sex is not an independent risk factor for recurrence of differentiated thyroid cancer: a propensity score-matching study
      Joonseon Park, Kwangsoon Kim, Dong-Jun Lim, Ja Seong Bae, Jeong Soo Kim
      Scientific Reports.2021;[Epub]     CrossRef
    • Evaluation of the 2015 ATA Guidelines in Patients With Distant Metastatic Differentiated Thyroid Cancer
      Evert F S van Velsen, Merel T Stegenga, Folkert J van Kemenade, Boen L R Kam, Tessa M van Ginhoven, W Edward Visser, Robin P Peeters
      The Journal of Clinical Endocrinology & Metabolism.2020; 105(3): e457.     CrossRef
    • Usefulness of a 3D‐Printed Thyroid Cancer Phantom for Clinician to Patient Communication
      Dayeong Hong, Sangwook Lee, Taehun Kim, Jung Hwan Baek, Won Woong Kim, Ki‐Wook Chung, Namkug Kim, Tae‐Yon Sung
      World Journal of Surgery.2020; 44(3): 788.     CrossRef
    • Estimating the Growth Rate of Lung Metastases in Differentiated Thyroid Carcinoma: Response Evaluation Criteria in Solid Tumors or Doubling Time?
      Eyun Song, Jonghwa Ahn, Min Ji Jeon, Sang Min Lee, Jeong Hyun Lee, Tae Yong Kim, Jung Hwan Baek, Won Bae Kim, Young Kee Shong, Won Gu Kim
      Thyroid.2020; 30(3): 418.     CrossRef
    • Personalized management of differentiated thyroid cancer in real life – practical guidance from a multidisciplinary panel of experts
      Alfredo Campennì, Daniele Barbaro, Marco Guzzo, Francesca Capoccetti, Luca Giovanella
      Endocrine.2020; 70(2): 280.     CrossRef
    • Unusual metastases from differentiated thyroid cancers: A multicenter study in Korea
      Jee Hee Yoon, Min Ji Jeon, Mijin Kim, A. Ram Hong, Hee Kyung Kim, Dong Yeob Shin, Bo Hyun Kim, Won Bae Kim, Young Kee Shong, Ho-Cheol Kang, Domenico Albano
      PLOS ONE.2020; 15(8): e0238207.     CrossRef
    • Extended Real-World Observation of Patients Treated with Sorafenib for Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma and Impact of Lenvatinib Salvage Treatment: A Korean Multicenter Study
      Hye-Seon Oh, Dong Yeob Shin, Mijin Kim, So Young Park, Tae Hyuk Kim, Bo Hyun Kim, Eui Young Kim, Won Bae Kim, Jae Hoon Chung, Young Kee Shong, Dong Jun Lim, Won Gu Kim
      Thyroid.2019; 29(12): 1804.     CrossRef
    • Clinical outcomes and prognostic factors in patients with no less than three distant organ system metastases from differentiated thyroid carcinoma
      Xin-Yun Zhang, Jian-Wen Sun, Zhong-Ling Qiu, Yang Wang, Xiao-Yue Chen, Jin-Hua Zhao, Quan-Yong Luo
      Endocrine.2019; 66(2): 254.     CrossRef
    • Molecular Profile and Clinical Outcomes in Differentiated Thyroid Cancer Patients Presenting with Bone Metastasis
      Nilma Malik, Alyaksandr V. Nikitski, Elie Klam, Jason Hunt, Benjamin Witt, Barbara Chadwick, Yuri E. Nikiforov, Devaprabu Abraham
      Endocrine Practice.2019; 25(12): 1255.     CrossRef
    • Improved survival after early detection of asymptomatic distant metastasis in patients with thyroid cancer
      Hosu Kim, So Young Park, Jaehoon Jung, Jung-Han Kim, Soo Yeon Hahn, Jung Hee Shin, Young Lyun Oh, Man Ki Chung, Hye In Kim, Sun Wook Kim, Jae Hoon Chung, Tae Hyuk Kim
      Scientific Reports.2019;[Epub]     CrossRef
    • Unusual metastases from differentiated thyroid carcinoma: analysis of 36 cases
      Anabela Zunino, Fabián Pitoia, Eduardo Faure, Adriana Reyes, Mónica Sala, Rosana Sklate, Verónica Ilera, Inés Califano
      Endocrine.2019; 65(3): 630.     CrossRef
    • The Prognosis of Papillary Thyroid Cancer with Initial Distant Metastasis is Strongly Associated with Extensive Extrathyroidal Extension: A Retrospective Cohort Study
      Young Ki Lee, Daham Kim, Dong Yeob Shin, Cho Rok Lee, Eun Jig Lee, Sang-Wook Kang, Jandee Lee, Jong Ju Jeong, Kee-Hyun Nam, Woong Youn Chung, Cheong Soo Park
      Annals of Surgical Oncology.2019; 26(7): 2200.     CrossRef
    • Risk Factors for Distant Metastasis in Follicular Thyroid Carcinoma in Korea
      Shin Dol Jo, Joon-Hyop Lee, Suk Ha Kang, Yun Yeong Kim, Yong Soon Chun, Heung Kyu Park, Sang Tae Choi, Jin Mo Kang, Yoo Seung Chung
      Journal of Endocrine Surgery.2019; 19(1): 1.     CrossRef
    • Expression levels of ARHI and Beclin1 in thyroid cancer and their relationship with clinical pathology and prognosis
      Houwei Zhu, Yanqing Qu
      Oncology Letters.2019;[Epub]     CrossRef
    • 甲状腺腫瘍治療の最新情報

      Nippon Jibiinkoka Gakkai Kaiho.2018; 121(11): 1336.     CrossRef
    • Clinical Outcomes of Differentiated Thyroid Cancer Patients with Local Recurrence or Distant Metastasis Detected in Old Age
      Ji Min Han, Ji Cheol Bae, Hye In Kim, Sam Kwon, Min Ji Jeon, Won Gu Kim, Tae Yong Kim, Young Kee Shong, Won Bae Kim
      Endocrinology and Metabolism.2018; 33(4): 459.     CrossRef
    • Efficacy and Affecting Factors of 131I Thyroid Remnant Ablation After Surgical Treatment of Differentiated Thyroid Carcinoma
      Chen Wang, Hongcui Diao, Ping Ren, Xufu Wang, Yangang Wang, Wenjuan Zhao
      Frontiers in Oncology.2018;[Epub]     CrossRef

    Figure

    Endocrinol Metab : Endocrinology and Metabolism