Skip Navigation LinksHome > September 2012 - Volume 37 - Issue 9 > Comparison of Clinical Outcomes in Differentiated Thyroid Ca...
Clinical Nuclear Medicine:
doi: 10.1097/RLU.0b013e318262c5d6
Original Articles

Comparison of Clinical Outcomes in Differentiated Thyroid Carcinoma Between Children and Young Adult Patients

Kim, Sang Soo MD*†; Kim, Seong-Jang MD, PhD†‡; Kim,, In Joo*†; Kim, Bo Hyun MD, PhD*; Jeon, Yun Kyung MD*; Kim, Yong-Ki MD, PhD§

Free Access
Article Outline
Collapse Box

Author Information

From the *Department of Internal Medicine, †Biomedical Research Institute, and ‡Department of Nuclear Medicine, Pusan National University Hospital; and §Kim Yong Ki Internal Medicine Clinic, Busan, Korea.

Received for publication March 29, 2012; revision accepted May 14, 2012.

Conflicts of interest and sources of funding: none declared.

Reprints: Seong-Jang Kim MD, PhD, Department of Nuclear Medicine, Pusan National University Hospital and Medical Research Institute, 179 Gudeok-Ro, Seo-Gu, Busan 602-739, Korea. E-mail: growthkim@daum.net; growthkim@pusan.ac.kr.

Collapse Box

Abstract

Objective: The aim of the present study was to evaluate differences between children and young adult patients in presentation, clinical course, and outcome of well-differentiated thyroid carcinoma (DTC).

Methods: We retrospectively reviewed the medical records of 61 children and young adults (50 female and 11 male; aged <25 years) with DTC who were treated with radioiodine (RI) and followed up between June 2002 and May 2010. All patients had undergone total thyroidectomy with lymph node dissection if enlarged lymph nodes were present and had been referred for initial radioiodine ablation. Recurrence-free survival was evaluated with the Kaplan-Meier method.

Results: At diagnosis, extrathyroidal extension of DTC was more prevalent and mean tumor size was bigger in children than in young adults (P = 0.045 and P = 0.002, respectively). However, there was no significant difference between the 2 groups with regard to the presence of lymph node or distant metastases (P = 0.885 and P = 1.000, respectively). During follow-up, the recurrence in the thyroid bed or cervical lymph nodes occurred in 6 children (20.7%) and in 3 young adults (9.4%; P = 0.323). The recurrence-free survival rate was similar in children and in young adults (log-rank test, χ21 = 2.424, P = 0.120).

Conclusions: Our result shows that, although the presentation of DTC at the time of diagnosis was more aggressive in children, intensive management elicited a similar clinical outcome in children and in young adults.

Well-differentiated thyroid carcinoma (DTC) in children and adolescents is an uncommon disease, accounting for 1.5% to 3.0% of all childhood cancers.1–4 There is an increased incidence in during puberty, but thyroid cancer can occur at any age.5 In England and Wales, there are 0.19 cases/million per year in those up to 14 years; this increases to 3 cases/million per year between ages of 15 and 25 years.6 The incidence of thyroid cancer seems to be steadily increasing among children, in part because of the treatment of head and neck malignancies with ionizing radiation from the 1930s to the 1960s and also because of increased vigilance and early diagnosis.7,8 Differentiated thyroid carcinoma comprises 90% to 95% of all childhood thyroid cancers with similar frequency in adults. However, children tend to present more often with advanced disease than adults do at the time of diagnosis.9,10 As with adult disease, primary treatment of pediatric DTC generally comprises some combination of 3 modalities, such as surgery, radioiodine ablation, and thyroid hormone suppression therapy, applied at varying levels of intensity with controversy about the optimal treatment.

It has been suggested that DTC has a more aggressive presentation in prepuberty than in puberty.11 However, they demonstrated that an intensive initial treatment (extensive surgery and high-dose radioiodine ablation) followed by thyrotropin [thyroid-stimulating hormone (TSH)] suppression and careful surveillance results in a similar clinical outcome between the 2 groups. Until now, only 1 study has analyzed pediatric DTC, with young adults (<25 years) contrary to most clinical studies.12 However, there are no data about characteristics of children versus young adults with DTC.

The aim of the present study was to evaluate differences between children and young adult patients underwent intensive treatment in presentation, clinical course, and outcome of DTC.

Back to Top | Article Outline

MATERIALS AND METHODS

Patients

We retrospectively reviewed the medical records of 61 children and young adults (50 female and 11 male; aged <25 years) with DTC who were treated with radioiodine and followed up at our hospital between June 2002 and May 2010. None of the patients had a history of head and neck irradiation. Three surgeons performed thyroid surgeries during the study period. In our hospital, total thyroidectomy was the surgical procedure of choice for DTC. Of the 61 patients, 58 patients (95.1%) underwent total thyroidectomy, whereas 3 patients (4.9%) underwent lobectomy followed by completion thyroidectomy. A bilateral central compartment neck dissection was performed during thyroidectomy in 53 patients (86.9%) and a lateral or modified neck dissection (n = 17, 27.9%) was performed for patients with clinically overt or ultrasound-detected metastatic cervical lymph nodes. Preoperative assessment for lateral cervical lymph node metastasis included preoperative neck ultrasonography, fine-needle aspiration cytology, and CT scans. Postoperative data on tumor characteristics included histological type, tumor size, extrathyroidal extension, number of neoplastic foci, and local and distant metastases. Extrathyroid extension was defined by pathological report according to the American Joint Committee on Cancer/Union Internationale Contre le Cancer pathological TNM classification criteria.

Postoperative radioiodine ablation was given to all patients. All patients received levothyroxine in a suppressive dose (TSH levels below 0.05–0.1 mIU/mL). Radioiodine was administered usually 4 weeks after withdrawal of levothyroxine or 2 weeks after withdrawal of liothyronine. All patients were advised to start a low-iodine diet 2 weeks before radioiodine administration. Radioiodine was administered by fixed doses empirically, taking into account the site and extent of metastatic disease: 2.22 to 3.70 GBq (60–100 mCi) for thyroid remnant ablation, 5.55 to 6.48 GBq (150–175 mCi) for disease confined to the neck, and 7.40 GBq (200 mCi) for distant metastases. All patients underwent a posttherapy whole-body scan (WBS) 1 week after radioiodine administration. Blood samples for determination of serum TSH and thyroglobulin (Tg) were taken just before radioiodine administration and at posttherapy WBS.

Physical examination was regularly performed on all the patients. A diagnostic WBS was routinely scheduled every 1 to 2 years after surgery and 131I ablation treatment was done. Serum Tg measurements, anti-Tg antibody assays, and TSH measurements were done at the time of each WBS. When the clinical or biochemical data suggested recurrence, the normal and/or malignant thyroid tissue was localized by nonradioiodine imaging methods, including neck ultrasonography, 18F-FDG PET or chest CT. Recurrence was defined as the reappearance of disease after complete ablation of the postsurgical thyroid remnants, and this was confirmed by cytological and/or histopathological examination or by the posttreatment 131I WBS showing persistently definite 131I uptake outside the thyroid bed. In assessing the outcome, because there were no deaths, the end point of the analysis was recurrence-free survival (RFS). This was defined as the time from the first operation until the first thyroid bed or lymph node event or, if no event occurred, until the last follow-up visit to our hospital.13

Informed consent was obtained from each participant at the time of surgery; the retrospective review protocol was approved by the institutional review board at the Pusan National University Hospital.

Back to Top | Article Outline
Statistical Analysis

All continuous variables were expressed as mean (SD). Differences in the 2 groups were tested with independent-samples t tests for continuous variables and χ2 tests or Fisher exact tests for categorical variables. Recurrence-free survival was evaluated with the Kaplan-Meier method. Comparison of the overall RFS in children and young adults was examined with the log-rank test. Statistical analyses were performed using MedCalc for Windows version 8.1 (MedCalc, Mariakerke, Belgium), and statistical significance was defined as P < 0.05.

Back to Top | Article Outline

RESULTS

Patient Characteristics

Of the 61 patients younger than 25 years at presentation with DTC, 29 were children (≤18 years) and 32 were young adults (19–24 years). Table 1 compares clinical characteristics between the 2 groups. The mean age at the diagnosis was significantly different between the 2 groups [15.7 (2.5) vs 22.4 (1.4), P < 0.001]. Of them, 55 patients (90.2%) had been diagnosed with papillary thyroid carcinoma and 6 (9.8%) had been diagnosed with follicular carcinoma. At diagnosis, extrathyroidal extension of the tumor was more prevalent in children (P = 0.045). In addition, mean tumor size was larger in children than in the young adults [3.26 (1.98) vs 1.95 (1.05), P = 0.002]. However, there was no significant difference in the frequency of intrathyroidal multifocality, lymph node metastasis, and distant metastasis between the 2 groups. Positive nodal disease in the neck was manifested in 21 children (72.4%) and in 24 young adults (75%; P = 0.885). Two patients had distant metastases in the lung.

Table 1
Table 1
Image Tools
Back to Top | Article Outline
Initial Treatment

The initial treatment protocol was the same in both groups, consisting of total thyroidectomy with dissection of suspicious enlarged lymph nodes and radioiodine therapy (Table 2). All patients underwent total thyroidectomy or lobectomy followed by completion of thyroidectomy, and the type of operation was similar in the 2 groups (P = 0.613). There were no significant differences in the frequency of central and lateral neck dissection between the 2 groups (P = 0.542 and P = 0.536, respectively). The radioiodine dose was in the range of 60 to 200 mCi. Although there was no statistically significant difference, the administered dose was more in the young adults than in the children [6.01 (1.05) GBq (162.5 {28.4} mCi) vs 5.44 (1.36) GBq (146.9 {36.8} mCi), P = 0.067].

Table 2
Table 2
Image Tools
Back to Top | Article Outline
Clinical Courses and Outcomes

The complications after surgical and radioiodine treatments were similar in both groups, well tolerated with mild adverse effects (Table 3). Recurrent laryngeal nerve damage was observed in 1 patient in the young adult group. The development of hypoparathyroidism (transient or permanent) was documented in 9 children (31.0%) and in 10 young adults (31.3%; P = 0.986). Early complications related to radioiodine therapy such as gastritis, neck pain, and sialadenitis were common in both group, although these adverse effects were well tolerated and temporary. Mild myelosuppression was documented in 1 child and in 2 young adults (P = 0.613). The median follow-up duration was similar between 2 groups [35 months (13-101 months) in children vs 38 months (12–90 months), P = 0.561]. During follow-up, the recurrence in the thyroid bed or cervical lymph nodes occurred in 6 children (20.7%) and in 3 young adults (9.4%; P = 0.323). The Kaplan-Meier curves showed that the RFS rate was similar in children and in young adults (Fig. 1; log-rank test, χ21 = 2.424, P = 0.120). Two patients with lung metastasis had persistent disease foci in the imaging modalities until the last follow-up time, although they demonstrated decreased serum Tg and extent of metastatic lesion compared to the initial evaluation.

Table 3
Table 3
Image Tools
Figure 1
Figure 1
Image Tools
Back to Top | Article Outline

DISCUSSION

To date, DTC has been considered to constitute a distinct disease in young patients and in adults.14 This is the first study showing clinical characteristics between children and young adult patients with DTC.

In the present study, tumor size was larger and extrathyroidal extension was more prevalent in children than in the young adults, which is consistent with previous reports. Mean tumor volume at diagnosis has been much larger in patients younger than 20 years than in those aged 20 to 50 years.14 It should also be considered that the thyroid gland is smaller in children than in adults, which can lead to earlier involvement of the thyroid capsule and surrounding tissues.15

The optimal management of DTC in children is controversial. The extent of initial surgery (total thyroidectomy and lymph node dissection vs partial thyroidectomy), 131I dosing for initial ablation [low dose (30 mCi) vs higher doses on the basis of tumor extension and body weight], and the degree of TSH suppression (TSH values between 0.1 and 0.5 mIU/L or <0.1 mIU/L) are still being debated.16,17 Some investigators recommended routine near-total or total thyroidectomy, arguing that such surgery removes all malignant thyroid tissue, improves patient outcome, and makes follow-up more reliable.18–21 The proponents for radical surgery are based on the rationale that DTC in young patients is frequently multifocal and shows bilateral involvement.12 On the contrary, others advocated less aggressive treatment to decrease the risk of surgical complications.22–24

Remnant thyroid ablation with radioiodine improves subsequent WBS and Tg sensitivity, allowing earlier diagnosis and greater effectiveness of repeated radioiodine therapy for patients with persistent or metastatic disease.12 Radioiodine ablation was demonstrated to be the most important factor that reduced local recurrence, distant metastasis, and cancer death.25

Although sodium iodide symporter (NIS) expression is reduced compared with that of healthy thyroid cells, childhood tumors seem to have greater and more frequently detectable expression than do adult tumors.26–28 The greater NIS expression in childhood than in adult DTC implies greater differentiation and radioiodine responsiveness in the former, which may be relevant to the outcome. In young patients, recurrence risk was increased in NIS-negative versus NIS-positive tumors, even when TNM status and treatment were similar.27 A low level of expression of NIS in the PTC tissue with BRAF gene point mutation has been demonstrated.29 The frequency of BRAF mutation in childhood PTC is very low.30–32 Thus, this molecular, biological finding advocates radioiodine therapy.

In our study, all patients underwent extensive surgery (total thyroidectomy with or without lymph node dissection) and received relatively high radioiodine doses and suppressive doses of thyroid hormone intended to achieve undetectable TSH levels (below 0.05–0.1 mIU/L). Because, in this age group, DTC cells have been found to be very sensitive to TSH,33 the lack of stimulation manifested in undetectable TSH levels could serve to act against tumor cell proliferation and thus reduce the risk of recurrence.

In general, children have higher local and distant recurrence rates for thyroid cancer than do adults.5 However, in the present study, despite more aggressive presentation of DTC at the time of diagnosis in children, intensive management elicited a similar RFS rate in children and in young adults. Considering our findings and previously published reports, more intensive management may be essential to avoid recurrence in younger patients with DTC.

A limitation of the current study is that follow-up durations were not long enough to detect late recurrence. Compared to the adults, children with thyroid cancers have to be followed up during their lifetime because radioiodine therapy may potentially be a risk factor for second primary malignancy and childhood thyroid cancers have a higher risk for relapses in comparison with adults.34 However, since high-dose radioiodine ablation had been first started on 2002 at our institution, mean follow-up duration was only 3.5 years. In our study, the number of enrolled patients was small, which weakens the strength of our findings. Thus, a larger, well-designed study that has a long follow-up duration is required to confirm our findings in the future.

Back to Top | Article Outline

CONCLUSIONS

Based on the data presented, our results showed that, although the presentation of DTC at the time of diagnosis was more aggressive in children, intensive management elicited a similar clinical outcome in children and in the young adults. It is suggested that more intensive initial management may be essential to avoid recurrence in young patients with DTC.

Back to Top | Article Outline

REFERENCES

1. Miller RW, Young JL, Novakovic B. Childhood cancer. Cancer. 1995; 75: 395–405.

2. Leboulleux S, Baudin E, Hartl DW, et al.. Follicular cell–derived thyroid cancer in children. Horm Res. 2005; 63: 145–151.

3. Shapiro NL, Bhattacharyya N. Population-based outcomes for pediatric thyroid carcinoma. Laryngoscope. 2005; 115: 337–340.

4. Steliarova-Foucher E, Stiller CA, Pukkala E, et al.. Thyroid cancer incidence and survival among European children and adolescents (1978–1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer. 2006; 42: 2150–2169.

5. Parisi MT, Mankoff D. Differentiated pediatric thyroid cancer: correlates with adult disease, controversies in treatment. Semin Nucl Med. 2007; 37: 340–356.

6. Harach HR, Williams ED. Childhood thyroid cancer in England and Wales. Br J Cancer. 1995; 72: 777–783

7. Liu S, Semenciw R, Ugnat AM, et al.. Increasing thyroid cancer incidence in Canada, 1970-1996: time trends and age-period-cohort effects. Br J Cancer. 2001; 85: 1335–1339.

8. Colonna M, Grosclaude P, Remontet L, et al.. Incidence of thyroid cancer in adults recorded by French cancer registries (1978–1997). Eur J Cancer. 2002; 38: 1762–1768.

9. Dinauer CA, Breuer C, Rivkees SA. Differentiated thyroid cancer in children: diagnosis and management. Curr Opin Oncol. 2008; 20: 59–65.

10. Halac I, Zimmerman D. Thyroid nodules and cancers in children. Endocrinol Metab Clin North Am. 2005; 34: 725–744.

11. Lazar L, Lebenthal Y, Steinmetz A, et al.. Differentiated thyroid carcinoma in pediatric patients: comparison of presentation and course between pre-pubertal children and adolescents. J Pediatr. 2009; 154: 708–714.

12. Hod N, Hagag P, Baumer M, et al.. Differentiated thyroid carcinoma in children and young adults: evaluation of response to treatment. Clin Nucl Med. 2005; 30: 387–390.

13. Handkiewicz-Junak D, Wloch J, Roskosz J, et al.. Total thyroidectomy and adjuvant radioiodine treatment independently decrease locoregional recurrence risk in childhood and adolescent differentiated thyroid cancer. J Nucl Med. 2005; 48: 879–888.

14. Mazzaferri EL, Kloos RT. Clinical review 128: current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab. 2001; 86: 1447–1463.

15. Farahati J, Reiners C, Demidchik EP. Is the UICC/AJCC Classification of primary tumor in childhood thyroid carcinoma valid? J Nucl Med. 1999; 40: 2125.

16. Dinauer CA, Francis GL. Thyroid cancer in children. Endocrinol Metab Clin North Am. 2007; 36: 779–806.

17. Dinauer CA, Breuer C, Rivkees SA. Differentiated thyroid cancer in children: diagnosis and management. Curr Opin Oncol. 2008; 20: 59–65.

18. Mazzaferri EL, Massoll N. Management of papillary and follicular (differentiated) thyroid cancer: new paradigms using recombinant human thyrotropin. Endocr Relat Cancer. 2002; 9: 227–247.

19. Jarzab B, Handkiewicz-Junak D, Wloch J, et al.. Multivariate analysis of prognostic factors for differentiated thyroid carcinoma in children. Eur J Nucl Med. 2000; 27: 833–841.

20. Grigsby PW, Gal-or A, Michalski JM, et al.. Childhood and adolescent thyroid carcinoma. Cancer. 2002; 95: 724–729.

21. Haveman JW, van Tol KM, Rouwe CW, et al.. Surgical experience in children with differentiated thyroid carcinoma. Ann Surg Oncol. 2003; 10: 15–20.

22. La Quaglia MP, Corbally MT, Heller G, et al.. Recurrence and morbidity in differentiated thyroid carcinoma in children. Surgery. 1988; 104: 1149–1156.

23. Borson-Chazot F, Causeret S, Lifante JC, et al.. Predictive factors for recurrence from a series of 74 children and adolescents with differentiated thyroid cancer. World J Surg. 2004; 28: 1088–1092.

24. Hay ID, Thompson GB, Grant CS, et al.. Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940–1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg. 2002; 26: 879–885.

25. Degroot LJ, Kaplan EL, McCormick M, et al.. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab. 1990; 71: 414–424.

26. Ringel MD, Anderson J, Souza SL, et al.. Expression of the sodium iodide symporter and thyroglobulin genes are reduced in papillary thyroid cancer. Mod Pathol. 2001; 14: 289–296.

27. Patel A, Jhiang S, Dogra S, et al.. Differentiated thyroid carcinoma that express sodium-iodide symporter have a lower risk of recurrence for children and adolescents. Pediatr Res. 2002; 52: 737–744.

28. Faggiano A, Coulot J, Bellon N, et al.. Age-dependent variation of follicular size and expression of iodine transporters in human thyroid tissue. J Nucl Med. 2004; 45: 232–237.

29. Xing M, Westra WH, Tufano RP, et al.. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005; 90: 6373–6379.

30. Kumagai A, Namba H, Saenko VA, et al.. Low frequency of BRAFT1796A mutations in childhood thyroid carcinomas. J Clin Endocrinol Metab. 2004; 89: 4280–4284.

31. Lima J, Trovisco V, Soares P, et al.. BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas. J Clin Endocrinol Metab. 2004; 89: 4267–4271.

32. Nikiforova MN, Ciampi R, Salvatore G, et al.. Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Cancer Lett. 2004; 209: 1–6.

33. Collini P, Mattavelli F, Pellegrinelli A, et al.. Papillary carcinoma of the thyroid gland of childhood and adolescence: morphologic subtypes, biologic behavior and prognosis: a clinicopathologic study of 42 sporadic cases treated at a single institution during a 30-year period. Am J Surg Pathol. 2006; 30: 1420–1426.

34. Kumagai A, Reiners C, Drozd V, et al.. Childhood thyroid cancers and radioactive iodine therapy: necessity of precautious radiation health risk management. Endocr J. 2007; 54: 839–847.

Keywords:

differentiated thyroid carcinoma; children; young adults

© 2012 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.