Management of thyroid nodules in children and adolescents

INTRODUCTION

Thyroid nodules are less common in children and adolescents than in adults, the prevalence of palpable thyroid nodules in childhood being about 1.5%, whereas in adulthood it is 4-7%.^1,2 In contrast, thyroid nodules are more often malignant in childhood than in adulthood: in children, 26% of thyroid nodules are malignant, while in adults the corresponding figure is 5-10%.^2,3 Risk factors for developing thyroid nodules in children are female sex, post-pubertalage, previous or co-existing thyroid disease, previous irradiation of the neck, and a family history of thyroid disease. Management of thyroid nodules in children and adolescents

CLASSIFICATION

Many thyroid diseases present clinically as thyroid nodules. Table 1 lists the relative frequency of the various etiologies among children and adolescents with solitary thyroid nodules. The data from two large studies (collecting cases of pediatric thyroid nodules over several decades) are combined in the Table.^4,5 The sex distribution oft he 128 children was 104 (81%) girls and 24 (19%) boys and the mean age was 13 years (range 1-18 yr). The vast majority of patients were euthyroid; only one subject was thyrotoxic, and some with lymphocytic thyroiditis were hypothyroid. Most cases of benign nodules represented colloid/ hyperplastic nodules or follicular adenomas. The histology of some benign nodules showed chronic lymphocytic thyroiditis. Nodular thyroid disease can thus be one phenotypic expression of Hashimoto’s thyroiditis. Other studies mention Pendred syndrome orteratomaastheunderlyingthyroiddiseasepresenting as nodules.^6,7

Thyroid nodules can be solid, cystic or of mixed nature. One specific study on cystic thyroid nodules in 24 children (19 girls, 5 boys, mean age 13 yr with range 6-18 yr) disclosed pure cysts in 5 and mixed cystic/solid lesions in 19 patients.⁸ Only one of the patients had suppressed TSH, and two had detect-able microsomal antibodies. Positive family history of thyroid disease was found in 30% of the cases. On thyroid scintiscan, 6 lesions were hot (increased uptake), 13 were cold (decreased uptake), 2 were mixed, and 3 showed normal uptake. The final diagnosis was follicular adenoma in 9, cystic degeneration in 6, multinodular goiter in 4, thyroid carcinoma in 2, bronchial cleft cyst in 1, and indeterminate in 2. Intrathyroidal thyroglossal duct cysts have also been detected.⁹

Thyroid nodules can be solitary, or multiple giving rise to a multinodular thyroid gland (MNTG). In one study on MNTG in 16 children (9 girls, 7 boys, mean age 13 yr with range 7-19 yr), two or more nodules on ultrasound were detected in all subjects (distributed over both thyroid lobes in all except one), whereas 12 patients had 2 or more palpable nodules but 4 patients had only one palpable nodule.¹⁰ These findings point to the fact that ultrasonography is more sensitive than palpation in detecting thyroid nodules. Many patients with a single palpable thyroid nodule may harbour more than one nodule. The etiology of these 16 childhood cases of multinodular thyroid glands is listed in Table 2 .

THE ROLE OF PREVIOUS NECK IRRADIATION

Previous neck irradiation is a risk factor for developing thyroid nodules which may turn into malignant ones. Whereas between 1940 and 1960 neck irradiation was mostly applied for radiotherapy of benign conditions like tinea capitis, scrofula, and an enlarged thymus, nowadays a history of previous neck irradiation is obtained mostly in childhood cancer survivors.

Two follow-up studies reporting on the incidence of thyroid nodules after neck irradiation for child-hood Hodgkin’s disease showed the following: in 93 children irradiated at a mean age of 12 yr, thyroid ultrasonography ten years later revealed abnormali-ties in all, including focal lesions in 37% and thyroid cancer in 5.4%.^11,12 Focal lesions were associated with younger age of irradiation, longer follow-up, and longer duration of an elevated TSH. Similar data were observed in the very large Childhood Cancer Survivor Study: the risk of thyroid nodules was 27 times, of hypothyroidism 17 times, and of hyperthyroidism 8 times higher than that in sibling controls.¹³ The actuarial risk of a female survivor of Hodgkin’s disease developing a thyroid nodule is 20% at 20 yr from diagnosis. Female sex, a radiation dose to the thyroid of 2500 cGy or more, and time from radiation of ≥10 yr were independent risk factors for thyroid nodules (Table 3 ).

Thyroid nodules continue to occur even decades after neck irradiation. From a cohort of individuals irradiated for benign conditions in the head and neck area between 1939 and 1962, 54 subjects were selected who in 1974-1976 had a normal thyroid by palpation and by scan and were restudied twenty years later.¹⁴ One or more discrete ultrasound-detected nodules were present in 47 of the 54 (87%) subjects. There was a total of 157 nodules, 40 of which were ≥1.0 cm. These 40 nodules occurred in 28 (52%) subjects; 10 of the 40 nodules were not recognised on the scan. Of these nodules, only 5 were palpable. None of the 5 fine needle aspirations were suggestive of malignancy. However, in one of these patients, who died of unrelated causes, the large nodule (diameter 16 mm on ultrasound) was a papillary cancer. The authors express concern that the high sensitivity of ultra sonography may give rise to unneeded additional tests and surgery.

Ultrasound screening of the thyroid gland has been performed in 3,051 Belarus children 4-14 years of age who had been exposed to radioactive fallout due to the Chernobyl accident in 1986.15 Screening done in 1990, 1993, and 1998 demonstrated that with time the prevalence of thyroid nodules increased from 1.2% to 3.5%, but the prevalence of thyroid carcinoma decreased from 0.6% in 1990 to 0.3% in 1993 and 0% in 1998. Systematic ultrasound screening is thus useful for the early detection of thyroid carcinoma in children exposed to radioactive fallout.

The value of regular ultrasound screening in survivors of childhood Hodgkin’s disease who received neck irradiation is debated. Some argue against ultrasound screening because the majority of thyroid nodules have an indolent clinical source and do not undergo malignant transformation.¹⁶ They favour further investigation only in the case of a palpable nodule. Others favour regular ultrasound screening.^11,12

Children and adolescents are much more sensitive to the effects of ionizing irradiation than adults, as became again all too evident in the aftermath of the Chernobyl accident. One explanation of this interesting biologic phenomenon is that thyrocytes have a very low division rate at adult age compared to younger agegroups. Radiation-induced mutations are thus less likely to be transmitted to later generations of cells in higher age groups in view of the early expiration of the potency of thyrocytes to divide.¹⁷

DIAGNOSIS

The diagnostic steps for thyroid nodules in children and adolescents are not different from those in adults. The first step is the clinical examination of the patient, which specifically serves the purpose of assessing the pretest likelihood of malignancy. Risk factors for malignancy of thyroid nodules are a fast growing nodule, a family history of (medullary) carcinoma, previous neck irradiation, hoarseness, a very firm nodule, fixation of the nodule to adjacent structures, and cervical lymphadenopathy. Further work-up consists of:

1. blood tests: TSH (and calcitonin if medullary carcinoma is suspected);
2. thyroid scan: in cases of a suppressed TSH;
3. thyroid ultrasound: very useful, also for guidance to perform FNAC (fine-needle aspiration cytology); Management of thyroid nodules in children and adolescents
4. FNAC: in suspicious nodules, and in nodules ≥1 cm.

Whereas serum TSH should be assayed in every patient with a thyroid nodule, opinions differ as to whether or not serum calcitonin should also always be measured. In terms of cost-effectiveness, it is apparently preferable to order a calcitonin assay only if medullary carcinoma is suspected, e.g. in patients with a family history of MEN. One should be aware, however, that the reference range of serum calcitonin is wider in children than in adults.¹⁸

The diagnostic accuracy in recognizing malignant nodules is highest for FNAC. The performance of thyroid scan in this respect is poor, and that of ultra-sound intermediate. Table 4 lists comparative figures obtained in 46 children.¹⁹ Similar results are reported from Italy: the accuracy of diagnosing malignancy in thyroid nodules of 42 children was 53% for thyroid scans (cold nodule), 67% for thyroid ultrasound (hypoechogenecity), and 90% for FNAC.²⁰ Test characteristics of FNAC in childhood nodules as reported in the literature are given in Table 5 .

FNAC is thus currently the best method—short of surgery with histologic examination—for assessing the benign or malignant nature of the nodule. Nonetheless, there remain difficulties in distinguishing thyroid carcinoma from benign lesions, particularly in the case of follicular thyroid carcinoma versus follicular adenoma or the follicular variant of papillary thyroid carcinoma. The employment of immunocytochemical and molecular studies in fine-needle aspirates from nodules may offer greater precision in this respect. So far it has not been proven that evaluation of galectin-3 in the aspirate as a marker of malignancy improves the diagnostic accuracy of FNAC,²¹ and the same holds true for other proposed markers.²² Nevertheless, new data arising from cDNA arrays identifying novel markers of malignancy make this a growing area of interest.²³

Several ultrasound characteristics have been studied as potential predictors of thyroid malignancy. These characteristics are solid lesions, hypoechogenecity, microcalcifications, irregular margins, no halo, intranodular vascularity, and lesions more tall than wide.^29-31 Although there are certain trends in the ultrasound distinction between benign and malignant thyroid nodules, there is also overlap in their appearances. A consensus conference statement recommended US-guided FNAC of solitary nodules in the event of: a) microcalcifications and diameter ≥1cm, b) solid nature or coarse calcifications and diameter ≥1.5 cm, c) mixed solid and cystic nature or almost entirely cystic with solid mural component and diameter ≥2 cm, d) substantial growth since prior ultrasound examination.²⁹ It remains to be seen how valid these recommendations are for childhood thyroid nodules. In a study of 103 pediatric patients with solid thyroid nodules living in Belarus, the most reliable diagnostic criteria for malignancy in nodules with a diameter ≤1.5 cm were irregular margin, subcapsular location, and increased intranodular vascularization.³² However, for thyroid nodules >1.5 cm the accuracy of ultrasound diagnosis was much lower; the only reliable criterion for cancer in this group was hypoechogenecity with a sensitivity of 60% and a specificity of 84%.

THERAPEUTIC APPROACH

Treatment options for solitary benign thyroid nodules are listed in Table 6 .² A few papers mention the outcome of treatment. In a series of 46 children with thyroid nodules, six (13%) were sent immediately to surgery because of malignant or suspicious FNAC, 15 (33%) had a satisfactory response to thyroxine treatment for 6 months (i.e. nodules either disappeared or decreased in number and/or size), and 25 (54%) were sent to surgery later because nodule size did not change or increased despite thyroxine treatment.¹⁹ In pediatric Hodgkin lymphoma survivors, 10 of 67 patients (15%) with thyroid nodules had lesions that disappeared on follow-up 24 months later (some of them were receiving thyroid hormone therapy at the time the nodules were diagnosed by ultrasonography).¹⁶

Thyroxine treatment thus has some benefit, but its efficacy remains low. Recent guidelines address thyroxine therapy for FNAC-benign thyroid nodules:³²

1. T₄ treatment may be considered: in iodine-deficient areas, in young patients with small nodules;
2. T₄ treatment should be avoided: in large nodules, in cases of inadequate or suspicious FNAC;
3. T₄ treatment results: reduction of nodule volume only in a minority; full TSH suppression (<0.1 mU/L) should be avoided; nodule regrowth usually occurs after discontinuation of T₄; growth of the nodule during T₄, consider FNAC and surgery.

Thyroidectomy (usually restricted to lobectomy) thus remains the most effective treatment modality. This is also true for cystic thyroid nodules in childhood. In a series of 24 children with cystic lesions, one child (4.1%) did not receive any treatment.⁸ The remaining 23 children received T₄ suppression therapy, but only two(8.3%) responded. Cystaspiration was attempted in six children, but was successful in only four(16.6%), requiring repeat aspirations in three of them; two were sent to surgery subsequently. Thyroidectomy was done in 17 of the 24 children (71%).

Recommendations for follow-up of survivors of childhood Hodgkin’s disease are:¹²

1. Careful palpation of the thyroid gland;
2. TSH and FT4 assay every 6 months for 5 yr, thereafter annually;
3. If TSH is elevated, thyroxine treatment aiming at TSH <1.0 mU/l;
4. First ultrasound 3 yr after radiotherapy, and yearly thereafter;
5. FNAC for thyroid lesions ≥1 cm.

REFERENCES

1. Rallison ML, Dobyns BM, Keating FR, Rall JE, Tyler FH, 1975 Thyroid nodularity in children. JAMA 233: 1060-1072.
2. Hegedüs L, 2004 The thyroid nodule. N Engl J Med 351: 1764-1771.
3. Niedziela M, 2006 Pathogenesis, diagnosis and management of thyroid nodules in children. Endocr Relat Cancer 13: 427.
4. Hung W, Anderson KD, Chandra RS, et al, 1992 Solitary thyroid nodules in 71 children and adolescents. J Ped Surg 11: 1407-1409.
5. Raab AA, Silverman JF, Elsheikh TM, Thomas PA, Wakely PE, 1995 Pediatric thyroid nodules: disease demographics and clinical management as determined by fine needle aspiration biopsy. Pediatrics 95: 46-49.
6. Massa G, Jaenen N, Janssens de Varebeke S, Peeters N, Wuyts W, 2003 Solitary thyroid nodule as present-ing symptom of Pendred syndrome caused by a novel splice-site mutation in intron 8 of the SLC26A4 gene. Eur J Pediatr 162: 674-677.
7. Thompson LDR, Rosai J, Heffess CS, 2000 Primary thyroid teratomas, a clinicopathologic study of 30 cases. Cancer 88: 1149-1158.
8. Yoskovitch A, Laberge JM, Rodd C, Sinsky A, Gaskin D, 1998 Cystic thyroid lesions in children. J Ped Surg 33: 866-870.
9. McHenry CR, Danish R, Murphy T, Marty JJ, 1993 Atypi-cal thyroglossal duct cyst: a rare cause for a solitary cold Management of thyroid nodules in children and adolescents thyroid nodule in childhood. Am Surg 59: 223-228.
10. Garcia CJ, Daneman A, Thorner P, Daneman D, 1992 Sonography of multinodular thyroid gland in children and adolescents. Am J Dis Childhood 146: 811-816.
11. Healy JC, Shafford EA, Reznek RH, et al, 1996 Sonographic abnormalities of the thyroid gland following radio therapy in survivors of childhood Hodgkin’s disease. Br J Radiology 69: 617-623.
12. Shafford EA, Kingston JE, Healy JC, Webb JAW, Plowman PN, Reznek RH, 1999 Thyroid nodular disease after radiotherapy to the neck for childhood Hodgkin’s disease. Br J Cancer 80: 808-814.
13. Sklar C, Whitton J, Mertens A, et al, 2000 Abnormalities of the thyroid in survivors of Hodgkin’s disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinal Metab 85: 3227-3232.
14. Schneider AB, Bekerman C, Leland J, et al, 1997 Thyroid nodules in the follow-up of irradiated individuals: comparison of ultrasound with scanning and palpation. J Clin Endocrinol Metab 82: 4020-4027.
15. Drozd V, Polyanskaya O, Ostapenko V, Demidchik Y, Biko I, Reiners C, 2002 Systematic ultrasound screening as a significant tool for early detection of thyroid carcinoma in Belarus. J Ped Endocrin Metab 15: 979-984.
16. Metzger ML, Howard SC, Hudson MM, et al, 2006 Natural history of thyroid nodules in survivors of pediatric Hodgkin lymphoma. Ped Blood Cancer 46: 314-319.
17. Jarzab B, Handkiewicz-Junak D, Wloch I, 2005 Juvenile differentiated carcinoma and the role of radioiodine in its treatment: a qualitative review. Endocr Relat Cancer 12: 773-803.
18. Verga U, Morpurgo PS, Vaghi J, Radetti G, Beck-Pec-coz P, 2006 Normal range of calcitonin measured by a chemiluminescent two-site immunometric assay. Horm Res 66: 17-20.
19. Arda IS, Yildirim S, Demirhan B, Firat S, 2001 Fine needle aspiration biopsy of thyroid nodules. Arch Dis Child 85: 313-317.
20. Corrias A, Einaudi S, Chiorboli E, et al, 2001 Accuracy of fine needle aspiration biopsy of thyroid nodules in detecting malignancy in childhood: comparison with conventional clinical, laboratory, and imaging approaches. J Clin Endocrinal Metab 86: 4644-4648.
21. Niedziela M, Maceluch J, Korman E, 2002 Galectin-3 is not a universal marker of malignancy in thyroid nodular disease in children and adolescents. J Clin Endocrinol Metab 87: 4411-4415.
22. Niedziele M, 2006 Pathogenesis, diagnosis and manage-mentofthyroidnodulesinchildren.EndocrRelatCancer 13: 427-453.
23. Ringel MD, 2004 Diagnostic molecular markers in thyroid cancer. Cancer Treatment Research 122: 295-316.
24. Degnan BM, Mc Clellan R, Francis GL, 1996 An analysis of fine-needle aspiration biopsy of the thyroid in children and adolescents. J Ped Surg 31: 903-907.
25. Lugo-Vincente H, Ortiz VN, Irizarry H, et al, 1998 Pe-diatric thyroid nodules: management in the era of fine needle aspiration J Pediatr Surg 33: 1302-1305.
26. Khurana KK, Labrador E, Izquierdo R, et al, 1999 The role of fine-needle aspiration biopsy in the management of thyroid nodules in children, adolescents, and young adults: a multi-institutional study. Thyroid 9: 383-386.
27. Al-Shaikh A, Ngan B, Daneman A, Daneman D, 2001 Fine-needle aspiration biopsy in the management of thyroid nodules in children and adolescents. J Pediatr 138: 140-142.
28. Amrikachi M, Ponder TB, Wheeler TM, Smith D, Ramzy I, 2005 Thyroid fine-needle aspiration biopsy in children and adolescents: experience with 218 aspirates. Diagn Cytopathol 32: 189-192.
29. Frates MC, Benson CB, Charboneau JW, et al, 2005 Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radiology 237: 794-800.
30. Varverakis E, Neonakis E, 2002 Contribution of high-resolution ultrasonography in the differential diagnosis of benign from malignant thyroid nodules. Hormones (Athens) 1: 51-56.
31. Varverakis E, Neonakis E, Tzardi M, Chrysos E, 2007, Role of color Doppler ultrasonography in the preoperative management of cold thyroid nodules. Hormones (Athens) 6: 44-51.
32. AACE/AME Task Force on Thyroid nodules, 2006 American Association of Clinical Endocrinologists and Associazone Medici Endocrinologi Medical Guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 12: 63-102.

Address for correspondence:
Wilmar M. Wiersinga, Dept. of Endocrinology & Metabolism,
Academic Medical Center, University of Amsterdam, the Netherlands

Received 12-04-07, Revised 05-06-07, Accepted 15-06-07