P e d i a t r i c T h y ro i d N o d u l e s and Malignancy Kris R. Jatana,



, Donald Zimmerman,




KEYWORDS  Pediatric thyroid  Thyroid nodule  Thyroid cancer  Neck mass  Pediatric thyroidectomy KEY POINTS  Pediatric thyroid cancer occurs more frequently than in the past, so an understanding of risk factors and available diagnostic testing is critical.  Pediatric thyroid nodules behave differently than adult nodules, as the rate of malignancy in pediatric nodules may be as high as 25% compared with the rate of 5% in adult nodules.  Fine-needle aspiration cytology can be helpful when definitive, but the diagnostic category “indeterminate” presents a clinical challenge.  Experienced pediatric endocrinologists and thyroid surgeons should mange thyroid nodules in children.


It has been reported that between 1973 and 2004, the incidence of thyroid cancer in patients younger than 20 years increased by 1.1% per year based on the Surveillance, Epidemiology, and End Results registry at the National Cancer Institute.1 Pediatric thyroid nodules exhibit several differences compared with nodules in adults. The prevalence of nodules in adults ranges from about 5% by physical examination to up to 35% by ultrasound scan and up to 65% in autopsy studies. However, there is limited knowledge of the prevalence of thyroid nodules in the pediatric population.2 Although several studies have looked at this issue, many have used different diagnostic approaches, so it is difficult to know the true prevalence of malignant thyroid nodules. A study in the United States found that the prevalence of palpable thyroid nodules in children was 1.5%.3 A recent ultrasound study in Japan found

No conflicts of interest or financial disclosures. a Department of Otolaryngology-Head and Neck Surgery, Nationwide Children’s Hospital, The Ohio State University, 555 South 18th Street, Suite 2A, Columbus, OH 43205, USA; b Department of Pediatrics, Lurie Children’s Hospital, Northwestern University Feinberg School of Medicine, 225 East Chicago Avenue, Chicago, IL 60611, USA * Corresponding author. E-mail address: [email protected] Otolaryngol Clin N Am 48 (2015) 47–58 http://dx.doi.org/10.1016/j.otc.2014.09.005 0030-6665/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.



Jatana & Zimmerman

Abbreviations ETT FNA MEN TSH

Endotracheal tube Fine-needle aspiration Multiple endocrine neoplasia Thyroid-stimulating hormone

that thyroid cysts were present in 56.88% and thyroid nodules in 1.65%. Cysts and nodules with diameters greater than 5 mm occurred in 4.58% and 1.01%, respectively.4 One factor affecting detection on physical examination is nodule location; a posteriorly located nodule may be missed in some patients and only found on ultrasound examination. Pediatric thyroid carcinoma incidence was higher in women, highest in the 15- to 19-year age group, and more common in whites compared with African Americans in the Surveillance, Epidemiology, and End Results database between 1973 and 2007. It has been reported that there is a distinct difference between the rate of malignancy of thyroid nodules in adults and children. Although approximately 5% of adult nodules are malignant, 26.4% (range, 9.2%–50%) of pediatric nodules are malignant.5 Pediatric thyroid malignancies are nearly all well-differentiated subtypes of papillary, follicular, and medullary. Anaplastic carcinoma is typically seen in older adults. As in adults, papillary carcinoma is the most common subtype of thyroid carcinoma in the pediatric population. Follicular cancer is second in prevalence, and medullary is least prevalent. Pediatric patients with papillary thyroid cancer typically present at a more advanced stage than do adults. However, pediatric patients do have better outcomes.6 Pediatric thyroid surgery is extremely safe, especially when performed at a highvolume endocrine surgery center. Pediatric centers often select surgical treatment for benign nodular thyroid disease because of the less-intensive follow-up required with this approach. In addition, pediatric thyroid surgeons choose total thyroidectomy over limited resection. This may reflect increasing confidence in the safety and efficacy of surgery.7 The differential diagnosis for cystic thyroid lesions includes benign cystic degeneration, thyroglossal duct cyst, parathyroid cyst, branchial cleft cyst, follicular adenoma, chronic lymphocytic thyroiditis, multinodular goiter, and thyroid carcinoma.8 PATHOPHYSIOLOGY AND ETIOLOGY Radiation

Radiation—especially for the treatment of primary pediatric malignancies—has been associated with a higher rate of thyroid cancer.9 A fairly recent example of radiation effects on the thyroid come from Chernobyl when the incidence of thyroid cancer in younger children correlated to radiation exposure in the form of various radioactive isotopes of iodine. Typically, a papillary cancer was present in these patients. Radiation treatment to the head, neck, and upper chest for treatment of other childhood malignancies has been associated with the development of a secondary thyroid malignancy. The risk of thyroid cancer increases in proportion to increasing radiation doses up to 20 to 29 Gy but then decreases with higher doses. It is likely that higher radiation doses result in cell death rather than resulting in carcinogenic mutations. There is also some evidence that chemotherapy may be a contributing factor, but this has not been well elucidated in children.10

Pediatric Thyroid Nodules and Malignancy


In addition, some patients are genetically prone to thyroid malignancy development. This is most evident in multiple endocrine neoplasia (MEN) type 2 in which medullary thyroid carcinoma is nearly ubiquitous. More recently, nonmedullary thyroid cancer has been described in several familial settings.11 CLINICAL PRESENTATION/EXAMINATION

A detailed history and physical examination is needed. Both benign and malignant nodules can present with variable states of thyroid function: euthyroid, hypothyroid, or hyperthyroid. Symptoms associated with hypothyroidism include:     

Fatigue Weight gain Cold intolerance Constipation Dry skin

Symptoms associated with hyperthyroidism include:       

Sweating Heat intolerance Anxiety Rapid heart rate/palpitations Frequent stools Insomnia Tremors

A family history of thyroid neoplasms or a family history of inherited condition or syndromes that are associated with thyroid cancer and exposure to ionizing radiation are important risk factors for the development of pediatric thyroid cancer. Familial conditions that may be associated with thyroid nodules and malignancy are listed in Table 1. In addition to these conditions, nonmedullary thyroid carcinoma may occur without other tumors or abnormalities. Table 1 Thyroid nodule and cancer-related inherited conditions Gene Involved



PTEN tumor suppressor

Thyroid, GI, breast, uterine tumors

Familial adenomatous polyposis

APC gene (AD)

Increased risk of thyroid cancer, GI polyps with increased risk of malignant transformation


APC gene (AD)

Increased risk thyroid cancer, jaw osteomas, GI polyps with increased risk of malignant transformation


STK11 gene (AD)

Increased risk thyroid cancer, GI hamartomas, pigmented oral lesions


RET proto-oncogene (AD)

Medullary thyroid carcinoma, pheochromocytoma, parathyroid


RET proto-oncogene (AD)

Medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, Marfanoid

Abbreviations: AD, autosomal dominant; GI, gastrointestinal.



Jatana & Zimmerman

On physical examination, vital signs can suggest altered thyroid function. Bradycardia and narrow pulse pressure are often seen in hypothyroidism, whereas tachycardia and widened pulse pressure are characteristic of hyperthyroidism. Height percentile is particularly useful when compared with weight percentile (hyperthyroidism is often characterized by height percentile greater than weight percentile and hypothyroidism by weight percentile greater than height percentile). Growth velocity is also informative (accelerated in hyperthyroidism and slowed in hypothyroidism.) Physiognomy can reveal associated syndromes. The most characteristic is the Marfanoid habitus (long arms and legs) and lumpy-bumpy lips and tongue characteristic of MEN type 2B. Both thorough palpation of the thyroid gland and of all levels of the neck for lymphadenopathy are critical. DIAGNOSTIC PROCEDURES Laboratory Studies

The levels of thyroid-stimulating hormone (TSH) in 125 pediatric patients with benign and malignant nodules were retrospectively evaluated by Mussa and colleagues. The TSH level in those with malignant nodules was significantly higher (3.23  1.59 vs 1.64  0.99; P

Pediatric thyroid nodules and malignancy.

Proper management of pediatric thyroid nodules is crucial to achieving good outcomes. It is important to obtain a thorough history, including prior ra...
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