Thyroid Nodules in Pediatric Patients: Sonographic Characteristics and Likelihood of Cancer.

Purpose To determine the relationship between demographic and sonographic characteristics of thyroid nodules and malignancy in a pediatric population. Materials and Methods All thyroid nodules in patients younger than 19 years that underwent ultrasound (US)-guided fine-needle aspiration biopsy between January 2004 and July 2017 were retrospectively identified. Age, sex, and background appearance of the thyroid gland were recorded for each patient, and sonographic characteristics and pathologic diagnosis were recorded for each nodule. Demographic and sonographic characteristics were assessed to determine which were associated with malignancy. Categorical and continuous variables and interobserver variability were assessed. Results A total of 404 nodules in 314 patients (82.8% female) (age range, 2-18 years; mean age, 14.9 years) were analyzed. A total of 77 nodules (19.1%) were malignant, the majority of which were papillary thyroid carcinoma (n = 68 [88.3%]). The likelihood of malignancy did not differ between boys and girls (27.8% vs 22.7%, P = .64), nor did it differ between prepubertal and pubertal patients (18.8% vs 19.1%, P > .99). The cancer rate in patients with a solitary nodule was higher than that in patients with multiple nodules (29.4% vs 14.2%, P = .003). Sonographic characteristics associated with malignant nodules included larger size, solid parenchyma, taller-than-wide shape, presence of speckled calcifications, lack of a smooth margin, and presence of abnormal lymph nodes. Interobserver variability for assessment of sonographic characteristics ranged from moderate to very strong. Conclusion In children with thyroid nodules, solitary nodules, larger nodule size, solid parenchyma, taller-than-wide shape, speckled calcifications, irregular margins, and abnormal lymph nodes raise concern for malignancy.

Ectopic Intrathyroidal Thymic Tissue Mimicking Thyroid Nodules in Children.

Ectopic intrathyroidal thymic tissue is a benign lesion of nonthyroid origin occasionally found in the pediatric thyroid gland. Accurate diagnosis of such lesions is critical to avoid unnecessary biopsy or surgery. Twelve children referred to our center for the concern of thyroid nodules were found to have intrathyroidal thymic tissue. Most of the lesions had a classic sonographic appearance of a hypoechoic mass with sharp margins and multiple focal internal nonshadowing echogenicities identical to thymic tissue. Sonography and, in select cases, fine-needle aspiration can be used to diagnose benign thymic tissue within the thyroid and avoid unnecessary surgery.

Prevalence and Significance of Thyroglobulin Antibodies in Pediatric Thyroid Cancer.

Context: Circulating thyroglobulin antibodies (TgAb) can confound measurement of serum thyroglobulin and impair thyroid cancer surveillance. Few data exist on the significance of TgAb in pediatric thyroid cancer. Objective: To describe the prevalence, natural history, and clinical significance of TgAb in children with thyroid cancer. Design: Retrospective cohort study. Setting: Single academic pediatric center. Patients: Seventy-three consecutive children (≤18 years) with nonmedullary thyroid cancer who had serum TgAb measured within 6 months after diagnosis. Main Outcome Measures: Prevalence and natural history of TgAb; association of TgAb status and resolution with patient and disease characteristics. Results: TgAb were detected in 41% of subjects (30 of 73) and were associated with lymph node metastasis (83% vs 53%, P = 0.01) but not distant metastasis. In patients with TgAb, resolution occurred in 44% (11 of 25) over a median follow-up of 3.8 years. Median time to clear TgAb was 10.7 months, and 10 of 11 patients who cleared (91%) did so within 2 years. Resolution of TgAb was associated with lower initial TgAb level (median 4.5 vs 76 normalized units, P = 0.003). TgAb positivity at diagnosis was not independently associated with persistent or recurrent disease (odds ratio 3.20, 95% confidence interval 0.95 to 10.80, P = 0.06). Conclusions: TgAb are common at diagnosis in children with thyroid cancer but resolve in nearly half of patients within 1 to 2 years. TgAb are associated with the presence of lymph node metastasis at diagnosis, but the long-term prognostic significance remains to be determined.

Features and Outcome of Autonomous Thyroid Nodules in Children: 31 Consecutive Patients Seen at a Single Center.

CONTEXT: Most thyroid nodules are benign and their accurate identification can avoid unnecessary procedures. In adult patients, documentation of nodule autonomy is accepted as reassurance of benign histology and as justification to forgo biopsy or thyroidectomy. In contrast, the negative predictive value of nodule autonomy in children is uncertain. Some recent publications recommend surgical resection as initial management, but few address the degree of TSH suppression or the specific scintigraphic criteria used to diagnose autonomy. OBJECTIVE: The objective of the study was to study the presenting features and cancer risk of children with autonomous nodules. DESIGN AND SETTING: Medical records of all 31 children diagnosed with autonomous nodules at our center from 2003 to 2014 were retrospectively reviewed. PATIENTS AND RESULTS: All children met full diagnostic criteria for autonomous nodules, defined by both autonomous 123I uptake into the nodule and the suppression of uptake in the normal thyroid parenchyma on scintigraphy performed during hypothyrotropinemia. The median age of presentation was 15 years (range 3-18 y) with a female to male ratio of 15:1. Fifty-eight percent of patients had solitary nodules and 42% had multiple nodules. The median size of each patient's largest autonomous nodule was 39 mm (range 18-67 mm). Most of the children in this series (68%) had diagnostic biopsies and/or operative pathology of their largest autonomous nodule, which showed benign cytology or histology in all cases. CONCLUSIONS: In this pediatric series, the cancer rate observed in biopsied or resected autonomous nodules was 0%. Whereas larger studies are needed to confirm our findings, these results agree with earlier reports suggesting that thyroid cancer is rare in rigorously defined autonomous nodules and support that conservative management may be offered to selected children who meet strict diagnostic criteria for autonomous nodules, deferring definitive therapies until adulthood when the risks of thyroidectomy and 131I ablation are lower.

Thyroid hormone inactivation in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib. The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism. Multiple mechanisms of this effect have been proposed, including decreased iodine organification and glandular capillary regression. Here we report the finding of consumptive hypothyroidism caused by marked overexpression of the thyroid hormone-inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. Affected patients warrant increased monitoring and may require supernormal thyroid hormone supplementation.

How are childhood thyroid nodules discovered: opportunities for improving early detection.

In a retrospective analysis of childhood thyroid nodules, 18% were radiographic incidentalomas and 41% were discovered by a clinician's palpation; 40% were discovered by patients' families. The latter group had the largest nodules and highest rates of thyroid cancer metastasis, suggesting opportunities for earlier detection through annual well-child visits.

A standardized assessment of thyroid nodules in children confirms higher cancer prevalence than in adults.

CONTEXT: Thyroid cancer is the most common endocrine malignancy, but due to its rare occurrence in the pediatric population, the cancer risk of childhood thyroid nodules is incompletely defined, and optimal management of children with suspected nodules is debated. OBJECTIVE: The aim was to study the presenting features and cancer risk of sporadic childhood thyroid nodules using a standardized clinical assessment and management plan. DESIGN AND SETTING: Boston Children's Hospital and Brigham and Women's Hospital collaborated to create a multidisciplinary pediatric thyroid nodule clinic and implement a standardized assessment plan. Upon referral for a suspected nodule, serum TSH was measured and hypothyrotropinemic patients underwent (123)I scintigraphy. All others underwent thyroid ultrasonography, and if this confirmed nodule(s) ≥ 1 cm, ultrasound-guided fine-needle aspiration was performed. Medical records were retrospectively reviewed and compared to a control population of 2582 adults evaluated by identical methods. PATIENTS AND RESULTS: Of 300 consecutive children referred for the initial evaluation of suspected thyroid nodules from 1997 to 2011, 17 were diagnosed with autonomous nodules by scintigraphy. Neck ultrasonography performed in the remainder revealed that biopsy was unnecessary in over half, either by documenting only sub-centimeter nodules or showing that no nodule was present. A total of 125 children met criteria for thyroid biopsy, which was performed without complication. Their rate of cancer was 22%, significantly higher than the adult rate of 14% (P = .02). CONCLUSIONS: Neck ultrasonography and biopsy were key to the evaluation of children with suspected thyroid nodules. Although the relative cancer prevalence of sonographically confirmed nodules ≥ 1 cm is higher in pediatric patients than adults, most children referred for suspected nodules have benign conditions, and efforts to avoid unnecessary surgery in this majority are warranted.

Simulation of post-thyroidectomy treatment alternatives for triiodothyronine or thyroxine replacement in pediatric thyroid cancer patients.

BACKGROUND: As in adults, thyroidectomy in pediatric patients with differentiated thyroid cancer is often followed by (131)I remnant ablation. A standard protocol is to give normalizing oral thyroxine (T(4)) or triiodothyronine (T(3)) after surgery and then withdraw it for 2 to 6 weeks. Thyroid remnants or metastases are treated most effectively when serum thyrotropin (TSH) is high, but prolonged withdrawals should be avoided to minimize hypothyroid morbidity. METHODS: A published feedback control system model of adult human thyroid hormone regulation was modified for children using pediatric T(4) kinetic data. The child model was developed from data for patients ranging from 3 to 9 years old. We simulated a range of T(4) and T(3) replacement protocols for children, exploring alternative regimens for minimizing the withdrawal period, while maintaining normal or suppressed TSH during replacement. The results are presented with the intent of providing a quantitative basis to guide further studies of pediatric treatment options. Replacement was simulated for up to 3 weeks post-thyroidectomy, followed by various withdrawal periods. T(4) vs. T(3) replacement, remnant size, dose size, and dose frequency were tested for effects on the time for TSH to reach 25 mU/L (withdrawal period). RESULTS: For both T(3) and T(4) replacement, higher doses were associated with longer withdrawal periods. T(3) replacement yielded shorter withdrawal periods than T(4) replacement (up to 3.5 days versus 7-10 days). Higher than normal serum T(3) concentrations were required to normalize or suppress TSH during T(3) monotherapy, but not T(4) monotherapy. Larger remnant sizes resulted in longer withdrawal periods if T(4) replacement was used, but had little effect for T(3) replacement. CONCLUSIONS: T(3) replacement yielded withdrawal periods about half those for T(4) replacement. Higher than normal hormone levels under T(3) monotherapy can be partially alleviated by more frequent, smaller doses (e.g., twice a day). LT(4) may be the preferred option for most children, given the convenience of single daily dosing and familiarity of pediatric endocrinologists with its administration. Remnant effects on withdrawal period highlight the importance of minimizing remnant size.

Thyroid surgery at Children's Hospital Boston: a 35-year single-institution experience.

BACKGROUND/PURPOSE: Thyroidectomy is the primary therapy for thyroid cancer and an established treatment of hyperthyroidism. Because of the relative rarity of these conditions in childhood, few single-institution series exist in the pediatric literature. Here we analyze our institution's experience to assess patient demographics, operative risks, and the role of preoperative testing. METHODS: This is a retrospective chart review of 175 consecutive patients not older than 18 years who underwent thyroid surgery at Children's Hospital Boston from 1970 to 2004. RESULTS: The most common indication for thyroidectomy was thyroid nodules (83%), followed by hyperthyroidism (7%) and goiter (7%). For children referred for nodules, we observed a peak incidence in adolescence and a female to male ratio of 3.7:1. Cancer was found in 36%, with papillary thyroid cancer the most common subtype (85%). Operative complications were rare, with permanent hypocalcemia in 2 (4.7%) of 43 patients who underwent bilateral resection for thyroid nodules (no cases of permanent hypocalcemia in other procedures). Permanent unilateral vocal cord paralysis was documented in 2 children after the resection of malignant nodules. CONCLUSIONS: Pediatric thyroidectomy can be performed with low operative risk. Because permanent hypocalcemia remains an obligate risk of bilateral thyroidectomy, we recommend the routine use of preoperative fine-needle aspiration to guide the extent of initial surgical resection, reserving near-total thyroidectomy for those cases where cytology is positive for malignancy.

Thyroid nodules and cancer in children with PTEN hamartoma tumor syndrome.

CONTEXT: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a complex disorder caused by germline-inactivating mutations of the PTEN tumor suppressor gene. Carriers develop benign and malignant tumors of multiple tissues, including the breast, thyroid, intestine, and skin. Surveillance to facilitate the early detection and treatment of malignancies is recommended but, because thyroid cancers have been reported almost exclusively in adults, childhood risk is considered to be low, and consensus guidelines recommend that surveillance imaging begin at 18 yr of age. OBJECTIVE/PATIENTS: Seven children with PHTS referred to two thyroidologists form the basis of this report. Medical records, operative histology, and PTEN mutational analysis were reviewed to evaluate the pediatric presentation of PHTS-associated thyroid neoplasia. RESULTS: Five of the seven children presented with thyroid nodules or thyroid cancer between the ages of 6 and 12 yr, often as the initially identified component of their PHTS. Two others were diagnosed with PHTS on the basis of extrathyroidal features but had markedly abnormal screening ultrasounds with solid thyroid nodule(s) of at least 2 cm, despite the documentation of normal physical examinations. Five of the seven children in this cohort developed thyroid cancer. CONCLUSIONS: Patients with PHTS can develop thyroid nodules and thyroid cancer in early childhood. This argues both for a high index of suspicion for PHTS in children diagnosed with multiple thyroid nodules and for careful thyroid surveillance in children diagnosed with PHTS. Because early detection improves the outcome of thyroid cancer, we recommend ultrasound surveillance for all patients upon the confirmation of a germline PTEN mutation, regardless of their age.

Knockdown of the type 3 iodothyronine deiodinase (D3) interacting protein peroxiredoxin 3 decreases D3-mediated deiodination in intact cells.

The type 3 iodothyronine deiodinase (D3) is the primary deiodinase that inactivates thyroid hormone. Immunoprecipitation of D3, followed by fluorescent two-dimensional difference gel electrophoresis and mass spectrometry, identified peroxiredoxin 3 (Prx3) as a D3-associated protein. This interaction was confirmed using reverse coimmunoprecipitation, in which pull-down of Prx3 resulted in D3 isolation, and by fluorescence resonance energy transfer between cyan fluorescent protein-D3 and yellow fluorescent protein-Prx3. Prx3 overexpression did not change D3 activity in transfected HEK 293 cells; however, Prx3 knockdown resulted in a 50% decrease in D3-mediated whole-cell deiodination. Notably, D3 activity of cell lysates with dithiothreitol as an exogenous reducing factor and D3 protein levels were not decreased with Prx3 knockdown, indicating that the observed reduction in whole-cell deiodination was not simply due to a decrease in D3 enzyme levels. Prx3 knockdown did not change D3's affinity for T3 because saturation of D3-mediated whole-cell deiodination occurred between 20 and 200 nm T3 both with and without Prx3. Furthermore, the decrease in D3 activity in whole cells was not attributable to nonspecific oxidative stress because pretreatment with the antioxidant N-acetyl cysteine did not reverse the effects of Prx3 knockdown. Thioredoxin, the cofactor needed for Prx3 regeneration, supported D3 microsomal activity; however, Prx3 knockdown did not change D3 activity in this system. In conclusion, knockdown of Prx3 decreases D3 activity in whole cells, whereas absolute levels of D3 are unchanged, consistent with Prx3 playing a rate-limiting role in the regeneration of the D3 enzyme.

Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton.

Thyroid hormone (TH) plays a key role on post-natal bone development and metabolism, while its relevance during fetal bone development is uncertain. To study this, pregnant mice were made hypothyroid and fetuses harvested at embryonic days (E) 12.5, 14.5, 16.5 and 18.5. Despite a marked reduction in fetal tissue concentration of both T4 and T3, bone development, as assessed at the distal epiphyseal growth plate of the femur and vertebra, was largely preserved up to E16.5. Only at E18.5, the hypothyroid fetuses exhibited a reduction in femoral type I and type X collagen and osteocalcin mRNA levels, in the length and area of the proliferative and hypertrophic zones, in the number of chondrocytes per proliferative column, and in the number of hypertrophic chondrocytes, in addition to a slight delay in endochondral and intramembranous ossification. This suggests that up to E16.5, thyroid hormone signaling in bone is kept to a minimum. In fact, measuring the expression level of the activating and inactivating iodothyronine deiodinases (D2 and D3) helped understand how this is achieved. D3 mRNA was readily detected as early as E14.5 and its expression decreased markedly ( approximately 10-fold) at E18.5, and even more at 14 days after birth (P14). In contrast, D2 mRNA expression increased significantly by E18.5 and markedly ( approximately 2.5-fold) by P14. The reciprocal expression levels of D2 and D3 genes during early bone development along with the absence of a hypothyroidism-induced bone phenotype at this time suggest that coordinated reciprocal deiodinase expression keeps thyroid hormone signaling in bone to very low levels at this early stage of bone development.

Rapid resolution of consumptive hypothyroidism in a child with hepatic hemangioendothelioma following liver transplantation.

We report a unique case of a 3-mo-old female with consumptive hypothyroidism and liver hemangioendothelioma who required pharmacological doses of thyroid hormones and was cured following liver transplantation. Liver hemangioendotheliomas are capable of producing an excess of the thyroid hormone inactivating enzyme, type-3 iodothyronine deiodinase. The increased tumoral enzyme activity leads to rapid degradation of thyroid hormones, resulting in consumptive hypothyroidism. Review of similar cases indicated variable outcomes. We focus on our patient's clinical course and describe in detail the thyroid hormone replacement therapy and a unique outcome of this rare type of hypothyroidism. This first example of a prompt and complete resolution of consumptive hypothyroidism in an infant after liver transplantation confirms the concept and the reversibility of consumptive hypothyroidism and provides novel insights into the rapidity of response of the infant's hypothalamic-pituitary-thyroid axis to thyroid hormone replacement.

Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study.

In humans, there is a significant decrease in serum T(3) and increase in rT(3) at different time points after myocardial infarction, whereas serum TSH and T(4) remain unaltered. We report here a time course study of pituitary-thyroid function and thyroid hormone metabolism in rats subjected to myocardial infarction by left coronary ligation (INF). INF- and sham-operated animals were followed by serial deiodination assays and thyroid function tests, just before, and 1, 4, 8, and 12 wk after surgery. At 4 and 12 wk after INF, liver type 1 deiodinase activity was significantly lower, confirming tissue hypothyroidism. Type 3 deiodinase (D3) activity was robustly induced 1 wk after INF only in the infarcted myocardium. Reminiscent of the consumptive hypothyroidism observed in patients with large D3-expressing tumors, this induction of cardiac D3 activity was associated with a decrease in both serum T(4) ( approximately 50% decrease) and T(3) (37% decrease), despite compensatory stimulation of the thyroid. Thyroid stimulation was documented by both hyperthyrotropinemia and radioiodine uptake. Serum TSH increased by 4.3-fold in the first and 3.1-fold in the fourth weeks (P < 0.01), returning to the basal levels thereafter. Thyroid sodium/iodide-symporter function increased 1 wk after INF, accompanying the increased serum TSH. We conclude that the acute decrease in serum T(4) and T(3) after INF is due to increased thyroid hormone catabolism from ectopic D3 expression in the heart.

The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation.

Disturbances in energy homeostasis can result in obesity and other metabolic diseases. Here we report a metabolic pathway present in normal human skeletal muscle myoblasts that is activated by the small polyphenolic molecule kaempferol (KPF). Treatment with KPF leads to an approximately 30% increase in skeletal myocyte oxygen consumption. The mechanism involves a several-fold increase in cyclic AMP (cAMP) generation and protein kinase A activation, and the effect of KPF can be mimicked via treatment with dibutyryl cAMP. Microarray and real-time PCR studies identified a set of metabolically relevant genes influenced by KPF including peroxisome proliferator-activated receptor gamma coactivator-1alpha, carnitine palmitoyl transferase-1, mitochondrial transcription factor 1, citrate synthase, and uncoupling protein-3, although KPF itself is not a direct mitochondrial uncoupler. The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an approximately 10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of approximately 2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans.

Atypical expression of type 2 iodothyronine deiodinase in thyrotrophs explains the thyroxine-mediated pituitary thyrotropin feedback mechanism.

T(4), the main product of thyroid secretion, is a critical signal in plasma that mediates the TSH-negative feedback mechanism. As a prohormone, T(4) must be converted to T(3) to acquire biological activity; thus, type 2 iodothyronine deiodinase (D2) is expected to play a critical role in this feedback mechanism. However, the mechanistic details of this pathway are still missing because, counterintuitively, D2 activity is rapidly lost in the presence of T(4) by a ubiquitin-proteasomal mechanism. In the present study, we demonstrate that D2 and TSH are coexpressed in rat pituitary thyrotrophs and that hypothyroidism increases D2 expression in these cells. Studies using two murine-derived thyrotroph cells, TtT-97 and TalphaT1, demonstrate high expression of D2 in thyrotrophs and confirm its sensitivity to negative regulation by T(4)-induced proteasomal degradation of this enzyme. Despite this, expression of the Dio2 gene in TalphaT1 cells is higher than their T(4)-induced D2 ubiquitinating capacity. As a result, D2 activity and net T(3) production in these cells are sustained, even at free T(4) concentrations that are severalfold above the physiological range. In this system, free T(4) concentrations and net D2-mediated T(3) production correlated negatively with TSHbeta gene expression. These results resolve the apparent paradox between the homeostatic regulation of D2 and its role in mediating the critical mechanism by which T(4) triggers the TSH-negative feedback.

Physiology and pathophysiology of type 3 deiodinase in humans.

Type 3 iodothyronine deiodinase (D3) is the physiologic inactivator of thyroid hormones, catalyzing the inner ring deiodination of thyroxine (T(4)) to reverse triiodothyronine (rT(3)) and (T(3)) to 3, 3'-diiodothyronine (T(2)), both of which are biologically inactive. Its physiologic role and pathophysiologic effects in humans can be understood in this context. D3 activity in the normal uteroplacental unit regulates the transfer of maternal thyroid hormone to the fetus and, in patients with consumptive hypothyroidism, the rapid destruction of circulating thyroid hormone by tumoral D3 can produce severe hypothyroxinemia. D3 is expressed in multiple fetal structures, but the uterine endometrium and the placenta are the only normal tissues known to express high levels of D3 activity in the mature human. D3 has also been found in vascular anomalies, in human brain tumors, and in some malignant cell lines. These data have led to the categorization of D3 as an oncofetal protein, but recent data indicate that postnatal expression can be reactivated in normal tissues during critical illness and other pathologic conditions.