Management of pediatric differentiated thyroid cancer: An overview for the pediatric oncologist

Differentiated thyroid cancer (DTC) is the most common childhood thyroid malignancy. The standard of care for pediatric DTC is total thyroidectomy followed by radioactive iodine (RAI) treatment when indicated. Molecular changes and potential therapeutic targets have been recently described in pediatric thyroid cancer. Pediatric oncologists are increasingly involved in the evaluation of thyroid nodules in childhood cancer survivors and in the management of advanced thyroid cancer. In 2015, the American Thyroid Association published management guidelines for children with DTC. We provide an overview of the current standard of care and highlight available targeted therapies for progressive or RAI refractory DTC.     

Thyroid cancer in adolescents and young adults

In adolescents and young adults, thyroid cancer accounts for 13% of all invasive neoplasms, being three times more frequent in females, but overdiagnosis and overtreatment are common. There are two therapeutic approaches, one radical and no longer preferred in all instances, and the other conservative. Permanent complications of surgery and metabolic irradiation can affect quality of life and carry an economic burden. The overall survival rate approaches 100% for patients with differentiated thyroid cancer regardless of the extent of treatment. Medullary thyroid carcinoma is a very different entity, occurring most frequently in the context of hereditary tumor susceptibility syndromes.     

Ultrasonography for thyroid screening after head and neck irradiation in childhood cancer survivors

We prospectively used ultrasonography to detect thyroid abnormalities in 96 long-term survivors of childhood cancer, who received head and neck radiation therapy at a median age of 8.9 years. The median time interval since irradiation was 10.8 years (range 5.6–22.8 years). Most survivors of leukemia received 24 Gy cranial irradiation for central nervous system prophylaxis; patients with solid tumors received between 20 and 66 Gy (median 37.5 Gy). The total evaluation included clinical history, physical examination, thyroid function tests, and thyroid ultrasonography; radionuclide scans were performed in patients whose abnormalities persisted on subsequent ultrasound exams. Clinical history and physical examination revealed thyroid abnormalities in 14 patients (15%), but ultrasound detected abnormalities in 42 patients (44%). These findings included inhomogeneity (n = 29), cysts (n = 15), and nodules (n = 22) and occurred in nearly half of patients treated with 15 Gy or more directly to the thyroid gland. Radionuclide scans confirmed the presence of thyroid nodules in 13 of 15 patients with ultrasonographic evidence of nodules. Six patients had thyroid neoplasia, including one case of papillary carcinoma. All patients with neoplasia had nodules demonstrated on ultrasonography. Our experience suggests that in childhood cancer survivors, ultrasonography is a sensitive, affordable, and noninvasive means of detecting subtle parenchymal abnormalities. We recommend thyroid ultrasonography for childhood cancer survivors who recieved head and neck irradiation. A baseline study should be obtained within 1 year of completion of therapy. The frequency of subsequent examinations should be based on the radiation dose and the patient's age at the time of irradiation. © 1997 Wiley-Liss, Inc.     

Natural history of thyroid nodules in survivors of pediatric Hodgkin lymphoma

BACKGROUND: Survivors of Hodgkin lymphoma and other patients who receive neck irradiation are at increased risk of thyroid cancer. Ultrasonography provides an inexpensive and non-invasive method of thyroid screening, but the clinical significance of thyroid nodules detected by ultrasound screening is uncertain. PROCEDURE: We reviewed the demographics, clinical characteristics, method of detection, and outcome of patients who developed thyroid nodules after treatment for pediatric Hodgkin lymphoma at our institution. One radiologist reviewed all imaging studies. RESULTS: Sixty-seven children treated for Hodgkin lymphoma from 1962 to 2001 developed thyroid nodules. The study group represented 9,024 person-years of follow-up after the diagnosis of Hodgkin lymphoma and 581 person-years after diagnosis of a thyroid nodule. A median of 10.5 years (range, 0.2-24.8 years) elapsed between the diagnoses of Hodgkin lymphoma and thyroid nodule(s). All but one patient had received neck irradiation for Hodgkin lymphoma, with a median thyroid radiation dose of 35 Gy (range, 12-45 Gy). Thyroid nodules were found to be malignant in seven patients (10%), at a median of 16.2 years (range, 8.4-23.7 years) after diagnosis of Hodgkin lymphoma. Only one malignancy was found through screening ultrasonography. All patients with thyroid cancer remained disease-free at 0.4-16.2 years of follow-up. CONCLUSIONS: Thyroid nodules are common in Hodgkin lymphoma survivors treated with neck irradiation, but the majority of these lesions have an indolent clinical course and do not undergo malignant transformation. Only patients with a palpable mass or clinical symptoms need more extensive evaluation, including Doppler-flow ultrasonography and fine-needle aspiration.     

THYROID CANCER IN LEBANESE CHILDREN AND ADOLESCENTS: A 15-Year Experience at a Single Institution

Background and Aim: Thyroid carcinomas are rare in childhood and adolescence. Management of this entity remains controversial. The aim of this study is to review our experience with multidisciplinary management of papillary thyroid cancer in the pediatric population at a tertiary care specialized medical center in Lebanon. Procedure: The medical records of all patients with thyroid cancer younger than 20 years who presented to our center between January 1991 and January 2006 were reviewed. Results: Thirteen patients with papillary thyroid carcinoma (PTC) were identified. No patient had previous exposure to ionizing radiation. The mean age at diagnosis was 14.5 years. There were 8 females; all patients presented with a cervical mass. Ten patients underwent total thyroidectomy and three subtotal thyroidectomy. Eight patients (61.5%) had regional lymph node metastases, only one of whom (7.6%) had lung metastases. All received radioactive “131I” ablation postsurgical excision. Five (38.5%) had recurrences and needed multiple surgeries and/or “131I” ablation. At a median follow-up time of 8.3 years all patients are disease free. Conclusion: Pediatric thyroid cancer in Lebanon is a rare tumor that presents mainly as a primary malignancy. The main clinical presentation is a cervical mass with locoregional lymph nodes metastasis. The mainstay of therapy is total thyroidectomy with lymph node dissection when indicated and radioactive “131I” ablation. Despite recurrences the prognosis is excellent.     

单光子发射计算机断层显像对新生儿甲状腺功能减低的诊断价值

目的采用甲状腺单光子发射计算机断层显像(SPECT)探讨其对新生儿先天性甲状腺功能减低(甲低)的诊断价值。方法对经新生儿疾病筛查发现的19例甲低患儿,静脉注射99mTcO418.5～37.0MBq,15min后行甲状腺显像。结果甲状腺SPECT基本正常5例,单纯性肿大1例,肿大且放射性分布增加2例,异位、缺如各4例,显影不清3例。结论甲状腺SPECT对甲低原因如甲状腺发育不全、缺如和异位等可做出满意的判断,结合甲状腺显像和血清T3、T4、TSH检查,对新生儿甲低诊断具有重要意义。     

Thyroid cancer after radiotherapy for childhood cancer*

The thyroid gland in children is among the most sensitive organs to the carcinogenic effects of ionizing radiation, and very young children are at especially high risk. Risk associated with exposure to external X‐ or γ‐radiation increases linearly with increasing dose to the thyroid gland at low‐to‐moderate doses, but the dose–response relationship appears to flatten at the very high doses characteristic of cancer radiotherapy. Because of the extreme sensitivity of the thyroid gland in children, there is a risk of radiation‐induced thyroid cancer even when the thyroid gland is outside of the irradiated field. Increased incidence of thyroid cancer has been noted following radiotherapy for childhood Hodgkin disease, non‐Hodgkin lymphoma, neuroblastoma, Wilms tumor, acute lymphocytic leukemia and tumors of the central nervous system. Radiation‐induced tumors begin to appear 5–10 years after irradiation and excess risk persists for decades, perhaps for the remainder of life. The background incidence of thyroid cancer is two‐ to threefold higher among females than males, and the absolute increase in risk due to irradiation is higher in females as well. Most of the thyroid cancers that occur in association with irradiation are of the papillary type, for which the cure rate is high if tumors are detected early. This highlights the importance of long‐term surveillance of persons irradiated during childhood. Important areas for research include the possibility that children with certain types of first cancer are especially susceptible, the basis of the greater female susceptibility, the joint effects of radiation and other factors, and genetic mechanisms in radiation‐induced and spontaneously occurring thyroid cancer. Med. Pediatr. Oncol. 36:568–573, 2001. © 2001 Wiley‐Liss, Inc.     

Papillary thyroid cancer with pulmonary metastases beginning in childhood: Clinical course over three decades

We present a case of childhood papillary thyroid cancer with persistent but stable pulmonary metastases for over three decades in order to highlight the natural history and clinical features of this unusual disease entity. A nine-year-old girl had thyroidectomy and cervical lymph node dissection followed by neck irradiation for invasive papillary thyroid cancer. Diffuse pulmonary metastases were present at the time of diagnosis and were treated with radioactive iodine 10 and 30 years later; both the chest radiographs and the patient remained stable throughout. This case illustrates the potential indolence of thyroid cancer when it presents during childhood. © 1995 Wiley-Liss, Inc.     

Changing face of paediatric and adolescent thyroid cancer

OBJECTIVES: The aims of our study were to review the Royal Children's Hospital cohort of children having thyroidectomy for thyroid nodules over the last 8 years and to report the changing pattern of thyroid cancer seen in our institution over that time. METHODS: We undertook a retrospective case-note review of all patients who underwent thyroid surgery between 1997 and 2004. RESULTS: Of 69 patients identified, the pathological diagnoses were 51 benign tumours, 14 thyroid cancers and four cases of multiple endocrine neoplasia type 2, who were treated with prophylactic thyroidectomy. Sixteen of the 69 patients had a history of childhood cancer and 10/16 had cancer treatment which included direct or scatter radiation. Of the 10 patients who received irradiation, four had follicular adenomas and six developed thyroid cancer. All six patients were euthyroid: one patient was presented with a palpable nodule and the other five were detected on surveillance ultrasound. CONCLUSIONS: Our results confirm a high detection of malignancy in thyroid nodules in childhood. Compared to an earlier study at this institution, the number of thyroid malignancies appears to be increasing. Surveillance at the Royal Children's Hospital has changed, with increased long-term cancer survival. Prospective 2-yearly evaluation of those with a past history of radiation exposure has resulted in earlier detection of benign and malignant thyroid lesions. Nodular changes are usually not clinically apparent for many years and lifelong surveillance is necessary for cancer detection in this group.     

Differentiated thyroid cancer

Objective: The retrospective analysis of the case files of children with differentiated thyroid carcinoma (DTC) was performed to define the disease by its presentation, clinical course and outcome of radioiodine therapy.Methods: Between 1967 to October 2002,1754 patients with thyroid cancer were treated in the Dept of Neuclear Medicine, AIIMS, out of which 122 (7%) were ≶ 20 years of age (71 girls and 51 boys). The mean age was 15.8 ± 3.6 years and the mean duration of follow-up was 90 ± 59.3 months. Mean tumor size was 4.4 cm. Histologically, 85% of the patients had papillary and rest follicular carcinoma. Cervical lymph node involvement was seen in 64%, and distant metastases, mainly pulmonary, in 23% of the patients. The presentation of the disease was very aggressive in the first decade of life with male preponderance. All but one patient in this age group had nodal and/or distant metastases; in 83.3% the disease had spread to the lymph nodes and 67% had metastases to the lungs. The post-surgery 48-hour mean radioiodine neck uptake was 10.5 ± 7.6%.Results: 94% of the residual thyroid, 88% of nodal metastases and 71% of pulmonary metastases were ablated requiring mean cumulative doses of 2.8 ± 2.7 GBq, 4.5 ± 2.7 GBq and 10.4 ± 7.9 GBq of¹³¹I, respectively. Average number of doses required for remnant, nodal and pulmonary metastases ablation were 1.3, 2.2 and 3.3, respectively. 80% of the patients with only remnant thyroid tissue and 50% with cervical lymph node metastases got ablated with a single dose of¹³¹I. Overall, 87% patients were currently free of disease. While, nine patients had nodal recurrence between surgery and radioiodine treatment, no recurrence was observed thereafter and 3 disease related deaths producing overall mortality of 2.5% (all in children ≶10 years of age) were seen in the mean follow-up of 7.5 years.Conclusion: Differentiated thyroid cancer in children and adolescents is rare but aggressive. The biological behavior differs from that in adults and is related to the age. Younger the age (≶10 years), more aggressive and widespread is the disease with male preponderance and high mortality. The Post-surgical radioiodine ablation/therapy is an important and effective adjuvant in the management of DTC in children and adolescents and even though they present with advance disease, long-term survival and overall prognosis is good.     

In situ breast carcinoma after treatment during adolescence for thyroid cancer with radioiodine

We reviewed the courses of patients treated during childhood or adolescence for thyroid cancer to estimate the frequency of, and to identify possible risk factors for, the occurrence of second malignant tumors in this population. We identified all patients treated for thyroid cancer in a cohort of 1,406 pediatric cancer patients who were diagnosed prior to 20 years of age during the period January 1, 1960 through December 31, 1988 and who were treated at Roswell Park Cancer Institute. Twelve patients were treated for thyroid cancer, of whom nine were women. In situ breast carcinoma was diagnosed 25 and 26 years after diagnosis of thyroid cancer in two of four women treated with radioiodine. No new cancers were diagnosed in the five women treated with thyroidectomy only. Two of four women treated for thyroid cancer during adolescence with radioiodine, which is concentrated in the breast as well as other organs, developed in situ breast carcinoma. Review of a large cohort of adolescent female thyroid cancer patients treated with radioiodine is necessary to provide an accurate estimate of their risk of developing breast cancer. These patients must remain under medical surveillance throughout their lifetimes to facilitate prompt diagnosis of and early intervention for new conditions, such as the occurrence of breast cancer. © 1995 Wiley-Liss, Inc.     

Thyroid Follicular Carcinoma in a Fourteen-year-old Girl with Graves’ Disease

Here we present the case of a 14-yr-old girl who developed thyroid follicular carcinoma accompanied by Graves’ disease. She was diagnosed with Graves’ disease at 10 yr of age and soon achieved a euthyroid state after starting treatment. When she was 13 yr of age, her hyperthyroidism and goiter worsened despite medical therapy. Multiple nodules were found in her enlarged thyroid gland by ultrasonography. Her serum Tg level seemed within the normal range. She underwent near-total thyroidectomy for control of thyroid function. Histopathological study demonstrated that multiple oxyphilic follicular neoplasms were surrounded by the thyroid tissue compatible with Graves’ disease. Capsular invasion was identified in one of the nodules, and thus the histological diagnosis was minimally invasive follicular carcinoma. She did not have signs suggesting metastasis, and has had no relapse for 18 mo after the operation. Although some previous studies showed a high prevalence of thyroid cancer with an aggressive nature in adult patients with Graves’ disease, few reports about thyroid cancer accompanied by Graves’ disease are available in children. The present case, however, suggests that careful investigation is needed when we detect thyroid nodules or progressive thyroid enlargement, especially in children with Graves’ disease.     

Thyroid function in a population of children with attention deficit hyperactivity disorder

To determine the prevalence of thyroid hormone abnormalities and generalized resistance to thyroid hormone in a population of children with attention deficit hyperactivity disorder (ADHD) as compared to reference ranges determined from a control population and hence to determine if routine thyroid hormone screening in children with non-familial ADHD is indicated.

Method:

Children attending the State Child Development Centre in Perth, Western Australia with ADHD, as defined by the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) provided the study population. The control population consisted of 353 normal children with a history of allergy in whom radioallergosorbent (RAST) testing was being performed.

Results:

The prevalence of thyroid hormone abnormalities in the study population was 2.3% (95% CI 0.6%, 5.7%). There were no cases of generalized resistance to thyroid hormone. The prevalence of thyroid hormone abnormalities in the general population of children and adolescents has been reported to vary between 1 and 3.7%.

Conclusion:

Routine thyroid hormone screening is not indicated in children with non-familial ADHD.     

Radiation Exposure and the Risk of Pediatric Thyroid Cancer

It has been more than three years since the unprecedentedly massive earthquake and tsunami struck eastern Japan on March 11, 2011, and the large accident occurred at the Fukushima Daiichi Nuclear Power Plant. To investigate the influence of radiation exposure, thyroid ultrasonography has been provided preliminarily for 360,000 children who lived in Fukushima Prefecture at the time of the accident. As of September 2013, 59 children had been diagnosed with thyroid cancer by fine-needle aspiration cytology, and 34 children had been treated surgically and ultimately diagnosed with papillary thyroid cancer. Here, I would like to describe the characteristics of pediatric thyroid cancer and typical thyroid images obtained by ultrasonography.     

Risk factors of primary thyroid dysfunction in early infants born to mothers with autoimmune thyroid disease

AIM: To assess whether the state of maternal thyroid function and the pattern of thyroid alterations during gestation would affect the infants' thyroid function and to evaluate the risk factors affecting early infants' thyroid function by means of multiple logistic regression. METHODS: In a cross-sectional study, 78 neonates born to mothers with Graves disease or Hashimoto thyroiditis were examined and followed clinically and biochemically. Neonates born to healthy mothers during the same period were set as controls. Tests of thyroid function, antithyroid peroxidase antibody (TPOAb), antithyroglobulin antibody (TGAb), anti-TSH receptor antibody (TRAb) and antithyroid-stimulating antibody (TSAb) were performed both in early infants and their mothers. All possible maternal and/or infantile risk factors for thyroid dysfunction during early infancy were analysed by means of multiple-factor logistical regression. RESULTS: The overall prevalence of underlying subtle thyroid abnormalities in these 78 infants was 52.6%, which was significantly higher than that witnessed among infants from healthy mothers (5.4 per thousand, p<0.01). By using multiple logistic regression analysis, the state of maternal thyroid function in gestation, the type of autoimmune thyroid disease during pregnancy and the level of TRAb in the newborn were significantly correlated with the early infants' thyroid dysfunction. CONCLUSION: Maternal autoimmune thyroid disease during pregnancy will affect infant thyroid function. Therefore, appropriate management of maternal autoimmune thyroid disease throughout pregnancy is essential in the prevention of undesirable neonatal outcomes.     

Thyroid function and volume in epileptic children using carbamazepine, oxcarbazepine and valproate

BACKGROUND: The aim of the present study was to investigate the effects of carbamazepine (CBZ), oxcarbazepine (OXC), and valproic acid (VPA) on thyroid function and volume in epileptic children. METHODS: Fifty-three epileptic children (age, 3-17 years) treated with OXC (n = 10), CBZ (n = 12), or VPA (n = 31) at least for 1 year were evaluated in terms of thyroid hormones, thyroid-stimulating hormone (TSH) levels, response to thyrotropin-releasing hormone (TRH) stimulation test, and thyroid volumes. RESULTS: The patients in the OXC and CBZ groups had similar total thyroxin (TT4) and free T4 (fT4) median levels that were significantly lower than those of the VPA group (P < 0.016). Total tri-iodothyrosin median levels were lower in the CBZ group compared to the VPA group (P < 0.016). Basal TSH levels and thyroid volumes were similar in all groups (P > 0.016). One child from the OXC group (10%), one from the CBZ group (%8.3), and six from the VPA group (19.3%) had hypothyroidic status according to the TRH stimulation test. No statistically significant correlations were found between thyroid gland volume and thyroid function variables and between anti-epileptic drug receiving time and thyroid function or thyroid volume, respectively, in any of the groups (P > 0.05). CONCLUSIONS: Thyroid function should be evaluated periodically in children using CBZ, OXC or VPA. The children taking VPA seems to be at greater risk compared to children onr CBZ or OXC therapy. Except for the basal TSH values in the VPA group, the parameters predictive for the subclinical hypothyroid status remain to be evaluated in further studies.     

Functioning lingual and median ectopic cervical thyroid

The combination of lingual thyroid and median ectopic cervical thyroid in the same patient has not been described previously. A 10-year-old girl presented with a midline anterior neck tumour initially thought to be a thyroglossal cyst. Examination revealed a lobulated, nontranslucent lesion and a noncontiguous lingual thyroid. Thyroid scan showed two separate areas of thyroid activity.     

Relation of basic and clinical research on foetal and neonatal thyroid pathology to neonatal thyroid screening

In this short review the importance is emphasized of basic and clinical research in regard to the interpretation of screening results. This review covers foetal thyroid physiology during the first 48 h of life, the importance of thyroid hormones for normal brain development, the definition of a critical period which might explain intellectual abnormalities in 10-15% of detected hypothyroid children and the importance of autoimmunity in the aetiology and diagnosis of transient congenital hypothyroidism.     

Thyroid function abnormalities among first‐degree relatives of Iranian congenital hypothyroidism neonates

Background: Congenital hypothyroidism (CH) is a relatively common metabolic disease in neonates. Until recent years the disorder was usually regarded as occurring in a sporadic manner. Over the past few years, however, a considerable proportion of familial cases have been identified, and possible roles of autoimmune factors suggested. The aim of the present study was to evaluate abnormality of thyroid function tests in first‐degree relatives of CH neonates and compared this to the normal population. Methods: From 2002 until 2007 thyroid function tests (T4 and thyroid‐stimulating hormone [TSH]) were done in randomly selected CH and normal neonates (n= 194 and n= 350, respectively) and their first‐degree relatives. Most mothers of the CH neonates and control groups were also evaluated for thyroid peroxidase antibody (TPOAb). Results: Thyroid function test in first‐degree relative of neonates with CH (361 parents, 136 siblings) were compared with those in control groups (665 parents, 478 siblings). Abnormal thyroid function tests were found in 85 patients in the CH group versus 96 patients in the control group; hypothyroidism was found in 75 (15.1%) and 57 subjects (5%) person in the CH and control groups, respectively (P < 0.05). Positive TPO antibody was found in 22 mothers (17.3%) of CH neonates in comparison with 65 mothers (32.5%) of control groups (P < 0.05). Frequency of hyperthyroidism in parents of control group had trend to be higher than parents of CH neonates (P= 0.05) Conclusion: Familial and genetic components play a role in inheritance of CH, but maternal thyroid autoimmunity may not play an important role in the development of CH in Iran.