Genotype Analyses in the Japanese and Belarusian Populations Reveal Independent Effects of rs965513 and rs1867277 but Do Not Support the Role of FOXE1 Polyalanine Tract Length in Conferring Risk for Papillary Thyroid Carcinoma.

BACKGROUND: Several functional single-nucleotide polymorphisms (SNPs) at the FOXE1 locus on chromosome 9q22.33 have been associated with the risk for papillary thyroid carcinoma (PTC). This study set out to elucidate whether their effects are independent, using genotyping results in populations of Asian and European descent. METHODS: SNPs rs965513 and rs1867277 and a polymorphic region determining the length of the FOXE1 polyalanine (poly-Ala) tract were genotyped in 501 patients with PTC and 748 healthy individuals from Japan, and in 660 patients and 820 population controls from Belarus. Functional analysis of transactivation activities of FOXE1 isoforms with varying number of alanine repeats was performed by a Dual-Luciferase® Assay. RESULTS: All three polymorphisms were significantly associated with PTC in both populations on univariate analysis. However, conditional analysis revealed independent effects of rs965513 and rs1867277 SNPs but not of the FOXE1 poly-Ala polymorphism. The independent effect of the lead rs965513 SNP was observed in both populations, while that of rs1867277 was only identified in the Japanese population, in which linkage disequilibrium between the three polymorphisms is markedly weaker. Despite the strong decrease in transcriptional activity with increasing FOXE1 poly-Ala tract length, no difference in transactivation potential of the FOXE1 poly-Ala isoforms could be seen after adjustment for the minimal promoter activity in the reporter vectors. Plasmids encoding FOXE1 isoforms of increasing poly-Ala tract length were also found to produce less FOXE1 protein after cell transfection. CONCLUSIONS: The functional variants rs965513 and rs1867277 independently contribute to genetic predisposition to PTC, while a contributing role of the FOXE1 poly-Ala polymorphism could not be confirmed.

Risk of thyroid follicular adenoma among children and adolescents in Belarus exposed to iodine-131 after the Chornobyl accident.

Several studies reported an increased risk of thyroid cancer in children and adolescents exposed to radioactive iodines, chiefly iodine-131 ((131)I), after the 1986 Chornobyl (Ukrainian spelling) nuclear power plant accident. The risk of benign thyroid tumors following such radiation exposure is much less well known. We have previously reported a novel finding of significantly increased risk of thyroid follicular adenoma in a screening study of children and adolescents exposed to the Chornobyl fallout in Ukraine. To verify this finding, we analyzed baseline screening data from a cohort of 11,613 individuals aged ≤18 years at the time of the accident in Belarus (mean age at screening = 21 years). All participants had individual (131)I doses estimated from thyroid radioactivity measurements and were screened according to a standardized protocol. We found a significant linear dose response for 38 pathologically confirmed follicular adenoma cases. The excess odds ratio per gray of 2.22 (95% confidence interval: 0.41, 13.1) was similar in males and females but decreased significantly with increasing age at exposure (P < 0.01), with the highest radiation risks estimated for those exposed at <2 years of age. Follicular adenoma radiation risks were not significantly modified by most indicators of past and current iodine deficiency. The present study confirms the (131)I-associated increases in risk of follicular adenoma in the Ukrainian population and adds new evidence on the risk increasing with decreasing age at exposure.

Major Factors Affecting Incidence of Childhood Thyroid Cancer in Belarus after the Chernobyl Accident: Do Nitrates in Drinking Water Play a Role?

One of the major health consequences of the Chernobyl Nuclear Power Plant accident in 1986 was a dramatic increase in incidence of thyroid cancer among those who were aged less than 18 years at the time of the accident. This increase has been directly linked in several analytic epidemiological studies to iodine-131 (131I) thyroid doses received from the accident. However, there remains limited understanding of factors that modify the 131I-related risk. Focusing on post-Chernobyl pediatric thyroid cancer in Belarus, we reviewed evidence of the effects of radiation, thyroid screening, and iodine deficiency on regional differences in incidence rates of thyroid cancer. We also reviewed current evidence on content of nitrate in groundwater and thyroid cancer risk drawing attention to high levels of nitrates in open well water in several contaminated regions of Belarus, i.e. Gomel and Brest, related to the usage of nitrogen fertilizers. In this hypothesis generating study, based on ecological data and biological plausibility, we suggest that nitrate pollution may modify the radiation-related risk of thyroid cancer contributing to regional differences in rates of pediatric thyroid cancer in Belarus. Analytic epidemiological studies designed to evaluate joint effect of nitrate content in groundwater and radiation present a promising avenue of research and may provide useful insights into etiology of thyroid cancer.

Morphological and clinical presentation of papillary thyroid carcinoma in children and adolescents of Belarus: the influence of radiation exposure and the source of irradiation.

OBJECTIVE: The aims were to analyse the features of papillary thyroid carcinoma in a large cohort of children and adolescents in Belarus and to study the influence of radiation exposure as well as the source of irradiation on the morphological and clinical presentations of tumours. DESIGN AND PATIENTS: The clinical and pathological features of 1086 young patients (age range=4 to 18 inclusive, followed up for ≥18years) with papillary thyroid carcinoma diagnosed during the years 1990 to 2010 were reviewed. The patients were divided into three groups: "external radiation-related", "post-Chernobyl" (internal irradiation-related) and "sporadic". Besides, patients from "post-Chernobyl" cohort (n=936) were further divided into the three equal subgroups according to the dates of surgery, which were corresponding to the early (4-9years), intermediate (10-12years) and long (14-18years) latency periods. RESULTS: Patients in the "external radiation-related" group often showed extra-thyroidal extension in tumours sized ≤10mm (p=0.002). Distant metastases were more frequently (p=0.006) discovered in patients with papillary thyroid carcinoma in post-Chernobyl group (104 of 936, 11.1%) when compared to juveniles from other two groups. Lateral nodal disease and distant metastases were often noted in post-Chernobyl patients operated during the early and intermediate latency periods only. CONCLUSION: Young patients in Belarus with papillary thyroid carcinoma in the "post-Chernobyl" group differed in many clinical and pathological parameters from those in the "sporadic" group. "External radiation related" papillary thyroid carcinomas were distinguished from other two groups of carcinoma in more advanced local spread and more aggressive behaviour of micro-carcinomas.

Analysis of thyroid malignant pathologic findings identified during 3 rounds of screening (1997-2008) of a cohort of children and adolescents from belarus exposed to radioiodines after the Chernobyl accident.

BACKGROUND: Recent studies of children and adolescents who were exposed to radioactive iodine-131 (I-131) after the 1986 Chernobyl nuclear accident in Ukraine exhibited a significant dose-related increase in the risk of thyroid cancer, but the association of radiation doses with tumor histologic and morphologic features is not clear. METHODS: A cohort of 11,664 individuals in Belarus who were aged ≤18 years at the time of the accident underwent 3 cycles of thyroid screening during 1997 to 2008. I-131 thyroid doses were estimated from individual thyroid activity measurements taken within 2 months after the accident and from dosimetric questionnaire data. Demographic, clinical, and tumor pathologic characteristics of the patients with thyroid cancer were analyzed using 1-way analysis of variance, chi-square tests or Fisher exact tests, and logistic regression. RESULTS: In total, 158 thyroid cancers were identified as a result of screening. The majority of patients had T1a and T1b tumors (93.7%), with many positive regional lymph nodes (N1; 60.6%) but few distant metastases (M1; <1%). Higher I-131 doses were associated with higher frequency of solid and diffuse sclerosing variants of thyroid cancer (P < .01) and histologic features of cancer aggressiveness, such as lymphatic vessel invasion, intrathyroidal infiltration, and multifocality (all P < .03). Latency was not correlated with radiation dose. Fifty-two patients with self-reported thyroid cancers which were diagnosed before 1997 were younger at the time of the accident and had a higher percentage of solid variant cancers compared with patients who had screening-detected thyroid cancers (all P < .0001). CONCLUSIONS: I-131 thyroid radiation doses were associated with a significantly greater frequency of solid and diffuse sclerosing variants of thyroid cancer and various features of tumor aggressiveness.

Initial presentation and late results of treatment of post-Chernobyl papillary thyroid carcinoma in children and adolescents of Belarus.

BACKGROUND: The aim of this population-based study was to evaluate the clinical and pathological characteristics and outcome of papillary thyroid carcinoma (PTC) that have arisen in the Belarusian childhood population exposed to the radioactive fallout from the Chernobyl accident within a long-term period. PATIENTS AND METHODS: The long-term treatment results were investigated in 1078 children and adolescents (<19 years old) with PTC who were surgically treated during the years 1990 through 2005. RESULTS: Patients had high rates of metastatic PTC at presentation, with 73.8% of cases having lymph node involvement and 11.1% having distant spread. The most influential factor for lymph node metastases at initial treatment was lymphatic vessel invasion (P < .0001) and for distant metastases, lateral lymph node involvement (P < .0001). The overall survival was 96.9% ± 0.9% with a median follow-up of 16.21 years, and 20-year event-free survival and relapse-free survival were 87.8% ± 1.6% and 92.3% ± 0.9%, respectively. Patients had significantly lower probability of both loco-regional (P < .001) and distant relapses (P = .005) after total thyroidectomy (TT) and radioactive iodine therapy (RAI). For loco-regional relapses after TT, only RAI influenced the prognosis significantly (P < .001). For distant relapses after TT, the refusal to treat with RAI (hazard ratio [HR] = 9.26), vascular invasion (HR = 8.68), and age at presentation (HR = 6.13) were significant risk factors. For loco-regional relapses after non-TT, the principal risk factors were age less than 15 years old at presentation (HR = 5.34) and multifocal growth of tumor (HR = 5.19). For distant relapses after non-TT, the lateral neck metastases were the only unfavorable factor (HR = 9.26). CONCLUSION: The outcome of PTC both in children and in adolescents exposed to the post-Chernobyl radioiodine fallout was rather favorable. TT with RAI is recommended for minimizing loco-regional or distant relapses.

Twenty-five years after Chernobyl: outcome of radioiodine treatment in children and adolescents with very high-risk radiation-induced differentiated thyroid carcinoma.

CONTEXT: After severe reactor emergencies with release of radioactive iodine, elevated thyroid cancer risk in children and adolescents is considered the main health consequence for the population exposed. DESIGN: We studied thyroid cancer outcome after 11.3 years' median follow-up in a selected, very high-risk cohort, 234 Chernobyl-exposed Belarusian children and adolescents undergoing postsurgical radioiodine therapy (RIT) in Germany. INTERVENTIONS: Cumulatively 100 children with or (without; n = 134) distant metastasis received a median 4 (2) RITs and 16.9 (6.6) GBq, corresponding to 368 (141) MBq/kg iodine-131. MAIN OUTCOME MEASURES: Outcomes were response to therapy and disease status, mortality, and treatment toxicity. RESULTS: Of 229 patients evaluable for outcome, 147 (64.2%) attained complete remission [negative iodine-131 whole-body scan and TSH-stimulated serum thyroglobulin (Tg) < 1 µg /L], 69 (30.1%) showed nearly complete remission (complete response, except stimulated Tg 1-10 µg/L), and 11 (4.8%) had partial remission (Tg > 10 µg/L, decrease from baseline in radioiodine uptake intensity in ≥ 1 focus, in tumor volume or in Tg). Except for 2 recurrences (0.9%) after partial remission, no recurrences, progression, or disease-specific mortality were noted. One patient died of lung fibrosis 17.5 years after therapy, 2 of apparently thyroid cancer-unrelated causes. The only RIT side effect observed was pulmonary fibrosis in 5 of 69 patients (7.2%) with disseminated lung metastases undergoing intensive pulmonary surveillance. CONCLUSIONS: Experience of a large, very high-risk pediatric cohort with radiation-induced differentiated thyroid carcinoma suggests that even when such disease is advanced and initially suboptimally treated, response to subsequent RIT and final outcomes are mostly favorable.

Clinical and pathologic features of "sporadic" papillary thyroid carcinoma registered in the years 2005 to 2008 in children and adolescents of Belarus.

BACKGROUND: A systematic analysis of the clinical and pathologic patterns of childhood "sporadic" thyroid carcinoma in Belarus, in the absence of the "Chernobyl radioactive iodine factor," has never been performed. The aim of this study was to establish the essential features of "sporadic" papillary thyroid carcinoma (PTC) in Belarusian children and adolescents, and the relationship of tumor pathology to extrathyroidal extension (ETE) and lymph node metastases. METHODS: This was a retrospective population-based study with assessment of histological samples of 119 cases of thyroid cancer in Belarusian children and adolescents of 0-18 years old registered during 2005-2008 years. Sporadic PTC was noted in 94 children who were not exposed to the Chernobyl radiation release. None of the 119 cases of thyroid were follicular thyroid cancer. RESULTS: The incidence rate of PTC was 1.13 per 100,000 persons. The median age at diagnosis was 15.1 years with fourfold predominance of diagnosis in female patients. Relapse was detected in 2% of cases with median follow-up of 4.2 years. Median tumor size was 12 mm. Three percent of the cases of PTC had multifocal growth. The classical variant of PTC was registered in 46% of the patients with thyroid cancer, the follicular variant of PTC was noted in 20% of the cases. The percent of rare types of PTC (tall cell and diffuse sclerosing) were equal to that for solid PTCs (13%, 12%, and 10%, respectively). Adolescents had a pure papillary carcinoma more often compared to children who represented tumors with mixed papillary/follicular patterns more frequently (p<0.05). Two-thirds of the patients with PTC had regional lymph node metastases. ETE was established in 39 of 74 patients in whom ETE could be assessed by morphology. Multivariate analysis showed that lymphatic invasion was the strongest independent factor associated with both ETE (p<0.0001) and lymph node metastases (p<0.0001). CONCLUSION: In 2005-2008, sporadic thyroid cancer in children of Belarus was represented by high prevalence of PTC and absence of follicular thyroid cancer. Sporadic cases of PTC in Belarus were characterized by smaller tumor size, a small number of cases with multifocal growth, an equal number of rare types and solid PTCs, a relatively high prevalence of pure papillary variant of PTC in adolescents, and a low frequency of early relapses. A high frequency of ETE and lymph node metastases was detected. The strongest morphologic factor associated with both of them was lymphatic invasion.

Cytotoxic effects of chemotherapeutic drugs and heterocyclic compounds at application on the cells of primary culture of neuroepithelium tumors.

Neuroepithelial tumor cells were cultured in vitro. The biopsy material was taken from 93 children at removal of the brain tumors during neurosurgical operations. The individual features of the cells sensitivity of primary cultures in respect to protocol-approved chemotherapy drugs and changes in the Interleukin-6 (Il-6) level in the culture medium after the application of chemotherapy were established. The initial level of Il-6 exceeded 600.0 pg/ml in the cultural medium with histologically verified pilomyxoid astrocytoma cells, and ranged from 100.0 to 200.0 pg/ml in the medium at cultivation of ganglioneuroblastoma and pilocytic astrocytoma. A decrease in the Il-6 level in the medium culture of primary tumors cells was observed after the application of chemotherapeutic agents on the cells of pilomyxoid astrocytoma, astrocytomas, and pilocytic desmoplastic/nodular medulloblastoma. The production of Il-6 increased after application of cytostatic drugs on the cells of oligoastrocytomas. A decrease in Il-6 level after application of Cisplatin and Methotrexate and a 5-10 fold increase in the level of Il-6 after application of Etoposide, Carboplatin, Cytarabine, and Gemcitabine were registered in the medium with ganglioneuroblastoma. To improve the cytotoxic action of chemotherapeutic agents, the combined application of cytostatics with heterocyclic compounds was carried out. A computer modeling of ligand-protein complexes of carbamide using the Dock 6.4 and USF Chimera program packages was performed with molecular mechanics method. Special attention was drawn to the ability of several isoxazole heterocycles and isothiazolyl to inhibit the tyrosine kinase. It was proved in vitro that the joint application of chemotherapeutic agents and heterocyclic compounds could reduce the concentration of the cytostatic factor by 10 or more times, having maintained the maximum cytotoxic effect. It was assumed that the target amplification of cytotoxic action of chemotherapeutic agents had prospects for reducing toxic side effects of chemotherapy in vivo, which would be carried out only after the preclinical studies.

Pulmonary fibrosis in youth treated with radioiodine for juvenile thyroid cancer and lung metastases after Chernobyl.

PURPOSE: The objective of this project was to systematically determine the prevalence and consequences of pulmonary fibrosis in youth with thyroid carcinoma and lung metastases from Belarus who were treated with radioiodine ((131)I). METHODS: A total of 69 patients treated for juvenile thyroid carcinoma and lung metastasis with (131)I were assessed. A group of 29 patients without lung metastases and prior (131)I treatment served as controls. The assessments included a CT scan of the lungs, extensive pulmonary function testing and an incremental cycle test to volitional fatigue with measurements of oxygen uptake (VO(2)), oxygen saturation and alveolar-arterial difference in oxygen partial pressure (ΔaaO(2)). RESULTS: Five patients with lung metastases showed advanced pulmonary fibrosis on CT scans and also had poorer lung functions compared with the 62 patients with none or minor signs of fibrosis and the 29 controls. Furthermore, these five patients showed lower peak VO(2), lower oxygen saturation at peak exercise and higher exercise ΔaaO(2). They were younger at the time of cancer diagnosis and had received chemotherapy more frequently than youth with pulmonary metastases who did not develop fibrosis. One of the five patients subsequently died from pulmonary fibrosis. CONCLUSION: Following the Chernobyl catastrophe, about 7% of children treated with radioiodine for thyroid carcinoma and lung metastases displayed pulmonary fibrosis which was associated with functional impairments. Based on the characteristics of affected individuals, the number of radioiodine courses may have to be limited, especially in young children, and chemotherapy should be avoided.

I-131 activities as high as safely administrable (AHASA) for the treatment of children and adolescents with advanced differentiated thyroid cancer.

AIM: Differentiated thyroid carcinoma (DTC) in children and young adults is rare, can be aggressive, and often presents at advanced stages. In a population of young Belarusian patients with advanced DTC after the nuclear reactor accident at Chernobyl, we determined the activities that are as high as safely administrable (AHASA). PATIENTS AND METHODS: In 180 children and adolescents, we studied 133 courses of I-131 thyroid remnant ablation (median age at ablation, 14.3 yr) and 250 courses of I-131 therapy (median age at therapy, 15.7 yr). Remnant ablation was performed with weight-adapted I-131 activities of a median of 51.8 MBq/kg (range, 23.9-73.8 MBq/kg); and residual disease therapy was performed with a median activity of 98.0 MBq/kg (range, 56.7-164.7 MBq/kg). The radiation absorbed dose to the blood (BD) per unit of activity administered for each treatment was deduced from whole-body retention data measured twice daily using ceiling probes. The AHASA activity was calculated assuming an upper limit of 2 Gy BD. RESULTS: For I-131 ablation, the median weight-adjusted AHASA activity leading to a BD of 2 Gy was 407 MBq/kg (range, 137-661 MBq/kg). In three patients with extensive diffuse pulmonary metastases, the AHASA was lower than 200 MBq/kg. For patients receiving additional I-131 treatments after ablation, a median body weight-adapted AHASA activity of 406 MBq/kg (range, 210-775 MBq/kg) was calculated. CONCLUSION: Children and adolescents with advanced DTC can be treated with I-131 activities of at least 200 MBq/kg. For children with extensive pulmonary metastases, pretherapeutic dosimetry is needed to determine the AHASA.

Success of the postoperative 131I therapy in young Belarusian patients with differentiated thyroid cancer after Chernobyl depends on the radiation absorbed dose to the blood and the thyroglobulin level.

PURPOSE: Differentiated thyroid carcinoma (DTC) in children and young adults is rare but often aggressive and in an advanced stage at diagnosis. In a cohort of young Belarusian patients with advanced DTC after Chernobyl we retrospectively studied parameters influencing the success of the postoperative (131)I therapy. METHODS: Included in the study were 136 patients (83 female, 53 male; median age 14.3 years, range 9.4-22.8 years) who had had total thyroidectomy in Belarus and subsequent (131)I therapy and follow-up in Germany. Of the 136 patients, 34 were classified as M1 and 102 as M0 (N0 1, N1 101). The median weight-adjusted (131)I activity administered after thyroid hormone withdrawal was 52 MBq/kg (range 24-74 MBq/kg). TNM stage, gender, administered activity, whole-body residence time and blood dose during ablation, Tg and TSH levels, date, and age at time of treatment were tested for their effect on the rate of complete remission (CR). CR was defined as a negative scan and a stimulated Tg level of <1 ng/ml at follow-up. RESULTS: CR was observed in 1 of 34 M1 and in 51 of 102 M0 patients after the first treatment. Multivariate analysis in the M0 group identified the Tg level (P < 0.0001 for log(Tg)) and the radiation absorbed dose to the blood (P < 0.001) as independent determinants; all other parameters were unimportant (P > 0.3). The regression model was able to correctly predict CR in 82 of 102 patients (80.4%). CONCLUSION: In children and young adults with advanced DTC, the rate of CR after postoperative (131)I therapy is dependent on the preablative Tg level and the radiation absorbed dose to the blood. Though the present results must be confirmed in a prospective study, they imply that preablative dosimetry may improve rates of CR.

Favourable course of disease after incomplete remission on (131)I therapy in children with pulmonary metastases of papillary thyroid carcinoma: 10 years follow-up.

PURPOSE: The aim of this study is to report on a collective of 20 children from Belarus who had developed papillary thyroid carcinoma with pulmonary metastases after the Chernobyl disaster. In all children fractionated radioiodine therapy (RIT) was ceased before achieving complete remission due to a lack of further effects of (131)I therapy and an increased risk of pulmonary fibrosis. METHODS: The 20 children (12 girls) were treated with (131)I using 50 MBq/kg body weight for thyroid remnant ablation and 100 MBq/kg for further therapy in intervals of 5-12 months. After five to six courses and a cumulative activity of about 24 GBq (131)I no further RIT was conducted; the median thyroglobulin (TG) was 56 µg/l at this time. All patients were followed for at least 10 years after cessation of RIT using diagnostic whole-body scintigraphy, CT of the chest, lung function testing and stimulated TG measurements every 1-3 years. RESULTS: During follow-up after the last RIT a continuous decline of values for TG levels of ∼35% per year was observed between individual visits. The median Tg level at the time of cessation of (131)I therapy was 56 µg/l; however, at the last visit 16 of 20 patients had a TG level ≤10 µg/l (median 2.4 µg/l). Neither on diagnostic radioiodine whole-body scan nor on CT was progression of lung metastases observed. No significant pulmonary fibrosis developed. CONCLUSION: In spite of incomplete remission of thyroid cancer at cessation of RIT, a continuing spontaneous decline of TG and clinically stable partial remissions were observed in this collective of children. Therefore, if RIT does not show further effects, the administration of further courses should be handled restrictively.

The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl.

Papillary thyroid cancer (PTC) among individuals exposed to radioactive iodine in their childhood or adolescence is a major internationally recognized health consequence of the Chernobyl accident. To identify genetic determinants affecting individual susceptibility to radiation-related PTC, we conducted a genome-wide association study employing Belarusian patients with PTC aged 0-18 years at the time of accident and age-matched Belarusian control subjects. Two series of genome scans were performed using independent sample sets, and association with radiation-related PTC was evaluated. Meta-analysis by the Mantel-Haenszel method combining the two studies identified four SNPs at chromosome 9q22.33 showing significant associations with the disease (Mantel-Haenszel P: mhp = 1.7 x 10(-9) to 4.9 x 10(-9)). The association was further reinforced by a validation analysis using one of these SNP markers, rs965513, with a new set of samples (overall mhp = 4.8 x 10(-12), OR = 1.65, 95% CI: 1.43-1.91). Rs965513 is located 57-kb upstream to FOXE1, a thyroid-specific transcription factor with pivotal roles in thyroid morphogenesis and was recently reported as the strongest genetic risk marker of sporadic PTC in European populations. Of interest, no association was obtained between radiation-related PTC and rs944289 (mhp = 0.17) at 14p13.3 which showed the second strongest association with sporadic PTC in Europeans. These results show that the complex pathway underlying the pathogenesis may be partly shared by the two etiological forms of PTC, but their genetic components do not completely overlap each other, suggesting the presence of other unknown etiology-specific genetic determinants in radiation-related PTC.

The usual ultrasonographic features of thyroid cancer are less frequent in small tumors that develop after a long latent period after the Chernobyl radiation release accident.

BACKGROUND: The Chernobyl accident resulted in an unprecedented number of radiation-induced thyroid cancers in young individuals as detected by national and international screening programs. The vast majority of thyroid malignancies were papillary carcinomas that, despite being similar by histopathology, displayed large variability in clinical course. The correlations between ultrasound (US) and clinicopathological features in young patients with radiation-induced thyroid cancer, however, have not been well studied. Because of the importance of US for deciding which subjects should have fine-needle aspiration biopsy, we assessed the US features of papillary thyroid carcinoma in patients exposed to Chernobyl fallouts. DESIGN: We performed a retrospective multivariate logistic regression analysis of US features, clinicopathological data, and the latency period between radiation exposure and the diagnosis of cancer in 94 patients who were 10.6-34.3 years old (16.5 +/- 6.2, mean +/- standard deviation) at the time of diagnosis and 0.1-18.0 years old (5.6 +/- 4.2) at the time of the Chernobyl accident. RESULTS: Nodules greater than 10 mm were associated with the higher frequency of irregular margins (p = 0.001), longer period of latency (p = 0.016), and bilateral lymph node involvement (p = 0.025). Irregular tumor margins correlated with the shorter period of latency (p = 0.009) and unilateral nodal disease (p = 0.010). Hypoechoic nodules were observed more frequently in female patients (p = 0.012), in the absence of halo (p = 0.003) or calcifications (p = 0.005). Hypoechogenicity also correlated with the shorter latency (p = 0.015) and younger age of patients (p = 0.048). CONCLUSIONS: Irregular nodule margins, a usual sign of malignancy, are less useful in detecting thyroid cancers in radiation-exposed patients with tumors less than 10 mm. Thyroid cancers that are detected after longer latent periods display less of the US features characteristic of a malignant process, while benign US features are observed more frequently. Therefore, we recommend fine-needle aspiration biopsy to ensure early diagnosis of thyroid cancer for patients with a history of radiation exposure, even if their nodules are less than 10 mm.

Childhood thyroid cancer in Belarus, Russia, and Ukraine after Chernobyl and at present.

Thyroid cancer in children is usually rare, but in the individuals exposed to radiation risk of disease increases considerably. After the Chernobyl accident in 1986, an over 10-fold maximal elevation in the incidence of thyroid cancer was registered about a decade later, cumulatively resulting in more than a thousand of newly diagnosed cases in children who lived in the territories of Belarus, Russia, and Ukraine affected by radioactive fallouts. Experience from the epidemic substantially promoted knowledge in clinical pediatric oncology, pathology and basic sciences. This article overviews epidemiology, clinical features, results of treatment and follow-up of childhood patients with radiation-induced Chernobyl thyroid cancer in comparison to sporadic cases diagnosed at present. In addition, we discuss general issues of pathology and molecular findings in childhood thyroid carcinomas.

Childhood thyroid cancer in Belarus, Russia, and Ukraine after Chernobyl and at present

Thyroid cancer in children is usually rare, but in the individuals exposed to radiation risk of disease increases considerably. After the Chernobyl accident in 1986, an over 10-fold maximal elevation in the incidence of thyroid cancer was registered about a decade later, cumulatively resulting in more than a thousand of newly diagnosed cases in children who lived in the territories of Belarus, Russia, and Ukraine affected by radioactive fallouts. Experience from the epidemic substantially promoted knowledge in clinical pediatric oncology, pathology and basic sciences. This article overviews epidemiology, clinical features, results of treatment and follow-up of childhood patients with radiation-induced Chernobyl thyroid cancer in comparison to sporadic cases diagnosed at present. In addition, we discuss general issues of pathology and molecular findings in childhood thyroid carcinomas.

O câncer de tiróide é habitualmente raro em crianças, mas em indivíduos expostos a radiação o risco da doença aumenta consideravelmente. Cerca de uma década após o acidente de Chernobil, em 1986, foi registrado um aumento de mais de 10 vezes na incidência de câncer de tiróide, resultando cumulativamente em mais de mil novos casos diagnosticados em crianças que viviam nos territórios da Bielorrússia, Russia, e Ucrânia, afetadas pela chuva radioativa. A experiência com essa epidemia resultou em conhecimento substancial de oncologia pediátrica clínica, patologia e ciências básicas. Este artigo analisa a epidemiologia, os achados clínicos, os resultados do tratamento e a evolução de pacientes pediátricos com câncer de tiróide induzido pela radiação de Chernobil, em comparação com casos esporádicos diagnosticados atualmente. Adicionalmente, serão discutidos tópicos de patologia e achados moleculares no carcinoma de tiróide infantil.

Comprehensive clinical assessment of 740 cases of surgically treated thyroid cancer in children of Belarus.

OBJECTIVE: A retrospective study was designed to evaluate the results of surgical treatment and follow-up data in thyroid cancer patients less than 15 years old at the time of surgery. SUMMARY BACKGROUND DATA: Pediatric thyroid carcinomas have a high rate of lymph nodal and distant metastases. Risk factors for recurrences and postoperative morbidity have not been assessed yet in a representative series. METHODS: The group included 740 pediatric patients with thyroid cancer. Total thyroidectomy was performed in 426 (57.6%), lobectomy in 248 (33.5%), subtotal thyroidectomy in 58 (7.8%) cases, and 8 patients (1.1%) underwent partial lobectomy. RESULTS: The mean follow-up period was 115.8 months (range, 1.5-236.4 months). Recurrence was diagnosed in 204 cases (27.6%), including 73 local relapses (9.9%), 90 distant metastases (12.2%), and a combination of local and distant recurrences in 41 (5.5%) patients. Multivariate statistical assessment revealed the following independent parameters significantly associated with the risk of recurrent nodal disease: a young age at diagnosis, multifocal carcinomas, N1 status, and lack of neck lymph node dissection. For lung metastases, the significant risk factors were female gender, young age at diagnosis, and presence of symptoms. The observed 5- and 10-year survival for the entire group was 99.5% and 98.8%, respectively. Postoperative hypoparathyroidism was significantly associated with multifocal tumors, central compartment removal, and ipsilateral dissection. CONCLUSIONS: Total thyroidectomy followed by radioiodine therapy is an optimal treatment strategy that makes it possible to achieve a cure in a vast majority of pediatric patients with differentiated thyroid carcinomas. Risk of recurrence is strongly associated with tumor stage, extent of surgery, the young patient's age, and presence of symptoms at diagnosis.