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.

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.

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.

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.

Differentiated thyroid cancer in childhood: pathology, diagnosis, therapy.

The incidence of thyroid cancer in childhood amounts to approximately 0,5/100.000/year. However, after exposure to ionizing irradiation, the incidence may increase more than 20 fold. In children, lymph node metastases of differentiated thyroid cancer are frequent (more than 50%); distant metastases mainly to the lung are seen in 20-30%. The method of choice for the primary diagnosis of thyroid cancer today is ultrasonography with 7,5 - 10 MHz probes, accompanied by fine-needle aspiration biopsy. Differentiated thyroid cancer has to be treated with a multidisciplinary approach comprising total thyroidectomy and lymph node dissection, post-operative radioiodine treatment and TSH-suppression by levothyroxine. The long-term results of this treatment approach are generally good with 10-year survival rates of 95% and higher. The treatment of children with disseminated pulmonary metastases however, may be complicated due to the increased risk of the induction of pulmonary fibrosis by radioiodine.