Inherited thyroid tumours.

Inherited thyroid tumours are an important group which need clarification. This is partly because of the common use of the term Familial Non-Medullary Thyroid Cancer when some of the specific entities included under this heading really represent inherited benign tumours with a risk of progression to malignancy. The subject is briefly reviewed, and one syndromic and one non-syndromic type of inherited thyroid tumours of follicular cell origin discussed in more detail to emphasise the point that each of these groups need to be treated as separate entities.

On the Origin of Cells and Derivation of Thyroid Cancer: C Cell Story Revisited.

We will highlight and put into perspective new lineage tracing data from genetic studies in mice indicating that the genuine progenitors to C cells arise in the endoderm germ layer. This overturns the current concept of a neural crest origin of thyroid C cells referred to in every textbook and dedicated paper to this very day. As will become apparent, except for a single experiment, the neural crest theory has little or no support when the evolution and development of calcitonin-producing cells in the entire chordate family are considered. Instead, a unifying origin of all cells of the ultimobranchial bodies reopens questions on the histogenesis of certain thyroid pathologies previously difficult to explain. On this aspect, medullary thyroid cancer shows a stronger connection to gut neuroendocrine tumours than previously recognized. It is envisaged that novel factors implicated in C cell-derived tumour growth and progression will be discovered as the mechanisms that regulate lineage expansion of embryonic C cell precursors from pharyngeal endoderm are uncovered. We will not discuss why C cells go to the bother of burying themselves in the thyroid - this remains a mystery.

Thyroid Growth and Cancer.

It is proposed that most papillary thyroid cancers originate in infancy and childhood, based on the early rise in sporadic thyroid carcinoma incidence, the pattern of radiation-induced risk (highest in those exposed as infants), and the high prevalence of sporadic papillary thyroid cancers in children and adolescents (ultrasound screening after the Fukushima accident). The early origin can be linked to the growth pattern of follicular cells, with a high mitotic rate in infancy falling to very low replacement levels in adult life. The cell of origin of thyroid cancers, the differentiated follicular cell, has a limited growth potential. Unlike cancers originating in stem cells, loss of the usually tight link between differentiation and replicative senescence is required for immortalisation. It is suggested that this loss distinguishes larger clinically significant papillary thyroid cancers from micro-papillary thyroid cancers of little clinical significance. Papillary carcinogenesis can then be divided into 3 stages: (1) initiation, the first mutation in the carcinogenic cascade, for radiation-induced papillary thyroid cancers usually a RET rearrangement, (2) progression, acquisition of the additional mutations needed for low-grade malignancy, and (3) escape, further mutations giving immortality and a higher net growth rate. Most papillary thyroid cancers will not have achieved full immortality by adulthood, and remain as so-called micro-carcinomas with a very low growth rate. The use of the term 'cancer' to describe micro-papillary thyroid cancers in older patients encourages overtreatment and alarms patients. Invasive papillary thyroid tumours show a spectrum of malignancy, which at its lowest poses no threat to life. The treatment protocols and nomenclature for small papillary carcinomas need to be reconsidered in the light of the new evidence available, the continuing discovery of smaller lesions, and the model of thyroid carcinogenesis proposed.

Dental x-rays and the risk of thyroid cancer: a case-control study.

UNLABELLED: The thyroid gland is highly susceptible to radiation carcinogenesis and exposure to high-dose ionising radiation is the only established cause of thyroid cancer. Dental radiography, a common source of low-dose diagnostic radiation exposure in the general population, is often overlooked as a radiation hazard to the gland and may be associated with the risk of thyroid cancer. An increased risk of thyroid cancer has been reported in dentists, dental assistants, and x-ray workers; and exposure to dental x-rays has been associated with an increased risk of meningiomas and salivary tumours. METHODS: To examine whether exposure to dental x-rays was associated with the risk of thyroid cancer, we conducted a population-based case-control interview study among 313 patients with thyroid cancer and a similar number of individually matched (year of birth +/- three years, gender, nationality, district of residence) control subjects in Kuwait. RESULTS: Conditional logistic regression analysis, adjusted for other upper-body x-rays, showed that exposure to dental x-rays was significantly associated with an increased risk of thyroid cancer (odds ratio = 2.1, 95% confidence interval: 1.4, 3.1) (p=0.001) with a dose-response pattern (p for trend <0.0001). The association did not vary appreciably by age, gender, nationality, level of education, or parity. DISCUSSION: These findings, based on self-report by cases/controls, provide some support to the hypothesis that exposure to dental x-rays, particularly multiple exposures, may be associated with an increased risk of thyroid cancer; and warrant further study in settings where historical dental x-ray records may be available.

Twenty years' experience with post-Chernobyl thyroid cancer.

Chernobyl, the largest ever nuclear accident, caused a huge release of radioactive isotopes, including nearly 2x10(18) Bq of iodine-131. Four years later an increase in thyroid cancer incidence, virtually all papillary carcinomas in children, occurred in the highly exposed areas. The increase has continued, and with increasing latency the tumour molecular and morphological pathology has changed; further changes may occur in the future. Children under the age of 1 at exposure show the highest susceptibility, and carry this risk with them into adult life; 4000 cases have been attributed to the accident, but so far very few have died. The risk falls rapidly with increasing age at exposure; it is doubtful if there is any risk for adults at exposure. Other factors linked to susceptibility to thyroid carcinogenesis after Chernobyl include dose, iodine deficiency, and genetic factors. Other consequences are briefly covered.

The Chernobyl accident 20 years on: an assessment of the health consequences and the international response.

Twenty years after the Chernobyl accident the WHO and the International Atomic Energy Authority issued a reassuring statement about the consequences. Our objectives in this study were to evaluate the health impact of the Chernobyl accident, assess the international response to the accident, and consider how to improve responses to future accidents. So far, radiation to the thyroid from radioisotopes of iodine has caused several thousand cases of thyroid cancer but very few deaths; exposed children were most susceptible. The focus on thyroid cancer has diverted attention from possible nonthyroid effects. The international response to the accident was inadequate and uncoordinated, and has been unjustifiably reassuring. Accurate assessment in future health effects is not currently possible in the light of dose uncertainties, current debates over radiation actions, and the lessons from the late consequences of atomic bomb exposure. Because of the uncertainties from and the consequences of the accident, it is essential that investigations of its effects should be broadened and supported for the long term. The United Nations should initiate an independent review of the actions and assignments of the agencies concerned, with recommendations for dealing with future international-scale accidents. These should involve independent scientists and ensure cooperation rather than rivalry.

The Chernobyl accident 20 years on: an assessment of the health consequences and the international response

Twenty years after the Chernobyl accident the WHO and the International Atomic Energy Authority issued a reassuring statement about the consequences. Our objectives in this study were to evaluate the health impact of the Chernobyl accident, assess the international response to the accident, and consider how to improve responses to future accidents. So far, radiation to the thyroid from radioisotopes of iodine has caused several thousand cases of thyroid cancer but very few deaths; exposed children were most susceptible. The focus on thyroid cancer has diverted attention from possible nonthyroid effects. The international response to the accident was inadequate and uncoordinated, and has been unjustifiably reassuring. Accurate assessment in future health effects is not currently possible in the light of dose uncertainties, current debates over radiation actions, and the lessons from the late consequences of atomic bomb exposure. Because of the uncertainties from and the consequences of the accident, it is essential that investigations of its effects should be broadened and supported for the long term. The United Nations should initiate an independent review of the actions and assignments of the agencies concerned, with recommendations for dealing with future international-scale accidents. These should involve independent scientists and ensure cooperation rather than rivalry.

Vinte anos após o acidente de Chernobyl ocorrido em 1986, a OMS e a Autoridade Internacional sobre Energia Atômica lançaram um relatório sobre as conseqüências desse desastre. Nosso objetivo neste estudo é avaliar o impacto de tal acidente sobre a saúde e a reação internacional sobre o ocorrido, além de considerar se é possível melhorar as respostas em futuros desastres. Observamos que a radiação sobre a tireóide, proveniente de radioisótopos de iodo, causou milhares de casos de câncer, mas poucas mortes; as crianças expostas foram as mais suscetíveis. O foco no câncer de tireóide, porém, distraiu a atenção de especialistas sobre outros possíveis efeitos. A resposta internacional ao acidente foi inadequada, descoordenada e injustificavelmente tranqüilizadora. Acurada avaliação sobre efeitos futuros nem sempre é possível por causa de uma certa dose de incertezas frente ao estágio atual dos debates sobre radiação. É essencial que investigações sobre efeitos e conseqüências do desastre possam ser socializadas e apoiadas por um longo período de tempo. Por causa das inadequadas respostas internacionais ao problema, a ONU deveria iniciar uma revisão independente a respeito das ações e responsabilidades das agências, com recomendações de como agir em futuros desastres. Isso deveria envolver cientistas independentes e não que atuassem em competição.

Multiple brown tumors in primary hyperparathyroidism caused by an adenoma mimicking metastatic bone disease with false positive results on computed tomography and Tc-99m sestamibi imaging: MR findings.

We encountered an unusual case of hyperparathyroidism with both hemosiderin deposits on the ribs and low intensity on T2-weighted magnetic resonance imaging (MRI) caused by a parathyroid adenoma with multiple brown tumors that mimicked metastatic bone tumor due to false positive results on computed tomography (CT) and Tc-99m sestamibi (MIBI) imaging. The patient, a middle-aged woman, had very high serum levels of calcium (14.1 mg/dl), alkaline phosphatase (9,369 IU/l) and intact-PTH (12,400 pg/ml), and a large tumor (2.5 cm in diameter) in the lower portion of the left lobe of the thyroid. Plain X-ray revealed a soft tumor in the left chest wall. On CT scan, there were multiple destructive masses in the ribs, including large intramedullary masses on both 3rd ribs. On MIBI scintigraphy, there was strong late uptake in the lower portion of the left cervical region, both 3rd ribs, and the left 7th, 8th, and 10th ribs. T2-weighted image MRI scans showed that both 3rd ribs had a low intensity with hemosiderin deposits. These findings suggested that the patient had hyperparathyroidism with multiple bone metastases due to carcinoma of the parathyroid gland. However, on pathology, the resected tumor of lower portion of the left lobe of thyroid was diagnosed as a parathyroid adenoma, and the tumors of the left 3rd and 7th ribs, as well as the right 2nd rib, were shown to be brown tumors. After resection, the patient's serum levels of calcium, alkaline phosphatase, and intact-PTH normalized. At 1.5-years follow-up, CT, MIBI, and MRI scans showed no abnormal findings. It is necessary to determine whether MRI can be used to distinguish between brown tumors and metastases caused by carcinoma of the parathyroid gland.

The chernobyl accident 20 years on: an assessment of the health consequences and the international response.

BACKGROUND: The Chernobyl accident in 1986 caused widespread radioactive contamination and enormous concern. Twenty years later, the World Health Organization and the International Atomic Energy Authority issued a generally reassuring statement about the consequences. Accurate assessment of the consequences is important to the current debate on nuclear power. OBJECTIVES: Our objectives in this study were to evaluate the health impact of the Chernobyl accident, assess the international response to the accident, and consider how to improve responses to future accidents. DISCUSSION: So far, radiation to the thyroid from radioisotopes of iodine has caused several thousand cases of thyroid cancer but very few deaths ; exposed children were most susceptible. The focus on thyroid cancer has diverted attention from possible nonthyroid effects, such as mini-satellite instability, which is potentially important. The international response to the accident was inadequate and uncoordinated, and has been unjustifiably reassuring. Accurate assessment of Chernobyl's future health effects is not currently possible in the light of dose uncertainties, current debates over radiation actions, and the lessons from the late consequences of atomic bomb exposure. CONCLUSIONS: Because of the uncertainties over the dose from and the consequences of the Chernobyl accident, it is essential that investigations of its effects should be broadened and supported for the long term. Because of the problems with the international response to Chernobyl, the United Nations should initiate an independent review of the actions and assignments of the agencies concerned, with recommendations for dealing with future international-scale accidents. These should involve independent scientists and ensure cooperation rather than rivalry.

Risk of thyroid cancer after exposure to 131I in childhood.

BACKGROUND: After the Chernobyl nuclear power plant accident in April 1986, a large increase in the incidence of childhood thyroid cancer was reported in contaminated areas. Most of the radiation exposure to the thyroid was from iodine isotopes, especially 131I. We carried out a population-based case-control study of thyroid cancer in Belarus and the Russian Federation to evaluate the risk of thyroid cancer after exposure to radioactive iodine in childhood and to investigate environmental and host factors that may modify this risk. METHODS: We studied 276 case patients with thyroid cancer through 1998 and 1300 matched control subjects, all aged younger than 15 years at the time of the accident. Individual doses were estimated for each subject based on their whereabouts and dietary habits at the time of the accident and in following days, weeks, and years; their likely stable iodine status at the time of the accident was also evaluated. Data were analyzed by conditional logistic regression using several different models. All statistical tests were two-sided. RESULTS: A strong dose-response relationship was observed between radiation dose to the thyroid received in childhood and thyroid cancer risk (P<.001). For a dose of 1 Gy, the estimated odds ratio of thyroid cancer varied from 5.5 (95% confidence interval [CI] = 3.1 to 9.5) to 8.4 (95% CI = 4.1 to 17.3), depending on the risk model. A linear dose-response relationship was observed up to 1.5-2 Gy. The risk of radiation-related thyroid cancer was three times higher in iodine-deficient areas (relative risk [RR]= 3.2, 95% CI = 1.9 to 5.5) than elsewhere. Administration of potassium iodide as a dietary supplement reduced this risk of radiation-related thyroid cancer by a factor of 3 (RR = 0.34, 95% CI = 0.1 to 0.9, for consumption of potassium iodide versus no consumption). CONCLUSION: Exposure to (131)I in childhood is associated with an increased risk of thyroid cancer. Both iodine deficiency and iodine supplementation appear to modify this risk. These results have important public health implications: stable iodine supplementation in iodine-deficient populations may substantially reduce the risk of thyroid cancer related to radioactive iodines in case of exposure to radioactive iodines in childhood that may occur after radiation accidents or during medical diagnostic and therapeutic procedures.

BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas.

The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (PTC) (36-69%), which forms almost all of the over 2000 cases of thyroid carcinoma that have occurred in Chernobyl. BRAF is activated by point mutation, and were it to occur at a high frequency in Chernobyl-related tumors, it would challenge the dominant role of double-strand breaks in radiation-induced PTC. In a previous study, we detected the BRAF V600E mutation in 46% (23 of 50) of sporadic adult PTC. Using the same methodology, we have analyzed 34 post-Chernobyl PTC and detected RET/PTC rearrangements in 14 (41%) and BRAF mutations (V600E) in four (12%). These two alterations did not coexist in any PTCs. The mean age at exposure of patients with PTC showing BRAF mutation was higher than that of patients with tumors without BRAF mutation irrespective of their RET status. We have also analyzed 17 sporadic cases of childhood PTC and found that only one (6%) harbored the BRAF V600E mutation. We conclude that the frequency of BRAF mutations is significantly lower (P = 0.0008) in post-Chernobyl PTC than in adult sporadic PTC, whereas no significant difference was found between post-Chernobyl and sporadic childhood PTCs.

Germline succinate dehydrogenase subunit D mutation segregating with familial non-RET C cell hyperplasia.

C cell hyperplasia is associated with medullary carcinoma of the thyroid in the inherited MEN2 syndromes, in which the great majority of cases have been shown to be due to a mutation in the RET oncogene. We report a study of a family with C cell hyperplasia and hypercalcitoninemia in which no cases of medullary carcinoma have yet occurred and which lacked an identifiable causative RET mutation. Four of the family members showed hypercalcitoninemia, and marked C cell hyperplasia was present in each of the three in whom thyroidectomy has been performed. We investigated the possible involvement of the SDHD gene, because somatic and germline mutations in this gene have been found in a variety of tumors of neural crest-derived tissue. A germline mutation in exon 2 of the SDHD gene (c149 A-G, His 50 Arg) was found in six members of the family; all the four available members with hypercalcitoninemia possessed the mutation. One of the five available members without hypercalcitoninemia, an 18-yr-old female, also showed the mutation. We conclude that we have identified a new syndrome, characterized by familial non-RET C cell hyperplasia. Our studies suggest that a mutation in SDHD may be causative. These observations have implications for apparently incidental cases of hypercalcitoninemia or C cell hyperplasia.