Chronic iodine overload and apoptosis in cold nodules from endemic multinodular goiters

As apoptosis and necrosis are known to exist during experimental goiter development and involution, we studied them in ten Tunisian multinodular endemic goiters, five of them having received a chronic excess of iodine during six months. Apoptotic thyrocyte nuclei have been counted on hematoxylin-eosin stained semi-thin sections. Using immunoperoxidase on paraffin sections, bcl-2 and bax immunoreactivities have been evidenced, and CD34 positive microvessels counted; ultra-thin sections have also been observed. After six months of iodine overload, apoptotic thyrocytes were ten times more numerous; CD34 positive endothelial cells were diminished by one half bcl-2 immunoreactivity disappeared in thyrocytes and a bax one appeared in thyroid follicular and endothelial cells. Presence of numerous apoptotic follicular and endothelial cells was confirmed using electron microscopy. Chronic iodine excess induces apoptosis and necrosis of thyroid follicular and endothelial cells, leading to thyroglobulin accumulation in connective tissue.     

H-RAS gene expression in human multinodular goiter

The RAS protooncogene has an important, although not yet established role in thyroid neoplasia. In this study, we evaluated the H-RAS mRNA and protein levels in human samples of nontoxic and toxic multinodular goiter samples, according to serum TSH levels. The mean of H-RAS mRNA levels in nodules of nontoxic nodular goiter were significantly increased compared to nonnodular tissue (1.49+/-1.21 vs. 0.94+/-0.81 AU, P=0.016). Nine of the 18 specimens (50%) of nontoxic multinodular goiter exhibited increased levels of H-RAS mRNA. The increased H-RAS mRNA levels were paralleled by inRAcreased H-Ras protein levels in about 90% of the cases. Interestingly, no differences were observed in H-RAS expression between nodules and adjacent nonnodular tissue in toxic nodular goiters (0.58+/-0.27 vs. 0.58+/-0.20 AU, P=0.88). None of the 10 samples from toxic multinodular goiters exhibited overexpression of H-RAS. The H-RAS expression was positively correlated with thyroglobulin expression (r2=0.51; P=0.04). In conclusion, we demonstrated increased levels of H-RAS mRNA and protein in samples of nontoxic multinodular goiter, indicating that it might be involved in goiter pathogenesis. In contrast, H-RAS overexpression was not detected in any of the samples of toxic multinodular goiter, suggesting different mechanisms for cell proliferation in nodular goiter according to thyroid status.     

Comparison of morphonuclear features in normal, benign and neoplastic thyroid tissue by digital cell image analysis.

We analyzed the morphonuclear features of thyroid cell nuclei from 10 normal tissues (10 multinodular goiters), 10 benign tissues (10 adenomas) and 10 neoplastic tissues (10 carcinomas--2 follicular, 2 medullary and 6 papillary). These morphonuclear features quantitatively described the nuclear size, DNA content and chromatin texture of 200-400 Feulgen-stained cell nuclei that were digitized by means of a cell image processor. Nuclear DNA estimations revealed that the benign thyroid tumors showed an aneuploidy level that was not different from that of the neoplastic tissues. Morphometric measurements showed a significant and positive correlation between an increase in nuclear area and the development of thyroid pathology--i.e., from normal to a neoplastic stage. We also observed a significant decrease in chromatin condensation and heterogeneity from normal to neoplastic thyroid tissue. In the specific case of thyroid tumors, such criteria were not found sufficient per se for a diagnosis of malignancy. More detailed data banks will be necessary for this purpose.     

NON-TOXIC GOITER TREATMENT WITH I-TRIIODOTHYRONINE AND I-THYROXINE

Twenty-one patients with goiters—four diffuse and 17 nodular—were treated with I-triiodothyronine and I-thyroxine in doses to tolerance. The four diffuse goiters were barely palpable at the end of the treatment. The average dose of I-triiodothyronine required was 100 mcg. per day. The average dose of I-thyroxine was 0.3 mg. per day. Of the 17 multinodular goiters, 11 showed at least a 50 per cent reduction in size. The average dose of I-triiodothyronine used was 125 mcg. In six cases the gland did not change in size; in three of the six the lesion was diagnosed, at operation, as microfollicular and macrofollicular colloid goiter.Hypermetabolic symptoms may occur when doses of 100 mcg. or more of I-triiodothyronine are used.Results indicated that suppressive therapy with thyroid hormone to tolerance is effective in diffuse goiters. It is only partially effective in the treatment of multinodular goiters. In the cases in which operation was done, no change in the basic histological goiter structure was observed.     

The role of fine needle aspiration biopsy cytology in the evaluation of the clinically solitary thyroid nodule

The imputation that a clinically solitary nodule is a suspicious sign of carcinoma has been the cause of too many surgical procedures as well as the subject of much controversy. This study evaluated the effectiveness of fine needle aspiration (FNA) biopsy cytology in diagnosing the uninodular goiters in 286 patients who presented with clinically solitary nodules. The final diagnoses in these cases included carcinoma (4.7%), adenoma (6.3%), autonomous nodule (11.0%), colloid goiter (45.8%), colloid cyst (17.4%) and chronic thyroiditis (13.4%). The proportion of patients with cancer in this group was the same as in patients with multinodular and diffuse goiters. These findings call attention to (1) the fact that any thyroid disease may appear as a uninodular goiter and (2) the frequency with which lymphocytic thyroiditis was cytologically diagnosed, even in cases with negative antibody titers. The cytologic diagnosis of benign disease has contributed to a reduction in the number of unnecessary surgical procedures; only 24.1% of our patients with uninodular goiters underwent surgery.     

Characterization of ligands for galectins, natural galactoside-binding immunoglobulin G subfractions and sarcolectin and also of the expression of calcyclin in thyroid lesions

The purpose of this study was to characterize ligands for galectins, natural galactoside-binding immunoglobulin G subfractions and sarcolectin and also the expression of calcyclin in various benign and malignant thyroid lesions. The extent of the binding of eight glycochemical probes was quantitatively assessed using computer-assisted microscopy on 76 thyroid lesions including 10 not-otherwise-specified multinodular goiters (S_MNG), 11 multinodular goiters with adenomatous hyperplasia (AH_MNG), 8 normomacrovesicular (NM_ADE) and 12 microvesicular (MIC_ADE) adenomas, and 9 papillary (P_CAR), 10 follicular variants of papillary (FvarP_CAR), 7 follicular (F_CAR) and 9 anaplastic (A_CAR) carcinomas. The 8 histochemical probes included 5 animal lectins (including galectins and sarcolectin), 1 polyclonal antibody (raised against calcyclin) and 2 immunoglobulin G subfractions from human serum with selectivity to alpha- and beta-galactosyl residues. The results show that multinodular goiters with adenomatous hyperplasia exhibited histochemical characteristics intermediate to those of normal multinodular goiters and microvesicular adenomas. Normomacrovesicular adenomas behaved very distinctly from microvesicular ones. Microvesicular adenomas were more closely related to differentiated thyroid carcinomas than any other type of benign thyroid lesions of epithelial origin. Papillary and follicular carcinomas seemed to represent the two extremes of the same biological entity with the follicular variant of the papillary carcinoma serving as a biological link between these two extremes. Anaplastic carcinomas behaved in a significantly different manner when compared to the differentiated forms of thyroid carcinomas. The results suggest that the patterns of expression of the glycoconjugates investigated in the present study may constitute useful tools for characterizing lesions in the human thyroid.     

Trace elements status in multinodular goiter

Importance of iodine and selenium in thyroid metabolism is well known, but the roles of other essential trace elements including copper, zinc, manganese and iron on thyroid hormone homeostasis remain unclear. The aim of this study was to investigate the status of those trace elements in benign thyroid diseases and evaluate possible links between trace element concentrations and thyroid hormones.The study group was composed of 25 patients with multinodular goiter. Concentrations of thyroid hormones (plasma-free thyroxine, FT₄; free triiodothyronine, FT₃; and thyrotropin, TSH), selenium, copper, zinc, manganese and iron in plasma, and urinary iodine were determined. The results were compared with those of a healthy control group (n=20) with no thyroid disorder.A mild iodine deficiency was observed in the patients with multinodular goiter whereas urinary iodine levels were in the range of “normal” values in healthy controls. All patients were euthyroid, and their thyroid hormone concentrations were not significantly different from the control group. Plasma selenium, zinc and iron concentrations did not differ from controls, while copper and manganese levels were found to be significantly higher in the patients with multinodular goiter indicating links between these trace elements and thyroid function and possibly in development of goiter. Besides iodine, there was a significant correlation between plasma copper concentration and FT₃/FT₄ ratio.     

Planimetric studies on fine needle aspirates from follicular adenoma and follicular carcinoma of the thyroid

A planimetric study was performed on fine needle aspiration biopsy smears from 21 follicular thyroid adenomas, 13 follicular thyroid carcinomas and 7 nontoxic goiters. The nuclear and the cytoplasmic projected areas were measured in each smear on 50 cells with intact nuclei. The nuclear-cytoplasmic area was calculated. Significant differences in mean nuclear area were found between benign and malignant follicular neoplasms and between neoplastic cells and cells from nontoxic goiter. Planimetry of cells aspirated from follicular neoplasms permitted differentiation between carcinomas and adenomas with a high degree of statistical probability.     

Increased incidence of euthyroid and hyperthyroid goiters independently of thyrotropin in patients with acromegaly

The incidence of palpable goiters, the thyroid functional state and thyroid radioisotope uptake was analyzed retrospectively in 80 patients with acromegaly and 80 patients with prolactinomas. 71% of all patients with acromegaly had an enlargement of the thyroid (goiter); 49% of them had diffuse and 39% nodular goiters. The incidence of goiters in patients with prolactinomas from the same iodine deficient geographic region was only 35% (82% diffuse and 18% nodular). 17.5% of acromegalic patients underwent thyroid surgery before diagnosis of growth hormone excess. 17.5% of acromegalic patients with goiters had autonomous areas in their thyroids and 5% were clearly hyperthyroid. Goiters developed slightly more often in females (74%) than in males (67%). The mean preoperative growth hormone level was higher in acromegalic patients with goiter. The incidence of goiters was positively correlated with the documented time of elevated growth hormone concentration in serum. Two patients with exaggerated response of thyrotropin (TSH) (delta TSH greater than 20 mU/l) to the application of thyrotropin-releasing hormone (TRH) had no goiters. On the other hand most patients (61%) with goiters had a low TSH-response to TRH (delta TSH less than 10 mU/l) representing in part occult autonomy of thyroid function. No patient with prolactinoma has had previous thyroid surgery nor thyroid autonomy. One patient with prolactinoma suffered from Graves' disease and none of the acromegalic patients had this disease. We finally conclude that the elevation of growth hormone leads to increased incidence of euthyroid and hyperthyroid (autonomous) goiters independently of the influence of TSH.     

The treatment of multinodular large non-toxic goiter using repeated doses of radioiodine (preliminary report)

INTRODUCTION: The aim of study was to establish the effectiveness of radioiodine therapy using 131I in the group of patients with multinodular large non-toxic goiter. MATERIAL AND METHODS: Therapy was undertaken in female patients disqualified from surgery due to high risk and these patients who didn't agree to surgery. Studies were performed in 7 women (age range: 62-82 yrs) with large goiters (2nd degree according to WHO classification and goiter volume assessed by USG over 100 cm(3)). Serum TSH, fT4, fT3, antithyroid antibodies (TPOAb, TgAb, TRAb) levels, urinary iodine concentration (UIE) were estimated in all patients parallel with radioiodine uptake test (after 5 and 24 hours), 131I thyroid scintigraphy and fine needle biopsy to exclude neoplasmatic transformation. These studies and therapy with 22 mCi 131I were repeated every 3 months. RESULTS: Before therapy median thyroid volume was approximately 145 cm(3) and during therapy gradually decreased to 76 cm(3) after 6 months and to 65 cm(3) after 12 months. Increase of TRAb can be a inhibiting factor of thyroid volume reduction. Other antithyroid antibodies showed marked tendency to rise but without significant correlation with radioiodine uptake and goiter reduction. After 12 months we found 2 patients with clinical and laboratory hypothyroidism. CONCLUSIONS: In some cases of multinodular large non-toxic goiter, the radioiodine therapy can be the best alternative way for L-thyroxine treatment or surgery therapy. The fractionated radioiodine therapy of multinodular large non-toxic goiter is safe and effective method but continuation of nodules observation is necessary.     

Serum metabolic profiling and features of papillary thyroid carcinoma and nodular goiter

Thyroid carcinoma is a common endocrine malignancy worldwide, accounting for approximately 1% of all diagnosed cancers and about 91.5% of the malignancies of head and neck. However, differentiating malignant thyroid nodules from benign ones remains a diagnostic challenge. Thus, novel molecular markers that enable non-invasive diagnostics for malignant thyroid nodules are urgently needed. In the present study, a metabonomic investigation based on liquid chromatography-LTQ Orbitrap mass spectrometry was employed for serum metabolic profiling of 30 cases of papillary thyroid carcinomas (PTC), 80 cases of nodular goiters (benign thyroid nodules) and 30 cases of healthy controls. According to the results of multivariate statistical data analysis, the significantly changed metabolites among these three groups were defined. It was found that most of these metabolites decreased in the sera of both malignant and benign thyroid cases due to the increased metabolic rate, which is in accordance with clinical features. The major metabolic differences between benign and malignant nodules occurred in lipid metabolism. Especially, the content of 3-hydroxybutyric acid, an intermediate product of fatty acid metabolism, was much higher in the PTC group than that in the nodule goiter and control groups, indicating its potential as a diagnostic marker for PTC and nodular goiters. These results show that the serum metabolic profiling method is a powerful tool for distinguishing thyroid carcinoma from nodular goiter and healthy controls.     

分子生物学法分析青少年甲状腺肿物临床病理及特点

探讨青少年甲状腺肿物的临床病理学特点,甲状腺癌的复发、转移和结节性甲状腺肿复发的可能相关因素。按WHO病理分型标准和国际抗癌联盟(UICC)TNM分期标准回顾性分析青少年甲状腺肿物124例及其中部分甲状腺癌和结节性甲状腺肿的随访资料。124例甲状腺肿物患者男女比例约为1 3,甲状腺癌39例(31.5%),其中乳头状癌35例,滤泡癌3例,髓样癌1例;甲状腺腺瘤59例(47.6%),结节性甲状腺肿11例(8.9%),结节性甲状腺肿伴腺瘤7例(5.6%),甲状腺炎5例(4%),甲状舌管囊肿3例(2.4%)。本组资料显示,青少年甲状腺癌以乳头状癌为主,其复发、转移与组织学亚型为弥漫硬化型及甲状腺包膜和其外软组织受侵状态相关。虽然常见淋巴结转移、肺转移以及局部侵犯周围软组织,但患者总体预后较好。结节性甲状腺肿的复发与病变弥漫位于双叶有关,而与患者性别、年龄和是否伴有乳头样及腺瘤样增生关系不密切。     

Evaluation Of Various Doses Of Recombinant Human Thyrotropin In Patients With Multinodular Goiters

ObjectiveTo assess the safety, adverse effects, and radioactive iodine uptake (RAIU) of recombinant human thyrotropin (rhTSH) using a range of doses in patients with multinodular goiters.MethodsIn this open-label study conducted between June 2002 and December 2004, euthyroid patients with small nontoxic multinodular goiters and normal thyrotropin concentrations were recruited from 4 sites in the United States. Baseline assessments included thyroid function tests, electrocardiogram, Holter monitoring, hyperthyroid symptom scale, flow-volume loop, and measurement of thyroglobulin and thyroperoxidase antibodies. Patients had a baseline 24-hour scan and thyroid iodine I 123 (¹²³I) uptake evaluated at 6, 24, and 48 hours after rhTSH administration. Each patient received a single intramuscular injection of 0.03-mg, 0.1-mg, or 0.3-mg rhTSH followed 24 hours later by 400 μCi ¹²³I orally. Iodine 123 uptakes were again measured 6, 24, and 48 hours later, and a scintigram scan was performed at 24 hours. Thyroid function tests, flow-volume loop, Holter monitoring and/or electrocardiograms, and thyroid ultrasonography to assess thyroid size were performed serially.ResultsTwenty-eight patients participated. Median goiter size was 20 mL (range, 7-79 mL). After each rhTSH dose, the radioiodine uptake approximately doubled at each time point compared with baseline uptake. Small rises in serum thyroxine and triiodothyronine were seen in some patients, especially after 0.3-mg rhTSH, and mild symptoms of hyperthyroidism developed in several patients. Flow-volume loop showed transient, mild asymptomatic worsening in 1 patient with a 35.2 mL goiter, although thyroid volume measurements were unchanged. Minor electrocardiogram and/or Holter changes were seen in several patients.ConclusionsA flat dose-response curve exists over the range of rhTSH doses tested, with an approximate doubling of thyroid RAIU. All patients tolerated rhTSH well, but the rise in thyroid hormone levels and adverse effects after rhTSH doses of 0.1 mg or higher theoretically might not be well tolerated in older or sicker patients and appear unjustified given the lack of a greater rise in RAIU compared with the 0.03-mg dose. Future studies evaluating rhTSH doses less than 0.1 mg in patients with multinodular goiter are justified. (Endocr Pract. 2008;14:832-839)     

Suppression of thyroid cell growth by serum IgG in Graves' disease.

To determine whether serum immunoglobulin in addition to epidermal growth factor (EGF) augment growth in human thyroid cells, effects of these factors on thyrocytes were tested using IgG derived from 34 patients with Graves' disease and 12 normal subjects. The cell growth was estimated by [3H]-thymidine uptake, cell cycle determined by FACS analysis and the expression of c-fos mRNA in monolayer thyrocytes enzymatically prepared from Graves' thyroid. The addition of IgG taken from patients with Graves' disease inhibited the [3H]-thymidine uptake compared to that taken from control subjects. IgG taken from Graves' disease suppressed EGF-induced increase of S + G2/M phase in cell cycle and the expression of c-fos mRNA, while those taken from normal subjects did not affect at all. [3H]-thymidine uptake was more suppressed by IgG from patients with a smaller-sized goiter than by those with a larger-sized one. There was a negative correlation between the suppression of [3H]-thymidine uptake and levels of TBII (p less than 0.05). There was no correlation between the degree of suppression and the levels of T3, T4, TSAb, TSBAb or MCHA. Thus, in conclusion, IgG derived from sera of Graves' may inhibit the growth of Graves' thyrocytes, leading to the determination of the goiter size.     

Point mutations of ras oncogenes are an early event in thyroid tumorigenesis

Identifying the nature of the genetic mutations in thyroid neoplasms and their prevalence in the various tumor phenotypes is critical to understanding their pathogenesis. Mutational activation of ras oncogenes in human tumors occurs predominantly through point mutations in two functional regions of the molecules, codons 12, 13 (GTP-binding domain) or codon 61 (GTPase domain). We examined the prevalence of point mutations in codons 12, 13, and 61 of the oncogenes K-ras, N-ras, and H-ras in benign and malignant human thyroid tumors by hybridization of PCR-amplified tumor DNA with synthetic oligodeoxynucleotide probes. None of the eight normal thyroid tissues harbored point mutations. Four of nineteen nodules from multinodular goiters (21%), 6/24 microfollicular adenomas (25%), 3/14 papillary carcinomas (21%), and 0/3 follicular carcinomas contained ras point mutations. The predominant mutation was a valine for glycine substitution in codon 12 of H-ras. None of the multinodular goiter tumors known to be polyclonal (and thus due to hyperplasia) had point mutations, whereas one of the two monoclonal adenomas arising in nodular glands contained in H-ras codon 12 valine substitution, which was confirmed by sequencing the tumor DNA. These data show that ras activation is about equally prevalent in benign and malignant thyroid neoplasms, and thus may be an early event in the tumorigenic process.     

Thyroid cancer in patients with hyperthyroidism

Thyroid cancer can be associated with thyrotoxicosis caused by Graves' disease, toxic multinodular goiter, or autonomously functioning thyroid adenoma. The objective of this study was to summarize current evidence regarding the association of thyroid cancer and hyperthyroidism, particularly with respect to the type of hyperthyroidism found in some patients, and whether this affects the outcome of the patient. A PubMed search was performed up to August 2011. Articles were identified using combinations of the following keywords/phrases: thyroid cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, hyperthyroidism, Graves' disease, auto-nomous adenoma, toxic thyroid nodule, and toxic multinodular goiter. Original research papers, case reports, and review articles were included. We concluded that the incidence, as well as the prognosis of thyroid cancer associated with hyperthyroidism is a matter of debate. It seems that Graves' disease is associated with larger, multifocal, and potentially more aggressive thyroid cancer than single hot nodules or multinodular toxic goiter. Patients with Graves' and thyroid nodules are at higher risk to develop thyroid cancer compared to patients with diffuse goiter. Every suspicious nodule associated with hyperthyroidism should be evaluated carefully.     

Thyroid Nodules and Thyroid Cancer

A review of clinical and laboratory features of thyroid cancer, designed to help in a more precise selection of patients for operation, showed that factors contributing to a high index of suspicion of cancer include previous exposure to low doses of radiation, the presence of a firm, solitary thyroid nodule clearly different from the rest of the gland, a young patient, nodules that are “cold” on scan with radioiodine, and nodules that fail to regress after an adequate trial of thyroxine therapy. Factors contributing to a low index of suspicion of thyroid cancer include soft or cystic lesions, multinodular goiters, nodules that are “hot” on ¹³¹ I scan, and those that regress during thyroxine treatment.When these factors are used to select patients for surgical operation, about 30 percent are found to have thyroid cancer.Until more precise methods for preoperative diagnosis are established, it is suggested that this type of clinical selection may be very helpful in the management of patients with thyroid nodules or nontoxic goiter.     

Facultative polyploidy in endocrine tissues.

Adrenal tissue from 44 autopsies and 30 biopsies of thyroid gland were analyzed by flow--and scanning-cytophotometry. Most nuclei were diploid and the 4C fraction ranged from 1.9 to 6.1% according to the technique, but with no significant difference between controls and adenomas, hyperplasias, adenomatous goiters, or two carcinomas of the thyroid gland. The only significant increase of 4C fraction was found in normal adrenals of patients above 50 years of age (P less than 0,025). Similarly constant was the proportion of 8C nuclei which ranged from 0.5 to 1.3 per thousand. However, in one of 23 adenomatous goiters a total polyploidization was was observed. Comparable results in the literature show that the thyroid gland like the epithelium of seminal vesicles can facultatively become polyploidized, in contrast to the obligatory polyploid orgnas namely the liver and heart. This is not related to malignancy.     

Circulating chemokine (CXC motif) ligand (CXCL)9 is increased in aggressive chronic autoimmune thyroiditis, in association with CXCL10

Chemokine (CXC motif) ligand (CXCL)9 (CXCL9) has been shown to be involved in autoimmune thyroid disorders, however no data are present about CXCL9 circulating levels in chronic autoimmune thyroiditis (AT) vs controls. Serum CXCL9 (and for comparison CXCL10) has been measured in patients with AT vs normal control and nontoxic multinodular goiter, and this parameter has been related to the clinical phenotype. For this study we selected 189 consecutive patients with newly diagnosed AT, 63 euthyroid controls, 30 patients with nontoxic multinodular goiter. The three groups were similar in gender distribution and age; 26% of AT patients had subclinical hypothyroidism. Serum CXCL9 was significantly higher in AT (148±110 pg/mL) than in controls (71±34 pg/mL) or patients with multinodular goiter (87±35 pg/mL) (p<0.0001). Among AT patients, CXCL9 levels were significantly higher in patients older than 50 years, those with a hypoechoic ultrasonographic pattern or with hypothyroidism. Also CXCL10 was confirmed to be associated with AT, overall in presence of hypothyroidism. In a multiple linear regression model of CXCL9 (ln[pg/mL]) vs age, thyroid volume, TSH, AbTg, AbTPO, hypoechoic pattern, the presence of hypervascularity, and CXCL10 (ln[pg/mL]), only TSH and CXCL10 (ln[pg/mL]) were significantly related to serum CXCL9 levels. We show that circulating CXCL9 is increased in patients with aggressive thyroiditis and hypothyroidism. A strong relation between circulating CXCL9 and CXCL10 has been first shown, underlining the importance of a T helper 1 immune attack in the initiation of AT.     

Thyroid cancer risk 40+ years after irradiation for an enlarged thymus: an update of the Hempelmann cohort

Although ionizing radiation is a known carcinogen, the long-term risk from relatively higher-dose diagnostic procedures during childhood is less well known. We evaluated this risk indirectly by assessing thyroid cancer incidence in a cohort treated with "lower-dose" chest radiotherapy more than 55 years ago. Between 2004 and 2008, we re-surveyed a population-based cohort of subjects treated with radiation for an enlarged thymus during infancy between 1926 and 1957 and their unexposed siblings. Thyroid cancer occurred in 50 irradiated subjects (mean thyroid dose, 1.29 Gy) and in 13 nonirradiated siblings during 334,347 person-years of follow-up. After adjusting for attained age, Jewish religion, sex and history of goiter, the rate ratio for thyroid cancer was 5.6 (95% CI: 3.1-10.8). The adjusted excess relative risk per gray was 3.2 (95% CI: 1.5-6.6). The adjusted excess absolute risk per gray was 2.2 cases (95% CI: 1.4-3.2) per 10,000 person-years. Cumulative thyroid cancer incidence remains elevated in this cohort after a median 57.5 years of follow-up and is dose-dependent. Although the incidence appeared to decrease after 40 years, increased risk remains a lifelong concern in those exposed to lower doses of medical radiation during early childhood.