Localization of a susceptibility gene for familial nonmedullary thyroid carcinoma to chromosome 2q21.

The familial form of nonmedullary thyroid carcinoma (NMTC) is a complex genetic disorder characterized by multifocal neoplasia and a higher degree of aggressiveness than its sporadic counterpart. In a large Tasmanian pedigree (Tas1) with recurrence of papillary thyroid carcinoma (PTC), the most common form of NMTC, an extensive genomewide scan revealed a common haplotype on chromosome 2q21 in seven of the eight patients with PTC. To verify the significance of the 2q21 locus, we performed linkage analysis in an independent sample set of 80 pedigrees, yielding a multipoint heterogeneity LOD score (HLOD) of 3.07 (alpha=0.42), nonparametric linkage (NPL) 3.19, (P=.001) at marker D2S2271. Stratification based on the presence of at least one case of the follicular variant of PTC, the phenotype observed in the Tas1 family, identified 17 such pedigrees, yielding a maximal HLOD score of 4.17 (alpha=0.80) and NPL=4.99 (P=.00002) at markers AFMa272zg9 and D2S2271, respectively. These results indicate the existence of a susceptibility locus for familial NMTC on chromosome 2q21.

Familial non-medullary thyroid carcinoma: pathology review in 27 affected cases from 13 French families.

BACKGROUND AND OBJECTIVES: When familial non-medullary thyroid cancer (FNMTC) develops with no obvious associated pathogenetic factor, an inherited predisposition may underlie the process. The present study was conducted because detailed pathological findings are lacking in most series of FNMTC. PATIENTS AND METHODS: Thirteen families comprising 27 cases of FNMTC were included (1.8% of differentiated thyroid carcinoma). The family relationship (20 F, 7 M; age 46 +/- 16 years; mean +/- SD) was 'siblings' in eight families, 'parent and child' in four and 'aunt and niece' in one. Careful pathological review of the thyroid tumours (papillary/follicular: 25/2, size: 16 +/- 11 mm) was performed. RESULTS: Initial staging according to extension was as follows: grade I (n = 16), II (n = 2), III (n = 6), IV (n = 3). Fourteen tumours were papillary microcarcinomas (size: 8 +/- 2 mm). No tumour phenotype that may be considered specific for FNMTC was found when considering either age, pathological findings or tumour aggressiveness. Although rare events were found in both relatives of some families suggesting a putative 'familial' phenotype of FNMTC, this may be fortuitous. CONCLUSION: Micro familial non-medullary thyroid cancers are more common than previously reported and further studies are required to be able to distinguish this subgroup from sporadic papillary microcarcinomas. The careful pathological review of the familial non-medullary thyroid cancer in this study does not seem to point to a distinct subgroup of familial differentiated thyroid carcinoma although the data are intriguing. Genetic studies are now required to investigate this issue.

Optimized radioiodine therapy of Graves' disease: analysis of the delivered dose and of other possible factors affecting outcome.

The best approach to radioiodine dose selection in the treatment of Graves' hyperthyroidism remains highly controversial. The formula to calculate the individual dose of (131)I to be delivered has been used for half a century and takes into account the thyroid mass, the effective half-life and the maximum uptake of (131)I. The objective of the present study was to evaluate the accuracy of this formula by determining the relationship between the administered dose of (131)I calculated to deliver a target dose of 50Gy to the thyroid and the actual exact organ dose. We further analyzed if therapeutic success, defined by euthyroidism following the individually calculated dose, can be predicted by different pretreatment parameters and particularly by organ dose. One hundred patients with a first episode of Graves' disease and who had received optimal thyroid irradiation after precise dosimetry were retrospectively reviewed. The patients were categorized according to their thyroid function (plasma free thyroxine (T(4)) serum concentration) as eu-, hyper- or hypothyroid during and 1 year after treatment. The relationship between the administered dose and organ dose was assessed by simple regression. We compared free T(4), free tri-iodothyronine, thyroid weight, the number of patients with antithyroperoxidase antibodies and TSH receptor autoantibodies, 24h urinary iodine excretion, (131)I uptake, and the exact dose of (131)I delivered to the thyroid as pretreatment variables. Although we found a correlation between administered dose (mCi) and organ dose (Gy) (r=0.3, P=0.003), the mean coefficient of variation for organ dose was 45%. Individualized radioiodine therapy enabled euthyroidism in 26% of patients and failed in 74% of patients (33% had persistent or recurrent hyperthyroidism and 41% permanent hypothyroidism). (131)I uptake was significantly higher in the hyperthyroidism group in comparison with the euthyroid group. However, organ dose and other pretreatment variables did not differ among the three groups. In conclusion, these results confirm the low performance of individual dosimetry using what are established ratios, since the delivered dose to the gland, although correlated to the intended dose, is highly variable. The finding that other usual pretreatment variables are not different between groups, gives little hope for improving the way of calculating the ideal dose of radioiodine. We suggest to those not yet ready to give a standard or an ablative dose for Graves' hyperthyroidism that they abandon this way to calculate the (131)I dose.

Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.

Impaired DNA repair as assessed by the "comet" assay in patients with thyroid tumors after a history of radiation therapy: a preliminary study.

PURPOSE: Patients with a history of head and neck irradiation in childhood are at risk to develop thyroid tumors. The aim of this study was to determine if an impairement of DNA strand breaks repair could account for this observation. METHODS AND MATERIALS: Circulating unstimulated lymphocytes of a group of 13 patients who developed thyroid tumors after radiotherapy were submitted to the alkaline single-cell gel electrophoresis assay (SCGE or "comet" assay) after in vitro exposure to 2 and 5 Gy of gamma-rays. A control group of 8 healthy donors and 2 cases with a history of neck irradiation who did not develop a thyroid tumor were also analysed. The immediate response was compared to that observed after 15, 30, and 60 min of postexposure incubation periods. RESULTS: Induction of DNA strand breaks is a dose-dependent process. The SCGE assay parameters did not differ significantly between patients and controls immediately (t=0) after irradiation at the two doses used. As compared to healthy donors, a slower kinetics of repair was found in the patients. The proportion of residual damage at 60 min postirradiation was significantly (p < 0.01) higher in patients than in controls, at both doses analysed. Flow cytometric analysis of apoptosis and p53 protein status studied before and after irradiation showed no apparent relationship with the repair capacity. CONCLUSION: This preliminary study suggests that a subgroup of patients who develop thyroid tumors after a history of irradiation are partially defective in the late restitution of in vitro radiation-induced DNA strand breaks. This deficiency could be a predisposing factor to radiation-associated thyroid tumorigenesis. Detection of susceptible individuals using the simple and rapid comet assay, especially children receiving radiotherapeutic treatment, may allow a preventive surveillance for radiation-associated epithelial thyroid tumor development.

Telomerase activity in human thyroid carcinomas originating from the follicular cells.

Telomerase activity is known to be absent from most normal and well-differentiated tissues, although being detectable in the vast majority of malignant tumors. An increasing number of reports demonstrate that telomerase may be activated in benign tumors, such as adenomas. We have investigated a series of normal and neoplastic thyroid tissues for the presence of telomerase activity. As expected, all normal thyroid tissues (n = 20) had no display of telomerase activity. Amongst cancers, the incidence of telomerase activity varied with the histological subtypes. Telomerase activity was present in only 3/15 cases (20%) of papillary carcinomas. Telomerase activity was more frequently detected in follicular (4/6) and in undifferentiated (2/3) carcinomas. Unexpectedly, one case (1/12) of adenoma contained high levels of telomerase activity. Taken together, these results indicate that telomerase may play some role in the pathogenesis of thyroid tumors, in particular in follicular and undifferentiated carcinomas that are known to have the most aggressive behavior.

[Papillary microcarcinoma]. / Les microcarcinomes papillaires.

The incidence of thyroid papillary microcarcinoma has appeared to increase over the last decade, probably because of more extensive use of serial slices for pathology. Prognosis is generally good, but the aggressive nature of certain tumors justifies an examination of the different risk factors such as age, sex, histology type, tumor size, lymph node involvement, and extrathyroid extension in order to develop a management scheme. Published results have been rather heterogeneous and do not allow a clear conclusion.

[A study of biological and histological criteria of thyroid autoimmunity in diffuse goiters with hyperthyroidism]. / Etude des paramètres biologiques et histologiques d'autoimmunité thyroïdienne dans les goitres diffus avec hyperthyroïdie.

Hyperthyroidism is usually classified as follows: with diffuse or with toxic plurinodular goiter, respectively considered as autoimmune and non-autoimmune thyroid disorders. This classification seems partially inadequate as signs of thyroid immunity may be found in some plurinodular toxic goiter and alternatively may by lacking in some cases of Graves' disease. These observations led us to study the intensity of intrathyroidal autoimmune process (IAP) and the levels of TBIAb, TPO- and Thyroglobulin-antibodies in 105 cases with diffuse goiter, hyperthyroidism and elevated RAIU (92 women and 13 men, age 34 +/- 11, mean +/- SD). The intensity of intrathyroidal autoimmune process (IAP) was determined by one pathologist (HT) by semi quantitative method applicable to routine clinical use. Subtotal thyroidectomy was performed because of a large goiter (n = 29), a concomitant cold nodule (n = 20), a recurrent disease (n = 18), intolerance to antithyroid drugs (n = 5) or because patients chose surgical treatment (n = 33). All cases were rendered euthyroid at the time of surgery using antithyroid drugs or iodine. The results show a lack of IAP and undetectable levels of TBIAb, TPO- and Thyroglobulin-antibodies in 10%, 11%, 25% and 47% respectively. The intensity of IAP was not different in case of first episode or recurrence of hyperthyroidism and was not related to type or duration of medical treatment. Comparison of patients with or without IAP show higher levels of TPO- and thyroglobulin-antibodies but not of TBIAb in the former group (P < 0.005). TBIAb were higher when ophthalmopathy and/or dermopathy were present vs absent (p < 0.05) and were correlated with FT4 levels (p < 0.05). The negative predictive value of TBIAb, TPO- and thyroglobulin-antibodies to predict the lack of significant IAP was 42%, 65% and 64%. The total absence of clinical, biological and histological signs of thyroid autoimmunity was found in only one case (female aged 35 with first episode of hyperthyroidism and no family history of thyroid disease) (0.9%). These results suggest that routine available criteria of thyroid immunity (including IAP) have a low specificity. It follows that they are probably inadequate to screen cases of hereditary toxic familial hyperplasia, a rare entity of still unknown prevalence.

[Hormonal suppressive therapy of thyroid nodules]. / Le freinage hormonal des nodules thyroïdiens.

We studied 426 patients in order to analyse the effectiveness of levothyroxine in treating patients with cold thyroid nodules. Nodule volume ranged initially from 0.1 to 10 mL and was measured over a 3 to 18 month-period of treatment using ultrasonography. Nodule variation was studied in each case according to levels of TSH and others factors (age, sex, familial thyroid history, initial volume of nodule and of thyroid gland, date of diagnosis, ultrasonic findings, duration of treatment). Nodule volume increased in 32.6% and significantly decreased (> 50%) in 35.8%. In 2.8% the nodule disappeared. No correlation was found between variation of thyroid nodules and TSH levels under treatment. Similarly no relationship was found between volume variation and other criteria. These results suggest that TSH suppressing doses of levothyroxine are of no advantage in reducing the volume of cold thyroid nodules compared to lower doses.

[Diagnosis of Conn's adenoma. Comparative study of x-ray computed tomography and scintigraphy using 19-noriodocholesterol]. / Diagnostic d'adénome de Conn. Etude comparative de la tomodensitométrie et de la scintigraphie au 19-noriodocholestérol.

OBJECTIVE: In order to differentiate an aldosterone producing adenoma (APA) and a bilateral adrenal hyperplasia (BAH) in case of primary hyperaldosteronism, an adrenal CT-scan is usually used as first line exploration. The contribution of adrenal 19-noriodocholesterol (NP59)-scintigraphy is controversial. PATIENTS AND METHODS: We describe 17 cases of primary hyperaldosteronism referred to surgery for suspected APA. The value of abdominal CT-scan and of adrenal scintigraphy was studied. RESULTS: After unilateral adrenalectomy, 15 cases with confirmed APA were cured and 2 cases with an unilateral hyperplastic macro nodule showed persistence of the disease. The pathologic findings were concordant with CT-scan in 76% (13/17) and with scintigraphy in 88% (15/17). Similar sensitivity was found for CT-scan and scintigraphy (86% and 88%) with 2 false negative results with both techniques. False positive results were observed only with CT-scan (2 cases) suggesting that scintigraphy has a better specificity. No case was misdiagnosed by both techniques. CONCLUSION: These results suggest that NP59-scintigraphy is complementary to adrenal CT-scan for the recognition of APA and is particularly useful in case of a unilateral hyperplastic macro nodule mimicking an APA.

[Papillary microcarcinoma of the thyroid]. / Microcarcinome papillaire de la thyroïde.

Treatment of thyroid differentiated carcinoma is controversial. In case of papillary microcarcinoma a low malignancy is usually considered and a limited surgical excision is currently used. We describe 49 cases with papillary tumor < 1 cm. Their high frequency (51% of all differentiated carcinoma discovered in the same period), current mode of their diagnosis (incidental histological findings: N = 48), and constant tumoral situation in extra nodular parenchyma are emphasised. In spite of median tumor size < 2 mm, 8% had extra thyroidal tumoral extent at diagnosis (node metastasis: N = 3; bone: N = 1). In one case with multifocal lesions in both lobes, an unilateral thyroidectomy would have missed contralateral periglandular metastatic nodes. Diagnosis of the case with asymptomatic bone metastasis was clearly attributable to radioiodine therapeutic use. These results suggest an heterogeneous prognosis of papillary microcarcinoma, with some cases requiring total bilateral thyroidectomy and radioiodine remnants ablation (e.g. Tumors invading peripheral thyroid tissue that seem at higher risk of extra glandular extension).

Basal and stress-induced corticosterone secretion is decreased by lesion of mesencephalic dopaminergic neurons.

There is evidence that certain psychopathological conditions are accompanied by a dysfunction in both the hypothalamo-pituitary-adrenal axis and dopaminergic systems, although the relationship between these two systems is as yet unclear. In the present study we investigated the effect of a specific lesion of dopamine mesencephalic neurons (Ventral Tegmental Area) on basal and stress-induced corticosterone secretion. Three weeks after injection of 6-OHDA, there was a depletion in dopamine in the frontal cortex and in the ventral and dorsal striatum, whereas norepinephrine and serotonin levels were unchanged. The dopamine-lesioned rats exhibited a lower basal and stress-induced corticosterone secretion than the sham-lesioned animals. The results indicate that the dopaminergic system may have a stimulatory influence on the hypothalamo-pituitary-adrenal axis.

The mesolimbic dopaminergic system exerts an inhibitory influence on brain corticosteroid receptor affinities.

Central type I and type II corticosteroid receptors play a principle role in the regulation of corticosterone secretion. Although the binding capacity of these receptors is thought to be regulated essentially hormonally, there is also evidence for a direct neural control. For example, experimental manipulation of central serotoninergic and noradrenergic activities modifies the binding capacity of type I and type II corticosteroid receptors via a corticosterone-independent mechanism. In this study, we tested the effect of lesions of dopaminergic neurons in the ventral tegmental area on corticosteroid receptor binding capacity. The study was performed in adrenalectomized rats whose corticosterone levels were maintained within normal limits by corticosterone pellets and corticosterone in their drinking water during the dark period to generate the circadian rhythm. Binding properties of corticosteroid receptors were analysed in target regions of the lesioned neurons, including the ventral and dorsal striatum. Corticosteroid receptors in the hippocampus were also studied as a control as these lesions do not significantly affect dopamine content in this structure. Three weeks after the lesion, type II corticosteroid receptor affinity was increased in the ventral striatum. There was no effect on receptors in the dorsal striatum or hippocampus. Our results, together with other reports showing that dopamine inhibits the expression of corticosteroid receptors in the anterior pituitary, suggest that dopamine transmission exerts a negative control on central corticosteroid receptors.

[Bone risk of hormone-suppressing therapy in differentiated thyroid epithelioma. Study by dual photon absorptiometry]. / Risque osseux de l'opothérapie freinatrice dans l'épithélioma différencié de la thyroïde. Etude par absorptiométrie biphotonique.

A decreased bone mineral density is a well known complication of thyrotoxicosis. If bone is also adversely affected by a subclinical hyperthyroidism is still debated. Such a situation is deliberately induced for treatment of thyroid differentiated carcinoma. We compared bone mineral measurements in case of thyroid carcinoma exposed to prolonged suppressive hormonal treatment (288 patient year, LT3 in 87%) and in age and weight matched controls. We did not find any difference in both sexes between the two populations in term of fracture rate and vertebral mineral density measured by dual photon absorptiometry, nor any influence of gonadal status in women.

Usefulness of the corticotropin-releasing hormone test during bilateral inferior petrosal sinus sampling for the diagnosis of Cushing's disease.

Inferior petrosal sinus blood sampling for ACTH measurement (IPSS) is used for the differential diagnosis of ACTH-dependent Cushing's syndrome and for the preoperative location of pituitary microadenomas. Intermittent ACTH secretion from pituitary adenomas may result in insignificant differences between petrosal and peripheral ACTH levels at the time of sampling. Thus, pituitary stimulation during IPSS may improve the procedure. The aim of the study was to evaluate the usefulness of CRH injection in combination with IPSS. Twenty-two patients with Cushing's disease (CD; 5 macroadenomas, 16 microadenomas, and 1 corticotroph hyperplasia) and 5 patients with ectopic ACTH syndrome were studied. Bilateral IPSS was successfully carried out on 25 patients. Patients with ectopic ACTH syndrome had, before and after CRH injection, central to peripheral ACTH gradients below 1.7. Four patients with CD had basal gradients below 1.4. After CRH administration all patients with CD had gradients above 3.2. Despite correct location of central catheters, the predicted location of pituitary microadenomas was erroneous in 41% of the cases. It was not improved after CRH injection. In conclusion, the combination of CRH injection with IPSS was useful for the differential diagnosis of ACTH-dependent Cushing's syndrome, as it increased the discrimination of the procedure. On the contrary, it was useless for the preoperative location of pituitary microadenomas, which was poorly predicted by IPSS.

[Macronodule associated with bilateral adrenal hyperplasia. A rare misleading cause of primary aldosteronism (two cases)]. / Macronodule associé à une hyperplasie bilatérale des surrénales. Une cause rare et trompeuse d'hyperaldostéronisme primaire (2 cas).

Aldosterone-producing adrenal adenoma and bilateral hyperplasia are the two predominant subtypes of primary aldosteronism. Their recognition is based essentially on adrenal CT scan and on measurements of plasma aldosterone and 18-hydroxycorticosterone (18-OHB) concentrations in response to postural testing. We report 2 cases of primary aldosteronism associated with a unilateral hyperplastic macronodule resembling an aldosterone-producing adenoma on CT scan. Plasma aldosterone and 18-OHB concentrations were consistent with this diagnosis in one patient. In the light of these two cases and of those previously published, the investigations needed for the etiological diagnosis of primary aldosteronism are discussed.

The corticotropin-releasing factor test in the differential diagnosis of Cushing's syndrome: a comparison with the lysine-vasopressin test.

The diagnostic accuracy of the CRH test was compared with that of the LVP test in 28 consecutive patients with ACTH-dependent Cushing's syndrome. A false negative response to CRH was found in 3 of 21 patients with pituitary-dependent Cushing's disease and to LVP in 4. The 7 patients with ectopic ACTH secretion were unresponsive to CRH, whereas 2 did respond to LVP. CRH and high-dose dexamethasone tests combination led to concordant results in 79% of patients. In all cases the etiological diagnosis suggested was correct. LVP and high-dose dexamethasone tests combination led to concordant results in only 71% of patients and the etiological diagnosis suggested was erroneous in one. Individual tolerance to the CRH test was also clearly better than that to the LVP test. It is concluded that the CRH test, alone or in combination with the high-dose dexamethasone test must be preferentially used to the LVP test in the differential diagnosis of ACTH-dependent Cushing's disease.