Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism.

The thyrotropin receptor (TSHR), a member of the large family of G protein-coupled receptors, controls both the function and growth of thyroid cells via stimulation of adenylyl cyclase. We report two different mutations in the TSHR gene of affected members of two large pedigrees with non-autoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia), that involve residues in the third (Val509Ala) and seventh (Cys672Tyr) transmembrane segments. When expressed by transfection in COS-7 cells, the mutated receptors display a higher constitutive activation of adenylyl cyclase than wild type. This new disease entity is the germline counterpart of hyperfunctioning thyroid adenomas, in which different somatic mutations with similar functional characteristics have been demonstrated.

Use of m-[131I]iodobenzylguanidine in the treatment of malignant pheochromocytoma.

The efficacy and safety of m-[131I]iodobenzylguanidine ([131I]MIBG) were assessed in 15 patients with malignant pheochromocytomas in a nonrandomized, single arm trial, in which patients were treated with [131I]MIBG (SA, 740 megabequerel/mg) every 3 months. Seven of these patients had bone and soft tissue metastases, 4 had only soft metastases, and 4 had only bone metastases. The follow-up period ranged from 6-54 months; the number of doses ranged from 2-11, with 2.9 (78.4 mCi) to 9.25 gigabequerel (GBq) (250 mCi)/administration and a cumulative activity from 11.1-85.90 GBq (300-2322 mCi). The absorbed cumulative dose in tumors ranged from 12-155 Gy. A beneficial effect of the treatment was observed in 9 patients (60%). No complete remission of the disease was observed. Seven patients died during the study, among whom 4 never responded to the treatment. Seven had hormonal responses (4 complete and 3 partial), with a duration ranging from 5-48 months. Among these patients, 4 relapsed, and 3 died within 3 months. Five patients had partial tumoral responses mainly located in soft tissues and for a duration ranging from 29-54 months. All patients with a hormonal response had objective improvement in clinical status and blood pressure. There was no clear-cut relationship between the cumulative dose and the responses. The main side-effect observed in 1 patient with widespread bone metastases after three doses (12.9 GBq) was a pancytopenia, which resolved after treatment was discontinued. This study suggests that repeated [131I]MIBG treatment could be effective in patients with advanced malignant pheochromocytoma.

Genetic heterogeneity in familial nonmedullary thyroid carcinoma: exclusion of linkage to RET, MNG1, and TCO in 56 families. NMTC Consortium.

Epidemiological studies show a very high relative risk for first degree relatives of probands with thyroid cancer. The familial form of nonmedullary thyroid carcinoma (NMTC) gives a more severe phenotype and appears earlier than its sporadic counterpart. Moreover, benign thyroid pathologies are often observed in NMTC kindreds. Little is known about the genetic risk factors of the disease. To study them, an international consortium has been organized at the International Agency for Research on Cancer over the past 2 yr to collect biological samples from NMTC families. The only genes known to be directly involved in susceptibility to NMTC are MNG1 on chromosome 14q32 and TCO on chromosome 19q13.2, previously localized by us and others. In addition to those two genes, the genes for Cowden's syndrome and familial adenomatous polyposis are associated with thyroid cancer, but not as an indicative phenotype. Another important gene in thyroid carcinogenesis is RET, which is mutated in the majority of cases of hereditary medullary thyroid cancer and rearranged in an important fraction of sporadic cases of NMTC. Here we report the result of a linkage analysis performed on the 56 more informative kindreds we have collected through the international consortium. Linkage analysis using both parametric and nonparametric methods excluded MNG1, TCO, and RET as major genes of susceptibility to NMTC and demonstrated that this trait is characterized by genetic heterogeneity.

Thoracic and abdominal SPECT-CT image fusion without external markers in endocrine carcinomas. The Group of Thyroid Tumoral Pathology of Champagne-Ardenne.

UNLABELLED: Superimposition of SPECT and computed tomography (CT) slices from the thoracoabdominal region was achieved without the use of external markers for 14 studies in 13 patients with endocrine carcinoma. Technical feasibility and clinical validation of this retrospective fusion method were assessed. METHODS: Patients had a history of thyroid cancer or of carcinoid tumor. To detect tumor sites, CT scan and dual-isotope tomoscintigraphy were performed, with 99mTc-hydroxymethylene diphosphonate for bone scintigraphy and with 111In-pentetreotide, 131I or 131I-metaiodobenzylguanidine for tumor scintigraphy (TS). A superimposition method previously developed for the pelvic region was adapted to the nonrigid thoraco-abdominal region. CT-bone scintigraphy and CT-TS superimposed images were obtained. Clinical validation of the information obtained from the superimposed images was obtained from surgery or follow-up imaging studies performed after clinical evolution of the disease process. RESULTS: Reliable and reproducible registration was achieved in all patients. CT-TS superimposed images produced accurate localization of abnormal TS foci. Accuracy was limited primarily by variable relative displacements of the thoracoabdominal organs. For 10 sites in 8 patients, localization and/or characterization obtained from CT-TS images was confirmed by a reference technique. Superimposition enabled the localization of tumor sites that otherwise could not have been suspected from CT alone and allowed the characterization of CT suspicious masses and the confirmation of CT positive sites. Nonspecific tumor TS uptake sites were also localized. CONCLUSION: With standard CT and dual-isotope SPECT acquisitions, SPECT-CT fusion is feasible in the thoracoabdominal region without the use of external markers. Fused images were validated in 8 patients for 10 sites. The use of this technique could probably improve the management and care of patients with endocrine carcinoma.

Exposure to radioactive iodine-131 for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients.

UNLABELLED: Radiation is known to be mutagenic. The aim of the present study was to ascertain whether exposure to 131I induces genetic damage, as assessed by pregnancy outcomes and the health status of offspring of women previously exposed to 131I during thyroid carcinoma treatment. METHODS: Data on 2113 pregnancies were obtained by interviewing female patients treated for thyroid carcinoma who had not received any significant external radiation to the ovaries. RESULTS: The incidence of miscarriages was 11% before any treatment for thyroid cancer; this number increased slightly after surgery for thyroid cancer, both before (20%) and after (20%) 131I, but did not vary with the cumulative 131I dose. Miscarriages were more frequent (40%) in the ten women who were treated with 131I [mean dose: 3.8 GBq (108 mCi)] during the year preceding conception. Incidences of stillbirth, preterm birth, low birth weight, congenital malformation and death during the first year of life were not significantly different before or after 131I therapy. The incidence of thyroid disease and nonthyroidal malignancy was similar in children born either before or after their mothers were exposed to 131I. CONCLUSION: With the exception of miscarriages, there is no evidence that exposure to radioiodine affects the outcome of subsequent pregnancies and offspring. The question of whether an increased incidence of miscarriages within 1 yr of 131I administration relates to gonadal irradiation or to insufficient control of hormonal thyroid status remains to be established.

Ret and trk proto-oncogene activation in thyroid papillary carcinomas in French patients from the Champagne-Ardenne region.

OBJECTIVES: To investigate the presence of ret and trk proto-oncogene rearrangements in thyroid tumors. DESIGN AND METHODS: High-molecular-weight DNA was extracted from 36 thyroid tumors (1 multinodular goiter, 14 follicular adenomas, 16 papillary carcinomas, 1 lymph node metastasis of a papillary carcinoma, 1 follicular carcinoma, and 3 medullary carcinomas) and 22 adjacent tissues. Southern blot analysis was performed after digestion with EcoR1 or BamH1, using specific probes for ret and trk. RESULTS: Only 2 ret rearrangements were found in 2 papillary carcinomas (overall frequency: 6%; papillary carcinoma frequency: 13%). All normal or tumor samples were negative for the presence of a trk rearrangement. CONCLUSIONS: The previous data from the literature are highly conflicting, ranging from 0 to 30% of activation. Our results could be, therefore, classified as medium between these extreme values. It seems, therefore, that genetic and/or geographical factors could play a role in ret and trk proto-oncogene activation.

Contribution of quantitative cytology to the cytological diagnosis of thyroid neoplasms.

In a previous study we determined that the fine needle aspiration (FNA) biopsy of thyroid produces 16% of false-negative cases (FNC). In order to determine the value of quantitative cytology (QC) as a tool for predicting the FNC result, thirty-seven cases, 18 of which were operated (histologically benign: 13; malignant: 3; atypical adenoma; 2) were examined for quantitative morphologic characteristics. The smears were stained by the Feulgen method and nuclear parameters of morphometry, densitometry and texture were computed by a cell image processor. The system was first taught to recognize the benign and malignant cells from 3 histologically benign and malignant lesions. Thereafter, prospective cases were submitted to decisional analysis. For 10 histologically benign cases, the benign cell rate (bcr) ranged from 65% to 99.4 (95% confidence interval). Among the patients with a cytologically benign lesion (and an unknown histological diagnosis), 2 had a bcr less than 65% and so were not to be regarded as benign. The follow-up of these patients will show whether they represent FNC and whether QC can be of predictive value in assessing the FNC.

Evaluation of morphological criteria in the cytological diagnosis of thyroid cold nodules. A preliminary study.

Although cytological diagnosis plays a significant role in the management of thyroid cold nodules, the rather high rates of false negative cases diminishes its usefulness. The purpose of this preliminary study is to evaluate the utility of numerous morphological criteria used by the cytologist to exclude benign tumours. Thirty-one cytological criteria were routinely scored as binary (yes/no) or as categories: 6 referred to the general arrangement and frequency of thyroid cells, 9 to the associated cellular and cell product elements, and 16 to the morphological features of the cells. We examined the manner in which these criteria, alone or combined, contributed to the diagnosis. The data base consisted of 171 intraoperative imprint cytological samples (143 histologically benign, 1 atypical adenoma and 27 cancers), as well as 257 thyroid cold nodule aspirates from another set of patients (198 histologically benign, 7 atypical adenomas and 52 cancers). For the imprint cytology, the diagnostic power of each criterion was individually assessed by the likelihood ratio (LR) which eliminated 11 as being undiscriminatory. The remaining independent criteria were subjected to logistic regression analysis to determine the most discriminant. Three were selected: Cellular clustering organisation, nuclear hypertrophy and colloid quantity with the latter being somewhat less powerful. Furthermore, it appears that the diagnostic power of the criteria was significantly lower when there was at least one nucleolus (number of nucleoli greater than 0). The smears gave essentially the same results as the imprints.(ABSTRACT TRUNCATED AT 250 WORDS)

[Malignant lymphomas (primary and secondary) of the thyroid. Description of 9 case reports and review of the literature]. / Lymphomes malins (primitifs et secondaires) de la thyroïde. Description de 9 observations et revue de la littérature.

Malignant lymphomas of the thyroid are rare and represent approximately 0.3 to 8.9% of thyroid malignant neoplasms. We report 9 new cases; their clinical and histopathological features are discussed and compared with those of previously published series. Malignant lymphomas of the thyroid raise a number of issues: primary or secondary origin, histological typing (50% of cases are high grade lymphomas), differential diagnosis with either Hashimoto's chronic thyroiditis (often associated with thyroid lymphomas) or genuine anaplastic carcinoma of the thyroid. Routine histological study can be complemented by immunohistochemistry.

[Clinical signs in medullary cancers of the thyroid]. / Les signes cliniques des cancers médullaires de la thyroïde.

Medullary thyroid carcinoma is diagnosed with difficulty and at an advanced stage as a consequence of its rarity and its relatively recent knowledge. Therefore, the extent of the disease is already important at the therapeutic stage and the chance of cure is poor. One hundred and thirty four cases treated in the Gustave Roussy Institut (Villejuif) and the Jean Godinot Institut (Reims) between 1942 and 1983 have been studied retrospectively. One hundred and seventeen of them diagnosed after 1960 have been analyzed. We have pointed out the clinical features which should lead to diagnosis and with present means should assure it with the minimum of delay. We have outlined the multiple endocrine neoplasia syndromes IIa and IIb and repeated the necessity of clinical and biological familial screening, 11 per cent of cases are inherited.

[Metastatic cancers of the thyroid gland. Diagnostic difficulties]. / Cancers métastatiques de la glande thyroïde. Difficultés diagnostiques.

Metastatic carcinoma of the thyroid is uncommon in surgical pathology and may masquerade as primary thyroid cancer. We studied 6 cases of biopsied and/or surgically resected metastatic carcinoma of the thyroid and their corresponding primary carcinoma, with emphasis on the differential diagnosis. There were 4 men and 2 women patients aged 44 to 77. The primary carcinoma was a breast infiltrating duct carcinoma (3 cases), a colorectal adenocarcinoma (2 cases) and a bronchial oat-cell carcinoma (1 case). The interval between primary carcinoma and secondary thyroid carcinoma was 2 to 9 years in 4 cases; 2 other cases showed simultaneous occurrence. Five patients died with widespread metastases 1 to 14 months following the diagnosis of secondary carcinoma of the thyroid; 1 patient was alive after 24 months. The histological differentiation of secondary from primary thyroid cancer may be difficult in the following situations: clear-cell, Hürthle-cell and signet ring cell changes; positivity of mucins stains; production of melanin; epidermoid differentiation; very rare miscellaneous tumours ("columnar cell carcinoma" and primary thymoma of the thyroid). Immunoperoxidase methods and mucin histochemistry may help.

[Thyroid cancer in Champagne-Ardenne: 1967-1984. Epidemiologic findings in a regional register]. / Les cancers thyroïdiens en Champagne-Ardenne: 1967-1984. Exploitation épidémiologique d'un registre régional.

Between 1967 and 1984, 600 cases of clinically diagnosed thyroid carcinoma were collected in an area (Champagne-Ardenne) of about 1,500,000 inhabitants. During this period, the complete collection of the cases was progressively ensured by involving all the general practitioners and by creating a cooperative multidisciplinary group. The collected data were sex, age at diagnosis, histological classification and clinical extension in TNM system. We found 19 patients with previous neck irradiation. Thyroid cancer was diagnosed in association with thyrotoxicosis in 36 patients: 13 Graves disease and 23 nodular hyperthyroidism. Incidence rates were estimated on a well defined population of two districts (850,000 inhabitants) and limited to the last four years. The following results were obtained: incidence 4.3/100,000/year, age-specific incidence progressively increasing up to a value of 10/000,000/year in the course of the fifth decade. Sex-ratio was 0.26.

[Anatomo-clinical prognostic factors of papillary carcinoma of the thyroid. Multivariate analysis: report of a series of 52 cases]. / Facteurs pronostiques anatomo-cliniques des carcinomes papillaires de la thyroïde. Analyse multivariée: à propos d'une série de 52 cas.

A retrospective study about 52 cases of papillary thyroid carcinomas was carried out with emphasis on histopathological features. The mean follow up period was 10 years. The survival curves were estimated using the Kaplan-Meier method and compared using the log rank test. The multivariate analysis was performed using the Cox's regression model. In univariate analysis, age, Tp (histopathological extension of the tumor), histological differentiation, VAN score (Vascular invasion nuclear Atypia tumor Necrosis) of Akslen and the LeuM1 expression were significant prognostic factors. In multivariate analysis, the Tp and histological differentiation were associated with high risks of poor outcome.

[Prevalence of ophthalmopathy in Basedow disease. Follow-up of patients one year following diagnosis of hyperthyroidism]. / Prévalence de l'ophtalmopathie dans la maladie de Basedow. Suivi des malades à un an après la découverte de leur hyperthyroïdie.

During a study performed to estimate the prevalence and evolution of ophthalmologic symptoms in Graves' disease, we examined 85 patients suffering from diffuse hyperfunctional goiter, which was recently discovered. Forty-seven of these patients came back to the one year ophthalmologic control examination. The patients classed 1 in the Nospecs at first examination rarely remained in the same class either worsening or ameliorating. The worsening or amelioration were independent from the treatment employed for hyperthyroidism and from the results of this treatment. The patients classed 0 in the Nospecs mostly remained in the same class. The patients in which first examination discovered more severe signs and especially inflammatory signs (eyelid oedema for example) should be carefully followed up.

[Prevalence of eye diseases in Basedow disease. Apropos of a prospective study with 85 cases]. / Prévalence de l'ophtalmopathie au cours de la maladie de Basedow. A propos d'une étude prospective portant sur 85 cas.

The authors report the results of a prospective study, conducted between March 1990 and March 1991, on 85 patients suffering from Graves' disease, who were systematically examined to evaluate the prevalence of ophthalmopathy in Graves' disease. They were graded according to the Nospecs classification: 32 patients had no ophthalmopathy; 21 had only eyelid retraction (grade I in the Nospecs); 32 had a real ophthalmopathy (Grade II) or more in the Nospecs: 27 patients had signs of inflammation (grade II), that were often minor, 14 patients a moderate or intermediate exophtalmos (grade III), 4 patients had corneal injuries (grade V). The authors discuss the problems caused by this classification.

[Diagnostic circumstances, therapeutic measures and long-term surveillance of medullary cancers of the thyroid]. / Circonstances diagnostiques, moyens thérapeutiques et surveillance au long cours des cancers médullaires de la thyroïde.

Diagnosis of medullary thyroid carcinoma is often delayed as a consequence of its rarity and its recent discovery. Fine needle aspiration biopsies of all the cold thyroid nodules and plasma calcitonin (CT) measurement in case of suggestive clinical features allow an accurate pre-operative diagnosis and the best therapeutic conditions. A cervico-mediastinal check-up, a screening for a Multiple Endocrine Neoplasia type 2a or 2b, the removal of all tumoral cervico-thoracic tissue by total thyroidectomy, a careful node excision and the pathological examination by a skillful pathologist using immunohistochemistry are the main therapeutic methods. Additional treatment such as external radiotherapy, chemotherapy and radiopharmaceutics are indicated when surgery is incomplete, when the tumor is inoperable and when there are extensive distant metastases. Basal and pentagastrin stimulated CT is the best tool in post surgical follow-up. Disappearance may indicate a long remission, even a cure. Persistence of an abnormal level necessitates the search for secreting tumoral site with non invasive methods such as ultrasonography, computed tomography and scintigraphy, avoiding blind aggressive treatments. In case of recurrence or distant metastases, surgical excision has to be considered first.

[131 iodine for the initial treatment of thyroid cancer]. / L'iode 131 lors du traitement initial du cancer thyroïdien.

Retrospective studies justified the use of 131 iodine after surgery in the management of thyroid cancer for reducing recurrences and improving survival. Indications based on the evaluation of prognostic factors and on the quality of surgical excision are more advisable than systematic administration, particularly in small, non aggressive tumors which are diagnosed more and more frequently. A high level of endogenous TSH and absence of iodine overload are required. Standardized fixed ablative doses reach a high rate of success. Various scintigraphic procedures allow precise localization of residual or distant uptake. Radioprotection measures must be carefully applied to the patients and their environment by a skillful personnel. Side effects are rare after one ablation dose but must be systematically noted and treated. Genetic and carcinogenetic risks are very low.

[131 iodine and differentiated thyroid cancers]. / Iode 131 et cancers thyroïdiens différenciés.

By its dual gamma and beta emission, 131I permits both external detection and selective irradiation of residual or metastatic differentiated thyroid carcinoma. Indications based on the evaluation of prognostic factors and on the quality of surgical excision are more advisable than systematic use. Useless, even harmful after unilateral surgery decided because of a very good prognosis, 131I is recommended according to several retrospective studies for post surgical ablation of the remnants, the detection and the treatment of the recurrences and the distant metastases. The use of therapeutic doses in patients with an isolated elevation of thyroglobuline (Tg) without any clinical or radiological signs favors early diagnosis and cure of metastases with negative diagnostic scintigraphy. Dosimetric considerations and radioprotection measures must be guided by specific rules concerning radiometric material, adapted rooms and skilful personnel. Scintigraphic detection must be done in the best technical conditions. Protracted follow-up is based on Tg dosages and 131I whole body scintigraphies. Early diagnosis of metastases and positive response to 131I irradiation influence favorably remission rates. Even if a complete remission is not achieved, repeated treatments by a specialized team improve the quality of survival for metastatic patients.

[Ultrasensitive TSH : a new diagnostic approach to hyperthyroidism]. / TSH ultrasensible : une nouvelle approche diagnostique de l'hyperthyroïdie.

The value of new ultrasensitive and rapid immunoradiometric assay of thyroid stimulating hormone (TSH) for the diagnosis of hyperthyroidism was assessed in 130 patients with suspected hyperthyroidism and in 330 controls. The diagnosis was established by the clinical evaluation, thyroid scintigraphy and serum concentrations of thyroid hormones. Using the ROC (Receiver Operating Characteristic) curve methodology which allows the optimization of sensitivity and specificity, the physician can choose the "Cut-off" value between hyperthyroidism and euthyroidism. Two points of the curve seem to be interesting : using the "cut-off" value of 0.1 mUI/l, sensitivity is 0.98 and specificity is 0.98 ; using the "cut-off" value of 0.3 mUI/l, sensitivity is 1.00 and specificity is 0.92. Using the association TSH and FT4 (Free Thyroxin), sensitivity is 0.94 and specificity is 0.99. Sixty four per cent of euthyroid patients with TSH under 0.3 mUI/l have one or several hot nodules and only two have no thyroid disease. A TRH (Thyrotrophin Releasing Hormone) test was carried out in 63 patients with suspected thyrotoxicosis : basal and TRH stimulated TSH levels were under 0.1 mUI/l. This immunoradiometric assay for TSH may simplify the approach to thyroid function testing in patients with suspected thyrotoxicosis : a basal TSH under 0.3 mUI/l is sufficient to confirm a clinical suspicion of thyrotoxicosis without TRH test within four hours. In a department devoted to testing thyroid function, this new method provides a great benefit in cost and work.

[Role of adrenocortical scintigraphy in the exploration of incidentally discovered tumors]. / Place de la scintigraphie corticosurrénalienne dans l'exploration des incidentalomes.

To determine the utility of adrenocortical scintigraphy with I131-6 beta-iodomethyl-19-nor-cholesterol (NP59) in incidentally discovered adrenal masses, we studied 12 patients with a unilateral adrenal mass and without other primary tumors or signs of pheochromocytoma or hyperfunctioning adenoma. Ten patients had an adenoma (size: 12 to 35 mm), the diagnosis was made by surgery or by no change in size on repeated CT scans. The NP59 scintigraphy showed an increased uptake on the side of the tumor in 8 cases with a decreased uptake of contra-lateral gland in 7 cases. Hormonal investigations of glucocorticoid function suggested supranormal or fluctuant cortisol secretion in 5 cases as assessed by moderately elevated urinary free cortisol or by incomplete dexamethasone suppression test. These abnormalities disappeared after surgery. Two patients had normal bilateral uptake of NP59, the sizes of the tumors were 12 and 20 mm. Two patients had an extra-adrenal tumor. The NP59 scintigraphy showed a moderately decreased uptake on the side of the hematoma of one patient and a compression of the normal adrenal by ganglioneuroma of the other patient. Our results and those of other authors suggest that positive NP59 scintigraphy could confirm the cortical nature of an incidentally discovered adrenal mass, probably an adenoma that must be followed up morphologically and functionally. No uptake by a tumor greater than 2 cm suggests a primary malignancy or extra-adrenal origin which must be diagnosed by invasive methods.