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.

[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.

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.

[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.

Leukaemias and cancers following iodine-131 administration for thyroid cancer.

We studied 1771 patients treated for a thyroid cancer in two institutions. None of these patients had been treated with external radiotherapy and 1497 had received (131)I. The average (131)I cumulative activity administered was 7.2 GBq, and the estimated average dose was 0.34 Sv to the bone marrow and 0.80 Sv to the whole body. After a mean follow-up of 10 years, no case of leukaemia was observed, compared with 2.5 expected according to the coefficients derived from Japanese atomic bomb survivors (P = 0.1). A total of 80 patients developed a solid second malignant neoplasm (SMN), among whom 13 developed a colorectal cancer. The risk of colorectal cancer was found to be related to the total activity of (131)I administered 5 years or more before its diagnosis (excess relative risk = 0.5 per GBq, P = 0.02). These findings were probably caused by the accumulation of (131)I in the colon lumen. Hence, in the absence of laxative treatment, the dose to the colon as a result of (131)I administered for the treatment of thyroid cancer could be higher than expected from calculation of the International Commission on Radiological Protection (ICRP). When digestive tract cancers were excluded, the overall excess relative risk of second cancer per estimated effective sievert received to the whole body was -0.2 (P = 0.6).

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.

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.

[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.

Quantitative cytology and thyroperoxidase immunochemistry: new tools in evaluating thyroid nodules by fine-needle aspiration.

Fine-needle aspiration (FNA) of cold thyroid nodules is proposed to be the most useful diagnostic test for deciding which patients need surgery. A retrospective study of standard cytology (SC) performed in 776 patients who had been operated on, showed a sensitivity of 94% and a specificity of 80%. Quantitative cytology (QC) was carried out with a cell image analyzer, which classified the cases as benign or not benign. In 87 cases, sensitivity and specificity of QC alone were 100 and 76%. When SC and QC were combined, there were no false negative reports. A new monoclonal antithyroperoxidase (TPO) antibody (MoAb47) was tested. The sensitivity and specificity of TPO alone were 97 and 81%. When SC and TPO were combined, specificity rose 90%. As adjuncts to SC, QC and TPO represent useful tools for selecting patients for surgery.

[Cancers of the thyroid. Value of a regional registry on 627 patients diagnosed, treated and followed by a multidisciplinary team]. / Les cancers de la thyroïde. Intérêt d'un registre régional de 627 patients diagnostiqués, traités et suivis par une équipe multidisciplinaire.

Since 1966, data from 1536 patients with a thyroid carcinoma, living in the French region Champagne-Ardenne, a geographical area with 1,350,000 inhabitants were registered. The creation of a multidisciplinary group and the involvement of the general practitioners, allowed us to reach an exhaustive and continued registration process for the French administrative area of Marne and Ardennes (855,000 inhibitants, 627 patients). The sex-ratio F/M was 3.8 and the median ages were respectively equal to 46 [10-93] and 52 [13-82] in females and males. In the age groups 10-14 and 15-19, 3 cases and 13 cases were respectively registered. An history of external irradiation was noted in 2.9% of the patients. The study of the incidence around the Chooz nuclear plant (Ardennes) did not show an increase of the risk. For the French administrative area Marne and Ardennes, for the period 1975-1979, the incidence rates, standardized on the European population, were equal to 1.75/100,000 in males (SD = 0.15) and 6.38/100,000 (SD = 0.29) in females. These values among the highest from the data published by the other European registries should be explained by a more intensive diagnosis procedure and an improvement in the accuracy of histological diagnosis. An increase of the incidence rate was observed between the periods 1975-1983 and 1984-1992 from 1.04 to 2.05/100,000 and 4.99 to 6.39/100,000 in males and females respectively. This was associated with changes in clinical and histological features and an improvement in survival curves. For patients under the age of 19, we have compared both periods before and after the accident of Chernobyl. The incidence rates increased from 0.13 to 0.45/100,000 and 0.49 to 1.81/100,000 in the age groups 10-14 and 15-19 respectively. This change was at the order of magnitude to this observed in our adults population. We did not found the histological aggressiveness which characterized the Chernobyl-induced thyroid cancer in children. The knowledge of the significant prognostic factors determined by multifactorial analyses is a major foundation of our therapeutic strategy.

Treatment of advanced medullary thyroid cancer with an alternating combination of 5 FU-streptozocin and 5 FU-dacarbazine. The Groupe d'Etude des Tumeurs a Calcitonine (GETC).

Combinations of 5-fluorouracil (5-FU) and streptozocin and 5-FU and dacarbazine were given alternately to 20 patients with metastatic medullary thyroid carcinoma. Three partial responses and 11 long-term stabilizations were observed. No unexpected toxicity occurred.

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.

[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.

[Value of parathyroid scintigraphy in preoperative localization of parathyroid adenoma. Study apropos of 138 tests]. / Valeur de la scintigraphie parathyroïdienne dans le repérage pré-opératoire des adénomes parathyroïdiens. Etude à propos de 138 examens.

The authors have studied, about a total of 138 exams, the value of parathyroid nuclide scan. All the patients, who had primary hyper parathyroidism, have been operated upon. The results of parathyroid scintigraphy have been compared to the results of surgical exploration. Overall sensibility of the exam has been 80%, better with the MIBI (89%) than with the Thallium (78%). The specificity has also been better with the MIBI (95%) than with the Thallium (87%) with a global result of 88%). Computerized treatment of images with automatized subtraction especially studied in Institut Jean-Godinot, Rheims, explain the quality of these results.

Thyroid neoplasms. Can we do any better with quantitative cytology?

The differential diagnosis of thyroid neoplasms by routine cytology presents major difficulties. We therefore looked for measurable nuclear parameters that could be generated from Feulgen-stained smears obtained by fine needle aspiration biopsy (FNAB). These parameters would then be used to differentiate between benign and malignant lesions. Seventy-six patients whose cold thyroid nodule was surgically excised after FNAB and examined by a pathologist were used in this study: 56 benign, 18 malignant and 2 atypical adenomas. A set of 3,662 cells from the 33 benign cases was compared with the set of 1,712 cells from the 11 malignant nodules. Discrimination between the two populations was based on four nuclear features ranked according to their discriminating power. The first ranked was a textural parameter, followed by a densitometric and finally two other textural parameters. The rate of nuclei that could be regarded as benign was computed for each case using the ranked parameters. The average rate for the 33 benign cases was 85% (50.2 = 100%, set at the 95% confidence interval). In a prospective study of the 32 remaining patients, sensitivity and specificity were, respectively, 92% and 88%, which were higher than those obtained by conventional cytology.

[Medullary cancer of the thyroid and multiple endocrine neoplastic syndromes]. / Le cancer médullaire de la thyroïde et les syndromes de néoplasie endocrinienne multiple.

Despite its rarity, medullary thyroid carcinoma which is hereditary in a quarter of cases and often associated with multiple endocrine neoplasia 2a and 2b syndromes, avises much interest which has lead to the formation of a French multidisciplinary group for the study of calcitonin tumors. This collaboration has resulted in the establishment of a national register and has broadened the knowledge of all specialists concerned. Consequently diagnostic methods are improved, becoming quicker, more reliable and also more thorough due to the setting up of therapeutic protocols. An immunocytochemical staining for calcitonin allows a preoperative diagnosis, providing optimal therapeutic conditions for the patients, especially systematic research of pheochromocytoma and management by a specialized team. Total thyroidectomy and careful lymph node dissection are recommended for all cases. Such progress significantly modifies the prognosis of the disease. Family screening, using plasma calcitonin and, in the near future, genetic studies will hopefully enable the identification of abnormal gene carriers before the clinical stage, thus making total recovery possible.

[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.