The role of 18F-FDOPA and 18F-FDG-PET in the management of malignant and multifocal phaeochromocytomas.

BACKGROUND: (18)F-DOPA has emerged as a promising tool in the localization of chromaffin-tissue-derived tumours. Interestingly, phaeochromocytomas (PHEO) are also FDG avid. AIM AND METHODS: The aim of this study was to retrospectively evaluate the results of (18)F-FDOPA and/or (18)F-FDG-PET in patients with PHEO and paragangliomas (PGLs) and to compare the outcome of this approach with the traditional therapeutic work-up. Nine patients with non-MEN2 related PHEO or PGL were evaluated. At the time of the PET studies, the patients were classified into three groups based on their clinical history, conventional and SPECT imaging. The groups were malignant disease (n = 5, 1 VHL), apparently unique tumour site in patients with previous surgery (n = 1, SDHB) and multifocal tumours (n = 3, 1 VHL, 1 SDHD). (18)F-FDOPA and (18)F-FDG-PET PET/CT were then performed in all patients. RESULTS: PET successfully identified additional tumour sites in five out of five patients with metastatic disease that had not been identified with SPECT + CI. Whilst tumour tracer uptake varied between patients it exhibited a consistently favourable residence time for delayed acquisitions. (18)F-FDOPA uptake (SUVmax) was superior to (18)F-FDG uptake in cases of neck PGL (three patients, four tumours). If only metastatic forms and abdominal PGLs were considered, (18)F-FDG provided additional information in three cases (two metastatic forms, one multifocal disease with SDHD mutation) compared to (18)F-FDOPA. CONCLUSIONS: Our results suggest that tumour staging can be improved by combining (18)F-FDOPA and (18)F-FDG in the preoperative work-up of patients with abdominal and malignant PHEOs. (18)F-FDOPA is also an effective localization tool for neck PGLs. MIBG however, still has a role in these patients as MIBG and FDOPA images did not completely overlap.

[Multiple endocrine neoplasia type 2]. / Néoplasies endocriniennes multiples de type 2.

Multiple endocrine neoplasia type 2 (MEN2) is an hereditary disease with a prevalence of 1/5000. Three phenotypic variants have been identified: MEN2A associates medullary thyroid carcinoma (MTC) to pheochromocytoma in about 20-50% of cases and to primary hyperparathyroidism in 5-20% of cases; MEN2B associates MTC to pheochromocytoma in 50% of cases, to marphanoid habitus and to mucosal and digestive ganglioneuromatosis whereas in familial isolated medullary thyroid carcinoma (FMTC), the other components of the disease are absent. In MEN2, natural history of the disease and a common embryologic origin (neural crest) may explain the phenotypes observed in the organ involved, beginning from the stage of hyperplasia to adenoma and cancer. MEN2 is an inherited autosomal dominant disease with a complete penetrance, related to germline mutation in the proto-oncogene RET. MTC represent the most frequent circumstance of diagnosis. Pheochromocytoma and HPT may reveal the disease unfrequently and are systematically associated to undiagnosed MTC which is present yet. Analysis of the RET gene allows to confirm the diagnosis of MEN2 by identifying the causal germline mutation. Management of MEN2 patients include thyroidectomy associated to cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved, and selective resection of pathologic parathyroid glands for HPT. Familial genetic screening detects at risk subjects who will develop the disease and allows to manage them at the earliest stage of the disease by perform early or prophylactic thyroidectomy such giving them the best chance of cure. Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC, thus pointing the necessity of a complete thyroid surgery for index cases with MTC and the earliest thyroidectomy for screened at risk subjects.

[Medullary thyroid carcinoma]. / Cancer médullaire de la thyroïde.

Medullary thyroid carcinoma (MTC) is developed from thyroid C cells that secrete calcitonin (CT). MTC represents 5-10% of thyroid cancers with a 1-2% incidence in nodular thyroid diseases. Diagnosis is usually made by a solitary nodule often associated to nodal metastasis and confirmed by a high basal CT level which represents its biological marker. MTC may present as a sporadic form and in about 30% of case as a familial form as a part of multiple endocrine neoplasia syndrome, an hereditary dominant inherited disease related to germline mutation of the proto-oncogene RET. Both biological (CT) and genetic (RET) markers allows the optimal diagnosis and treatment of MTC; the former allows screening and early diagnosis of MTC by routinely CT measurements in nodular thyroid diseases that make the adequate and complete surgery required to be performed. The former leads to diagnose familial MTC and to identify at risk subjects in whom early or prophylactic surgery may be performed. Treatment of MTC is based on the complete surgical resection: total thyroidectomy associated to central and laterocervical nodal dissection. For locally advanced or metastatic MTC, complete cervical surgery is required and needs to be associated to other systemic treatments: as chemotherapy is not very efficient, radioimmunotherapy and RET target gene therapy (mainly tyrosine kinase inhibitors) appears as possible valuable therapeutic options for the future. Prognosis of MTC is mainly related to both the stage of the disease and the extend of the initial surgery. Ten-year survival is about 80% when the patients are not surgically cured and reaches 95% when the biological marker CT is normalized after surgery.

Human thyroperoxidase is largely retained and rapidly degraded in the endoplasmic reticulum. Its N-glycans are required for folding and intracellular trafficking.

Human thyroperoxidase (hTPO), a type I transmembrane heme containing glycoprotein, catalyzes iodide organification and thyroid hormone synthesis and plays a major role in thyroid autoimmunity. Whereas hormonosynthesis occurs at the apical membrane of thyroid cells, TPO localizes mainly in the perinuclear membrane and the endoplasmic reticulum. To establish the intracellular trafficking and the structural characteristics of hTPO in the various cell compartments, hTPO was stably expressed in the Chinese hamster ovary cell line, and its folding was studied with two monoclonal antibodies (mAbs): mAb 47, recognizing a linear epitope; and mAb 15, recognizing a conformational epitope present in the mature protein. The results show that only 15-20% of hTPO molecules were able to acquire a conformation suitable for the recognition by mAb 15. On the other hand, only a part (approximately 15%) of the latter were able to reach the plasma membrane. The hTPO, unable to fold correctly, was more rapidly degraded than that recognized by mAb 15 (half-time, 2 h vs. 7 h). Study of the carbohydrate content of hTPO showed that N-glycans with complex-type structure were found only on hTPO at the cell surface, whereas intracellular hTPO bore high-mannose-type structures. Taken together, these data demonstrate that the intracellular pool of enzyme is formed of newly synthesized molecules and is not caused by recycling of mature hTPO from the cell surface. Complete inhibition of hTPO N-glycosylation with tunicamycin led to a 95% decrease in hTPO at the plasma membrane and, thus, to a decrease in enzymatic activity at the cell surface, emphasizing the role of N-glycans in the intracellular trafficking of hTPO. However, inhibition of formation of complex-type structures with deoxymannojirimycin and of O-glycans with phenyl-alpha-GalNAc did not influence the intracellular trafficking and enzymatic activity of hTPO.

Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d'Etudes des Tumeurs a Calcitonine (GETC).

Medullary thyroid carcinoma (MTC) is a calcitonin (CT)-secreting endocrine tumor. Although plasma CT level is a specific and sensitive marker of MTC, its preoperative usefulness in predicting tumor size and postoperative CT normalization has not been documented. From a nationwide database set up by the French CT Tumor Study Group, 226 MTC patients were selected according to the following criteria: preoperative CT level determination by an immunoradiometric assay (normal value, < 10 pg/mL) within the 6 months prior to surgery, total thyroidectomy and diagnosis of MTC ascertained by histological report including tumor size. Patients were 129 females and 97 males (female/male ratio, 1.3). One hundred and twelve patients (49.6%) had the sporadic variety of the disease, 74 (32.7%) had multiple endocrine neoplasia 2A, three (1.3%) had multiple endocrine neoplasia 2B, and 37 (16.4%) had familial MTC. Median age at diagnosis was 44.8 yr (range, 4.9-80.1 yr). Complete neck dissection was performed in 159 patients (70.4%). Postoperative CT normalization was ascertained by negative response of CT to pentagastrin stimulation (< 10 pg/mL) in 94 patients. Seventy-one patients were considered as not cured because of residual tumor tissue and/or elevated CT levels. Median tumor size was 11.0 mm (range, 0.2-80.0 mm), significantly larger in females (15.0 vs. 8.0 mm, P < 0.05), and in sporadic forms (15.0 vs. 7.0 mm, P < 0.05). Tumor size was significantly correlated (r2 = 0.52, P < 0.01) with preoperative CT levels, the relationship being more straight in familial (r2 = 0.71) than in sporadic (r2 = 0.36) forms. Furthermore, preoperative CT levels under 50 pg/mL appeared to be predictive of postoperative CT normalization (44 of 45 patients). However, higher CT levels did not mean absence of postoperative CT normalization (50 of 120 patients). We conclude that low preoperative CT levels are predictive of tumor size and postoperative CT normalization.

Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients.

Familial medullary thyroid carcinoma only is related to germline mutations in the protooncogene RET, mainly in exons 10, whereas noncysteine mutations (exons 13-15) are considered infrequent. We analyzed 148 patients from 47 familial medullary thyroid carcinoma only families, and we found noncysteine RET mutations in 59.5% of these families. Of the index cases with noncysteine mutations, 43.4% presented with a multinodular goiter and high basal calcitonin; they were older at diagnosis than those with mutation in exon 10 and had more multifocal medullary thyroid carcinoma, but no difference in size, bilaterality, presence of C cell hyperplasia, or nodal metastases was found. Gene carriers with noncysteine RET mutations had a lower incidence of medullary thyroid carcinoma (78.2% vs. 94.1%) than those with mutation in exon 10; 20.2% had C cell hyperplasia only, although thyroidectomized at an older age. In conclusion, familial medullary thyroid carcinoma with noncysteine RET mutations are not infrequent and are overrepresented in presumed sporadic medullary thyroid carcinoma, suggesting that RET analysis should routinely be extended to exons 13, 14, and 15. The phenotype is characterized by a late onset of the disease, suggesting a delayed appearance of C cell disease rather than a less aggressive form. In familial medullary thyroid carcinoma gene carriers, the optimal timing for thyroidectomy remains controversial. Based on these data, we propose that surgery should be performed before elevation of the basal calcitonin level, potentially as soon as the pentagastrin test becomes abnormal.

Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study.

OBJECTIVE: The aim of this prospective study is to update our knowledge of the chronology of pheochromocytoma occurrence in multiple endocrine neoplasia type 2 (MEN 2), and to better manage MEN 2 patients after the genetic diagnosis. DESIGN: Eighty-seven non-index gene carrier MEN 2 patients were included in this prospective study: 84 patients with MEN 2A (from 52 families) and 3 with MEN 2B (from 3 families). METHODS: Medullary thyroid carcinoma (MTC) was diagnosed by measuring plasma calcitonin in basal conditions or after pentagastrin stimulation. The search for pheochromocytoma consisted of clinical evaluation, 24 h determination of urinary catecholamines and adrenal imaging. The mean age at genetic diagnosis of MEN 2 was 14.0+/-7.0 years, the mean duration for the follow-up was 7.6+/-2.8 years. RESULTS: All 87 patients had a MTC detected at the same time as the genetic diagnosis was made. Urinary catecholamine measurements led to the diagnosis of pheochromocytoma and a combination of imaging techniques enabled the correct localization of both unilateral or bilateral adrenal involvement. Pheochromocytoma was detected simultaneously with MTC in only seven patients, and seven others were detected throughout the follow-up. Of the 14 patients with pheochromocytoma, 11 had bilateral involvement: nine were initially bilateral and two became so during follow-up. CONCLUSION: This study demonstrates that in MEN 2, MTC is the lesion which appears earliest. Pheochromocytoma develops later during the evolution of the disease, and necessitates regular clinical and biological monitoring throughout follow-up. Determination of urinary and/or plasma catecholamines and metanephrines should be performed to detect pheochromocytoma. Imaging techniques lead to the detection of both unilateral and bilateral pheochromocytoma, thus making video-assisted laparoscopic adrenalectomy possible.

Advances in diagnostic practices affect thyroid cancer incidence in France.

OBJECTIVE: To analyse trends in diagnostic practices of thyroid diseases and to relate them to the increase in thyroid cancer incidence in France over time. DESIGN: From 1980 to 2000, a French retrospective multicentric (three endocrinology and three nuclear medicine centres) study of thyroid diseases was conducted on 20 consecutive unselected patients' records, sampled every 5 years in each centre. METHODS: Characteristics of the population and diagnosis procedures (thyroid ultrasonography (US), radionuclide scan, cytology and hormonal measurements) were described over time. Changing trends in operated patients and in cancer prevalence were analysed as well as the impact of practices on cancer incidence. RESULTS: The study included 471 patients (82% female, mean age 46.7, range 9-84 years), referred for nodular thyroid diseases (66.7%) or thyroid dysfunctions (33.3%). A significant increase in US (3 to 84.8%) and cytological practices (4.5 to 23%), and a decrease (89.4 to 49.6%) in radionuclide scan procedures were observed over time. Although the proportion of patients undergoing surgery remained constant (24.8%), the prevalence of cancer increased among operated patients from 12.5 to 37% (P=0.006). In a Cox's proportional hazard model stratified on the clinical characteristics of patients, only the cytological practice, regardless of its results, was significantly associated with the occurrence of cancer: relative risk (RR)=4.4 (95% confidence interval (CI): 1.1-16; P=0.04). CONCLUSIONS: From 1980 to 2000, a major evolution in clinical practices has led to the increase in thyroid cancer reported in France. Such changes in medical, as well as in surgical and pathological, practices must be taken into account in incidence measurement.

Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC).

BACKGROUND: Once genetic testing accurately identifies MEN 2 gene carriers, affected children are given the opportunity to undergo thyroidectomy at the earliest stages of the C-cell disease. OBJECTIVE: To define reliable parameters by which to identify the best moment for thyroidectomy in patients who are carriers of the MEN 2 gene. PATIENTS AND METHODS: Seventy-one MEN 2/FMTC gene carriers, collected through the national register of the French Calcitonin Tumours Study Group, were evaluated. All the patients included were younger than 20 years of age and underwent total thyroidectomy. Basal and pentagastrin-stimulated calcitonin were assayed using an immunoradiometric method (sensitivity less than 2pg/ml). Calcitonin measurement was evaluated on the basis of histopathological findings in surgical thyroid specimens. RESULTS: We found C-cell hyperplasia or medullary thyroid carcinoma in all the 71 gene carriers - even for the youngest patients - and nodal metastases were present in four cases. Calcitonin measurement (basal or pentagastrin-stimulated) detected C-cell disease preoperatively in all patients. Six of the 71 patients were not surgically cured: one had nodal metastases, one had an advanced staged disease and four had an incomplete nodal dissection or had not undergone lymph node surgery. CONCLUSIONS: Determination of calcitonin forms an integral part of the management of MEN 2 gene carriers. Thyroidectomy is undisputably indicated when basal calcitonin is abnormal. When basal calcitonin is undetectable, a pentagastrin-stimulated increase in calcitonin to more than 10 pg/ml indicates an early thyroidectomy to cure the patient.

Sporadic medullary microcarcinoma of the thyroid: a retrospective analysis of eighty cases.

Clinical characteristics and prognosis of 80 patients (53 women and 27 men) with sporadic medullary thyroid carcinomas (MTC), less than 1 cm in size (micro-MTC), operated on between 1971 and 1996 are reported (73 total and 7 partial thyroidectomies). These patients, obtained from a national database of 899 patients with MTC, were compared with 357 cases of sporadic MTC greater than 1 cm and 149 subjects with familial MTC less than 1 cm (familial micro-MTC). Median age at surgery was 52.5 years, a distribution similar to larger sporadic MTC. Micro-MTC was identified due to elevated calcitonin (47.5%), clinically identified lymph node (10.0%), distant metastases (6.3%) or pathologic finding at surgery (36.2%). Diarrhea and/or flushing were observed in 6 patients including 4 with clinically identified lymph node. Among patients who had lymph node dissection at surgery (68.8%), lymph node involvement with tumor was observed in 30.9%, and was significantly more frequent in multifocal (7/11) than in unifocal micro-MTC (p < 0.03). All sporadic micro-MTC were unilateral. Survival rate was 93.9% +/- 4.4% (SE) at 10 years, greater than that observed in sporadic macro-MTC (p = 0.04). Normal postoperative basal calcitonin (CT) was obtained in 71.1% of micro-MTC patients versus 33.6% in sporadic macro-MTC (p < 0.01). Sporadic micro-MTC is much more frequent than expected, 15% of MTC in our series. Although specific survival rate and percentage of biological cure in micro-MTC are significantly better than for larger tumors, the frequency of lymph node involvement, however, justifies an aggressive surgical approach including total thyroidectomy and bilateral central lymph node dissection.

[Von Hippel-Lindau disease: recent genetic progress and patient management. Francophone Study Group of von Hippel-Lindau Disease (GEFVH)]. / Maladie de von Hippel-Lindau: progrès génétiques récents et prise en charge des patients. GEFVHL. Groupe d'Etude Francophone de la Maladie de von Hippel-Lindau.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder, predisposing to the development of central nervous system (CNS) and retinal hemangioblastomas, endolymphatic sac tumors, renal cell carcinoma and/or renal cysts, pheochromocytomas, pancreatic cysts and/or tumors. Incidence of the disease is 1/36,000. CNS hemangioblastomas and renal cell carcinoma are the main causes of death. The VHL gene, located on 3p25-26, is a tumor-suppressor gene which plays a major role in regulation of VEGF expression. Germline mutations of the VHL gene are identified in about 70-99% of the patients. Mutations associated with VHL type 2 (with pheochromocytoma) are mainly missense mutations with hot-spot at codon 167. Somatic mutations of the VHL gene are found in both sporadic central nervous system hemangioblastomas and sporadic renal cell carcinoma. For endocrinologists search for VHL disease (as for MEN) should be imperative in presence of a patient with pheochromocytoma and neuroendocrine pancreatic tumor.

[Polyadenomatoses: type 2 multiple endocrine neoplasms]. / Polyadénomatoses: les néoplasies endocriniennes multiples de type 2.

FROM A CLINICAL POINT OF VIEW: Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant, inherited multiglandular disease with familial and individual age-related penetration and variable expression. A medullary thyroid carcinoma (MTC) is always concomitant to MEN2 and associated in varying proportion with pheochromocytoma (50%) and hyperparathyroidism (5 to 20%). PROGNOSTIC DATA: The prognosis of MEN2 is related to the carcinological evolution of MTC, which depends mainly on the stage of discovery and the quality of the first surgical treatment, emphasizing the need for early diagnosis. THE IMPORTANCE OF THE ERT GENE: The identification of mutations in proto-oncogene RET, responsible for the various forms of the disease allows subjects at risk in a family circle to be identified and early screening of various endocrine damage, notably MTC, should be performed. Biological explorations in all persons carrying this mutation would permit diagnosis and surgical treatment of the endocrine lesions, before their clinical manifestation.

Diagnosis and treatment of medullary thyroid cancer.

Medullary carcinoma of the thyroid (MTC) is a rare tumour derived from thyroid C cells with serum calcitonin as a specific and sensitive marker. MTC is inherited in 25% of cases, with an autosomal dominant transmission, age-related penetrance and variable expressivity. MTC is an obligatory component of multiple endocrine neoplasia type 2 (MEN2), which comprises three well defined syndromes: MEN2A, which may be associated with pheochromocytoma and/or hyperparathyroidism; the much rarer MEN2B, which occurs early and is accompanied by developmental abnormalities; while in contrast, familial MTC (FMTC) is not associated with any endocrinopathy. The RET proto-oncogene is the causative gene of the MEN2 syndromes and mutations in this gene are found in >90% of inherited cases, allowing easier and more reliable family screening than pentagastrin stimulation tests. Nevertheless, the correlation between the genotype and the different clinical phenotypes is not perfect. The prognosis of MTC depends on its staging at presentation, and the early appearance of cervical lymph node metastases emphasizes the need for extensive surgery, although many patients still do not normalize calcitonin levels post-operatively, and they remain a challenge for the further management.

Alternatively spliced form of human thyroperoxidase, TPOzanelli: activity, intracellular trafficking, and role in hormonogenesis.

Thyroperoxidase (TPO), a type I transmembrane heme containing glycoprotein, catalyzes iodide organification and thyroid hormone synthesis. One of the two main alternatively spliced forms of this enzyme, TPOzanelli, which is present in Graves's disease thyroid tissue, has a cytoplasmic domain completely modified. In the first stage of this study, the results of RT-PCR experiments showed that the TPOzanelli mRNA is present in normal thyroid tissue. We then generated CHO cell lines expressing the wild-type TPO (TPO1) and the alternatively spliced form TPOzanelli. Upon investigating a panel of 12 mAbs directed against the extracellular domain of TPO1 and sera from patients with a high titer of TPO autoantibodies, we observed that (i) the three-dimensional structure of this domain is similar in both isoforms; (ii) the autoantibodies recognize TPOzanelli as well as TPO1. The results of pulse chase and cell surface biotinylation experiments showed that the TPOzanelli has a shorter half-life (7 versus 11 h) and is expressed at the cell surface in lesser amounts than TPO1 (7 versus 15%). The total enzymatic activity and cell surface activity were determined in CHO cells expressing TPO1 and TPOzanelli, and TPO1 and TPOzanelli were found to have similar levels of activity. It was established that approximately 20% of the TPO purified from a Graves' disease thyroid gland was precipitated by polyclonal antibodies directed against a specific part of the cytoplasmic tail of TPOzanelli. This confirmed that the protein corresponding to the mRNA is present in the thyroid tissue. All in all, these results indicate that TPOzanelli can be expected to play a role in thyroid hormone synthesis and in thyroid autoimmunity.

Role of heme in intracellular trafficking of thyroperoxidase and involvement of H2O2 generated at the apical surface of thyroid cells in autocatalytic covalent heme binding.

Thyroperoxidase (TPO) is a glycosylated hemoprotein that plays a key role in thyroid hormone synthesis. We previously showed that in CHO cells expressing human TPO (hTPO) only 2% of synthesized hTPO reaches the cell surface. Herein, we investigated the role of heme moiety insertion in the exit of hTPO from the endoplasmic reticulum. Peroxidase activity at the cell surface and cell surface expression of hTPO were decreased by approximately 30 and approximately 80%, respectively, with succinyl acetone, an inhibitor of heme biosynthesis, and were increased by 20% with holotransferrin and aminolevulinic acid, precursors of heme biosynthesis. Results were similar with holotransferrin plus aminolevulinic acid or hemin, but hemin increased cell surface activity more efficiently (+120%) relative to the control. It had been suggested (DePillis, G., Ozaki, S., Kuo, J. M., Maltby, D. A., and Ortiz de Montellano, P. R. (1997) J. Biol. Chem. 272, 8857-8960) that covalent attachment of heme to mammalian peroxidases could be an H2O2-dependent autocatalytic processing. In our study, heme associated intracellularly with hTPO, and we hypothesized that there was insufficient exposure to H2O2 in Chinese hamster ovary cells before hTPO reached the cell surface. After a 10-min incubation, 10 microM H2O2 led to a 65% increase in cell surface activity. In contrast, in thyroid cells, H2O2 was synthesized at the apical cell surface and allowed covalent attachment of heme. Two-day incubation of primocultures of thyroid cells with catalase led to a 30% decrease in TPO activity at the cell surface. In conclusion, we provide compelling evidence for an essential role of 1) heme incorporation in the intracellular trafficking of hTPO and of 2) H2O2 generated at the apical pole of thyroid cells in the autocatalytic covalent heme binding to the TPO molecule.

Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma is a rare tumour derived from the thyroid parafollicular calcitonin-secreting cells. Calcitonin is a very specific marker of this cancer that allows preoperative diagnosis. Serum calcitonin assay is particularly useful to define the postoperative state of patients (cured, apparently cured, not cured) and, because of its great sensitivity, it has a major place in the postoperative follow-up. OBJECTIVE: To identify, among patients thyroidectomized for medullary thyroid carcinoma (MTC), the characteristics of authentic recurrent MTC [re-elevation of stimulated serum calcitonin (CT) level measured by a sensitive immunoradiometric assay, after postoperative normalization]. PATIENTS AND METHODS: We first collected, through the national registry of the French Calcitonin Tumour Study Group (GETC), patients who had undergone a total thyroidectomy with or without lymph node surgery and who were not cured at the last follow-up visit. Among 453 such patients included in the database, 15 patients met the criteria for authentic recurrence as defined in previous studies: they had been first considered as cured during the 6 months following the initial surgical procedure (basal and pentagastrin-stimulated serum calcitonin level