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Service d’Endocrinologie (P.N.S., B.C.D.) and Département d’Informatique Médicale (S.M.), CHU Timone, 13385 Marseilles; Service d’Endocrinologie (A.M.) and Laboratoire de Génétique Moléculaire (S.B.), 44035 Nantes; Service d’Endocrinologie (V.R.) and Laboratoire de Biologie Moléculaire (F.S.), CHU d’Angers, 49033 Angers; Service d’Endocrinologie, CHU Avicenne (S.F.), 93009 Bobigny; Service de Médecine Interne, CHU de Strasbourg (G.C.), 67098 Strasbourg; Service d’Endocrinologie, CHU de Montpellier (L.B.), 34295 Montpellier; Institut Jean Godinot (B.M.), 51056 Reims; Laboratoire de Génétique, Hôpital E. Herriot (S.G.), 69437 Lyon; and Unité de Génétique Moléculaire, Service de Biochimie Médicale, Hôpital Pitié-Salpétrière, 75651 Paris (M.L.K.), France
Address all correspondence and requests for reprints to: Dr. Patricia Niccoli-Sire, Service d’Endocrinologie, CHU Timone, 254 rue St. Pierre F., 13385 Marseilles Cedex 05, France. E-mail: pniccoli-sire{at}ap-hm.fr
Abstract
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.
MEN TYPE 2 (MEN 2) is an autosomal dominant inherited multiglandular syndrome with age-related penetrance and variable expressivity. Its three variants have been identified: MEN 2A (60% of MEN 2) associates medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism; MEN 2B (5% of MEN 2) associates MTC, pheochromocytoma, marfanoid habitus, and ganglioneuromatosis of the intestinal tract; and familial MTC only (FMTC; 35% of MEN 2) occurs in families in the absence of the other manifestations of MEN 2.
The protooncogene RET comprises 21 exons and encodes a receptor tyrosine kinase. It is the susceptibility gene for MEN 2. Germline RET mutations are observed in 95% of MEN 2B, 98% of MEN 2A, and 88% of FMTC kindreds (1, 2, 3, 4, 5). Previous reports have established that the nature and position of the RET mutations correlate to the three MEN 2 phenotypes; MEN 2B is associated in more than 95% of cases with a point mutation in the methionine residue in exon 16 (codon 918) in the intracellular tyrosine kinase domain of RET (6, 7, 8), whereas mutations in exon 15 at codon 883 have been found in only four de novo MEN 2B (9, 10, 11). Recently, infrequent germline missense mutations were reported in MEN 2B de novo cases: in exon 16, at codons 912 and 922 (11A ) and also in exon 14 at codons 804 and 806 from the same allele (12).
Approximately 93–98% of the MEN 2A families have mutations of one of the five conserved cysteine residues in exon 10 (codons 609, 611, 618, and 620) or exon 11 (codon 634) in the extracellular domain of the RET protooncogene. Mutations in cysteine 634 appear strongly associated with the MEN 2A phenotype (1, 3, 5, 7, 8). In-frame germline duplications of 9 and 12 bp in exon 11 were reported in one family and one case of MEN2A, respectively (13, 14), and de novo cases of MEN 2A were associated with two new germline mutations (at both codons 634 and 640) on the same RET allele (15) or at codon 624 (15A ).
Until recently the FMTC phenotype was related in 80–96% of cases to RET mutations located in exon 10 (mainly at codons 620 and 618) and in exon 11 (codon 634) (1, 7, 8). There are also three reports of germline RET missense mutation occurring in exon 11: at codon 630 in one FMTC family and in three unrelated patients, or at codon 631 (16, 17, 18). Germline mutations also occur in the intracellular domain of RET in FMTC: in exon 13 (codons 768, 790, and 791), in exon 14 (codon 804 and 844), and in exon 15 (codon 891) (17, 18, 19, 20, 21, 22, 23). Recently, a 9-bp duplication in exon 8 was described in one FMTC kindred (24). However, only a few number of families bearing the RET mutation within exons 13, 14, and 15 have been described to date. Note that mutations in exon 13 (codons 790 and 791) (21) and mutations in exon 14 at codon 804 (11A ), both until recently associated with the FMTC phenotype, are also found in MEN 2A.
The aim of our study was to analyze the clinical, biochemical, and histopathological features of 148 patients (both the index cases and the gene carriers from each family) from 74 independent families with FMTC phenotype collected through the French Calcitonin Tumors Study Group (GETC). In this work we attempted to establish the relationship between RET mutations and disease phenotype and to gain insight into the phenotype of FMTC patients with the infrequent mutations within RET exons 13, 14, or 15.
Subjects and Methods
Our study was based on data extracted from the GETC database, which is authorized by the French national ethical committee. For all patients included in the French database, informed consent was obtained for all diagnostic and therapeutic procedures and for including the familial history. It included 148 patients (96 females and 52 males) belonging to 47 independent FMTC kindreds whose RET mutation had been identified. Among them, we first analyzed only the 40 index cases in whom complete data were available; they were 32 females and 8 males, aged 18–77 yr (mean age, 46.1 yr), and all presented the FMTC phenotype, as no pheochromocytoma or hyperparathyroidism was detected at the time of diagnosis. We then analyzed the 108 patients (64 females and 44 males), aged 4–78 yr (mean age, 34.6 yr), identified as gene carriers through familial screening and identification of the familial RET mutation. All patients underwent physical examination and measurement of basal calcitonin (CT) level. Preoperative pentagastrin (Pg)-stimulated CT test was performed in 15 of 40 index cases and in all FMTC gene carriers.
FMTC phenotype was assessed on the basis of familial history of MTC in some families and on both the presence of RET mutation and the absence of the other features of MEN 2 for all patients included. All of them were annually screened for the presence of pheochromocytoma and hyperparathyroidism through biochemical tests, including measurement of urinary 24-h or plasma metanephrines, serum calcium, and PTH.
We studied the phenotype-genotype relationship in all FMTC patients who underwent thyroidectomy by considering independently index cases and gene carriers. For statistical evaluation to be reliable, we compared the clinical and histopathological features of the patients with RET mutation in exon 10 to those of patients with either RET mutation in exons 13, 14, or 15 or in the sole exon 14 for which the number of patients was sufficient to be statistically evaluated.
DNA analysis
All patients had germline protooncogene RET analysis. Before 1993, kindreds were studied by linkage analysis and were confirmed by direct RET sequence analysis thereafter. Since 1993, RET analysis has been performed by direct sequence analysis. Genomic DNA was extracted from peripheral blood leukocytes by standard procedures, then specific exons were PCR amplified, and products were directly sequenced on both strands using RET-specific oligonucleotides as primers. The search for RET mutations was systematically performed in exons 10, 11, 13, 14, 15, and 16. Each mutation was systematically checked in a second blood sampling.
CT assay
Before 1987, an RIA was used. Since 1987, we have used an immunometric assay (Elsa-hCT, Cis-BioInternational, Gif sur Yvette, France) specific for the mature CT monomere, with no cross-reaction with pro-CT. The functional sensitivity was 2 pg/ml. The intra- and interassay coefficients of variation were 6.7% and 7.9%, respectively, for values between 30–100 pg/ml. A basal CT value of 10 pg/ml was considered normal according to the data of the GETC (25).
Only CT values measured with this immunometric assay were considered reliable to be used in accessing the surgical outcome (potentially cured: basal and Pg-stimulated CT <10 pg/ml; not cured: high basal CT or Pg-stimulated peak >10 pg/ml). Only CT values measured with this immunometric assay were used to establish the relationship between preoperative basal or Pg-stimulated CT values and the histopathological findings; this was the case for 68 of 86 thyroidectomized gene carriers who had both pre- and postoperative CT measured with this same immunometric assay.
Pg stimulation test
An iv injection (0.5 µg/kg) of Pg (Peptavlon, Zeneca Pharmaceuticals, Cergy, France) was given for 3 min. Blood samples were collected before and 3, 5, and 10 min after the initiation of Pg injection. The CT response was expressed as the maximal CT peak after initiation of the Pg injection and was considered normal (i.e. negative Pg test) when it was less than 10 pg/ml with reference to previous data from the GETC (25).
Surgical procedures
All FMTC index cases had undergone total thyroidectomy. Cervical lymph node surgery was performed in 33 of 40 patients (82.5%).
Among the 108 FMTC gene carriers, 86 underwent early total thyroidectomy, 84 on the basis of either abnormal basal CT or Pg testing, whereas 5 had normal Pg test and were referred to surgery on the basis of genetic diagnosis alone. It was associated with nodal dissection in 73 patients (84.8%).
Surgery was postponed for various reasons in 22 of the 108 gene carriers (11 females and 11 males, aged 4–86 yr; mean age, 30.1 yr); 18 had RET mutation within exons 13, 14, or 15, and 4 had RET mutation in exon 10. Among these 22 gene carriers, 18 had normal basal or Pg-stimulated CT level (<10 pg/ml) and are still being followed, with annual clinical and biochemical monitoring. Four patients had abnormal basal CT levels (600, 38, 52, and 45 pg/ml, respectively): 3 of them will be referred to surgery in the coming months, and surgery was refused in 1 case.
Histopathological examination
The surgical thyroid specimens were examined by a standard histopathological technique. Search for C cell hyperplasia (CCH) or microscopic MTC loci was conducted by immunochemistry with an anti-CT polyclonal antibody (CT-205, Immunotech, Marseilles, France). Multifocality was defined as the presence of multiple microscopic MTC foci in a same lobe. CCH was defined as either a C cell density of more than 50 C cells/cm2 (magnification, x40) or microscopic foci containing more than 6–10 C cells/field (magnification, x40) (26).
Follow-up
A basal CT or Pg test measured by the immunometric assay was performed postoperatively and serially to detect recurrent MTC and was available for 37 of 40 index cases and 81 of 86 thyroidectomized gene carriers.
Considering patients with RET mutation in exon 10 and those with mutation in exon 13, 14, or 15, the mean length of follow-up of index cases was 6.1 yr (range, 6 months to 21 yr) and 3.5 yr (range, 6 months to 14 yr), respectively; for gene carriers, it was 7.1 yr (range, 6 months to 18 yr) and 2.5 yr (range, 3 months to 13 yr), respectively. All patients are screened annually to detect both pheochromocytoma and hyperparathyroidism.
Statistical analysis
Statistical evaluation included t, Pearson
2, or Fisher’s exact test as appropriate.
Results are expressed as the mean ± SD.
P < 0.05 was considered significant.
Results
Among the 47 FMTC kindreds analyzed, 19 (40%) had RET mutation in
exon 10, 15 (32%) in exon 14, 6 (13%) in exon 13, and 7 (15%) in
exon 15. Details on genotype are reported in Table 1
.
|
Mean age at MTC diagnosis did not differ statistically between the two
groups of patients (Table 2), but if we
only consider index cases with RET mutation in exon 14, MTC was
diagnosed at a significantly older age than for those with RET mutation
in exon 10 (54.4 vs. 41.8 yr; P = 0.02;
Table 2).
|
We found no difference in size, bilaterality, presence of CCH, or
frequency of nodal metastases between the patients (Table 2
) or in
preoperative basal or Pg-stimulated CT levels (data not shown). Only
the presence of multifocal microscopic MTC appeared significantly
associated with RET mutation in exons 13, 14, and 15 (P
= 0.02) and particularly with RET mutation in exon 14
(P = 0.01). We found a significantly higher incidence
of distant metastases in index cases with mutation in exon 10 than in
those with mutation in exon 13, 14, or 15 (P = 0.04;
Table 2).
Among the 37 of 40 index cases who had a CT determination during the follow-up, of the 14 with RET mutation in exon 10, 2 had normalized basal CT (with normal Pg test in one case), and 12 (85.7%) did not normalize CT postoperatively.
Of the 23 index cases with RET mutation in exon 13, 14, or 15, 13 (56.5%) had normal basal CT (among them 7 were considered potentially cured because basal and Pg-stimulated CT levels were <10 pg/ml), and 10 (43.4%) patients have not been surgically cured to date.
Of the 86 FMTC gene carriers referred to surgery, 17 and 69 had RET
mutation in exons 10 or in exon 13, 14, or 15, respectively (Table 3). Gene carriers with RET mutations in
exon 10 were referred to surgery at a significantly earlier age (22.5
vs. 38.1 yr) than patients with noncysteine RET mutations on
the basis of abnormal basal or Pg-stimulated CT.
|
.
Among FMTC gene carriers, the preoperative basal and Pg-stimulated CT
values were useful in predicting the extent of disease and surgical
outcome. We thus have considered the 68 of 86 thyroidectomized gene
carriers with both preoperative and postoperative CT data available and
measured by the same immunometric assay. Of the 5 patients who had a
negative preoperative Pg test, 3 had CCH, 1 had normal thyroid, and 1
had a microscopic MTC (2 mm). Of the 30 gene carriers with normal basal
CT and high Pg-stimulated CT (mean CT peak, 81 ± 110 pg/ml;
range, 10–480 pg/ml), 22 had microscopic MTC (<10 mm), and 8 had CCH.
None had nodal metastases (Table 4). Of
the 33 gene carriers with a high preoperative basal CT (mean, 637
± 1,748 pg/ml; range, 12–10,000 pg/ml), only 1 had CCH, 17 had
microscopic MTC, and 15 had tumors larger than 10 mm. Fifteen of these
patients had nodal metastases (Table 4). We found that the occurrence
of isolated CCH, MTC, and nodal metastases was statistically different
between the gene carriers with only a preoperative abnormal Pg test and
those with preoperative high basal CT (Table 4).
|
). Thirty-seven (54.4%) had normal
postoperative Pg tests; among them were 4 of the 5 gene carriers with
normal preoperative Pg tests, whereas 22 of 37 (59.4%) had abnormal
preoperative Pg tests with normal basal CT (mean CT peak, 51 ± 33
pg/ml; range, 11–118 pg/ml), and 11 of 37 (29.7%) had high
preoperative basal CT (mean, 107 ± 106 pg/ml; range, 13–277
pg/ml; Fig. 1). We found a significant relationship between the
surgical outcome and the preoperative CT values. A preoperative high
basal CT level was associated with the persistence of high basal CT or
Pg-stimulated CT peak after surgery (P < 0.001).
Furthermore, postoperative normalization of both basal and stimulated
CT (potential cure) was significantly higher in gene carriers with only
an abnormal preoperative Pg test than in those with high preoperative
basal CT (P < 0.001). Concerning the 16 gene carriers
(23.5%) with normal postoperative CT and no Pg test available, the
lack of postoperative Pg testing does not allow us to make conclusions
about the surgical outcome.
|
Discussion
The dataset provided by the GETC represents the largest series of FMTC kindreds and patients harboring RET mutation in exons 13, 14, or 15 reported to date. It thus allowed us to gain new insights into the phenotype of patients with these mutations.
To date, the FMTC phenotype has been mainly related to RET cysteine mutation (1, 3, 7, 8), and only a few cases have been associated with noncysteine RET mutations within exon 13, 14, or 15 (17, 18, 19, 20, 21, 22, 23). In the past 2 yr the frequency of detection of these RET mutations has increased; they are found in 59.6% of our FMTC kindreds and hence are not so infrequent as was thought. Furthermore, the detection rate of RET mutations associated with FMTC in the GETC database increased from 86% in 1997 to 92.5% today. This increase is mainly due to detection of these noncysteine RET mutations and may be explained 1) by the routine screening of RET mutations that we perform in all patients with MTC, even in presumed sporadic forms; and 2) by the procedure recommended by the GETC, that is, to include exons 13, 14, and 15 in routine RET analysis.
We found that 43.4% of FMTC index cases with noncysteine RET mutations presented with multinodular goiter associated with high basal CT and a mean age consistent with that classically found in sporadic MTC. Several studies reported that only 5–25% of the patients with presumed sporadic MTC have germline RET mutation detected through routine screening (17, 21, 28, 29). Indeed, in most of these reports RET mutations were screened only in exons 10 and 11. When the search for mutations was extended to other RET exons, some rare mutations in exons 13–15 were observed (17, 18, 19, 20, 21, 22, 23). When routinely performed in apparently sporadic MTC (21) in exons 10, 11, and 13, exon 13 mutations were found to represent one third of the germline RET mutations identified, in agreement with our findings. As noncysteine RET mutations seem overrepresented in presumed sporadic MTC, we suggest that RET analysis should routinely be extended to exons 13, 14, and 15 in all patients with MTC to improve the detection rate of new FMTC index cases. A cost-effective strategy would start with a search for RET mutations in exons 10, 11, and 16 and, if this is negative, proceed to exons 13, 14, and 15. An alternative strategy would be to extend DNA analysis to the 6 exons of RET, only in the patients selected on the basis of histological criteria such as bilateral or multifocal MTC or CCH associated with MTC. Indeed, we observed that multifocal MTC is significantly associated with noncysteine RET mutations, whereas CCH and bilaterality are related to familial disease whatever the genotype. Of course, the benefit of identifying the familial form of MTC is undisputed, as it offers the possibility to detect early stage C cell disease and perform early or prophylactic thyroidectomy in gene carriers (25, 30, 31, 32, 33, 34).
This large series of FMTC kindreds with noncysteine RET mutations allowed us to establish phenotype-genotype relations for comparison with those observed in patients with the RET mutation in exon 10. We show that FMTC index cases with RET mutation in exon 14 had a significantly older age at MTC diagnosis than did those with RET mutation in exon 10 and globally that index cases with noncysteine mutations tended to be older at diagnosis than did the latter. Our data are consistent with previous case reports showing a late onset of the disease for mutations both in exon 13, where 56% of the patients developed the first signs of the disease between 30–50 yr of age (21), and in exon 14 where the index cases of two unrelated families are 70 and 75 yr old (22). Note that the mean age of onset in the FMTC index cases with RET mutation in exon 14, i.e. 54.4 yr, overlaps the mean age classically reported in sporadic MTC, and that, in turn, would explain why mutations within exon 14 are preferentially found in apparently sporadic MTC.
It was reported that patients with RET mutation in exons 13 and 14 exhibit a mild C cell disease phenotype (21, 22). Data about exon 15 are inconclusive; in the sole family reported to date, the 48-yr-old index case had bilateral microscopic MTC and CCH, whereas three gene carriers had normal Pg tests (23). Such mild phenotype was supported by in vitro studies in which mutants expressing E768, V804, and S891 RET mutations had both weaker growth-transforming activity and oncogenic activation (30, 36) compared with mutations at codons 634, 918, and 883, which are strongly associated with MEN 2A and 2B, respectively. Our results differ from previous data, as we observed no significant difference in the stage of C cell disease (CCH, bilaterality, size of MTC, nodal metastases) in index cases harboring these noncysteine RET mutations compared with that in cases with RET mutation in exon 10. However, we found a lower frequency of distant metastases in the former: this apparently lesser aggressiveness of the disease must be taken with caution because the follow-up in patients with RET mutations in exons 13, 14, and 15 was shorter than in those with mutation in exon 10. Furthermore, the appearance of distant metastases cannot be ruled out for the future on account of the 10 index cases with noncysteine RET mutations operated on at a late stage of disease who remain not surgically cured. Furthermore, we 2 index patients with mutation in exon 13 died due to distant metastases. These data show that the phenotype of MTC in patients with mutations in exon 13, 14, or 15 is not as mild as was suggested.
We found that 26% of index cases with noncysteine RET mutations, at a mean age of 55.2 yr, had CCH associated with uni- or multifocal microscopic MTC. That may be explained by a delayed appearance of C cell disease rather than a less aggressive disease. According to in vitro data, C cell disease should develop at a slow rate due to a weak oncogenic effect, which may be modulated by environmental or genetic background. This delayed appearance of C cell disease should have been responsible for considering RET mutations in exon 13, 14, or 15 to be related to a mild phenotype (19, 21). It should also explain why some of these FMTC cases were detected only through MTC screening by routine CT measurement in thyroid disease at a mean age consistent with presumed sporadic forms.
Several retrospective studies (25, 31, 32, 33, 34, 37), have shown the early occurrence of C cell disease in MEN 2, which appears in most cases before the other features, hyperparathyroidism and pheochromocytoma (38, 39). Recently, a prospective study in MEN 2 gene carriers showed that MTC is the lesion that appears earliest and that pheochromocytoma develops later through the evolution of the disease (40). To date, we failed to detect pheochromocytoma or hyperparathyroidism in any of our kindreds. No other features of MEN 2 were found in reported families with mutations in exon 15, in agreement with our experience, even over three generations for one of our families. On the contrary, mutations within exons 13 and 14 have been related to MEN 2A (15A, 21), and this was the case for two families from the GETC database (data not shown). By considering the delayed appearance of C cell disease in these noncysteine mutations, it might be considered that the other features of MEN 2 may be delayed also. This points out the following question: must the existence of FMTC phenotype be revisited? For the moment, we suggest that the other manifestations of MEN 2 be sought also in noncysteine mutations, initially and through follow-up.
Diagnosis of familial forms of MTC allows the detection and early management of gene carriers, which, in turn, improves the prognosis associated with FMTC and MEN 2 (25, 32, 33, 34, 37). Early or prophylactic surgery is undisputed once gene carrier status is established. For MEN 2B, for which the course of disease is worse, surgery is required as early as at 1 yr of age (41); for MEN 2A/FMTC gene carriers, surgery is proposed either as early as 4–6 yr of age (33, 34) or as soon as Pg-stimulated CT rises above 10 pg/ml whatever the age (25). For gene carriers with noncysteine RET mutations, the moment for surgery remains to be determined. On the one hand, the appearance of disease is delayed: more than 20% of gene carriers had only CCH or no C cell disease at a mean age of 38.2 yr, and 44.1% of those not operated on still have a negative Pg test, suggesting the absence of biochemically detectable C cell disease. On the other hand, delaying thyroidectomy too long leads to patients being referred to surgery with relatively advanced C cell disease that is unable to be cured; in our series, all gene carriers not cured exhibited high preoperative basal CT level, which was significantly associated with a late stage disease, i.e. macroscopic MTC and nodal involvement; furthermore, we showed that the chance of postoperative cure was significantly related to the preoperative CT values, which is in accordance with the significant relationship previously shown between tumor size and preoperative CT level (42). Consequently, to give them the best chance of cure, these gene carriers must be referred to surgery before an increase in basal CT and at least as soon as Pg test becomes abnormal.
However, as it is the case for the other genotypes in MEN 2A (32, 33, 34, 37), the optimal management of the disease remains controversial in these gene carriers. Prophylactic thyroidectomy may also be proposed on the basis of genetic diagnosis alone. It remains to determine the best age to propose thyroidectomy with the least morbidity by taking into account the delayed appearance of C cell disease.
In conclusion, FMTC kindreds with RET mutations in exon 13, 14, or 15 are more frequent and are overrepresented in patients with a presumed sporadic MTC. We thus suggest that extension of RET analysis to exons 13, 14, and 15 should become a routine procedure for DNA testing in all patients with MTC, especially in the presence of multifocal, bilateral MTC associated with CCH. The phenotype of these FMTC patients is characterized by an age at diagnosis that overlaps the mean age classically reported in sporadic MTC, and it is not as mild as was previously thought, suggesting a delayed appearance of C cell disease rather than a less aggressive disease. Taking into account these data, the moment for thyroidectomy in these FMTC gene carriers remains difficult to determine, but surgery needs to be performed before basal CT increases and at least as soon as the Pg test becomes abnormal to give the best chance of cure.
Acknowledgments
We thank all the physicians of the GETC for contributing patients or histopathological examination of thyroid specimens. We also thank the surgeons of each center who participated in the GETC database for surgical management of the patients included in this study.
Footnotes
Abbreviations: CCH, C Cell hyperplasia; CT, calcitonin; FMTC, familial medullary thyroid carcinoma only; GETC, French Calcitonin Tumors Study Group; MEN 2, MEN type 2; MTC, medullary thyroid carcinoma; Pg, pentagastrin.
Received April 21, 2000.
Accepted April 18, 2001.
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