Total thyroidectomy for occult familial medullary carcinoma of the thyroid in children

Experience with 17 children in one kindred with familial medullary carcinoma of the thyroid and pheochromocytoma has demonstrated the utility and validity of periodic provocative testing by calcium infusion or pentagastrin injection in the identification of children with early medullary carcinoma of the thyroid or its premalignant precursor, C-cell hyperplasia. In these 17 patients with two consecutive elevations of calcitonin levels greater than 0.55 ng/ml after stimulation all but one have had MTC or CCH at operation. Total thyroidectomy has been well tolerated and can be performed with an acceptably low incidence of complications in this group of patients.     

Surgical Strategy in a Kindred with a Rare RET Protooncogene Mutation of Variable Penetrance with Regard to Multiple Endocrine Neoplasia

Prophylactic thyroidectomy is recommended for carriers of RET protooncogene mutations owing to their nearly complete penetrance for medullary thyroid carcinoma (MTC). However, this guideline is challenged by mutations exhibiting variable penetrance of C-cell pathology. A 38-year-old woman presented with pathologic basal and pentagastrin-stimulated calcitonin levels. Genetic analysis revealed a heterozygous RET protooncogene germline mutation in codon 791 (exon 13) (TAT(Tyr)-->TTT(Phe)), followed by thyroidectomy and systematic central lymph node dissection. Histology showed C-cell hyperplasia (CCH) only. Three additional carriers were identified among family members. The 71-year-old father refused surgery despite pathologic calcitonin levels. The index patient's 37-year-old sister had normal basal and stimulated calcitonin levels, and her 6-year-old son had a 10-fold rise of calcitonin after pentagastrin stimulation. Both patients underwent the same operation as the index patient. The sister had 25 hyperplastic C-cells, but the her son had extensive CCH without MTC. The eldest uncle of the index patient had died of metastatic MTC at the age of 52 with unknown carrier status. Despite variable penetrance, each carrier of a RET protooncogene germline mutation should undergo thyroidectomy, even if basal and stimulated calcitonin levels are normal because at present no test can exclude or predict the age of development of MTC. Moreover, pathologic calcitonin levels cannot differentiate between CCH and MTC. Central lymph node dissection is recommended, as lymph node metastases occur early, significantly worsening the prognosis.     

Presurgical assessment of the tumor burden of familial medullary thyroid carcinoma by calcitonin testing

BACKGROUND: Early diagnosis of familial medullary thyroid carcinoma (MTC) is currently done by genetic analysis. These techniques have replaced calcitonin stimulation testing, which was previously used for this purpose. Some studies suggest a relationship between MTC spread and calcitonin levels. The aim of this study was to assess whether the tumor burden of MTC associated with multiple endocrine neoplasia type 2A (MEN 2A) syndrome can be estimated from the plasma calcitonin values before surgery. STUDY DESIGN: We retrospectively studied the relationship of basal and peak calcitonin values before thyroidectomy with histopathologic findings in 53 patients with MEN 2A syndrome from 14 families. The MTC was classified according to TNM staging. Analysis of variance was used for statistical analysis complemented with equality contrasts for pairs of means by the least significant difference method with a Student's t-test and with the Bonferroni's adjustment. RESULTS: A positive association was found between tumor stage and basal and peak calcitonin levels. There were significant differences between the following: mean basal concentrations of patients with C cell hyperplasia (CCH) (34.3 pg/mL) and TNM stage II (1,097.4 pg/mL), p < 0.01; CCH and TNM stage III (2,940.8 pg/mL), p < 0.001; TNM stage I (165.3 pg/mL) and stage II (1,097.4 pg/mL), p < 0.01, and between TNM stages I and III, p < 0.001. Poststimulation mean concentrations were different between CCH (48.7 pg/mL) and TNM I (514.2 pg/mL), p < 0.001. CONCLUSIONS: Preoperative calcitonin testing may be useful for assessing tumor spread and should be considered when deciding the extent of surgery for MEN 2A MTC.     

Thyroid Venous Catheterization in the Early Diagnosis of Familial Medullary Thyroid Carcinoma

In kindreds with familial medullary thyroid carcinoma (MTC), individuals are often detected whose peripheral plasma calcitonin (CT) levels are undetectable in the basal state but increase minimally following provocative testing. The proper management of such patients has been uncertain, but most investigators have advocated repeat testing and evaluation after an interval of several months. The present study was conducted to evaluate the diagnostic implications of these modest increases in plasma calcitonin. In 25 kindred members at direct risk for familial medullary thyroid carcinoma (MTC), basal peripheral plasma calcitonin (CT) levels were less than 240 pg/ml. Following provocative testing with intravenous calcium or pentagastrin or both, calcitonin values remained below 240 pg/ml in eight subjects (Group A), however, they were mildly elevated (260-580 pg/ml) in 12 subjects (Group B) and moderately elevated (700-940 pg/ml) in five subjects (Group C). Following the transfemoral placement of a catheter into the inferior thyroid vein (ITV), provocative testing was repeated, and ITV and peripheral blood samples were collected simultaneously. Basal ITV plasma CT levels were below 240 pg/ml in all patients in Group A, however, they were mildly elevated (500 pg/ml) in one of the 12 patients in Group B and moderately elevated (800 pg/ml, 1400 pg/ml) in two of the five patients in Group C. Following provocation, ITV plasma CT levels became markedly elevated in one patient in Group A and in all of the patients in Groups B(2520±635 pg/ml) and C (6322±2598 pg/ml). Thyroidectomy was performed in patients whose ITV plasma CT level was elevated following provocative testing. Medullary thyroid carcinoma of C-cell hyperplasia were evident either on microscopic (1/1 patient in Group A;9/12 patients in Group B; and 2/5 patients in Group C), or gross (3/12 patients in Group B;3/5 patients in Group C) examination of thyroidectomy specimens. In only one of 14 patients was metastatic MTC noted on histologic examination of resected cervical lymph nodes. Postoperative peripheral plasma CT levels were unchanged from basal and less than 240 pg/ml following provocative testing in all but one patient. The present study then provides definitive evidence that patients at direct risk for familial MTC who have even minimally abnormal responses in peripheral plasma CT following provocative testing generally harbor some stage of a C-cell proliferative disorder. Identification of such individuals with early disease is important because thyroidectomy offers an extremely high cure rate.     

Medullary thyroid carcinoma in Northern Ireland, 1967-1997

BACKGROUND: The experience of managing medullary thyroid carcinoma (MTC) in a specialist endocrine surgery unit was reviewed. METHODS: The case records of 38 patients (19 male, 19 female) treated over a 30 year period were studied. RESULTS: There were 23 (60.5%) patients with sporadic MTC while the remainder had familial MTC--12 multiple endocrine neoplasia (MEN) type 2A, two MEN type 2B, one non-MEN familial medullary thyroid carcinoma (FMTC). Sporadic MTC patients were significantly older at presentation (median 56 years, interquartile range 41.5-61.3 years) compared to MEN 2A patients (median 26 years interquartile range 17.5-34 years) and had more advanced stage of disease. Survival of MTC patients was significantly worse in sporadic disease than in those with MEN 2A (P < 0.0001). All familial cases had bilateral multifocal tumour whereas in sporadic patients only unilateral disease was seen. The availability of genetic testing now allows early identification of affected members of familial MTC kindreds. This has led to total thyroidectomy being performed on the basis of positive genetic screening alone in three patients (two MEN 2A, one FMTC), in all of whom widespread C-cell hyperplasia and microscopic multifocal invasive MTC were identified histologically. CONCLUSIONS: The management of MTC has changed during the study period with total thyroidectomy recommended as the primary procedure of choice for all patients. In the familial setting, positive genetic testing now allows thyroidectomy to be performed at an early pre-clinical stage, with the hope of permanent cure.     

Medullary thyroid carcinoma. The need for early diagnosis and total thyroidectomy

Forty patients with medullary thyroid carcinoma and 3 patients with C-cell hyperplasia were studied. Seventeen (40%) cases were sporadic and 26 (60%) were hereditary. Eight patients had type lla multiple endocrine neoplasia, 7 patients had type llb multiple endocrine neoplasia, and 11 patients had familial nonmultiple endocrine neoplasia medullary thyroid carcinoma. Mean follow-up was 6.3 years, with actuarial survival of 88% and 78% at 5 and 10 years (22 and 13 patients), respectively. Seven patients died 1.5 to 10 years after the initial operation; all had advanced disease at presentation (6 with distant, 1 with lymph node metastasis). No deaths occurred in patients with familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, C-cell hyperplasia, or medullary thyroid carcinoma limited to the thyroid gland. Nineteen (68%) of 28 patients diagnosed without screening had regional or distant metastases, whereas only 6 (40%) of 15 patients diagnosed by screening had metastases. Twenty-six patients treated initially with total thyroidectomy and central neck clearance required an average of one reoperation, whereas those with lesser initial procedures required an average of two reoperations. We concluded that (1) familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, early medullary thyroid carcinoma or C-cell hyperplasia, and asymptomatic patients have a good prognosis; (2) screening for medullary thyroid carcinoma by measuring serum calcitonin levels results in earlier diagnosis; and (3) total thyroidectomy and central neck clearance is the procedure of choice for medullary thyroid carcinoma.     

When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations?

BACKGROUND: Once familial medullary thyroid carcinoma gene carrier status is established, thyroidectomy must be performed in infancy for mutations in exon 10, but in familial medullary thyroid carcinoma with non-cysteine RET mutations, which is characterized by a late onset of C-cell disease, the appropriate timing of thyroidectomy is unclear. METHODS: We analyzed the cases of 76 patients who underwent thyroidectomy (mean age, 35.2 years); 66 patients underwent concomitant lymphadenectomy. RESULTS: Before the operation, 35 patients had abnormal basal calcitonin levels. Nine and 30 patients had negative or positive pentagastrin test results, respectively. We found normal thyroid in 4% of the patients, C-cell hyperplasia in 29% of the patients, medullary thyroid carcinoma in 67% of the patients (microscopic in 82.4%), and nodal metastases in 19.6% of the patients. The aggressiveness of the disease varied significantly between those patients with preoperative positive pentagastrin test results and those patients with high basal calcitonin levels, with a surgical cure rate of 60% and 34.3%, respectively. All patient who did not achieve cure had high basal preoperative calcitonin levels, which were related to macroscopic medullary thyroid carcinoma and nodal metastases in 5 of 9 patients. CONCLUSION: Thyroidectomy should not be delayed until basal calcitonin level becomes abnormal, at which time advanced disease may be present. As soon as the pentagastrin stimulation test becomes abnormal, operation should be undertaken on early staged disease to achieve cure for the patient. When performed while pentagastrin stimulation test is still negative, thyroidectomy may be truly prophylactic and should be recommended at 5 to 6 years.     

Early thyroidectomy for medullary thyroid carcinoma in children and young adults with the multiple endocrine neoplasia type 2A (MEN 2A) syndrome.

A South African family, at risk for the multiple endocrine neoplasia type 2A (MEN 2A) syndrome, was identified. The Bloemfontein MEN Study Group was founded, inter alia, to study the effects of early detection of medullary carcinoma of the thyroid (MTC) and treatment by total thyroidectomy in children and young adults with MEN 2A. Genotypes were identified by DNA probe and MTC diagnosed by basal and stimulated calcitonin levels. Between 1986 and 1989, 10 members of the family underwent total thyroidectomy and central lymph node dissection for MTC. There were 6 female and 4 male patients (mean age 22,0 years; range 10 - 35 years). Histological examination of the resected thyroid revealed MTC in all patients; 8 had bilateral disease and 2 unilateral. Lymph nodes were negative for MTC in all patients. None of the patients suffered injury to the recurrent nerve, while 1 experienced transient hypoparathyroidism postoperatively. Replacement therapy is maintaining thyroid hormone levels in all patients. Screening should probably begin at the age of 1 year, and total thyroidectomy should be performed when an elevated calcitonin level is observed.     

Emergence of medullary thyroid carcinoma in a family with the Cys630Arg RET germline mutation

BACKGROUND: Individual germline mutations in the RET (REarranged during Transfection) proto-oncogene may set the time window for malignant progression from C-cell hyperplasia to familial medullary thyroid carcinoma. Owing to the close genotype-phenotype correlation, genetic information may lend to individual timing of prophylactic thyroidectomy according to RET genotype. Limited information exists on the Cys630 RET genotype. Most of the few published carriers of this genotype who developed medullary thyroid carcinomas (MTCs) were in their mid-30s. METHODS: This case series of a German RET family with the Cys630Arg genotype was assembled to study malignant progression of MTC in this rare RET genotype. RESULTS: There was considerable variability of malignant progression from C-cell hyperplasia to MTC in carriers of the Cys630Arg genotype. In these persons, MTCs had developed by the age of 32 years (index patient, pT2bN0M0), and 15 years and 1 year (non-index patients; pT1apN1bM0 and pT1bpN0M0, respectively). The Cys630Arg genotype always segregated with the familial medullary thyroid carcinoma phenotype. CONCLUSIONS: The Cys630 RET genotype may have a more vigorous transforming activity than currently thought and can cause MTC in RET gene carriers within the first year of life. Starting in early infancy, identified RET gene carriers should be scrutinized until stimulated serum calcitonin levels become positive or, when these remain normal, should undergo prophylactic thyroidectomy before they reach 5 years of age.     

Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients

BACKGROUND: The surgical management and follow-up strategy in patients with medullary thyroid carcinoma (MTC) remain controversial because of the lack of data on the natural history of these tumors and their patterns of progression. METHODS: We reviewed the records of all patients who underwent a cervical operation for MTC between 1991 and 2002. Compartment-oriented surgery (COS) was performed to minimize the risk of cervical recurrence. RESULTS: We identified 92 consecutive patients who underwent a cervical operation for MTC: 80 had invasive MTC, and 12 had C-cell hyperplasia after prophylactic thyroidectomy for familial MTC. Ten (13%) of the 80 patients with invasive MTC presented with distant metastases and underwent COS to achieve local-regional control; cervical recurrence developed in none, but three have died of MTC. The remaining 70 patients underwent COS for primary (n=23) or recurrent (n=47) MTC. Disease recurred in 18 (26%) of these 70 patients at a median follow-up of 35 months, with 10 (14%) of the recurrences being cervical. Recurrent disease was associated with a basal calcitonin level of >250 pg/mL in all but four patients, two of whom showed tumor dedifferentiation. In contrast, only 5 (11%) patients without evidence of recurrence had basal calcitonin levels of >250 pg/mL at last follow-up. CONCLUSIONS: Complete COS minimizes cervical recurrence. Radiographic evidence of recurrent disease is unlikely when the calcitonin level is < or =250 pg/mL. These data could be used to develop a logical, cost-effective treatment and follow-up strategy for patients with MTC.     

Can Sporadic Medullary Thyroid Carcinoma Be Biochemically Predicted? Prospective Analysis of 66 Operated Patients with Elevated Serum Calcitonin Levels

Measuring serum calcitonin (CT) in patients with thyroid diseases allows preoperative diagnoses of sporadic medullary thyroid carcinoma (MTC) and C-cell hyperplasia (CCH). The aim of this prospective study was to distinguish biochemically between CCH and MTC. Basal CT (bCT) was determined in 7276 consecutive patients referred for thyroid disease. Patients with recurrent, persistent, or familial MTC were excluded. When bCT was > 10 pg/ml a pentagastrin-stimulated CT (sCT) assay was performed. Patients were routinely operated on when bCT > 30 pg/ml or sCT > 100 pg/ml or when other indications for surgery were present. An extensive search for CCH or microscopic MTC was conducted by immunochemistry. Pathologic findings were correlated with the bCT and sCT values. In this study 66 patients were included. No morphologic alterations of C-cells were observed in 5 patients; 16 patients presented with CCH and 45 with MTC. Statistical analysis revealed a correlation of sCT and overall bCT with tumor size and staging (p <0.001). Considering cutoff values for bCT of ≤ 30 pg/ml and for sCT of ≤ 200 pg/ml, the positive predictive value of the test to detect MTC was 100% and the negative predictive value 63%. No patients with MTC at stage 2 to 4 had bCT <30 pg/ml or sCT <200 pg/ml. A bCT value of ≤ 30 pg/ml or sCT ≤ 200 pg/ml (or both) is highly predictive of MTC, requiring total thyroidectomy with lymph node dissection. Values of bCT <30 pg/ml and sCT <200 pg/ml do not distinguish between CCH and MTC at stage 1. In this case total thyroidectomy at least is recommended, and the role of nodal dissection might be discussed.     

Importance of Early Screening and Prophylactic Thyroidectomy in Asymptomatic Nonindex RET Germline Carriers

Genetic testing for RET germline mutations affords rapid identification of germline carriers, offering the prospect of cure before C-cell hyperplasia (CCH) has progressed to medullary thyroid carcinoma (MTC). Although nonindex RET mutation carriers have a better prognosis than do the index patients, it remains to be ascertained whether age represents a risk factor for MTC when screening patients. The current institutional study (October 1994 through June 1999) was set up to compare asymptomatic nonindex patients who were grouped by age: < 20 years and ≥ 20 years. Inclusion criteria were confirmed RET mutations in the germline, with no MTC being more advanced than pT1pN1M0. Adult patients (≥ 20 years) had MTC significantly more often (84% vs. 43%), significantly larger tumors (5 mm vs. 3 mm), and significantly higher basal calcitonin levels preoperatively (78.0 vs. 9.7 pg/ml) than their pediatric/adolescent counterparts (< 20 years). There was a close correlation between pT1 MTC and an elevated basal serum calcitonin level (r= 0.67; Spearman's rho). All three patients with lymph node metastases from MTC had elevated basal calcitonin levels. The two groups did not differ in terms of multifocality of MTC (pT1b), lymph node involvement (pN1) or bilateral lymph node metastasis (pN1b), or preoperative stimulated and postoperative basal and stimulated serum calcitonin. Prophylactic thyroidectomy should not be postponed beyond the age of 20, and it should be performed before basal serum calcitonin has turned positive. Pathologic conversion of stimulated serum calcitonin obviously marks the time in carriers of RET germline mutations when surgery should be scheduled at the latest to be prophylactic.     

甲状腺髓样癌临床诊疗方案分析

目的:探讨影响甲状腺髓样癌（medullary thyroid carcinoma,MTC）治疗方案制订与转归的关键要素。方法:回顾性分析2007年4月至2020年3月湖南省人民医院乳甲外科收治的23例MTC患者病例资料、典型病例的临床特点及生存随访结果,结合ATA等指南对MTC治疗方案和转归进行分析。结果:23例MT...     

The calcitonin levels can sometimes mislead parathyroid surgeons in patients with chronic kidney disease and renal hyperparathyroidism: report of a case

Renal hyperparathyroidism (rHPT) as a consequence of an abnormal calcium balance is a frequent complication in patients with chronic kidney disease (CKD). However, calcium homeostasis is also regulated by calcitonin. The relevance of elevated calcitonin levels in patients with rHPT is unclear. This report presents a case of a patient with CKD and mild rHPT scheduled for thyroidectomy for a suspected medullary thyroid carcinoma (MTC) within a mononodular goiter. A hemithyroidectomy with resection of both adjacent parathyroid glands and unilateral central lymph node dissection was performed. Histopathology revealed no evidence of MTC. The rHPT, calcitonin and pentagastrin test subsequently normalized and follow-up revealed no evidence for MTC within the remaining right thyroid lobe. Elevated calcitonin levels in patients with CKD may reflect a physiological response to rHPT than rather represent MTC. The thresholds for calcitonin levels need to be better defined in affected patients to determine the optimal extent of surgical resection.     

Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas.

BACKGROUND: This study evaluated the outcome of total thyroidectomy and modified radical neck dissection in primary treatment of patients with medullary thyroid carcinoma (MTC). METHODS: Thirty-six patients with sporadic (n = 16) and hereditary (n = 20) MTC underwent thyroidectomy and systematic central and lateral lymph node dissection (unilateral, 23; bilateral, 13) between 1994 and 2000. Postoperative serum calcitonin levels were correlated with immediate or delayed surgery, tumor categories, and lymph node metastases. RESULTS: Sixteen of 36 (44%) patients with clinically evident MTC treated with central and lateral neck dissection exhibited normal basal and stimulated calcitonin levels at a median follow-up of 3.7 years. Lymph node involvement was detected in 75% of these patients and correlated with the TNM stages. Biochemical cure was achieved according to the T categories in 83% of the patients in stage T1, 42% in stage T2, and none of the patients in stage T4 (P = .011). Basal and stimulated calcitonin levels were found to be normal in 89% of the patients without lymph node involvement and in 30% of the patients with lymph node metastases (P = .005). CONCLUSIONS: Screening for MTC and primary treatment with total thyroidectomy and modified radical neck dissection are essential for biochemical cure of MTC.     

Surgical strategy for the treatment of medullary thyroid carcinoma

OBJECTIVE: To evaluate surgical complications, patterns of lymph node metastases, and calcitonin response to compartment-oriented lymphadenectomy in patients with primary or recurrent medullary thyroid carcinoma (MTC). SUMMARY BACKGROUND DATA: The majority of patients with invasive MTC have metastasis to regional lymph nodes at the time of diagnosis, as evidenced by the frequent finding of persistently elevated calcitonin levels after thyroidectomy and the high rates of recurrence in the cervical lymph nodes reported in retrospective studies. These data have provided the rationale for surgeons to perform a more extensive lymphadenectomy at the time of initial thyroidectomy and to consider reoperative cervical lymphadenectomy in patients with persistently elevated calcitonin levels after thyroidectomy. METHODS: Forty patients underwent surgery for MTC from 1991 to 1997 (23 sporadic cases, 17 familial cases). Patients were divided into three groups based on whether they had undergone previous thyroidectomy and on the results of standardized staging studies performed after referral to the authors' institution. Group 1 (11 patients) had received no previous surgery; group 2 (13) underwent thyroidectomy before referral and had an elevated calcitonin level without radiologic evidence of local regional or distant metastases; and group 3 (16) underwent thyroidectomy before referral and had an elevated calcitonin level with radiologic evidence of local-regional recurrence. The central neck compartment was dissected in all patients; preoperative staging and the extent of previous surgery dictated the need for lateral (modified radical) neck dissection. After primary or reoperative surgery, calcitonin levels were assessed. RESULTS: All patients had major reductions in postoperative calcitonin levels. Seven (29%) of 24 patients in groups 1 and 2 achieved normal calcitonin values compared with only 1 (6%) of 16 in group 3. Postoperative complications included seven cases (17%) of permanent hypoparathyroidism; five (71%) of these occurred in group 3. There were no iatrogenic recurrent laryngeal nerve injuries; one patient required recurrent nerve resection to achieve complete tumor extirpation. At a median follow up of 35 months, local recurrence was documented in 5 (13%) of 40 patients. CONCLUSIONS: Compartment-oriented lymphadenectomy performed early in the course of MTC is safe and may return calcitonin levels to normal in up to 25% of carefully selected patients. However, reoperation for bulky cervical disease (group 3) rarely results in normal calcitonin levels and is associated with a high incidence of permanent hypoparathyroidism.     

Useful and limits of the biochemical markers for the diagnosis of thyroid carcinoma

A series of biochemical parameters are useful for the diagnosis and follow-up of differentiated thyroid carcinomas. The measurement of serum thyroglobulin (Tg) is considered for the post-surgical/radioiodine follow-up of papillary/follicular carcinomas. Other than in basal conditions, the importance of Tg levels during TSH stimulation is underlined, either by discontinuation of L-T4 therapy or by recombinant human TSH test. The finding of undetectable Tg levels during TSH stimulation is highly correlated with clinical remission; otherwise, peak Tg levels > 1-2 ng/ml can be suggestive of recurrence/persistence of the disease. The accuracy of Tg measurements for the detection of metastases seems to be higher when compared to 131-1 whole-body scan. The evaluation of basal serum calcitonin levels is recommended for the screening of medullary thyroid carcinoma (MTC). High basal levels suggest the presence of a tumor but a calcitonin increase can be observed also in parafollicular C cell hyperplasia (CCH) and other extra-thyroidal conditions. The pentagastrin test can by pass this obstacle as the calcitonin response seems to be typical of pathological thyroid C cells. The cut-off value of calcitonin response between patients with MTC and CCH remains to be established; the latter condition, however, being considered by some authors as pre-cancerous. After thyroid surgery the measurement of calcitonin constitutes a valid tool for the detection of cure and/or recurrence of the disease. The screening by means of RET oncogene analysis is also described for patients with MTC with Multiple Endocrine Neoplasia (MEN) type 2 syndrome.     

Reoperation of medullary thyroid carcinoma: long-term results]

STUDY AIM: The impact of iterative surgery in medullary thyroid carcinoma is still debated. The study aim was to evaluate long-term results following reoperation for residual or recurrent medullary thyroid carcinoma. PATIENTS AND METHOD: Among the 136 patients operated on in our centre for medullary thyroid carcinoma (MTC) between 1970 and 2000, 25 patients (10 men and 15 women) were reoperated on for locoregional residual or recurrent lesions. Their mean age was 46 years (range: 19-73 years). The MTC was sporadic in 21 patients and familial in 4: NEM 2A (n = 3), NEM 2B (n = 1). In 11 patients (44%) operated in another centre, the first procedure was a total thyroidectomy; in 2 patients (8%) a total thyroidectomy with central lymphadenectomy was performed, and in 12 patients (48%) a total thyroidectomy with central and jugulo-carotid lymphadenectomy. After the first operation, 6 patients (24%) were classified stage II, 15 (60%) stage III and 4 (16%) stage IV. Basal and post-stimulation calcitonin dosages were performed for all the patients before and after reoperation. RESULTS: Thirty three reoperations were performed. In 24 cases, the recurrence was located in the laterocervical site; in 5 cases, the lymph node involvement was both central and laterocervical, in 2 cases, there was a mediastinal involvement and in 2 cases a spinal involvement. After reoperation, the calcitonin rate became normal in 4 patients (16%); in the other 21 (84%), the calcitonin rate was still high. With a mean 110 month--follow-up (range: 320-12 months), 4 patients (16%) were alive without disease, 2 (8%) died of their disease, 19 (76%) were alive with their disease, five of them with hypercalcitonemia without detectable metastasis. In addition to patients having metastasis at the time of reoperation, seven developed metastases secondarily (liver, bone, lung). CONCLUSION: Biological cure of medullary thyroid carcinoma is rarely obtained with reoperation. Reoperations may reduce progression of the disease in selected patients. Complete removal of the lesions at the time of the first procedure must be the ideal treatment for medullary thyroid carcinoma.     

RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease

BACKGROUND: RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene. METHODS: Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients. RESULTS: A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2. CONCLUSIONS: This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.     

Medullary Carcinoma of the Thyroid Gland

Medullary thyroid carcinoma (MTC) is an uncommon thyroid tumor that has attracted a great deal of interest because of its frequent presentation as a familial tumor and its primary involvement in the type II multiple endocrine neoplasia (MEN) syndromes MEN-IIA and MEN-IIB and familial medullary thyroid carcinoma (FMTC). The MTC tumor cells secrete the polypeptide hormone calcitonin, which serves as an excellent tumor marker, useful for defining the presence of disease, preoperatively or following thyroidectomy. The discovery that mutations in the RET proto-oncogene are associated with MEN-II syndromes was highly significant in that it demonstrated a clear correlation between genotype and phenotype; and most importantly it provided a mechanism whereby family members at risk could be identified by direct DNA analysis. Virtually all patients with MEN-IIA, MEN-IIB, and FMTC develop MTC; therefore there is a clear rationale for performing thyroidectomy as soon as a RET mutation has been identified. Because MTC appears to be much more aggressive in patients with MEN-IIB, thyroidectomy is performed during the first year of life in this setting, whereas in patients with MEN-IIA, where the tumor appears to be more indolent, the procedure can be safety delayed until age 5 years. Reoperative neck exploration in patients with evidence of persistent or recurrent MTC has been effective in a significant number of patients, although the success of the operation requires careful patient selection and preoperative assessment. MTC, as expressed in the MEN-II syndromes, is an excellent model to evaluate the usefulness of interventional therapy in patients demonstrated to have a genetic predisposition for cancer.