Molecular Genetics of Thyroid Tumors and Surgical Decision-making

The study of thyroid tumor genetics has great relevance to surgeons and facilitates understanding tumor pathogenesis, prediction of tumor behavior, and management decisions. The genes implicated can be broadly categorized as oncogenes or tumor-suppressor genes. The RET oncogene has well established roles in the development of both papillary (PTC) and medullary (MTC) thyroid carcinoma. Genetic screening for germline RET mutations in members of multiple endocrine neoplasia type II (MEN-II) families is now widely performed, and prophylactic thyroidectomy in gene carriers is advisable at an early age. Patients with apparently sporadic MTC can also be screened to rule out familial disease. The demonstration of a RET rearrangement in a patient's PTC may have prognostic significance, but as yet there are no management implications. The thyrotropin receptor (TSH-R) and Gsα become oncogenic through point mutation and are associated with the development of toxic thyroid adenomas. The ras oncogene is implicated in the early stages of development of several thyroid tumor types. Tumor-suppressor genes also have a role in thyroid tumor formation. The p53 gene appears to be involved in the process of transformation to the anaplastic phenotype and the PTEN gene in the development of follicular adenomas but not carcinomas. There is still limited evidence for the so called adenoma–carcinoma sequence of the thyroid follicular cell. Loss of heterozygosity studies have enabled identification of tumor-suppressor genes, and their findings suggests differences in the pathogenesis of PTCs compared with follicular cancers. Surgical decision-making will benefit from these basic molecular advances, which rapidly translates into improved patient management.     

Prophylactic thyroidectomy in children at risk for medullary thyroid carcinoma

The medullary thyroid carcinoma (MTC) is a rare neoplasia occurring during childhood. At present time the molecular examination of the proto-oncogen RET, related to syndromes of multiple endocrine neoplasia (MEN II) and familial medullary thyroid carcinoma (FMTC) to allows identify patients with risk of suffering of medullary thyroid carcinoma in early ages, before the disease becomes clinically pronunced. Children with familial antecedents of MEN II or FMTC were biochemically (pentagastrin-stimulated) and genetically studied with the purpose of determining the risk of developing a MTC and in order to assess the possibilities of making a prophylactic thyroidectomy.     

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.     

Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma (FMTC) are autosomal dominantly inherited cancer syndromes that predispose to C-cell hyperplasia and MTC. MEN 2A and FMTC are caused by mutations in the RET proto-oncogene. METHODS: We used a multiplex polymerase chain reaction-based assay to screen exons 10, 11, 13, and 14 of RET for mutations in 2 families with FMTC. We correlated mutation status with calcitonin and pathologic studies to determine genotype-phenotype correlations. RESULTS: We identified a mutation in codon 804 in exon 14 (GTG-->ATG; V804M) in both families. An 86-year-old person who was a gene carrier and other individuals over age 70 who were suspected by pedigree analysis to be gene carriers had no overt clinical evidence of MTC. Four of 21 patients who underwent a thyroidectomy also had papillary thyroid cancer. One individual in each family had metastatic MTC at age 30 and 32 years, and all 26 people having thyroidectomies had either MTC or C-cell hyperplasia, leading us to continue to recommend prophylactic thyroidectomy for all identified patients who were gene carriers. CONCLUSIONS: Because of active MTC in younger members of these families, including metastases, we have continued to advocate thyroid surgery in mutation-positive individuals. While DNA diagnosis of gene carriers and subsequent genetic counseling was relatively straightforward, the acceptance of surgical recommendations was more difficult for some individuals. These families demonstrate that the search for RET mutations should include exons 13, 14, 15, and 16 in patients whose studies in exons 10 and 11 are negative.     

Prophylactic thyroidectomy in multiple endocrine neoplasia: the impact of molecular mechanisms of<Emphasis Type="Italic"> RET</Emphasis> proto-oncogene

BACKGROUND: Multiple endocrine neoplasia (MEN) type 2, a cancer syndrome inherited in the dominant fashion, is defined by the occurrence of medullary thyroid carcinoma (MTC), either as a singular lesion (familial medullary thyroid carcinoma, FMTC) or with the variable expression of pheochromocytoma, hyperparathyroidism (MEN 2A), ganglioneuromas, buccal neuromas and Marfanoid-like phenotype (MEN 2B). DISCUSSION: Germline mutations of the RET proto-oncogene, localized on chromosome 10q11.2, have been identified as the underlying genetic cause of the disorder. In the majority of patients with MEN 2A/FMTC missense mutations at exon 10 or exon 11 are identifiable. Cysteine to arginine exchange at codon 634 is the mutation most frequently found. In MEN 2B approximately 95% of patients present with a mutation at codon 918 (exon 16). Additionally, less frequent mutations in other codons have been found in both syndromes. The DNA-based genotype analysis enables the identification of gene carriers at risk of developing MTC and offer them prophylactic thyroidectomy prior to development of any thyroid pathologies. Prophylactic surgery is generally recommended for MEN 2A/FMTC gene carriers at the age of 4-6 years. Due to the aggressiveness of the MEN 2B syndrome gene carriers should be operated by the age of 1 year. Presumably some less virulent mutations allow postponement of the prophylactic treatment to the second to fourth decade of life. CONCLUSIONS: Compared to standard presymptomatic biochemical screening, genetic testing and consecutive prophylactic treatment contribute to better outcome of individuals at risk for MTC.     

Unilateral Surgery Supported by Germline RET Oncogene Mutation Analysis in Patients with Sporadic Medullary Thyroid Carcinoma

Compared to hereditary medullary thyroid carcinoma (MTC), sporadic MTC tends to be unicentric and confined to one lobe. Patients with sporadic MTC usually undergo total thyroidectomy because of a possible hereditary or bilateral process. We evaluated the usefulness of germline RET oncogene mutation analysis in surgery for apparently sporadic MTC and performed unilateral surgery on patients without detectable mutation. In 36 patients with a preoperative diagnosis of apparently sporadic MTC, we performed germline RET oncogene mutation analyses: before surgery in 8 recent patients and after surgery in 28 who had been treated before 1996. Of the latter, 5 had bilateral MTC. DNA samples were extracted from their peripheral blood, and the polymerase chain reaction products of the RET proto-oncogene were analyzed using single-strand conformation polymorphism analysis and the direct sequencing methods. Before 1996 we often performed total thyroidectomy but changed to hemithyroidectomy thereafter, except in one patient with associated Graves' ophthalmopathy. Our minimal standard practice included systematic central and ipsilateral neck dissection. The outcome was assessed in terms of gastrin- and calcium-stimulated plasma calcitonin levels. Germline RET mutations were found in six patients. Five of these patients had bilateral MTC, whereas all 30 patients without mutation had unilateral disease. Hemithyroidectomy in seven of our recent patients resulted in normalization of plasma calcitonin levels in all, although four were found to have microscopic lymph node involvement. In conclusion, hemithyroidectomy with systematic central and ipsilateral neck dissection is an appropriate procedure for patients with sporadic MTC without detectable germline RET mutations.     

Prophylactic Thyroidectomy in 75 Children and Adolescents with Hereditary Medullary Thyroid Carcinoma: German and Austrian Experience

RET proto-oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i.e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age ≤ 20 years, (3) clinically asymptomatic thyroid C cell disease; and (4) TNM classification pT0–1/pNX/pN0–1/M0. Seventy-five patients were identified, and fifteen mutations were detected in six codons. Two adolescents had unilateral pheochromocytomas as part of the multiple endocrine neoplasia II (MEN-II) syndrome. No hyperparathyroidism was noted. All patients underwent total thyroidectomy, and 57 patients went on to have lymph node dissection. Parathyroid glands were removed in 34 patients and autografted in 11. Histopathology revealed MTC in 46 patients (61%, youngest 4 years); C cell hyperplasia (CCH) only was detected in the other 29 patients. Three patients had lymph node metastases (LNMs) the youngest being age 14 years. Calcitonin levels were not useful for differentiating between CCH and MTC, but in all patients with LNMs at least the stimulated calcitonin levels were assayed. After surgery, five patients (6.7%) sustained permanent hypoparathyroidism, and one patient (1.3%) had a permanent unilateral recurrent nerve palsy. All but three patients (96%) were biochemically cured. In conclusion, prophylactic total thyroidectomy can be performed safely in experienced centers. We recommend prophylactic total thyroidectomy at age 6. Cervicocentral lymph node dissection should be included when calcitonin levels are elevated or if patients are older than 10 years. Bilateral lymph node dissection should be performed if LNMs are suspected or when patients with elevated calcitonin are older than 15 years.     

Medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is subdivided into sporadic (75 %) and hereditary (25 %) forms. Several germline mutations in the RET proto-oncogene are the source of distinct clinical phenotypes in hereditary MTC including familial MTC (FMTC) and multiple endocrine neoplasia 2A (MEN 2A) and 2B (MEN 2B). The higher the penetrance of the MEN 2 phenotype the earlier the progression of MTC which forms the basis for the currently recommended codon-related concept of prophylactic thyroidectomy. In patients with sporadic MTC, routine calcitonin (CT) measurement in nodular goiter patients has been shown to reduce the frequency of advanced tumor stages. Patients with CT levels over 100 pg/ml after pentagastrin stimulation are recommended for total thyroidectomy. In patients with unexpected sporadic MTC after histological examination, completion thyroidectomy is currently only recommended when CT levels remain elevated. The extent of lymph node dissection in patients with MTC is controversial. However, with respect to lymphonodal micrometastases, systematic compartment-oriented microdissection has been shown to reduce the frequency of lymphonodal recurrence. On the other hand, to avoid unnecessary lymph node dissection, a more individualized concept is required in the future. New chemotherapeutic agents (tyrosine kinase inhibitors), therapeutic nuclids (90Yttrium-labeled octreotide), and chemoembolization of liver metastases are currently the most promising therapeutical concepts in patients with distant metastases.     

家族性甲状腺髓样癌诊断与治疗

家族性甲状腺髓样癌（FMTC）作为甲状腺髓样癌（MTC）的一个重要分型，恶性程度较高，具有早期侵犯区域淋巴结和远处转移的倾向，预后相对较差，且有发病率不断增高的趋势。近年来关于FMTC临床的诊断和治疗进展较多，血清降钙素水平检测、基因检测等诊断方法提供了更精准的术前评估与复发监测的手段；疾病早期，根治性手术治疗仍占FMTC治疗的主要地位。根据基因检测的结果，进行预防性甲状腺切除以及分子靶向治疗也得到了快速的发展和应用，使传统手术与新兴治疗方法相结合，进一步提高了FMTC的治疗效果。     

Treatment of familial medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy, which is familial in 25-29% of cases. Familial MTC is due to germ-line mutations in the RET proto-oncogene. It can occur either alone or as the thyroid manifestation of MEN 2 syndromes; the disease is inherited in an autosomal dominant fashion with age-related penetrance. The treatment of choice is surgery. Early diagnosis and an adeguate initial operation provide the best chance of cure. Hence, the diagnosis should be made preoperatively. Genetic testing can identify almost all affected individuals with hereditary disease and permits prophylactic/early thyroidectomy in gene carriers. Total thyroidectomy and lymphadenectomy of the cervicocentral compartment is mandatory in all patients. In addition, bilateral dissection of the cervicolateral compartment should be done in all cases with more than microscopic disease. Plasma calcitonin is an excellent marker for postoperative follow-up. Treatment of persistent/recurrent disease is primarily surgical. Hence, a reoperative cervical lymphadenectomy should be considered in patients with persistently elevated calcitonin levels and no signs of distant metastases. Chemotherapy and external radiotherapy have little impact on the course of avanced disease; more promising is metabolic radiotherapy with Y90-DOTATOC in patients with somatostatin receptor-positive tumours.     

家族性甲状腺髓样癌诊断与治疗

家族性甲状腺髓样癌（FMTC）作为甲状腺髓样癌（MTC）的一个重要分型,恶性程度较高,具有早期侵犯区域淋巴结和远处转移的倾向,预后相对较差,且有发病率不断增高的趋势。近年来关于FMTC临床的诊断和治疗进展较多,血清降钙素水平检测、基因检测等诊断方法提供了更精准的术前评估与复发监测的手段;疾病早期,根治性手术治疗仍占FMTC治疗的主要地位。根据基因检测的结果,进行预防性甲状腺切除以及分子靶向治疗也得到了快速的发展和应用,使传统手术与新兴治疗方法相结合,进一步提高了FMTC的治疗效果。     

When Is Prophylactic Thyroidectomy Indicated for Patients with the RET Codon 609 Mutation?

Background  Mutations in the RET proto-oncogene cause multiple endocrine neoplasia type 2A (MEN2A), and prophylactic thyroidectomy has generally been recommended before the age of 5 years. Patients with codon 609 mutations develop MTC at a later age and therefore the timing of prophylactic thyroidectomy is less clear. We report a three-generation family with C609Y RET mutation where members having prophylactic or therapeutic thyroidectomy call the current recommendations for age at thyroidectomy into question. Methods  Sixteen family members underwent thyroidectomy, for which clinical, laboratory, and pathological data were analyzed. A literature review of RET codon 609 mutations was carried out. Results  Data were collected from 16 patients from this 38-member kindred. None of these affected members had pheochromocytoma, and one had a parathyroid adenoma. Nine of 16 patients had MTC (mean age 44.7 years, range 29–59 years) and elevated basal calcitonin levels; 6 of these 9 had lymph node metastases. Two patients had C-cell hyperplasia (CCH) at ages 18 and 37 years, and five patients had normal thyroid pathology (mean age 16 years, range 5–37 years). In the literature, a family with C609Y mutation was reported, with 15 members having MTC (mean age 42 years, range 21–59 years), and 6 with CCH (mean age 24 years, range 15–37 years). Conclusion  The youngest patient with C609Y RET mutation and MTC was 21 years old, and the youngest patient with CCH was 15 years old at diagnosis. These data suggest that patients with RET C609Y mutations can delay thyroidectomy until 10–15 years of age, with annual calcitonin screening prior to thyroidectomy.     

Alternative Surgical Strategies and Favorable Outcomes in Patients with Medullary Thyroid Carcinoma in Japan: Experience of a Single Institution

Background  Medullary thyroid carcinoma (MTC) accounts only for 1.4% of all thyroid malignancies in Japan. Since 1996, we have performed hemithyroidectomy, instead of total thyroidectomy, for sporadic nonhereditary MTC when the primary lesion is located in only one lobe. Regarding lymph node dissection, modified radical neck dissection (MND) at least ipsilateral to the tumor has been routinely performed, even if there is no clinically apparent metastasis. We investigated the clinical outcomes of MTC patients in our department. Methods  A series of 118 patients with MTC who underwent initial surgery between 1975 and 2005 were enrolled in this study. The RET gene mutations were analyzed for all patients and 46 had germline RET gene mutations. Of those 46 patients, 26 were diagnosed as MEN 2A and 2 were diagnosed as MEN 2B. Postoperative follow-up periods averaged 141 months. Results  Of 115 patients who did not have distant metastasis at surgery and who underwent locally curative surgery, 78 (67.8%) were biochemically cured. All patients without pathological lymph node metastasis were biochemically cured, and 44.8% of patients with node metastasis were also biochemically cured. The 10-year and 20-year disease-free survival rates were 89.0% and 82.5%, respectively. None of the patients who did not show lymph node metastasis and only 2 (2.6%) of 78 patients who were biochemically cured showed clinically apparent carcinoma recurrence. The 10-year and 20-year cause-specific survival rates were 96.6% and 91.7%, respectively. Lymph node metastasis, tumor size >4 cm, extrathyroid and extranodal tumor extensions significantly affected cause-specific survival of patients. Conclusions  Clinical outcomes of MTC patients in our series were better than those in Western countries, a result that might have resulted in part because of our routine MND regardless of whether clinically apparent node metastasis was detected.     

Familial nonmultiple endocrine neoplasia medullary thyroid carcinoma: an evolving clinical entity.

BACKGROUND. A rare kindred of familial nonmultiple endocrine neoplasia medullary thyroid carcinoma arising from a 73-year-old proband case is reported to further define this distinct entity. METHODS. Twenty-four family members across four generations, four with medullary thyroid carcinoma (MTC) and two with C-cell hyperplasia (CCH), were studied. RESULTS. Basal calcitonin levels were elevated in three patients with MTC and were normal in one patient with microscopic MTC and two patients with CCH who had persistent subtle elevation in calcium and/or pentagastrin-stimulated calcitonin levels. One patient had unilateral MTC without CCH. Associated abnormalities included papillary carcinoma (2), thyroiditis (4), adenoma (2), and colloid nodule (1). Minimum treatment was total thyroidectomy. Two patients with MTC and marked hypercalcitonemia have recurrent disease at 2.5-year and 11-year follow-up. Two patients with MTC and normal or minor elevations in basal calcitonin and two with CCH had normal provocative calcitonin testing at 6 to 18 months follow-up. CONCLUSIONS. Unilateral MTC without CCH and MTC in the elderly do not preclude a familial cause. Microscopic MTC or CCH may be seen with subtle elevations in stimulated calcitonin levels, and recognition allows for curative thyroidectomy. Other apparent dominant thyroid pathologic conditions may occur concomitantly with familial medullary thyroid carcinoma and thus routine calcitonin, and immunohistochemical testing should be performed in patients with an appropriate family history.     

A novel Czech kindred with familial medullary thyroid carcinoma and Hirschsprung's disease

Purpose

The RET proto-oncogene is involved in neural crest disorders. Activating germline mutations in the RET proto-oncogene cause the development of familial medullary thyroid carcinoma (FMTC) or medullary thyroid carcinoma (MTC) as a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. Inactivating germline mutations in the RET proto-oncogene are detected in Hirschsprung's disease (HSCR). Only in a very small number of families are these 2 diseases expressed together.

Methods

This study presents a novel Czech kindred with FMTC-HSCR phenotype. Two family members (mother and daughter) were tested for RET germline mutations in exons 10, 11, 13, 14, 15, and 16.

Results

Direct fluorescent sequencing of genomic DNA revealed a heterozygous mutation in the RET proto-oncogene in exon 10 at codon C609Y in both persons tested. This family was reclassified, thanks to genetic screening from the apparently sporadic MTC-HSCR to FMTC-HSCR.

Conclusion

The germline mutation was detected because of the systematic genetic screening of the RET proto-oncogene, which is useful for genetic counseling of potential risk of HSCR and MTC in other family members. This family could be added to the small worldwide cohort of families with MEN2A/FMTC-HSCR.     

Medullary thyroid carcinoma in a 2-month-old male with multiple endocrine neoplasia 2B and symptoms of pseudo-Hirschsprung disease: a case report

A 5-week-old male patient was seen for symptoms suggestive of Hirschsprung disease (abdominal distension, failure to thrive, and explosive defecation). Rectum biopsies revealed an intestinal ganglioneuromatosis, which is usually associated with multiple endocrine neoplasia (MEN) syndrome type 2B. The ensuing molecular genetic analysis revealed a M918T mutation of the RET protooncogene, which is associated with early-onset medullary thyroid carcinoma (MTC). Therefore, total thyroidectomy and central lymphadenectomy were performed at the age of 9 weeks. Histology showed a medullary microcarcinoma.This report of MTC occurrence within the first weeks of life underlines the importance of early diagnosis and thyroidectomy in patients with MEN 2B syndrome. Because many patients with MEN 2A and B show gastrointestinal symptoms before the development of MTC, the possibility of MEN 2 should be recognized, and genetic testing for the presence of RET mutations should be included in the explorative diagnosis for megacolon.     

Genetic screening in hereditary medullary thyroid carcinoma

Summary Background: Medullary thyroid carcinoma (MTC) is sporadic in the great majority of cases but is the sine qua non of multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominantly inherited cancer syndrome. Depending on the tissues affected, MEN 2 is divided into 3 subtypes. MEN 2A is characterized by the presence of MTC, pheochromocytoma and hyperparathyroidism. MEN 2B is characterized by MTC, pheochromocytoma and typical stigmata. FMTC comprises MTC as the only disease feature. Germline mutations in theRET protooncogene, which encodes a receptor tyrosine kinase, have been shown to cause all 3 subtypes of MEN 2. Methods: Analyses utilize PCR-based protocols targeted at exons 10, 11, 13, 14 and 16: target exonic sequences are amplified either for direct sequencing and/or restriction endonuclease digestion where mutations would create or cause loss of specific sites. Results: Mutations in one of codons 609, 611, 618, 620 (exon 10) and 634 (exon 11) are associated with MEN 2A while mutation in codon 916 (codon 16) causes MEN 2B. Recently mutations in codons 768 and 804 were shown to be associated with FMTC only. Conclusions: These findings have made accurate DNA-based genetic testing possible, thus targettingRET mutation positive individuals for prophylactic surgery and/or surveillance while mutation negative individuals can be reassured.      

Excellent Prognosis of Patients with Nonhereditary Medullary Thyroid Carcinoma with Ultrasonographic Findings of Follicular Tumor or Benign Nodule

Background  Medullary thyroid carcinoma (MTC) accounts for only 1.4% of all thyroid malignancies in Japan. Generally, MTC shows ultrasonographic findings typical of thyroid carcinoma. However, in our experience, some MTC may be diagnosed as a follicular tumor or a benign nodule on ultrasonography because ultrasonographic findings of malignancy are lacking. In this study we investigated differences in biological behavior between these two types of MTC. Methods  Seventy-seven patients with nonhereditary MTC who underwent surgery in our department between 1988 and 2007 were enrolled in this study. Of these patients, 54 were diagnosed as having thyroid carcinoma (malignant, or M-type) but the remaining 23 were diagnosed as having follicular tumor or benign nodule (benign, or B-type) on ultrasonography. Results  Clinically apparent lateral node metastasis, extrathyroid extension, and extranodal tumor extension were observed in 37%, 17%, and 11% of M-type patients, respectively, but none of the B-type patients showed any of these features. All B-type patients but only 59% of M-type patients were biochemically cured. Lymph node metastasis was pathologically confirmed in 38 and 65% of B-type and M-type patients, respectively. Eight patients showed recurrence and three have died of carcinoma to date; all of these patients were M-type patients. Conclusions  B-type MTC is highly indolent and shows an excellent prognosis. However, thyroidectomy and lymph node dissection for B-type MTC should be the same as for M-type MTC because 38% of B-type MTC showed pathologic node metastasis.     

Factors Predicting Outcome of Total Thyroidectomy in Young Patients with Multiple Endocrine Neoplasia Type 2: A Nationwide Long-Term Follow-up Study

Background  

Multiple endocrine neoplasia type 2 (MEN 2) is caused by a RET mutation in chromosome 10. All MEN 2 patients develop medullary thyroid carcinoma (MTC). The age-related risk of MTC is associated with the type of RET mutation. Our aim was to identify prognostic factors associated with recurrent MTC in MEN 2 patients.     

C-cell cancer – prevention and treatment

Introduction: C-cell cancer of the thyroid or medullary thyroid carcinoma (MTC) exists in a sporadic and a hereditary form, the latter of which is part of the multiple endocrine neoplasia type-2 (MEN-2) syndromes. Discussion: MTC metastasises early to local (lymph nodes) and distant sites (liver, lung, bone). Therefore, early detection is mandatory to enable a chance of cure. In sporadic MTC, the sensitive tumour marker calcitonin enables detection of the disease at an early stage. In hereditary MTC, more than 95% of the patients have germline RET mutations. Thus, MEN-2 has become the paradigm for the practice of molecular medicine, and gene carriers can be identified before MTC even occurs. Surgery is the only chance of cure and recently developed surgical techniques provide the therapeutic prerequisite to achieve calcitonin normalisation in both sporadic and hereditary MTC. Received: 19 November 1998 Accepted: 25 November 1998