Long-term outcome after DNA-based prophylactic neck surgery in children at risk of hereditary medullary thyroid cancer.

Advances in sequencing technology, providing unprecedented insights into cancer progression, have shifted the treatment paradigm towards precision medicine for hereditary medullary thyroid cancer (MTC), away from the 'one-size-fits-all' approach predicated on genetic risk alone. The DNA-based/biochemical concept, factoring serum calcitonin into the benefit-risk equation, optimizes biochemical cure while minimizing extent of prophylactic surgery and operative morbidity in children at risk. The transformative effect that has taking effect on medical practice has been impressive: Increasingly earlier molecular diagnosis and more limited prophylactic neck operations yielded excellent clinical outcomes at expert facilities 7-16 years postoperatively: biochemical cure rates approximating 100%; absence of residual structural disease or recurrence; and rarely any permanent operative morbidity. These excellent results, contingent on proper health care funding and pediatric surgical specialization, make a case for early prophylactic thyroidectomy in experienced hands once calcitonin serum levels exceed the upper normal limit of the assay in young gene carriers.

Cirugía profiláctica en cáncer medular de tiroides hereditario / Prophylactic surgery in hereditary medullary thyroid cancer

Introducción: Se estima que del total de los cánceres, el 5-10% tendría una base genética. Actualmente es posible identificar a los individuos con predisposición genética en algunos cánceres como manera de intervenir precozmente en el desarrollo de esta enfermedad. Objetivos: Evaluar la utilidad de la cirugía profiláctica en el cáncer medular de tiroides hereditario. Material y métodos: Este trabajo es una revisión de literatura de diferentes estudios extraídos de bibliotecas electrónicas como Scientific Electronic Library Online (SciELO), MedLine-PubMed y UpToDate, mediante la construcción de preguntas clínicas y términos MeSH enfocados principalmente en la búsqueda específica de información sobre el cáncer medular de tiroides hereditario. Resultados: Los estudios revisados demuestran que la tiroidectomía profiláctica con resección linfática cervical representa el único tratamiento eficaz en el caso del cáncer medular de tiroides hereditario. Conclusiones: La cirugía profiláctica ha demostrado una importante disminución del riesgo de cáncer de tiroides y se considera una conducta de rigor en portadores del gen RET en el cáncer medular de tiroides.

Introduction: Approximately 5-10% of global cancer has a genetic base. Nowadays it is possible to identify those who have a genetic predisposition for some cancers, so they can be treated in short term. Objectives: Evaluate how useful is prophylactic surgery on hereditary Medullary Thyroid Cancer. Materials and methods: This investigation is a literature review of different research papers from electronic databases such as Scientific Electronic Library Online (SciELO), MedLine-PubMed and UpToDate. The research was made with clinical queries and MeSH terms, specially focused on hereditary Medullary Thyroid Cancer. Results: This research shows that prophylactic Thyroidectomy with cervical lymph node resection is the only effective and curative treatment for hereditary Medullary Thyroid Cancer. Conclusions: Prophylactic surgery has proof an important role decreasing the risk on Hereditary Thyroid cancer Syndrome and in RET carriers surgery is considered a must.

Tiroidectomía profiláctica en mutación del protooncogén RET / Prophylactic thyroidectomy in RET proto-oncogen mutation

Objetivo. Analizar los casos de tiroidectomía profiláctica realizados en nuestro centro en pacientes con mutaciones del gen RET. Material y métodos. Estudio retrospectivo de 25 pacientes con mutación del protooncogén RET a los que se les realizó tiroidectomía profiláctica entre enero del 2000 y enero de 2016. Se estudiaron variables epidemiológicas, técnica quirúrgica, resultados anatomopatológicos y seguimiento. Resultados. Nuestra serie consta de 25 pacientes, 15 varones y 10 mujeres. La mediana de la edad fue de 5 años con un rango de 7 meses a 12 años. Obtuvimos 21 casos con MEN2A de los que 19 (76%) presentaban la mutación 634 y 2 (8%) la mutación 611. Cuatro casos fueron MEN2B, todos con la mutación 918. Los hallazgos microscópicos revelaron microcarcimona, carcinoma in situ o carcinoma medular de tiroides en 16 casos (64%). 8 presentaron hiperplasia (32%) y 1 (4%) fibrosis. La presencia de calcitonina elevada se correlacionó con alteraciones anatomopatológicas en 7 casos (43,7%), pero no mostró diferencias significativas (χ² 0,3; p 0,6). De los 16 pacientes con carcinoma, (13 MEN2A, 3 MEN2B), 10 de ellos (62,5%) tenían 5 años o menos en el momento de la intervención. En todos los casos se realizó tiroidectomía total. No existieron complicaciones intra ni postoperatorias. Durante el seguimiento, los valores de calcitonina, calcio, paratohormona, catecolaminas y metanefrinas se han mantenido normales, excepto en 1 paciente. Conclusiones. El estudio del protooncogén RET permite identificar pacientes susceptibles de realizar tiroidectomía profiláctica, la cual debe ser realizada de forma precoz, y en centros con experiencia (AU)

Objetive. Analysis of prophylactic thyroidectomy cases carried out in our Center in patients with RET gene mutations. Material and methods. Retrospective study of 25 patients with RET proto-oncogene mutations subjected to prophylactic thyroidectomy between January 2000 and January 2016. Epidemiologic variables, surgical technique, histological results and follow-up were studied. Results. Our sample consists of 25 patients, 15 males and 10 females. The range of age was from 7 months to 12 years old, with a median of 5 years old. We obtained 21 cases with NEM2A, from which 19 (76%) presented 634 mutation and 2 (8%) presented 611 mutation. Four cases were NEM2B, all with 918 mutation. Microscopical findings showed microcarcinoma, in situ carcinoma or medullary thyroid carcinoma in 16 patients (64%). Eight of them showed hyperplasia (32%) and 1 presented fibrosis (4%). The presence of elevated calcitonin was correlated with histologic alterations in 7 cases (43.7%), without significant differences (χ2 0.3; p 0.6). From 16 patients with carcinoma (13 NEM2A and 3 NEM2B), 10 were 5 years old or less at the moment of the surgery. A total thyroidectomy was performed in all patients. There were no intra or post-surgical complications. During the follow-up of the patients, levels of calcitonin, calcium, parathormone, catecholamines and metanephrines were normal, except from one case. Conclusions. The study of RET proto-oncogene allows the identification of patients susceptible of performing a prophylactic thyroidectomy, which have to be carried out early, in an experienced centers (AU)

Multifocality in Sporadic Medullary Thyroid Carcinoma: An International Multicenter Study.

BACKGROUND: Current surgical standard of care in sporadic medullary thyroid carcinoma (sMTC) consists of a minimum of total thyroidectomy with central neck dissection. Some have suggested thyroid lobectomy with isthmusectomy and central neck dissection for patients with sMTC, given their lower frequency of bilateral disease, although this topic has not been thoroughly studied. This study assessed the prevalence of multifocality in sMTC via a large international multi-institutional retrospective review to quantify this prevalence, including the impact of geography, to assess more accurately the risks associated with alternative surgical approaches. METHODS: A retrospective chart review of sMTC patients from 11 institutions over 29 years (1983-2011) was undertaken. Data regarding focality, extent of disease, RET germline analysis plus family and clinical history for multiple endocrine neoplasia type 2 (MEN2), and demographic data were collected and analyzed. RESULTS: Patients from four continents and seven countries were included in the sample. Data for 313 patients with documented sMTC were collected. Of these, 81.2% were confirmed with negative RET germline testing, while the remaining 18.8% demonstrated a negative family history and no manifestations of MEN2 syndromes other than MTC. Bilateral disease was identified in 17/306 (5.6%) patients, while multifocal disease was noted in 50/312 (16.0%) sMTC patients. When only accounting for germline negative patients, these rates were not significantly different (5.6% and 17%, respectively). Among them, when disease was unifocal in the ipsilateral lobe and isthmus, bilateral disease was present in 6/212 (2.8%) cases. When disease was multifocal in the ipsilateral lobe or isthmus, then bilateral disease was present in 8/37 (21.6%) cases (p < 0.001). No geographic differences in focality were identified. CONCLUSIONS: The 5.6% prevalence of bilateral foci in sMTC suggests that total thyroidectomy should remain the standard of care for initial surgery, as less complete thyroid surgery may fail to address fully the primary site of disease. Whether ipsilateral tumor focality should be an independent factor determining the need for completion thyroidectomy when sMTC is diagnosed after hemithyroidectomy remains to be determined.

Iodine deficiency and thyroid nodular pathology--epidemiological and cancer characteristics in different populations: Portugal and South Africa.

BACKGROUND: The prevalence and pathology pattern of iodine deficiency (ID) related disorders are influenced by the dietary iodine intake: low iodine leads to thyroid nodular enlargement, to an increase in the incidence of thyroid cancer, an increase in anaplastic carcinomas and to an alteration in the papillary to follicular neoplasia ratio. This study aims at highlighting the effects of ID by comparatively evaluating the pattern of thyroid nodular pathology in different populations that, although geographically distant and heterogeneous, both had iodine deficiency at the time of data gathering and are at high altitude: Beira Interior (BI) in Portugal and Johannesburg (JHB) in South Africa. (S.A.) Mandatory salt iodization introduced in S. A. in 1995 has recently been shown to have resulted in the correction of ID. METHODS: Evaluation of thyroid histology reports over a 6 year period in BI and a 5 year period in the JHB area. RESULTS: Region of BI: 278 patients with histology reports-60 were malignancies (21.2 %): 31 papillary carcinomas, 22 follicular cancers (18 follicular carcinomas and 4 Hürthle cell tumours), 3 medullary carcinomas and 4 anaplastic carcinomas. Region of JHB: 136 histology reports- 33 were malignancies (24.3 %): 13 papillary carcinomas, 15 follicular cancers (10 follicular carcinomas and 5 Hürthle cell tumours), 1 medullary carcinoma, 3 anaplastic carcinomas and 1 metastatic carcinoma into the thyroid. There was an overlap in the frequencies of all histology types, of particular relevance in the relatively high anaplastic carcinoma incidences and in the papillary to follicular carcinoma ratios which was close to 1 in both areas- BI area ratio: 1.4 and JHB area ratio: 0.87, with overlapping 95 % CI's, also confirmed by the results of the chi-square calculations. CONCLUSIONS: During the study periods evaluated both study areas displayed pathology patterns usually found in ID. Public information regarding the negative consequences of ID combined with the availability of affordable iodized salt are likely to achieve the goal of the elimination of ID. Sea based nutrition, (naturally iodine containing), may also contribute to the elimination of ID, particularly at times when salt restriction tends to be generally advised.

Early, Prophylactic Thyroidectomy in Hereditary Medullary Thyroid Carcinoma: A 26-year Monoinstitutional Experience.

PURPOSE: Prophylactic thyroidectomy has been encouraged for children with REarranged during Transfection (RET) germline mutations to prevent the onset, persistence, or recurrence of medullary thyroid carcinoma (MTC). The American Thyroid Association (ATA) recently published guidelines on the timing of prophylactic thyroidectomy. Our aim here was to seek information on the optimal timing of surgery for carriers of RET gene mutations with no clinical evidence of disease, bearing in mind the ATA recommendations. METHODS: From 1986 to 2012, total thyroidectomy was performed at our institute on 31 carriers of RET gene mutations, 28 of them found on family screening in the post-RET era, and the other 3 under 20 years of age and classified as "early cases" in the pre-RET era. The following parameters were studied: age at surgery, MTC risk, basal calcitonin (bCT) and pentagastrin-stimulated calcitonin (sCT), surgery outcomes, and persistence of disease. RESULTS: By family, the most prevalent mutation was codon 634 (30%) RET mutation. The youngest MTC patient was 5 years old. Overall, MTC was found in 68% of cases; 52% of the sample had a normal bCT and 25% had an sCT unresponsive to pentagastrin. The only factor predicting the risk of MTC at final histology was an ATA-RET risk level C. On receiver oparating curves analysis, a cutoff at age over 24 years predicted (P=0.06) a yield of MTC in the resected specimen. Interestingly, none of the patients with MTC had nodal involvement (0/21 patients with MTC). Yet, none of the patients had permanent nerve palsy, and only 1 patient had permanent hypocalcemia. bCT was normal postoperatively and during the follow-up in all but 3 patients. CONCLUSIONS: It is noteworthy that the yield of cancer in removed thyroid was 100% for codon 634 (9/9 patients, 5 families) and for codons 891 and 768 (2/2 patients in each of the 2 families with those codon mutations), followed by 67% for codon 609 (4/6 patients, 1 family), and 60% for codon 618 (3/5 patients in 4 families) RET mutation. In cases of ATA-RET levels B and C, waiting for an increase in bCT and/or sCT may not guarantee that prophylactic surgery is performed before MTC develops (which would assure patients a life free of diseases and a less-invasive surgical procedure, without any need for central lymph-node dissection).

RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.

The rapid technical advances in molecular biology and accelerating improvements in genomic and proteomic diagnostics have led to increasingly personalized strategies for cancer therapy. Such an approach integrates the genomic, proteomic, and molecular information unique to the individual to provide an accurate genetic diagnosis, molecular risk assessment, informed family counseling, therapeutic profiling, and early preventative management that best fits the particular needs of each patient. The discovery of mutations in the RET proto-oncogene resulting in variable onset and severity of multiple endocrine neoplasia type 2 (MEN2) was the first step in developing direct genetic testing for at-risk individuals. Patients with germline RET mutations may undergo risk assessment and appropriate intervention based on specific mutations. Moreover, family members of affected individuals receive counseling based on understanding of the genetic transmission of the disease. Increasingly, clinicians are able to make therapeutic choices guided by an informative biomarker code. Improvements in detection and management of patients with MEN2 resulting from understanding of the RET proto-oncogene are evidence of the benefits of personalized cancer medicine. This review describes the discovery of the RET proto-oncogene, the association between genotype and phenotype, and the role of mutation analysis on diagnosis and treatment of MEN2.

Role of preoperative basal calcitonin levels in the timing of prophylactic thyroidectomy in patients with germline RET mutations.

BACKGROUND: The American Thyroid Association (ATA) published recommendations for the timing of prophylactic surgery for medullary thyroid carcinoma based on the specific mutation, patient age, family history, and serum calcitonin levels. The aim of this study was to assess the role of preoperative basal calcitonin (prebCt) levels in predicting the presence of medullary carcinoma of the thyroid in patients with RET mutations. METHODS: We conducted a retrospective study in two endocrine surgery departments. Between 1986 and 2012, a total of 32 patients with RET mutations underwent prophylactic thyroidectomy. The patients were stratified into four ATA risk levels: A, B, C, and D. RESULTS: All of the patients were biologically cured. Microcarcinoma was observed in the final pathology report for four of the 20 patients with normal prebCt (25 %) and for nine of the 12 patients with elevated prebCt (75 %). In the level A group, four patients with normal prebCt and one patient with elevated prebCt presented with microcarcinoma. In the level C group, one patient with normal prebCt and six of the seven patients with elevated prebCt (86 %) presented with microcarcinoma. CONCLUSIONS: PrebCt can predict the presence of microcarcinoma according to surgical pathological analysis. Patients with microcarcinoma can be biochemically and clinically cured using prophylactic thyroidectomy.

Prophylactic thyroidectomy for MEN 2-related medullary thyroid carcinoma based on predictive testing for RET proto-oncogene mutation and basal serum calcitonin in China.

INTRODUCTION: Early and normative surgery is the only curative method for multiple endocrine neoplasia type 2 (MEN 2)-related medullary thyroid carcinoma (MTC). AIMS: To study the timing of prophylactic total thyroidectomy (TT) for MEN 2-related MTC with different RET mutations in a Chinese population, and to compare the sensitivity and accuracy of fully-automated chemiluminescence immunoassay (FACLIA) and radioimmunoassay (RIA) for serum calcitonin (Ct). METHODS: We collected 24 asymptomatic individuals from 8 unrelated Chinese families with MEN 2, and analyzed RET mutation and Ct levels. Then we performed TT on 17 of the 24 individuals, including TT (2/17), TT with bilateral level VI lymph-node dissection (B-LND(VI); 12/17) and TT with B-LND(VI) + modified unilateral/bilateral/local neck dissection (3/17). RESULTS: Histopathology revealed bilateral/unilateral MTC in 15/17 (88.2%; median diameter, 1.0 cm) and bilateral C-cell hyperplasia in 2/17 (11.8%; p.V292M/R67H/R982C and p.C618Y). Lymph-node metastasis/fibro-adipose tissue invasion (p.C634R) or solely fibro-adipose tissue invasion (p.C634Y) were found in 2/17 (11.8%). Elevated pre-surgical Ct (pre-Ct) was identified by FACLIA in 17/17 (median age, 24.0), while pre-Ct by RIA was found in only 6/15 (P < 0.001). The median follow-up was 22.0 months, during which 16/17 had no abnormality (one p.C634R individual had elevated Ct), and another 7 carriers still had consistently undetectable Ct by FACLIA. CONCLUSIONS: Our study highlights the importance and feasibility of individualized prophylactic TT for MEN 2-related MTC, based on predictive integrated screening of RET and pre-Ct levels. Besides, we recommend FACLIA to measure Ct for earlier diagnosis, treatment and follow-up monitoring of MTC.

Hereditary medullary thyroid cancer: age-appropriate thyroidectomy improves disease-free survival.

BACKGROUND: Twenty-five percent of medullary thyroid cancer (MTC) cases are hereditary. The ideal age for prophylactic thyroidectomy is based on the specific RET mutation involved. The purpose of this study was to determine whether such age-appropriate prophylactic thyroidectomy results in improved disease-free survival. METHODS: Twenty-eight patients underwent thyroidectomy for hereditary MTC at our institution. Age-appropriate thyroidectomy was defined according to the North American Neuroendocrine Tumor Society (NANETS) guidelines. Patients who had age-appropriate surgery (group 1, n = 9) were compared to those who had thyroidectomy past the recommended age (group 2, n = 19). RESULTS: The mean age was 13 ± 2 years, and 61 % were female. Patients in group 1 were younger than in group 2 (4 ± 1 vs. 17 ± 2 years, p < 0.01). There were no significant differences in gender or RET mutation types between these two groups. Group 1 patients were cured with no disease recurrence compared with group 2 patients who had a 42 % recurrence rate (p = 0.05). Subanalysis of group 2 identified that patients who underwent surgery without evidence of disease did so at a shorter period following the guidelines compared with those who underwent therapeutic surgery (2 ± 2 vs. 16 ± 2 years, p = 0.01) and had longer disease-free survival (100 vs. 27 %, p = 0.005). CONCLUSIONS: Patients with hereditary MTC should undergo age-appropriate thyroidectomy based on RET mutational status to avoid recurrence. Patients who are past the recommended age should have surgery as early as possible to improve disease-free survival.

Surgical management of medullary thyroid cancer.

Although thyroid cancer accounts for only 1.5% of all malignancies in the US it is the most rapidly increasing cancer in incidence and it is the most common endocrine malignancy that accounts for over 95% of the endocrine malignancies. Medullary thyroid cancer (MTC) originates from the parafollicular C cells and it represents 6-8% of all thyroid cancer cases. As many as 25% of the MTCs are familial and carry a specific germline mutation as compared to only than 10% familial inheritance in non-medullary thyroid cancers. While well-differentiated thyroid malignancies carry a very good prognosis, recurrence and survival rates of patients with MTC are significantly worse. The difference in cell origin and differentiation also results in different available adjunct therapy. The aim of this study is to review in detail the surgical management of patients with MTC.

Changing clinical characteristics of thyroid carcinoma at a single center from Turkey: before and after the Chernobyl disaster.

AIM: The aim of the study was to determine the possible role of Chernobyl disaster on changing clinical features of thyroid carcinoma (TC) in a moderately iodine deficient region. METHODS: We retrospectively reviewed demographical features, presenting symptoms, tumor size, histopathological diagnosis and distant metastates in 160 patients with TC diagnosed between 1990-2007. We compared our findings with the database of 118 TC patients diagnosed between 1970-1990 in the same center. RESULTS: There were 123 female (76.9%) and 37 (23.1%) male patients with a mean age of 44.89±14.84. Sex distribution and age at diagnosis were similar between 1970-1990 and 1990-2007 (P=0.77 and P=0.42, respectively). Histopathological diagnoses were papillary in 114 (73.1%), follicular in 22 (14.1%), medullary in 9 (5.8%), hurthle cell in 7 (4.5%) and anaplastic TC in 4 (2.6%) patients. We observed a marked increase in papillary TC (P<0.001) and marked decreases in follicular (P<0.001) and anaplastic TC (P=0.01) compared to the period between 1970-1990. Thyroid microcarcinomas accounted for 27.1% and 37.1% of carcinomas in 1970-1990 and 1990-2007, respectively (P<0.05). CONCLUSION: We showed that incidence of papillary TC increased and incidences of follicular and anaplastic TC decreased in a period that might be affected by Chernobyl fallout in a moderately iodine deficient area. Presenting symptoms of TC have changed and microcarcinomas are diagnosed more frequently compared to past. Further large scale trials are needed to find out whether Chernobyl disaster has role on changing characteristic of TC in countries that are not very near but also not very far from Chernobyl such as Turkey.

Multiple endocrine neoplasia: the Chilean experience.

Multiple endocrine neoplasia (MEN) types 1 and 2 are genetic diseases that are inherited as autosomal traits. The major clinical manifestations of multiple endocrine neoplasia type 1 include the so-called "3 P's": parathyroid, pituitary, and pancreatic tumors, including gastroenteroneuroendocrine tumors. Genetic testing can be performed on patients and the potential carriers of the menin gene mutation, but the genotype-phenotype correlation in multiple endocrine neoplasia type 1 is less straightforward than multiple endocrine neoplasia type 2. Most likely, the main advantage of genetic testing in MEN1 is to exclude from further studies those who are negative for the genetic mutation if they belong to a family with a known history of MEN1. In Chile, we started with rearranged during transfection proto-oncogene genetic testing (MEN2) 15 years ago. We carried out a prophylactic total thyroidectomy to prevent medullary thyroid carcinoma in a three-year-old girl who presented with microscopic medullary thyroid carcinoma. More than 90% of the individuals who tested positive using a genetic test achieved a biochemical cure compared with only 27% of patients who receive a clinical diagnosis. Mutations are mainly located in exon 11; the most common is C634W, rather than C634R. Hypertensive crisis was the cause of death in three patients, and extensive distant metastases occurred in nine (including two patients with multiple endocrine neoplasia type 2B) of 14 patients. Earlier recognition of medullary thyroid carcinoma and the other features of the disease, especially pheochromocytoma, will improve the survival rate of patients with multiple endocrine neoplasia.

[Prophylactic thyroidectomy in medullary thyroid cancer]. / La chirurgie prophylactique du cancer médullaire de la thyroïde.

Medullary thyroid cancer (MTC) is genetically determined in 30% to 35% of cases, notably through multiple mutations in the RET protooncogene located on chromosome 10, for which a genotype-phenotype relationship determines age of onset. There are three phenotypes: MEN 2 A and B, and isolated familial MTC. The type of mutation determines 3 levels of aggressiveness. Current guidelines recommend thyroidectomy during the first months of life for patients with very-high-risk (level 3) mutations and before 5 years of age for high-risk (level 2) mutations. There are no precise recommendations for lower-risk mutations, for which the surgical decision also depends on the calcitonin level and family history. We describe 18 patients who underwent prophylactic surgery. Regardless of the mutation, all patients with a normal preoperative calcitonin level were cured. However, surgery was performed later than recommended, for various reasons, including late genetic diagnosis and parents' opposition.

Multiple endocrine neoplasia: the Chilean experience

Multiple endocrine neoplasia (MEN) types 1 and 2 are genetic diseases that are inherited as autosomal traits. The major clinical manifestations of multiple endocrine neoplasia type 1 include the so-called "3 P's": parathyroid, pituitary, and pancreatic tumors, including gastroenteroneuroendocrine tumors. Genetic testing can be performed on patients and the potential carriers of the menin gene mutation, but the genotype-phenotype correlation in multiple endocrine neoplasia type 1 is less straightforward than multiple endocrine neoplasia type 2. Most likely, the main advantage of genetic testing in MEN1 is to exclude from further studies those who are negative for the genetic mutation if they belong to a family with a known history of MEN1. In Chile, we started with rearranged during transfection proto-oncogene genetic testing (MEN2) 15 years ago. We carried out a prophylactic total thyroidectomy to prevent medullary thyroid carcinoma in a three-year-old girl who presented with microscopic medullary thyroid carcinoma. More than 90% of the individuals who tested positive using a genetic test achieved a biochemical cure compared with only 27% of patients who receive a clinical diagnosis. Mutations are mainly located in exon 11; the most common is C634W, rather than C634R. Hypertensive crisis was the cause of death in three patients, and extensive distant metastases occurred in nine (including two patients with multiple endocrine neoplasia type 2B) of 14 patients. Earlier recognition of medullary thyroid carcinoma and the other features of the disease, especially pheochromocytoma, will improve the survival rate of patients with multiple endocrine neoplasia.

Role of RET codonic mutations in the surgical management of medullary thyroid carcinoma in pediatric age multiple endocrine neoplasm type 2 syndromes.

PURPOSE: Hereditary medullary thyroid carcinoma (MTC) therapy is surgical resection. Because the genetic screening was available, the early diagnosis of the disease has been possible. The purpose of this study was to evaluate the role of the genetic test in the management of these children and to draw some information about the surgical timing. METHODS: Thirteen patients underwent total thyroidectomy at our institute between 1995 and 2007. Seven patients underwent a curative thyroidectomy, and 6 patients underwent a prophylactic thyroidectomy. Two patients were operated with a minimally invasive video-assisted technique. We studied the following parameters: age, risk level associated to the RET gene mutations, aim of surgery (curative or prophylactic), tumor histopathologic features, lymph node involvement, and distal metastases. RESULTS: We found a statistical association between cancer maximum diameter and some parameters analyzed: age of patients, aim of surgery, single or multifocal MTC, and number of organs involved by distal metastases. Cancer diameter at the moment of diagnosis seems to increase according to the aggressiveness of RET gene mutation found. CONCLUSIONS: The best strategy to cure MTC is to prevent it. Genetic screening could be a fundamental tool in the management of multiple endocrine neoplasm type 2 children. An improvement of scientific knowledge regarding RET gene alterations and an early and appropriate use of genetic tests could allow a better understanding of the correct surgical timing and a wider use of less aggressive surgical procedures.

Prophylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing.

OBJECTIVE: To evaluate the impact of genetic testing in the management of familial multiple endocrine neoplasia 2A patients. DESIGN: Retrospective study. SETTING: University teaching hospital, Hong Kong. PATIENTS: Twenty-two patients from eight multiple endocrine neoplasia 2A families underwent prophylactic total thyroidectomy based on a positive RET mutation genetic testing. All mutations were located at codon 634 of exon 11. Nineteen patients had preoperative basal serum calcitonin measured, and the 12 with normal levels had pentagastrin stimulation tests. Preoperative thyroid ultrasound examination was performed for 17 patients. RESULTS: There were 13 females and 9 males with a median age of 25.1 (range, 6.1-71.9) years. Histopathology revealed medullary thyroid carcinoma in 17 (77%), C-cell hyperplasia in four (18%), and normal pathology in one (5%) of the patients. Five patients with either C-cell hyperplasia or normal pathology were among the youngest (age range, 6-9 years). The youngest patient with medullary thyroid carcinoma was nearly 9 years old. The median size of medullary thyroid carcinomas was 8.3 (range, 0.1-18) mm, but there were no lymph node metastases. Of 15 patients with normal basal calcitonin levels, 10 had medullary thyroid carcinoma, though two tested negative with the pentagastrin-stimulated calcitonin assay. Five of six patients with normal preoperative ultrasonographic examinations had medullary thyroid carcinoma. Three (14%) of the patients were prescribed long-term calcium and vitamin D supplementation. After a median follow-up of 49 (range, 13-128) months, no patient had recurrence of medullary thyroid carcinoma. CONCLUSIONS: Genetic testing has replaced conventional biochemical and radiological modalities to identifying multiple endocrine neoplasia 2A carriers, in order to offer them prophylactic thyroidectomy. Chinese multiple endocrine neoplasia 2A patients with codon 634 mutation seem to have less aggressive forms of medullary thyroid carcinoma, for whom prophylactic thyroidectomy can be considered at the age of 8 years.

Long-term outcome of "prophylactic therapy" for familial medullary thyroid cancer.

BACKGROUND: About one quarter of all medullary thyroid cancers (MTC) are determined genetically due to a mutation in the RET proto-oncogene. The most common site of mutation is in codon 634. Therapeutic approaches toward patients at risk for the development of MTC identified by family screening programs range from total thyroidectomy to total thyroidectomy with lymphadenectomy of all 4 compartments. METHODS: We report 17 patients (median age, 13 years; range, 4-36) carrying a mutation in codon 634 of the RET proto-oncogene who were operated on prophylactically at our department. All patients underwent thyroidectomy with bilateral cervicocentral lymphadenectomy. Current calcitonin level, overall survival, and disease-free survival were analyzed by contacting general practitioners and patients. RESULTS: Tumor classification was as follows: C-cell hyperplasia, 18% (n = 3); T1 (<1 cm), 71% (n = 12); and T1 (>1 cm), 12% (n = 2). Only 2 patients had lymph node metastases (12%). These patients developed recurrent disease (median observation time, 147 months; range, 90-181). In 1 patient, the calcitonin level normalized after unilateral cervicolateral lymphadenectomy. The other patient (9 years old at primary operation) still has a persistently increased serum calcitonin level after 140 months of follow-up despite several operations for MTC. CONCLUSION: Total thyroidectomy with bilateral cervicocentral lymphadenectomy is sufficient as routine "prophylactic therapy" for patients with mutations in codon 634 of the RET proto-oncogene. Cervicolateral lymphadenectomy is indicated if calcitonin remains elevated after primary surgery. Prophylactic thyroidectomy should be performed before the development of lymph node metastases.